Innate Immunity and Autoimmunity

*Innate Immunity in Health and Disease*

drug resistance mutations in HIV type 1-infected Senegalese children in virological failure on first-line treatment according to the World Health Organization guidelines. AIDS Research and Human Retroviruses.

[49] World Health Organization. HIV drug resistance report. Global perspective on all forms of HIV drug resistance in both adults and children focussing on systematic literature reviews of nationally representative

[50] Prasitsuebsai W, Teeraananchai S, Singtoroj T, Truong KH, Ananworanich J, Do VC, et al. Treatment outcomes and resistance patterns of children and adolescents on second-line antiretroviral therapy in Asia. Journal of Acquired Immune Deficiency Syndromes.

surveys in LMICs; 2017

2016;**72**(4):380-386

[44] Salou M, Dagnra AY, Butel C, Vidal N, Serrano L, Takassi E, et al. High rates of virological failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo. Journal of the International AIDS Society.

[45] Muri L, Gamell A, Ntamatungiro AJ, Glass TR, Luwanda LB, Battegay M, et al. Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania: An emerging public health concern. AIDS.

[46] Cisse AM, Laborde-Balen G, Kebe-Fall K, Drame A, Diop H, Diop K, et al. High level of treatment failure and drug resistance to firstline antiretroviral therapies among HIV-infected children receiving decentralized care in Senegal. BMC

[47] Makadzange AT, Higgins-Biddle M, Chimukangara B, Birri R, Gordon M, Mahlanza T, et al. Clinical, Virologic, immunologic outcomes and emerging HIV drug resistance patterns in children and adolescents in public ART Care in Zimbabwe. PLoS One.

Pediatrics. 2019;**19**(1):47

2015;**10**(12):e0144057

2017;**72**(2):365-371

[48] Boerma RS, Sigaloff KC, Akanmu AS, Inzaule S. Boele van Hensbroek M, Rinke de Wit TF, et al. alarming increase in pretreatment HIV drug resistance in children living in sub-Saharan Africa: A systematic review and meta-analysis. The Journal of Antimicrobial Chemotherapy.

2013;**29**(2):242-249

2016;**19**(1):20683

2017;**31**(1):61-70

**316**

**319**

autoantigens.

DAMP tolerance, autoimmunity

**Chapter 13**

**Abstract**

Innate Immunity and

Autoimmune Diseases

The innate immune response is responsible for the initial defense against invading pathogens and signs of damage; in turn, it activates the adaptive immune response to result in highly specific and lasting immunity, mediated by the clonal expansion of antigen-specific B and T lymphocytes. Inflammation is the acute response to infection and tissue damage to limit aggression to the body. It is a complex reaction of vascularized tissues to infection, toxin exposure or cell injury that includes extravasation of plasma proteins and leukocytes. Paradoxically, uncontrolled and prolonged inflammation can result in secondary damage and the development of immune pathology in the host. The components of the innate immune system have recently been studied as responsible mechanisms in various chronic diseases such as diabetes mellitus, atherosclerosis, asthma and allergies, among others. Autoimmune disease is an attack on auto tissues by the adaptation of the immune system. In general, such diseases are characterized by autoantibodies and/or autoreactive lymphocytes directed at antigens against themselves. The innate immune system is often considered an effector of self-reactive lymphocytes, but also provides protection. Studies in mice with specific gene-directed mutations show that defects in innate immune system proteins may predispose to the development of a systemic lupus erythematosus-like syndrome (lupus) characterized by autoantibodies against double-stranded DNA (ds DNA) or nuclear components. This seems to be due to a failure in the removal of apoptotic cells or nuclear waste. These observations imply that the innate immune system has a general protective role against autoimmune disease. For example, in systemic diseases such as lupus, innate immunity is important in the elimination of nuclear antigens and, therefore, in the improvement of tolerance to B lymphocytes. Alternatively, in specific organ disorders such as type diabetes 1 o Crohn's disease, the innate immune system can be protective by eliminating pathogens that trigger or exacerbate the disease or regulate the presentation of antigens for T lymphocytes. Discuss various disease models in which the innate immune system could provide a protective role, deficiencies in the regulation of B lymphocyte signaling through the antigen/receptor or in the clearance of lupus antigens, (dsDNA and nuclear proteins), can lead to a disease similar to lupus. The repertoire of B cells seems to be very biased toward self-activity, as, possibly, that of the T-cell. This tendency toward self-activity is not surprising because B and T cells are positively selected against highly conserved

**Keywords:** toll, antigens, dendritic cells, lymphocytes, lupus, PAMP,

*Marcela Catalina Fandiño Vargas*

#### **Chapter 13**

## Innate Immunity and Autoimmune Diseases

*Marcela Catalina Fandiño Vargas*

#### **Abstract**

The innate immune response is responsible for the initial defense against invading pathogens and signs of damage; in turn, it activates the adaptive immune response to result in highly specific and lasting immunity, mediated by the clonal expansion of antigen-specific B and T lymphocytes. Inflammation is the acute response to infection and tissue damage to limit aggression to the body. It is a complex reaction of vascularized tissues to infection, toxin exposure or cell injury that includes extravasation of plasma proteins and leukocytes. Paradoxically, uncontrolled and prolonged inflammation can result in secondary damage and the development of immune pathology in the host. The components of the innate immune system have recently been studied as responsible mechanisms in various chronic diseases such as diabetes mellitus, atherosclerosis, asthma and allergies, among others. Autoimmune disease is an attack on auto tissues by the adaptation of the immune system. In general, such diseases are characterized by autoantibodies and/or autoreactive lymphocytes directed at antigens against themselves. The innate immune system is often considered an effector of self-reactive lymphocytes, but also provides protection. Studies in mice with specific gene-directed mutations show that defects in innate immune system proteins may predispose to the development of a systemic lupus erythematosus-like syndrome (lupus) characterized by autoantibodies against double-stranded DNA (ds DNA) or nuclear components. This seems to be due to a failure in the removal of apoptotic cells or nuclear waste. These observations imply that the innate immune system has a general protective role against autoimmune disease. For example, in systemic diseases such as lupus, innate immunity is important in the elimination of nuclear antigens and, therefore, in the improvement of tolerance to B lymphocytes. Alternatively, in specific organ disorders such as type diabetes 1 o Crohn's disease, the innate immune system can be protective by eliminating pathogens that trigger or exacerbate the disease or regulate the presentation of antigens for T lymphocytes. Discuss various disease models in which the innate immune system could provide a protective role, deficiencies in the regulation of B lymphocyte signaling through the antigen/receptor or in the clearance of lupus antigens, (dsDNA and nuclear proteins), can lead to a disease similar to lupus. The repertoire of B cells seems to be very biased toward self-activity, as, possibly, that of the T-cell. This tendency toward self-activity is not surprising because B and T cells are positively selected against highly conserved autoantigens.

**Keywords:** toll, antigens, dendritic cells, lymphocytes, lupus, PAMP, DAMP tolerance, autoimmunity

#### **1. Introduction**

The human immune system has two major divisions: innate and acquired. We will talk about innate immunity. Innate immunity can be defined as the first line of defense against pathogens, which represents a great machinery to create an adequate and definitive systemic response to prevent infections and maintain homeostasis of the organism. The elements of innate immunity include external physical barriers, humoral and cellular effector mechanisms. This type of immunity recognizes pathogens such as bacteria and viruses. This works thanks to the phagocytosis of the pathogens with the consequent induction of inflammatory reactions. It also has a critical role in the activation and regulation of adaptive immunity. This immunity has the ability to develop an induced response during primoinfection. This response is specific due to the expression of cell surface pattern recognition (PRR) receptors, which are capable of recognizing complex polysaccharides, glycolipids, lipoproteins, and nucleic acids. We know that pathogens contain in their structure various components that act as substances strange (antigens) and this in turn will induce an innate immune response that will subsequently activate the adaptive response. It is imperative to recognize that the important exploration of these innate mechanisms is essential for the understanding of the complex events involved in human innate immunity and is also crucial for the discovery of new antimicrobials, antitumor drugs, and immunomodulators with therapeutic applications [1]. Innate immunity, which is considered a simple immune system, is essential for the onset of acquired immunity and has been found to play an important role in the pathogenesis of the disease age [2]. Among them, it recognizes nucleic acids derived from pathogens. The innate immune pattern recognition (PRR) receptor recognizes self-derived nucleic acids. Innate pattern recognition receptors regulate antigens for the presentation and subsequent responses of B cells and T cells, for example, physiological management of autoantigens, induction of immature dendritic cells to detect tolerant signals to T cells. The activation of toll-like receptors (TLR), NOD type receptors (NLR) or Helicases similar to RIG (RLH) by molecular agents associated with pathogens where the patterns will induce dendritic cell maturation, costimulation.

T cell activation and production of antibodies by B cells. Therefore, recognition of innate patterns is now being considered as a central element of immunity modulation. There are at least 80 different autoimmune diseases discovered so far, which in the US alone, affect 20 million people [3]. These pathologies are established systemically or in a specific organ, but require for their expression certain conditions that are the result of multifactorial processes that involve a deregulation of the innate immune system and therefore adaptive that lead the body to erroneous responses with the subsequent attack itself of their own tissues. The innate immune system as discussed above is the first line of immediate defense against invading microorganisms that links to the adaptive response. Specific cells of the innate immune system, which are dendritic cells (DC) (antigen presenting), which are cells with an important and critical role in promoting the responses of B and T cells. This type of immunity is critical to maintain homeostasis and prevent microbial invasion, eliminating a wide variety of pathogens and contributing to the activation of the adaptive immune response.

#### **2. The entrance door: PAMP/DAMP**

It is the control point. A dendritic type receptor that bears the title of "access gate" for innate cellular immunity: this basically consists of a type of toll-like receptor. It has been found that it plays a fundamental role as a sensor in the recognition of pathogens in the innate immune system [4].

**321**

homeostasis [8, 9].

**4. DAMPs: (the antigenic gift of cells)**

In intracellular infections, in addition to antigens and PAMPs, the participation

of another series of molecules that participate in the activation of the immune response is necessary. Recently, some studies have shown that cells can die from a type of immunogenic "apoptosis" and thus expose their nuclear or cytoplasmic molecules to their membrane. These have a way of stimulating the immune response, thanks to their activity. They are also released during the process of necrosis and have been given the name of molecular patterns associated with damage or warning signs, the famous DAMPs. The NLR receptor is present in the cytoplasm. It has the particularity of recognizing not only PAMP but also several DAMP among them [uric acid, cholesterol, sterols crystals, extracellular ATP (adenosine triphosphate), silica] or even recognizing exogenous DAMP such as asbestos, origin of aseptic inflammation, such as gout, arteriosclerosis, and silicosis [10]. It is clear that it is a cause and attracts attention. The abnormalities in the immune system that are the basis and fertilizer for autoimmune diseases are mainly caused by an

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

This pattern recognition receptor acts on bacteria and viruses (PAMP) [5]. The innate immune response in immunological terms controls the infection and prevents its spread. And more recently it is known that to induce this series of reactions against pathogens, in addition to the existence of antigens, another series of molecules in the pathogens is required. These molecules are known as pathogen-associated molecular patterns (PAMPs). PAMPs play and interact with a series of receptors that are mainly present in phagocytic cells (macrophages), and these "gate" receptors have been called recognition patterns to pathogenassociated molecular patterns (PRRs). These receptors contain other subfamilies where we can find toll type receptors (TLRs), NOD type receptors (NLRs), RIG-1 type receptors (RLRs), and lectin C type (CLRs). This molecular pattern related to the associated damage known as DAMP comes to behave as a type of alert that recognizes signals and most importantly this does not involve pathogen detection. The main molecular recognition patterns (PRRs) include TLR and NLR receptors, also known as nucleotide binding oligomerization domains. TLR is the homologous receptor that has already been identified in the Drosophila genetic code, and that to date some TLRs have been found in humans mainly in the cell surface, membrane, and lipids [6]. Types 1, 2, 4, 5, and 6 are those that recognize proteins, nucleic acids located in the endoplasmic reticulum and those that are found in the endosomal membranes. 3, 7, 8, and 9 detect lipopolysaccharides in the outer membrane of gram-negative bacteria (endotoxins). The TLR4 type, which transmits inflammatory signals, is the best known in general and the most studied of the TLR. This receptor responds to MyD88, which becomes a station at the central point of the inflammation signal, and corresponds to the first phase of activation of the transcription factor NF-κB pathway (nuclear factor-kappa B), which a In turn, production begins and a kind of "chain reaction" of inflammatory cytokines to eliminate pathogens [7]. Meanwhile, these TLR receptors are incorporated into PAMPs, which by recognizing nucleic acids act as an inflammatory cytokine. Receptors that mediate innate immune responses, such as toll-like receptors (TLR) and specific C-type lectin receptors (CLR) that recognize associated molecular patterns (PAMP), have been implicated in autoimmune disease mechanisms, both directly through self-recognition ligands and indirectly through the regulation of immune

**3. Let's talk about PAMP**

## **3. Let's talk about PAMP**

*Innate Immunity in Health and Disease*

The human immune system has two major divisions: innate and acquired. We will talk about innate immunity. Innate immunity can be defined as the first line of defense against pathogens, which represents a great machinery to create an adequate and definitive systemic response to prevent infections and maintain homeostasis of the organism. The elements of innate immunity include external physical barriers, humoral and cellular effector mechanisms. This type of immunity recognizes pathogens such as bacteria and viruses. This works thanks to the phagocytosis of the pathogens with the consequent induction of inflammatory reactions. It also has a critical role in the activation and regulation of adaptive immunity. This immunity has the ability to develop an induced response during primoinfection. This response is specific due to the expression of cell surface pattern recognition (PRR) receptors, which are capable of recognizing complex polysaccharides, glycolipids, lipoproteins, and nucleic acids. We know that pathogens contain in their structure various components that act as substances strange (antigens) and this in turn will induce an innate immune response that will subsequently activate the adaptive response. It is imperative to recognize that the important exploration of these innate mechanisms is essential for the understanding of the complex events involved in human innate immunity and is also crucial for the discovery of new antimicrobials, antitumor drugs, and immunomodulators with therapeutic applications [1]. Innate immunity, which is considered a simple immune system, is essential for the onset of acquired immunity and has been found to play an important role in the pathogenesis of the disease age [2]. Among them, it recognizes nucleic acids derived from pathogens. The innate immune pattern recognition (PRR) receptor recognizes self-derived nucleic acids. Innate pattern recognition receptors regulate antigens for the presentation and subsequent responses of B cells and T cells, for example, physiological management of autoantigens, induction of immature dendritic cells to detect tolerant signals to T cells. The activation of toll-like receptors (TLR), NOD type receptors (NLR) or Helicases similar to RIG (RLH) by molecular agents associated with pathogens where the patterns will induce dendritic cell maturation, costimulation. T cell activation and production of antibodies by B cells. Therefore, recognition of innate patterns is now being considered as a central element of immunity modulation. There are at least 80 different autoimmune diseases discovered so far, which in the US alone, affect 20 million people [3]. These pathologies are established systemically or in a specific organ, but require for their expression certain conditions that are the result of multifactorial processes that involve a deregulation of the innate immune system and therefore adaptive that lead the body to erroneous responses with the subsequent attack itself of their own tissues. The innate immune system as discussed above is the first line of immediate defense against invading microorganisms that links to the adaptive response. Specific cells of the innate immune system, which are dendritic cells (DC) (antigen presenting), which are cells with an important and critical role in promoting the responses of B and T cells. This type of immunity is critical to maintain homeostasis and prevent microbial invasion, eliminating a wide variety of pathogens and contributing to the activation of the adaptive immune response.

**1. Introduction**

**320**

**2. The entrance door: PAMP/DAMP**

of pathogens in the innate immune system [4].

It is the control point. A dendritic type receptor that bears the title of "access gate" for innate cellular immunity: this basically consists of a type of toll-like receptor. It has been found that it plays a fundamental role as a sensor in the recognition

This pattern recognition receptor acts on bacteria and viruses (PAMP) [5]. The innate immune response in immunological terms controls the infection and prevents its spread. And more recently it is known that to induce this series of reactions against pathogens, in addition to the existence of antigens, another series of molecules in the pathogens is required. These molecules are known as pathogen-associated molecular patterns (PAMPs). PAMPs play and interact with a series of receptors that are mainly present in phagocytic cells (macrophages), and these "gate" receptors have been called recognition patterns to pathogenassociated molecular patterns (PRRs). These receptors contain other subfamilies where we can find toll type receptors (TLRs), NOD type receptors (NLRs), RIG-1 type receptors (RLRs), and lectin C type (CLRs). This molecular pattern related to the associated damage known as DAMP comes to behave as a type of alert that recognizes signals and most importantly this does not involve pathogen detection. The main molecular recognition patterns (PRRs) include TLR and NLR receptors, also known as nucleotide binding oligomerization domains. TLR is the homologous receptor that has already been identified in the Drosophila genetic code, and that to date some TLRs have been found in humans mainly in the cell surface, membrane, and lipids [6]. Types 1, 2, 4, 5, and 6 are those that recognize proteins, nucleic acids located in the endoplasmic reticulum and those that are found in the endosomal membranes. 3, 7, 8, and 9 detect lipopolysaccharides in the outer membrane of gram-negative bacteria (endotoxins). The TLR4 type, which transmits inflammatory signals, is the best known in general and the most studied of the TLR. This receptor responds to MyD88, which becomes a station at the central point of the inflammation signal, and corresponds to the first phase of activation of the transcription factor NF-κB pathway (nuclear factor-kappa B), which a In turn, production begins and a kind of "chain reaction" of inflammatory cytokines to eliminate pathogens [7]. Meanwhile, these TLR receptors are incorporated into PAMPs, which by recognizing nucleic acids act as an inflammatory cytokine. Receptors that mediate innate immune responses, such as toll-like receptors (TLR) and specific C-type lectin receptors (CLR) that recognize associated molecular patterns (PAMP), have been implicated in autoimmune disease mechanisms, both directly through self-recognition ligands and indirectly through the regulation of immune homeostasis [8, 9].

## **4. DAMPs: (the antigenic gift of cells)**

In intracellular infections, in addition to antigens and PAMPs, the participation of another series of molecules that participate in the activation of the immune response is necessary. Recently, some studies have shown that cells can die from a type of immunogenic "apoptosis" and thus expose their nuclear or cytoplasmic molecules to their membrane. These have a way of stimulating the immune response, thanks to their activity. They are also released during the process of necrosis and have been given the name of molecular patterns associated with damage or warning signs, the famous DAMPs. The NLR receptor is present in the cytoplasm. It has the particularity of recognizing not only PAMP but also several DAMP among them [uric acid, cholesterol, sterols crystals, extracellular ATP (adenosine triphosphate), silica] or even recognizing exogenous DAMP such as asbestos, origin of aseptic inflammation, such as gout, arteriosclerosis, and silicosis [10]. It is clear that it is a cause and attracts attention. The abnormalities in the immune system that are the basis and fertilizer for autoimmune diseases are mainly caused by an

abnormal acquired immunity [11]. In recent years, in contrast to the concept that autoimmune or auto-inflammatory diseases are mainly due to abnormal innate immunity, it is attracting more attention.

#### **5. Innate immunity cells: "soldiers of the first line of defense"**

Dendritic cells, macrophages, and other myeloid cells also play an important role in the innate immune response, both as antigen presenting cells as effector cells that mediate the tissue damage [12–14]. Therefore, they are fundamental and will be as in conflicts, "the first line of defense" in the face of a bacterial or other stimulus. We will also take them into account in relation to autoimmune diseases, because of their responsiveness and because they are important mediators of innate immunity, an interest has arisen in this potential to contribute to the pathology of these diseases. Proinflammatory cytokines: mainly TNFa (tumor necrosis factor alpha), induce the activation of endothelial cells, resulting in an increase in the expression of different adhesion molecules (CD62E, CD62P, ICAM-1, and VCAM-1). This causes the leukocytes to roll over them, and during this bearing, they are activated by the intracellular signals that are generated through their adhesion molecules and different chemokine receptors, which interact with the ligands found on the surface of the cells endothelial. Subsequently, these activated leukocytes adhere firmly to the endothelium, change their morphology (cell polarization) and carry out their transendothelial migration, and then migrate to the inflammatory focus, guided by the gradient of chemotactic substances that are released. Macrophages are multifunctional antigen presenting cells, with an important role in innate immunity and, therefore, in the inflammation process [15]. Macrophages are found in almost all organs, and recent studies have demonstrated their multifunctionality and heterogeneous capacities established by their numerous subpopulations, adaptation in specific tissue microenvironments and different stages of maturation. For example, during a bacterial infection, classically activated macrophages show inflammatory functions (type 1 or M1 macrophages), while with alternative activation (by Th2 type cytokines, such as IL-4 or IL-13), macrophages acquire anti-inflammatory functions (type 2 macrophages or M2). In addition to depletion or inhibition of macrophage function, reprogramming of M2 has also been explored. Recently, it has been shown that paracoccin, a protein contained in a fungal human pathogen, induces the repolarization of M1 macrophages through interaction with toll as a receptor (TLR) 4, being a new possible immunotherapeutic agent for pathologies related to M2 macrophages. Macrophage-related therapies have been proposed for various autoimmune and inflammatory pathologies. In the case of PPARγ and PPARδ, which are nuclear receptors that control different genes associated with M2 macrophages, and their agonists have been proposed as a therapy directed at macrophages to induce M2 pathways. In addition, the demonstration that TLR9 receptor signaling can reverse the aberrant M2 macrophage phenotype.

Dendritic cells (DC) are professional antigen presenting cells (APC), often referred to as "orchestra directors of the innate immune response" due to their ability to capture, process, and present antigens to T cells. Depending on the nature of the antigen may exhibit an immunogenic or tolerogenic effect, which will be defined by cytokine secretion. They are often considered tolerogenic, because they have autoantigens in the absence of costimulation and, together with antiinflammatory stimuli, (TGF-β), can promote the induction of regulatory T cells and/or induce anergy of T cells [16]. After activation by proinflammatory stimuli, they mature and generate an expression of costimulatory molecules and the major histocompatibility complex (HCM) class II, which causes a potent response of

**323**

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

the efficacy of cellular treatment in autoimmunity.

**6. Innate lymphoid cells (ILC): "the element of surprise"**

production can exacerbate and exaggerate the inflammatory process.

**7. The eye of the hurricane: autoimmunity and innate immune system. How can an autoimmune disease use machinery of innate immunity?**

Recent research has revealed new knowledge about the respective roles of these cells in relation to cellular and humoral immunity as well as the extension to adaptive immunity [18]. There is talk of a recent study in which a genetically modified mouse prototype model was developed with an autoimmune disease similar to lupus

They are a growing family of immune cells that reflect the phenotypes and functions of T cells. Natural killer cells (NK) can be considered innate homologs of cytotoxic CD8 + T cells, while ILC1, ILC2, and ILC3 correspond to innate homologs of T cells CD4 + (TH1), TH2, and TH17. However, in contrast to T cells, they do not express antigen receptors or undergo clonal selection and expansion when stimulated [4]. The ILCs react and respond to the signs of tissue damage and produce a series of cytokines, which direct the immune response and this adapts to contain the lesion. Therefore, these cells can control or unleash the immune response. As with B cells and T cells, these also originate from the common lymphoid lineage but the specific transcription factors of these suppress and modify their development until the generation of the different types of ILC. The precursors of these can migrate from their primary production site in infected and injured tissues, where they complete their maturation, in a process very similar to the differentiation of virgin T cells into TH effectors. The cytokines produced by local cells, as well as some trauma and stress response ligands as well as bacterial and dietary compounds regulate the maturation and activation of ILC in effectors that play an important role in early immune responses to pathogens in particular has been found relationship with symbionts, helminths, and allergens. The cytokines they produce induce innate responses in stromal, epithelial, and myeloid cells that in turn will regulate the activity of dendritic cells and will also play a central role in the transfer of information between ILC and T cells. ILCs by activating DC found in tissues to migrate to the lymph nodes, where they cause specific T-type cellular responses. ILCs also regulate T cells directly through the presentation of peptide antigens through CMH type II. However, ILCs are also involved in autoimmunity, because their cytokine

specific T cells to the antigens. Therefore, they play a fundamental role in maintaining self-tolerance, and on the other hand, they initiate the response against foreign antigens for their subsequent elimination by effector immune cells. In a state of aberrant hyperreactivity, they could contribute to perpetuating immune responses, backed by evidence of a high frequency of immunogenic infiltration [17]. Due to their ability to modulate the cellular response, they have been considered a powerful target for immune modulation. Strategies such as pharmacological modulation to affect their maturation status and genetic engineering to improve their tolerance or immunogenic properties for the treatment of autoimmune diseases have been studied. In several murine models, they were transduced to express IL-4 and were able to prevent disease in 12-week NOD mice. In a murine model of collageninduced arthritis (CIA), it was shown that the injection of dendritic cells with tolerogenic activity improves the clinical and the outcome of the disease. Although the treatment was found to be safe and feasible, other studies are needed to evaluate

#### *Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

*Innate Immunity in Health and Disease*

immunity, it is attracting more attention.

abnormal acquired immunity [11]. In recent years, in contrast to the concept that autoimmune or auto-inflammatory diseases are mainly due to abnormal innate

Dendritic cells, macrophages, and other myeloid cells also play an important role in the innate immune response, both as antigen presenting cells as effector cells that mediate the tissue damage [12–14]. Therefore, they are fundamental and will be as in conflicts, "the first line of defense" in the face of a bacterial or other stimulus. We will also take them into account in relation to autoimmune diseases, because of their responsiveness and because they are important mediators of innate immunity, an interest has arisen in this potential to contribute to the pathology of these diseases. Proinflammatory cytokines: mainly TNFa (tumor necrosis factor alpha), induce the activation of endothelial cells, resulting in an increase in the expression of different adhesion molecules (CD62E, CD62P, ICAM-1, and VCAM-1). This causes the leukocytes to roll over them, and during this bearing, they are activated by the intracellular signals that are generated through their adhesion molecules and different chemokine receptors, which interact with the ligands found on the surface of the cells endothelial. Subsequently, these activated leukocytes adhere firmly to the endothelium, change their morphology (cell polarization) and carry out their transendothelial migration, and then migrate to the inflammatory focus, guided by the gradient of chemotactic substances that are released. Macrophages are multifunctional antigen presenting cells, with an important role in innate immunity and, therefore, in the inflammation process [15]. Macrophages are found in almost all organs, and recent studies have demonstrated their multifunctionality and heterogeneous capacities established by their numerous subpopulations, adaptation in specific tissue microenvironments and different stages of maturation. For example, during a bacterial infection, classically activated macrophages show inflammatory functions (type 1 or M1 macrophages), while with alternative activation (by Th2 type cytokines, such as IL-4 or IL-13), macrophages acquire anti-inflammatory functions (type 2 macrophages or M2). In addition to depletion or inhibition of macrophage function, reprogramming of M2 has also been explored. Recently, it has been shown that paracoccin, a protein contained in a fungal human pathogen, induces the repolarization of M1 macrophages through interaction with toll as a receptor (TLR) 4, being a new possible immunotherapeutic agent for pathologies related to M2 macrophages. Macrophage-related therapies have been proposed for various autoimmune and inflammatory pathologies. In the case of PPARγ and PPARδ, which are nuclear receptors that control different genes associated with M2 macrophages, and their agonists have been proposed as a therapy directed at macrophages to induce M2 pathways. In addition, the demonstration that TLR9

**5. Innate immunity cells: "soldiers of the first line of defense"**

receptor signaling can reverse the aberrant M2 macrophage phenotype.

Dendritic cells (DC) are professional antigen presenting cells (APC), often referred to as "orchestra directors of the innate immune response" due to their ability to capture, process, and present antigens to T cells. Depending on the nature of the antigen may exhibit an immunogenic or tolerogenic effect, which will be defined by cytokine secretion. They are often considered tolerogenic, because they have autoantigens in the absence of costimulation and, together with antiinflammatory stimuli, (TGF-β), can promote the induction of regulatory T cells and/or induce anergy of T cells [16]. After activation by proinflammatory stimuli, they mature and generate an expression of costimulatory molecules and the major histocompatibility complex (HCM) class II, which causes a potent response of

**322**

specific T cells to the antigens. Therefore, they play a fundamental role in maintaining self-tolerance, and on the other hand, they initiate the response against foreign antigens for their subsequent elimination by effector immune cells. In a state of aberrant hyperreactivity, they could contribute to perpetuating immune responses, backed by evidence of a high frequency of immunogenic infiltration [17]. Due to their ability to modulate the cellular response, they have been considered a powerful target for immune modulation. Strategies such as pharmacological modulation to affect their maturation status and genetic engineering to improve their tolerance or immunogenic properties for the treatment of autoimmune diseases have been studied. In several murine models, they were transduced to express IL-4 and were able to prevent disease in 12-week NOD mice. In a murine model of collageninduced arthritis (CIA), it was shown that the injection of dendritic cells with tolerogenic activity improves the clinical and the outcome of the disease. Although the treatment was found to be safe and feasible, other studies are needed to evaluate the efficacy of cellular treatment in autoimmunity.

#### **6. Innate lymphoid cells (ILC): "the element of surprise"**

They are a growing family of immune cells that reflect the phenotypes and functions of T cells. Natural killer cells (NK) can be considered innate homologs of cytotoxic CD8 + T cells, while ILC1, ILC2, and ILC3 correspond to innate homologs of T cells CD4 + (TH1), TH2, and TH17. However, in contrast to T cells, they do not express antigen receptors or undergo clonal selection and expansion when stimulated [4]. The ILCs react and respond to the signs of tissue damage and produce a series of cytokines, which direct the immune response and this adapts to contain the lesion. Therefore, these cells can control or unleash the immune response. As with B cells and T cells, these also originate from the common lymphoid lineage but the specific transcription factors of these suppress and modify their development until the generation of the different types of ILC. The precursors of these can migrate from their primary production site in infected and injured tissues, where they complete their maturation, in a process very similar to the differentiation of virgin T cells into TH effectors. The cytokines produced by local cells, as well as some trauma and stress response ligands as well as bacterial and dietary compounds regulate the maturation and activation of ILC in effectors that play an important role in early immune responses to pathogens in particular has been found relationship with symbionts, helminths, and allergens. The cytokines they produce induce innate responses in stromal, epithelial, and myeloid cells that in turn will regulate the activity of dendritic cells and will also play a central role in the transfer of information between ILC and T cells. ILCs by activating DC found in tissues to migrate to the lymph nodes, where they cause specific T-type cellular responses. ILCs also regulate T cells directly through the presentation of peptide antigens through CMH type II. However, ILCs are also involved in autoimmunity, because their cytokine production can exacerbate and exaggerate the inflammatory process.

#### **7. The eye of the hurricane: autoimmunity and innate immune system. How can an autoimmune disease use machinery of innate immunity?**

Recent research has revealed new knowledge about the respective roles of these cells in relation to cellular and humoral immunity as well as the extension to adaptive immunity [18]. There is talk of a recent study in which a genetically modified mouse prototype model was developed with an autoimmune disease similar to lupus that does not require to express the adaptive immune system machinery, but is triggered directly by the innate immune response [19]. For many autoimmune diseases, we largely know the roles that key cells (T cells and B cells) play and for example are evident in the success of existing therapies (anti-CD3 and anti-CD20). Then knowing this, each of the functions of myeloid cells, and in general of the innate immune response cells, can "autoimmune" disease occur in the absence of adaptive immunity and these cells act as effectors in disease progression? The answer to this could be yes [20]. The most recent example is the study of mice eaten by moths that have been genetically modified to have deficiencies in hematopoietic cells, and to express an autoimmune disease characterized by alopecia (giving a "peeled or eaten by moths") and edema in their legs. These were also accompanied by high antibody titers, with renal and pulmonary functions being compromised due to immune complex deposits [21, 22]. However, in another study, mice with deficiency in hematopoietic cell phosphatase were crossed with mice that lack the recombinase-1 activator gene (RAG-1) that caused a subsequent deficiency in the production of T and B cells and found that the disease autoimmune had progressed normally in the absence of an adaptive immune response [22, 23] even though these mice lacked high antibody titers and immune complex deposits, and they exhibited all other symptoms of the disease. Subsequently, although the onset and progression of the disease could not be defined, it was concluded that the autoimmune disease of this type of mice was mediated by an aggressive response of macrophages and other myeloid cells. Now, a study with murine models is also described, with mice with a genetic alteration associated with the deficiency in the enzyme α-mannosidase type II (αM-II) where there is premature aging with the clinical expression and the characteristic symptoms of SLE and Lupus nephritis (high titers of anti-DNA antibodies, glomerulonephritis, and renal compromise due to deposition of immunoglobulins in the kidney) that seems to be driven by a mechanism that also seems to involve the innate immune system [12, 24, 25]. In the case of the murine model, evidence was provided that the abnormal presence of hybrid glycoprotein structures acts as a trigger for the induction of an innate immune response mediated by members of the C-type lectin family that is specific for mannose. Serum mannosebinding lectins (MBL-A and MBL-B) are soluble lectins that mediate innate immunity to pathogenic bacteria and fungi that express glucans (mannose). It is also believed that the macrophage of the mannose receptor cell surface (MMR) participates in innate immune responses, and its expression has been documented in mesangial renal cells [26, 27]. In mice with αM-II deficiency, MBL lectins are deposited in renal glomeruli which, when they express high levels of mannose glucans in mesangial cells, also express higher levels of MMR, which can bind mannose ligands in the serum. Monocyte chemoattractant protein 1 (MCP-1) levels, produced by activated mesangial cells, represent the entry of activated macrophages. By aberrantly expressing mannose-containing glucans in mice with αMII deficiency, they act as triggers for an innate immune response mediated by mannose-specific C-type lectins programmed to recognize mannose glucans as PAMP.

The second point in importance is the role of antibodies in stimulating the innate immune response. How can this be to the production of autoantibodies in autoimmune diseases, such as our old friend, lupus? Systemic lupus erythematosus (SLE) is an autoimmune disease that translates inflammation and exaggerated immune responses and thus with a large generalized associated tissue damage. We are clear that innate immunity plays a great role in its development and sequentially its clinical expression, and it has been shown that defects found in any of the immune recognition pathways will promote autoimmunity. First, dendritic cells and macrophages activated by TLR receptors can regulate the differentiation of selfreactive B cells through the expression of CD40 and the action of IL-6. Second, by

**325**

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

nucleic acids. These can activate and in a powerful and disorderly way certain TLR and RLH receptors; therefore, these are normally protected from immune recognition by multiple mechanisms (epigenetic modifications, nuclear compartmentalization, and the rapid elimination of cells that have entered apoptosis and extracellular compartments by a type of DNase and RNAse enzymes). These immune complexes containing chromatin or circulating RNA particles can avoid being "digested" by these enzymes in the extracellular space and facilitate the uptake of the complex in intracellular compartments through Fc receptor-mediated endocytosis (FcR) in dendritic cell-mediated uptake or by B cell receptor (BCR) in B cells. And it has also been confirmed by studies with lupus-prone mice deficient in TLR receptors and their respective signaling molecules. As an exception, mice with TLR-9 deficiency with a predisposition to lupus produce more autoantibodies against it, indicating that TLR-9s have additional functions in the regulation of systemic autoimmunity. Innate pattern recognition (PRR) receptors regulate the production of autoantibodies associated with lupus and self-reactive T cells by modulating the presentation of autoantigens and also contribute directly to the end result that is tissue or organ injury secondary to autoimmunity. In general, it is believed that this "injury" or tissue damage is generated from the deposition of the immune complex, complement activation, and subsequent release of cytokines and chemokines to trigger local inflammation. This concept has been redefined. For example in glomerulonephritis, in the glomerular immune complex, deposits are not always associated with innate and adaptive immune responses. These are traditionally seen as separated from each other, but emerging evidence suggests that they overlap and interact with each other. Recently discovered cell types, particularly innate lymphoid cells and myeloid cell-derived suppressors that are gaining increasing attention. It is a rapidly evolving field with molecular pathways and new types of discovered cells and multiple constantly changing paradigms. In general, it is believed that many autoimmune diseases are triggered by aggressive responses of adaptive immunity by an automatic antigen system, resulting in tissue damage and pathological sequelae. The third point is undoubtedly the role of infectious agents, which have the potential to trigger an exaggerated immune response, through molecular imitation, polyclonal activation or antigen release. For example, there are certain diseases that respond to certain infectious autoantigen peptides. This is the case of multiple sclerosis, where T cells are activated by Epstein-Barr virus peptides, type A flu, and human papilloma and that react with the myelin autoantigen peptide [28]. In this case, the viral infection could cause the activation of the lymphocytes, and the autoantigen could maintain this activation, even after the eradication of the infectious agent. Microbial infection can also cause polyclonal activation of lymphocytes, and this is the underlying mechanism in increasing the incidence of autoimmunity in murine models exposed to microbial pathogens [29]. Microbes (viruses or bacteria) that destroy cells also cause an inflammatory response and also the release of antigens that have been previously captured and this could also result in autoimmunity. There is another important point. Inflammation, even in the absence of infection, can trigger polyclonal activation and self-activity. This is that through the activation of annergic cells, by inflammatory mediators or the activation of new self-reactive cells in an inflammatory environment for example in the context of ischemia of any tissue, tissue autoreactivity could be caused and because not at a systematic level [3]. Within non-infectious detonators, we have those of the hormonal type that in many autoimmune diseases are more common in women than in men. Drugs can also alter the immune repertoire. One of the most common and studied procainamide induces antinuclear antibodies and sometimes induces a lupus-like syndrome. And even some substances produced by the same cells can act as haptens and make autoantigens immunogenic, for example, CD1 T

#### *Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

*Innate Immunity in Health and Disease*

that does not require to express the adaptive immune system machinery, but is triggered directly by the innate immune response [19]. For many autoimmune diseases, we largely know the roles that key cells (T cells and B cells) play and for example are evident in the success of existing therapies (anti-CD3 and anti-CD20). Then knowing this, each of the functions of myeloid cells, and in general of the innate immune response cells, can "autoimmune" disease occur in the absence of adaptive immunity and these cells act as effectors in disease progression? The answer to this could be yes [20]. The most recent example is the study of mice eaten by moths that have been genetically modified to have deficiencies in hematopoietic cells, and to express an autoimmune disease characterized by alopecia (giving a "peeled or eaten by moths") and edema in their legs. These were also accompanied by high antibody titers, with renal and pulmonary functions being compromised due to immune complex deposits [21, 22]. However, in another study, mice with deficiency in hematopoietic cell phosphatase were crossed with mice that lack the recombinase-1 activator gene (RAG-1) that caused a subsequent deficiency in the production of T and B cells and found that the disease autoimmune had progressed normally in the absence of an adaptive immune response [22, 23] even though these mice lacked high antibody titers and immune complex deposits, and they exhibited all other symptoms of the disease. Subsequently, although the onset and progression of the disease could not be defined, it was concluded that the autoimmune disease of this type of mice was mediated by an aggressive response of macrophages and other myeloid cells. Now, a study with murine models is also described, with mice with a genetic alteration associated with the deficiency in the enzyme α-mannosidase type II (αM-II) where there is premature aging with the clinical expression and the characteristic symptoms of SLE and Lupus nephritis (high titers of anti-DNA antibodies, glomerulonephritis, and renal compromise due to deposition of immunoglobulins in the kidney) that seems to be driven by a mechanism that also seems to involve the innate immune system [12, 24, 25]. In the case of the murine model, evidence was provided that the abnormal presence of hybrid glycoprotein structures acts as a trigger for the induction of an innate immune response mediated by members of the C-type lectin family that is specific for mannose. Serum mannosebinding lectins (MBL-A and MBL-B) are soluble lectins that mediate innate immunity to pathogenic bacteria and fungi that express glucans (mannose). It is also believed that the macrophage of the mannose receptor cell surface (MMR) participates in innate immune responses, and its expression has been documented in mesangial renal cells [26, 27]. In mice with αM-II deficiency, MBL lectins are deposited in renal glomeruli which, when they express high levels of mannose glucans in mesangial cells, also express higher levels of MMR, which can bind mannose ligands in the serum. Monocyte chemoattractant protein 1 (MCP-1) levels, produced by activated mesangial cells, represent the entry of activated macrophages. By aberrantly expressing mannose-containing glucans in mice with αMII deficiency, they act as triggers for an innate immune response mediated by mannose-specific C-type

lectins programmed to recognize mannose glucans as PAMP.

The second point in importance is the role of antibodies in stimulating the innate immune response. How can this be to the production of autoantibodies in autoimmune diseases, such as our old friend, lupus? Systemic lupus erythematosus (SLE) is an autoimmune disease that translates inflammation and exaggerated immune responses and thus with a large generalized associated tissue damage. We are clear that innate immunity plays a great role in its development and sequentially its clinical expression, and it has been shown that defects found in any of the immune recognition pathways will promote autoimmunity. First, dendritic cells and macrophages activated by TLR receptors can regulate the differentiation of selfreactive B cells through the expression of CD40 and the action of IL-6. Second, by

**324**

nucleic acids. These can activate and in a powerful and disorderly way certain TLR and RLH receptors; therefore, these are normally protected from immune recognition by multiple mechanisms (epigenetic modifications, nuclear compartmentalization, and the rapid elimination of cells that have entered apoptosis and extracellular compartments by a type of DNase and RNAse enzymes). These immune complexes containing chromatin or circulating RNA particles can avoid being "digested" by these enzymes in the extracellular space and facilitate the uptake of the complex in intracellular compartments through Fc receptor-mediated endocytosis (FcR) in dendritic cell-mediated uptake or by B cell receptor (BCR) in B cells. And it has also been confirmed by studies with lupus-prone mice deficient in TLR receptors and their respective signaling molecules. As an exception, mice with TLR-9 deficiency with a predisposition to lupus produce more autoantibodies against it, indicating that TLR-9s have additional functions in the regulation of systemic autoimmunity. Innate pattern recognition (PRR) receptors regulate the production of autoantibodies associated with lupus and self-reactive T cells by modulating the presentation of autoantigens and also contribute directly to the end result that is tissue or organ injury secondary to autoimmunity. In general, it is believed that this "injury" or tissue damage is generated from the deposition of the immune complex, complement activation, and subsequent release of cytokines and chemokines to trigger local inflammation. This concept has been redefined. For example in glomerulonephritis, in the glomerular immune complex, deposits are not always associated with innate and adaptive immune responses. These are traditionally seen as separated from each other, but emerging evidence suggests that they overlap and interact with each other. Recently discovered cell types, particularly innate lymphoid cells and myeloid cell-derived suppressors that are gaining increasing attention. It is a rapidly evolving field with molecular pathways and new types of discovered cells and multiple constantly changing paradigms. In general, it is believed that many autoimmune diseases are triggered by aggressive responses of adaptive immunity by an automatic antigen system, resulting in tissue damage and pathological sequelae.

The third point is undoubtedly the role of infectious agents, which have the potential to trigger an exaggerated immune response, through molecular imitation, polyclonal activation or antigen release. For example, there are certain diseases that respond to certain infectious autoantigen peptides. This is the case of multiple sclerosis, where T cells are activated by Epstein-Barr virus peptides, type A flu, and human papilloma and that react with the myelin autoantigen peptide [28]. In this case, the viral infection could cause the activation of the lymphocytes, and the autoantigen could maintain this activation, even after the eradication of the infectious agent. Microbial infection can also cause polyclonal activation of lymphocytes, and this is the underlying mechanism in increasing the incidence of autoimmunity in murine models exposed to microbial pathogens [29]. Microbes (viruses or bacteria) that destroy cells also cause an inflammatory response and also the release of antigens that have been previously captured and this could also result in autoimmunity. There is another important point. Inflammation, even in the absence of infection, can trigger polyclonal activation and self-activity. This is that through the activation of annergic cells, by inflammatory mediators or the activation of new self-reactive cells in an inflammatory environment for example in the context of ischemia of any tissue, tissue autoreactivity could be caused and because not at a systematic level [3]. Within non-infectious detonators, we have those of the hormonal type that in many autoimmune diseases are more common in women than in men. Drugs can also alter the immune repertoire. One of the most common and studied procainamide induces antinuclear antibodies and sometimes induces a lupus-like syndrome. And even some substances produced by the same cells can act as haptens and make autoantigens immunogenic, for example, CD1 T

cells, with receptors (gamma/delta), CD4+, CD25+, and cytokine-producing agents that monitor activity, reduce, and control self-reactive cells, and they can become pathogenic. As some must complete their maturation in the thymus, and others the activation of autoantigens in the periphery, in these processes alterations in the number and function of regulatory cells that can contribute to autoimmunization can be generated.

#### **8. "War": mechanisms of tissue damage of innate immunity**

Upon contact with the stimulus, whether microbial or of any substance, the recruitment and activation of macrophages will begin. The macrophages will serve as the primary effector cells that cause tissue damage and loss. And it has been concluded that the vast majority of autoimmune diseases could be explained by an aberrant adaptation as an immune response to the antigens themselves. On the other hand, autoimmunity as a disease contrasts with innate immunity. The first in which the term autoinflammatory was used was the periodic fever syndrome related to the TNF receptor (tumor necrosis factor), whose causative gene is TRAPS 4 and which was directly related to the presence of genetic abnormalities associated with innate immunity autoinflammatory diseases that are generally considered as a group of diseases where we can find an active responsibility for aberrant innate immunity and in which T cells are not detected and include TRAPS, cryopyrineassociated syndrome (secondary to mutations in the NLRP3 gene in children) (CAPS), Familial Mediterranean Fever (FMF), Bechet's disease, Still's disease in adults, Crohn's disease, Gout, Type 2 diabetes, and various metabolic disorders [30]. The mechanism of its many initiation is still unclear, but the symptoms and diseases themselves are caused by the collapse of immune tolerance. Thymus autoreactivity and subsequent and completely abnormal inactivation of receptive and regulatory (Th) T cells suppress the reaction to the foreign antigen. The other part of the aberrant response of the innate immune response is carried out in the recipients of recognition of autoimmune patterns and diseases recognized by nucleic acids (PRR). This recognition is transmembrane due to its location in the cell and is divided into two general and cytoplasmic phases. This receptor is found in the endoplasmic reticulum or endosome and is directly related to autoimmune diseases (SLE = TLR7/9). When comparing the sequence of own nucleic acids and pathogen derivatives by means of the TLR7/9TLR9 receptors, it is noted that it contains unmethylated CpG sequences, and these are derived from pathogens that in turn recognize a type of single stranded DNA. TLR7 on the other hand recognizes single stranded RNA derived from viruses and other types, as well as messenger RNA (mRNA). From this, TLR7/9 is self-sufficient, and this receptor can strictly distinguish between conventional nucleic acids and pathogen derivatives. Stimulates an immune response in response to auto-nucleic acid. In other words, viruses and infected cells are captured by endosomes, and these nucleic acids are recognized by TLR7/9. In the case of SLE, the TLR7/9 receptor, due to the genetic modification secondary to the aberrant response to the own nucleic acids that were released and transferred to the endosome and therefore increases the genetic expression of the type I IFN and is known as the "IFN signature." This signature of IFN is directly related to SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc) and its effects, suggesting the importance of type I IFN in autoimmune disease [31]. It also activates and stimulates plasma cells that in turn produce large amounts of type I IFN.

The TLR7/9 receptor also mediates the response of plasmacytoid cells and is considered an IFN type I producing cell, which through the TLR7/9 Fc receptor

**327**

**Author details**

San Luis Potosi, Mexico

Marcela Catalina Fandiño Vargas

provided the original work is properly cited.

Unidad de Reumatologia y Osteoporosis, Hospital Central Ignacio Morones Prieto,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: doctorcita.markitty@hotmail.com

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

and, in turn, the production of IL-1β and IL-18.

"The authors declare no conflict of interest."

**Conflict of interest**

activates the signal to induce the production of non-protein IFN type I histone in the core (HMGB1), to subsequently activate DAMP. The balance between TLR7 and TLR9 is also considered important for inflammation and immune response. The other transmembrane PRR receptors TLR3 and TLR8 also recognize double stranded and single stranded RNA. On the other hand, the cytoplasmic PRR receptor, type RIG-I, and MDA-5 normally identifies a specific structure of single stranded RNA. By recognizing double-stranded RNA, the specific proteins of these DAI, IFI16, and DDX41 receptors induce the production of IFN and inflamasome

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

activates the signal to induce the production of non-protein IFN type I histone in the core (HMGB1), to subsequently activate DAMP. The balance between TLR7 and TLR9 is also considered important for inflammation and immune response. The other transmembrane PRR receptors TLR3 and TLR8 also recognize double stranded and single stranded RNA. On the other hand, the cytoplasmic PRR receptor, type RIG-I, and MDA-5 normally identifies a specific structure of single stranded RNA. By recognizing double-stranded RNA, the specific proteins of these DAI, IFI16, and DDX41 receptors induce the production of IFN and inflamasome and, in turn, the production of IL-1β and IL-18.

## **Conflict of interest**

*Innate Immunity in Health and Disease*

can be generated.

cells, with receptors (gamma/delta), CD4+, CD25+, and cytokine-producing agents that monitor activity, reduce, and control self-reactive cells, and they can become pathogenic. As some must complete their maturation in the thymus, and others the activation of autoantigens in the periphery, in these processes alterations in the number and function of regulatory cells that can contribute to autoimmunization

Upon contact with the stimulus, whether microbial or of any substance, the recruitment and activation of macrophages will begin. The macrophages will serve as the primary effector cells that cause tissue damage and loss. And it has been concluded that the vast majority of autoimmune diseases could be explained by an aberrant adaptation as an immune response to the antigens themselves. On the other hand, autoimmunity as a disease contrasts with innate immunity. The first in which the term autoinflammatory was used was the periodic fever syndrome related to the TNF receptor (tumor necrosis factor), whose causative gene is TRAPS 4 and which was directly related to the presence of genetic abnormalities associated with innate immunity autoinflammatory diseases that are generally considered as a group of diseases where we can find an active responsibility for aberrant innate immunity and in which T cells are not detected and include TRAPS, cryopyrineassociated syndrome (secondary to mutations in the NLRP3 gene in children) (CAPS), Familial Mediterranean Fever (FMF), Bechet's disease, Still's disease in adults, Crohn's disease, Gout, Type 2 diabetes, and various metabolic disorders [30]. The mechanism of its many initiation is still unclear, but the symptoms and diseases themselves are caused by the collapse of immune tolerance. Thymus autoreactivity and subsequent and completely abnormal inactivation of receptive and regulatory (Th) T cells suppress the reaction to the foreign antigen. The other part of the aberrant response of the innate immune response is carried out in the recipients of recognition of autoimmune patterns and diseases recognized by nucleic acids (PRR). This recognition is transmembrane due to its location in the cell and is divided into two general and cytoplasmic phases. This receptor is found in the endoplasmic reticulum or endosome and is directly related to autoimmune diseases (SLE = TLR7/9). When comparing the sequence of own nucleic acids and pathogen derivatives by means of the TLR7/9TLR9 receptors, it is noted that it contains unmethylated CpG sequences, and these are derived from pathogens that in turn recognize a type of single stranded DNA. TLR7 on the other hand recognizes single stranded RNA derived from viruses and other types, as well as messenger RNA (mRNA). From this, TLR7/9 is self-sufficient, and this receptor can strictly distinguish between conventional nucleic acids and pathogen derivatives. Stimulates an immune response in response to auto-nucleic acid. In other words, viruses and infected cells are captured by endosomes, and these nucleic acids are recognized by TLR7/9. In the case of SLE, the TLR7/9 receptor, due to the genetic modification secondary to the aberrant response to the own nucleic acids that were released and transferred to the endosome and therefore increases the genetic expression of the type I IFN and is known as the "IFN signature." This signature of IFN is directly related to SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc) and its effects, suggesting the importance of type I IFN in autoimmune disease [31]. It also activates and stimulates plasma cells that in turn produce large

The TLR7/9 receptor also mediates the response of plasmacytoid cells and is considered an IFN type I producing cell, which through the TLR7/9 Fc receptor

**8. "War": mechanisms of tissue damage of innate immunity**

**326**

amounts of type I IFN.

"The authors declare no conflict of interest."

## **Author details**

Marcela Catalina Fandiño Vargas Unidad de Reumatologia y Osteoporosis, Hospital Central Ignacio Morones Prieto, San Luis Potosi, Mexico

\*Address all correspondence to: doctorcita.markitty@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[21] Linehan SA, Martínez-Pomares L, Stahl PD, Gordon S. Mannose Receptor and Its Putative Ligands in Normal Murine Lymphoid and Nonlymphoid Organs: In Situ Expression of Mannose Receptor by Selected Macrophages, Endothelial Cells, Perivascular Microglia, and Mesangial Cells, but not Dendritic Cells. Journal of Experimental Medicine [Internet]. Rockefeller University Press; 1999 Jun 21;**189**(12):1961-1972. DOI: http:// dx.doi.org/10.1084/jem.189.12.1961

[22] Marshak-Rothstein A, Rifkin IR. Immunologically Active Autoantigens: The Role of Toll-Like Receptors in the Development of Chronic

*Innate Immunity and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.91366*

the rheumatoid joint. Arthritis and Rheumatism. 2008;**58**:3377-3387

[16] Capolunghi F, Rosado MM, Cascioli S, Girolami E, Bordasco S, Vivarelli M, et al. Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients. Rheumatology (Oxford, England). 2010;**49**:2281-2289

[17] Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. International Reviews of Immunology. 2011;**30**(1):16-34. DOI: 10.3109/08830185.2010.529976

[18] Cañas C. Autoimmunity and autoinflammation. Acta Médica Colombiana. 2011;**36**(2):78-84. Source: http://www.actamedicacolombiana. com/anexo/articulos/v36n2a05.htm

[19] Akira S, Takeda K. Toll-like receptor signalling. Nature Reviews. Immunology. 2004;**4**(7):499-511

[20] Passineau MJ, Fahrenholz T, Machen L, Zourelias L, Nega K, Paul R, et al. Alpha-galactosidase a expressed in the salivary glands partially corrects organ biochemical deficits in the fabry mouse through endocrine trafficking. Human Gene Therapy. 2011;22:293-301

[21] Linehan SA, Martínez-Pomares L, Stahl PD, Gordon S. Mannose Receptor and Its Putative Ligands in Normal Murine Lymphoid and Nonlymphoid Organs: In Situ Expression of Mannose Receptor by Selected Macrophages, Endothelial Cells, Perivascular Microglia, and Mesangial Cells, but not Dendritic Cells. Journal of Experimental Medicine [Internet]. Rockefeller University Press; 1999 Jun 21;**189**(12):1961-1972. DOI: http:// dx.doi.org/10.1084/jem.189.12.1961

[22] Marshak-Rothstein A, Rifkin IR. Immunologically Active Autoantigens: The Role of Toll-Like Receptors in the Development of Chronic

Inflammatory Disease. Annual Review of Immunology [Internet]. Annual Reviews; 2007 Apr;**25**(1):419-441. DOI: http://dx.doi.org/10.1146/annurev. immunol.22.012703.104514

[23] Mensah-Brown E, Shahin A, Parekh K, Hakim AA, Shamisi MA, Hsu D, et al. Functional Capacity of Macrophages Determines the Induction of Type 1 Diabetes. Annals of the New York Academy of Sciences [Internet]. Wiley; 2006 Nov 1;**1084**(1):49-57. DOI: http://dx.doi.org/10.1196/ annals.1372.014

[24] Ohtsubo K, Marth JD. Glycosylation in Cellular Mechanisms of Health and Disease. Cell [Internet]. Elsevier BV; 2006 Sep;**126**(5):855-867. DOI: http:// dx.doi.org/10.1016/j.cell.2006.08.019

[25] Robinson MJ, Sancho D, Slack EC, LeibundGut-Landmann S, Reis e Sousa C. Nature Immunology. 2006;**7**:1258-1265

[26] Ronnblom L, Alm GV. A pivotal role for the natural interferon alpha producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. The Journal of Experimental Medicine. 2001;**194**(12):F59-F63

[27] Lastra MD. Facultad de quimica UNAM. Notas de Autoinmunidad. 2004

[28] Dong L, Ito S, Ishii KJ, Klinman DM. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus prone NZB×NZW mice. Arthritis and Rheumatism. 2005;**52**(2):651-658

[29] Pisetsky DS. The role of innate immunity in the induction of autoimmunity. Autoimmunity Reviews. 2008;**8**(1):69-72

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[15] Manzo A, Vitolo B, Humby F, Caporali R, Jarrossay D, Dell'accio F, et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of

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[31] Kramer JM, Klimatcheva E, Rothstein TL. CXCL13 is elevated in Sjogren's syndrome in mice and humans and is implicated in disease pathogenesis. Journal of Leukocyte Biology. 2013

**331**

cells [2].

**Chapter 14**

**Abstract**

of such condition were considered.

recognition of both body cells and foreign cells [2].

cell and perceived by the body defenses [3].

precision medicine

**1. Introduction**

Precision Medicine of

Autoimmune Diseases

*Ayodeji Ajayi, Oluwadunsin Adebayo and Emmanuel Adebayo*

Genomic-based information is an essential key to precise therapy referred to as personalized medicine. Its application in autoimmune disease treatment will bring the required breakthrough in medicine. Autoimmune diseases are the disease conditions where the body's immune system recognizes and generate an immune response against self-antigens. There exist different approaches of which precision medicine data can be utilized in the clinical management of autoimmune diseases; this includes diagnosis, prognosis, stratification and treatment response prediction. Different markers exist to guide clinical decision while several others are still being identified and proposed. This chapter highlights data and databases in precision medicine of autoimmune diseases and the pathway for data sharing. The precision medicine of selected autoimmune diseases was discussed, and the different biomarkers utilized in the diagnosis, prognosis, stratification and response monitoring

**Keywords:** autoimmune diseases, databases, genomic data, personalized medicine,

The functional responsibility of the immune system (humoral and cell-mediated alike) is to protect against infection by destroying various infectious agents when such agents attack the body or are introduced through vaccination [1]. The functioning of the immune system is coordinated and maintained by a sequence of highly regulated and physiological mechanisms which aids the identification and

The body's immune units usually coexist with other cells of the body that carries a self-marker molecule. Immune reactions are only triggered when an antigen which could be a microbe, part of a microbe or a molecule is presented to the surface of the

The immune system of humans is made up of two divisions which are innate and acquired immunity. The innate immunity forms the first line of defense immediately after infectious agents are recognized by the body while acquired immunity

When the immune system is stimulated, it targets and destroys foreign units. Still, in some abnormal situation, the immune system might be insensitive to antigens, hypersensitive to antigens or recognize the cells with self-marker as foreign

functions in the removal of pathogens at the later phase of infection [3].

#### **Chapter 14**

*Innate Immunity in Health and Disease*

[31] Kramer JM, Klimatcheva E, Rothstein TL. CXCL13 is elevated in Sjogren's syndrome in mice and humans and is implicated in disease pathogenesis. Journal of Leukocyte

Biology. 2013

Advancement of Science (AAAS); 2015 May 21;**348**(6237):879-887. DOI: http:// dx.doi.org/10.1126/science.aaa6566

**330**

## Precision Medicine of Autoimmune Diseases

*Ayodeji Ajayi, Oluwadunsin Adebayo and Emmanuel Adebayo*

#### **Abstract**

Genomic-based information is an essential key to precise therapy referred to as personalized medicine. Its application in autoimmune disease treatment will bring the required breakthrough in medicine. Autoimmune diseases are the disease conditions where the body's immune system recognizes and generate an immune response against self-antigens. There exist different approaches of which precision medicine data can be utilized in the clinical management of autoimmune diseases; this includes diagnosis, prognosis, stratification and treatment response prediction. Different markers exist to guide clinical decision while several others are still being identified and proposed. This chapter highlights data and databases in precision medicine of autoimmune diseases and the pathway for data sharing. The precision medicine of selected autoimmune diseases was discussed, and the different biomarkers utilized in the diagnosis, prognosis, stratification and response monitoring of such condition were considered.

**Keywords:** autoimmune diseases, databases, genomic data, personalized medicine, precision medicine

#### **1. Introduction**

The functional responsibility of the immune system (humoral and cell-mediated alike) is to protect against infection by destroying various infectious agents when such agents attack the body or are introduced through vaccination [1]. The functioning of the immune system is coordinated and maintained by a sequence of highly regulated and physiological mechanisms which aids the identification and recognition of both body cells and foreign cells [2].

The body's immune units usually coexist with other cells of the body that carries a self-marker molecule. Immune reactions are only triggered when an antigen which could be a microbe, part of a microbe or a molecule is presented to the surface of the cell and perceived by the body defenses [3].

The immune system of humans is made up of two divisions which are innate and acquired immunity. The innate immunity forms the first line of defense immediately after infectious agents are recognized by the body while acquired immunity functions in the removal of pathogens at the later phase of infection [3].

When the immune system is stimulated, it targets and destroys foreign units. Still, in some abnormal situation, the immune system might be insensitive to antigens, hypersensitive to antigens or recognize the cells with self-marker as foreign cells [2].

There are disease conditions that affect the immune system, which leads to different degree and types of conditions known as the Immune diseases. Diseases of the immune system include inherited and acquired immunodeficiency and immune-proliferative disorders which includes malignancies of the immune system (multiple myeloma, lymphoma, and leukemia), autoimmune diseases (rheumatoid arthritis), and immune hypersensitivities (allergies) [4]. Inherited immunodeficiency, also is known as primary immunodeficiency, refers to a large number of immune disorders which alters either or both development and function of the immune system. Primary immunodeficiency implies conditions resulting from loss of function, a gain of function or loss of expression due to monogenic germline mutations [5]. External and environmental factors can induce an adverse effect on the immune system, and this is regarded as secondary or acquired immunodeficiency, which is encountered commonly in clinical practice and could arise from quite a number of conditions [6].

The evolvement of medical practices especially diagnosis and treatment from the usual "one size fits all" approach to a more genetic and detailed patient stratification in a bit to acquire more information about the disease condition and the patient is known as personalized medicine [7].

The complexity of the body defense system and the ability of the cells associated with it to shift between different activation states under physiological and pathological conditions are some of the reasons for diversity in the treatment approach. The immune diseases at times are diverse, and this result in variations in response to therapy. The difference in the disease course also create reasons why there should be the identification of personalized marker for diagnosis of immune disease. Therefore, the use of genetic assessment to determine the best possible therapeutic approach from the numerous available options with different mechanisms, risks, and efficacy are essential [7, 8].

The Precision medicine data types, genomic data in precision medicine, genomic and personalized medicine databases, data sharing, access and use are discussed in this chapter. Also, the use of genomic methods and data in the understanding, diagnosis of diseases using specific biomarkers, monitoring of prognosis using prognosis biomarkers, personalized treatment of immune disorders, monitoring of response to treatment using response biomarkers are also described in this chapter.

#### **2. Precision medicine of specific autoimmune diseases**

#### **2.1 What is immunity?**

Immunity is the ability of the body to prevent infection by resisting the invasion of such a body by harmful microorganism knows as infectious agents. Immunity can be categorized broadly into two types which are:

i.Innate or Natural Immunity and

ii.Acquired Immunity

#### *2.1.1 Innate or natural immunity*

The initial host protection against diseases- causing agents is the innate immunity which is mediated by phagocytes. Through germline-encoded patternrecognition receptors (PRRs), the innate immunity of the human body recognizes

**333**

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

thereby activating immune cells [3, 9].

(NK) cells [3, 10].

immunity [11, 12].

*2.1.2.1 Mechanism of action of acquired immunity*

promotion of humoral immunity [12].

*2.1.3 Pathogenesis of immune diseases*

*2.1.2 Acquired immunity*

*2.1.1.1 Mechanism of action of innate or natural immunity*

microorganisms invading its body. For the immune cells to be activated, different classes of the PRRs, which include Toll-like receptors and cytoplasm receptors recognize distinct and important microbial component of invading microorganisms

Immediately after the detection of non-self-agents by PRRs which could be exhibited on the outer membrane of the cell, in intracellular parts, or released in the bloodstream and fluids of the body tissues, the PRRs then perform the function of opsonization, stimulation of complement and coagulation outflow, phagocytosis, initiation of pro-inflammatory signaling pathways, and inception of apoptosis. These cascades of intracellular signaling induce the expression of overlapping and unique genes which are involved in the inflammatory immune responses and essential in precision medicine. The reaction by the innate immune system is carried out by phagocytes (neutrophils, monocytes, and macrophages), inflammatory mediators releasing cells (basophils, mast cells, and eosinophils), and natural killer

Acquired immunity is the immunity that is developed against an infectious agent

When naïve T-helpers cells are stimulated by Antigen-presenting Cells otherwise known as APCs, they differentiate into two subsets of T helper (TH) cells such as TH1 and TH2. Interferon-γ (IFN-γ) is produced by TH1 cells that solely promote cellular immunity. TH2 cells, on the other hand, produce interleukin 4, 5, 10 and 13 (IL-4, IL-5, IL-10, and IL-13). Whereas, IL-12 is the propelling source of TH1 separation while IL-4 stimulates TH2 distinction. TH2 is majorly involved in the

The occurrence of the immunological disease is consequent to the dysregulation of numerous and different part of the human immune system. Fundamentally, the response of the immune system recognizes and eliminates antigens but tolerates its tissues. However, predominant immunopathology lesion is the basis on which the characterization of immune-mediated diseases is based. Immune-mediated disorders can be grouped into immediate hypersensitivity, autoimmunity, immunecomplex disease, and delayed-type hypersensitivity. Autoimmunity can be further classified into those mediated by adaptive immunity and those mediated by innate immunity. Most of the disorders lie between the two, which will be best described

by the body after the previous encounter with a pathogen or a type of immunity developed by a child by the exchange of protective materials from mother to child before and after birth or by the injection of such substances. The mediation of adaptive immunity is the function of clonally distributed T and B Lymphocytes whose characteristics are the possession of specificity and memory. Many at times, activation of the innate immune response can trigger acquired immunity. The generation of Helper T cells subsets and the production of cytokines influence adaptive

#### *Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Innate Immunity in Health and Disease*

quite a number of conditions [6].

and efficacy are essential [7, 8].

**2.1 What is immunity?**

patient is known as personalized medicine [7].

There are disease conditions that affect the immune system, which leads to different degree and types of conditions known as the Immune diseases. Diseases of the immune system include inherited and acquired immunodeficiency and immune-proliferative disorders which includes malignancies of the immune system (multiple myeloma, lymphoma, and leukemia), autoimmune diseases (rheumatoid arthritis), and immune hypersensitivities (allergies) [4]. Inherited immunodeficiency, also is known as primary immunodeficiency, refers to a large number of immune disorders which alters either or both development and function of the immune system. Primary immunodeficiency implies conditions resulting from loss of function, a gain of function or loss of expression due to monogenic germline mutations [5]. External and environmental factors can induce an adverse effect on the immune system, and this is regarded as secondary or acquired immunodeficiency, which is encountered commonly in clinical practice and could arise from

The evolvement of medical practices especially diagnosis and treatment from the usual "one size fits all" approach to a more genetic and detailed patient stratification in a bit to acquire more information about the disease condition and the

The complexity of the body defense system and the ability of the cells associated with it to shift between different activation states under physiological and pathological conditions are some of the reasons for diversity in the treatment approach. The immune diseases at times are diverse, and this result in variations in response to therapy. The difference in the disease course also create reasons why there should be the identification of personalized marker for diagnosis of immune disease. Therefore, the use of genetic assessment to determine the best possible therapeutic approach from the numerous available options with different mechanisms, risks,

The Precision medicine data types, genomic data in precision medicine, genomic and personalized medicine databases, data sharing, access and use are discussed in this chapter. Also, the use of genomic methods and data in the understanding, diagnosis of diseases using specific biomarkers, monitoring of prognosis using prognosis biomarkers, personalized treatment of immune disorders, monitoring of response to treatment using response biomarkers are also described in this chapter.

Immunity is the ability of the body to prevent infection by resisting the invasion of such a body by harmful microorganism knows as infectious agents. Immunity

The initial host protection against diseases- causing agents is the innate immunity which is mediated by phagocytes. Through germline-encoded patternrecognition receptors (PRRs), the innate immunity of the human body recognizes

**2. Precision medicine of specific autoimmune diseases**

can be categorized broadly into two types which are:

i.Innate or Natural Immunity and

ii.Acquired Immunity

*2.1.1 Innate or natural immunity*

**332**

microorganisms invading its body. For the immune cells to be activated, different classes of the PRRs, which include Toll-like receptors and cytoplasm receptors recognize distinct and important microbial component of invading microorganisms thereby activating immune cells [3, 9].

#### *2.1.1.1 Mechanism of action of innate or natural immunity*

Immediately after the detection of non-self-agents by PRRs which could be exhibited on the outer membrane of the cell, in intracellular parts, or released in the bloodstream and fluids of the body tissues, the PRRs then perform the function of opsonization, stimulation of complement and coagulation outflow, phagocytosis, initiation of pro-inflammatory signaling pathways, and inception of apoptosis. These cascades of intracellular signaling induce the expression of overlapping and unique genes which are involved in the inflammatory immune responses and essential in precision medicine. The reaction by the innate immune system is carried out by phagocytes (neutrophils, monocytes, and macrophages), inflammatory mediators releasing cells (basophils, mast cells, and eosinophils), and natural killer (NK) cells [3, 10].

#### *2.1.2 Acquired immunity*

Acquired immunity is the immunity that is developed against an infectious agent by the body after the previous encounter with a pathogen or a type of immunity developed by a child by the exchange of protective materials from mother to child before and after birth or by the injection of such substances. The mediation of adaptive immunity is the function of clonally distributed T and B Lymphocytes whose characteristics are the possession of specificity and memory. Many at times, activation of the innate immune response can trigger acquired immunity. The generation of Helper T cells subsets and the production of cytokines influence adaptive immunity [11, 12].

#### *2.1.2.1 Mechanism of action of acquired immunity*

When naïve T-helpers cells are stimulated by Antigen-presenting Cells otherwise known as APCs, they differentiate into two subsets of T helper (TH) cells such as TH1 and TH2. Interferon-γ (IFN-γ) is produced by TH1 cells that solely promote cellular immunity. TH2 cells, on the other hand, produce interleukin 4, 5, 10 and 13 (IL-4, IL-5, IL-10, and IL-13). Whereas, IL-12 is the propelling source of TH1 separation while IL-4 stimulates TH2 distinction. TH2 is majorly involved in the promotion of humoral immunity [12].

#### *2.1.3 Pathogenesis of immune diseases*

The occurrence of the immunological disease is consequent to the dysregulation of numerous and different part of the human immune system. Fundamentally, the response of the immune system recognizes and eliminates antigens but tolerates its tissues. However, predominant immunopathology lesion is the basis on which the characterization of immune-mediated diseases is based. Immune-mediated disorders can be grouped into immediate hypersensitivity, autoimmunity, immunecomplex disease, and delayed-type hypersensitivity. Autoimmunity can be further classified into those mediated by adaptive immunity and those mediated by innate immunity. Most of the disorders lie between the two, which will be best described

**Figure 1.** *Schematic representation of the pathogenesis of immune diseases.*

as positive pathological feedback between innate and adaptive immune mechanisms [13]. **Figure 1** below represents the pathogenesis of immune diseases.

#### **2.2 Personalized medicine**

Personalized medicine is the process of tailoring the diagnostic procedures, treatment, and preventive measures towards the characteristics of individual patients to get an optimal outcome for each patient while emphasizing easy accessibility and cost-effectiveness [14]. In the practice of personalized medicine, the characteristics of an individual, including the uniqueness of its genetic profile guide the clinical decision in the treatment. Prognostic, diagnostic and predictive biomarkers are always being searched to guide these clinical decisions, at the same time, ensure that the best treatment is offered to the right patient at the best time [15]. The division of personalized medicine is illustrated in **Figure 2**.

While the method of application of precision medicine is given in **Figure 3.**

#### *2.2.1 Personalized medicine and genomic data*

Generally, personalized medicine compose of a vast collection of genetic data. The development of power systems has helped to increase the effective use of big data in personalized or precisions medicine over time. Also, the evolution of genomics data offers limitless possibilities in the design of clinical procedures, diagnostic, prevention, addressing and prediction of most favorable therapeutics for many diseases that are related to different regions and lineage [16].

**335**

**Figure 3.**

**Figure 2.**

*2.2.2 Precision medicine data types*

*A flow chart representing application method of precision medicine.*

The systematic collection of patient information is now accumulating and gaining complexity, as seen in the case of neuroimaging, which is currently producing above ten petabytes of data every year [17]. Studies in the field of precision medicine research make use of relevant data types such as Imaging data (CT, PET, UltraSound and MRI), bio-sample data (serum, plasma and urine value), molecular data, genomics data (nucleotide sequences), proteomic profiling data (mass

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Diagram showing the different division of precision medicine.*

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Innate Immunity in Health and Disease*

as positive pathological feedback between innate and adaptive immune mechanisms

Personalized medicine is the process of tailoring the diagnostic procedures, treatment, and preventive measures towards the characteristics of individual patients to get an optimal outcome for each patient while emphasizing easy accessibility and cost-effectiveness [14]. In the practice of personalized medicine, the characteristics of an individual, including the uniqueness of its genetic profile guide the clinical decision in the treatment. Prognostic, diagnostic and predictive biomarkers are always being searched to guide these clinical decisions, at the same time, ensure that the best treatment is offered to the right patient at the best time

While the method of application of precision medicine is given in **Figure 3.**

Generally, personalized medicine compose of a vast collection of genetic data. The development of power systems has helped to increase the effective use of big data in personalized or precisions medicine over time. Also, the evolution of genomics data offers limitless possibilities in the design of clinical procedures, diagnostic, prevention, addressing and prediction of most favorable therapeutics

[13]. **Figure 1** below represents the pathogenesis of immune diseases.

*Schematic representation of the pathogenesis of immune diseases.*

[15]. The division of personalized medicine is illustrated in **Figure 2**.

for many diseases that are related to different regions and lineage [16].

*2.2.1 Personalized medicine and genomic data*

**2.2 Personalized medicine**

**Figure 1.**

**334**

**Figure 2.** *Diagram showing the different division of precision medicine.*

**Figure 3.**

*A flow chart representing application method of precision medicine.*

#### *2.2.2 Precision medicine data types*

The systematic collection of patient information is now accumulating and gaining complexity, as seen in the case of neuroimaging, which is currently producing above ten petabytes of data every year [17]. Studies in the field of precision medicine research make use of relevant data types such as Imaging data (CT, PET, UltraSound and MRI), bio-sample data (serum, plasma and urine value), molecular data, genomics data (nucleotide sequences), proteomic profiling data (mass

spectrometry), digital pathology data, biomedical instrument data (blood pressure, heart rate and insulin level) and clinical data (death/survival data, demographics and medical-based questionnaire) and others [18].

Some of the achievement in Precision medicine has led to solutions, such as the birth of personalized brain models for a patient with intractable epilepsy [19] and the success in epigenetics mechanism of hematopoiesis [20]. The combination and integration of these data types require a sound understanding of the different fields of informatics (data science, data management and data curation) and bioinformatics [18].

#### **2.3 Genomic and personalized medicine database**

A database is an ordered set of structured information or data usually controlled by the database management system (DBMS) in an electronic computer. The data, DBMS and the applications associated with them are called database system or database in short. Each database contains certain types of data; here, we will be introducing some of the database associated with personalized or precision medicine.

#### *2.3.1 Immune epitope database (IEDB)*

The IEDB is a free to use database that is very useful in vaccine and drug development, this database catalogs data such as experimental data on antibodies, Major histocompatibility complex (MHC) binding data from different antigenic sources, Helper T lymphocyte (HTL) and Cytotoxic T Lymphocytes (CTL) epitopes for human and other animal species. This database also aids in prediction and analysis of varieties of epitopes [21]. This database can be accessed through https://www. iedb.org/.

#### *2.3.2 Prostate cancer related lifestyle database (PCaLiStDB)*

Lifestyle medicine is the study of association between lifestyle, chronic and immune diseases. PCaLiStDB is a lifestyle database that is channeled towards precision in the prevention of prostate cancer and other diseases associated with lifestyle. The data found in this database are lifestyle associated genes, lifestyle type biomarkers and personalized lifestyle-disease associated predictors [22]. The database link is http://www.sysbio.org.cn/pcalistdb/.

#### *2.3.3 Clinical genome resources (ClinGen)*

ClinGen database provides data that are of clinical importance, this database is funded by the National Institute of Health (NIH), and it is aimed at collecting necessary data for use in precision medicine and research. Data such as clinically relevant gene and variants are retrieved from this database in making precise diagnosis and treatment [23]. This database is accessed via https://clinicalgenome.org/.

#### *2.3.4 Personal genome project (PGP)*

One of the breakthroughs of medical informatics is the personal genome project database. This is an open-access database that is channeled towards the development of a tool for personalized medicine and advancing research. The database provides a wide range of data for different regions (PGP-UK, PGP-AUSTRIA, PGP-CHINA, PGP-CANADA and PGP-UNITED STATE, etc.). Data such as Genome,

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*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

https://www.personalgenomes.org/.

omim.org/.

*2.3.5 Online mendelian inheritance in man (OMIM)*

*2.3.6 Human gene mutation database (HGMD)*

http://www.hgmd.cf.ac.uk/ac/index.php.

*2.3.7 Clinical genome database (CGD)*

research.nhgri.nih.gov/CGD/.

general and their links [30].

analyzed data) [31].

Methylome, transcriptome and phenotype data are retrieved from this database for use in the procedure of precise medicine [24]. The database can be linked through

This database was initiated in the early 1960s, and the online version was created in 1985. OMIM is an open-access database that is mainly built for professionals concerned with genetic disorders, a genetics researcher and advance students in medicine. Data such as human gene, genetic disorders, clinical features, phenotype and genes are available [25, 26]. This database address is https://www.

This is a variant-related database that collates already known gene lesion that is responsible for human inherited diseases. The database includes precision medicine data such as gene symbol, genomics coordinates, splicing, different disease, phenotype and mutations in the human genome [27, 28]. This database is accessible via

Clinical Genomic Database fills the critical niche in the field of clinical and genomic medicine; it also encompasses medically significant genetic data with available interventions. For each entry in the database, the CGD gives out data such as allelic conditions, gene symbol, clinical categorization (both manifestation and interventions), affected age groups mode of inheritance and pathogenic mutation for all diseases so far captured [27]. This database can be accessed via https://

There are other ongoing database projects to improve the existing ones, an example of this is The Human Variome Project [29]. Also, there are many websites and databases linked to precision medicine that this chapter cannot introduce all. **Table 1** below provides more of the database related to precision medicine in

Data sharing is the potential inherent in the exchange of the same data resource with many applications or users; it encompasses the transferring of copies, accessing and enabling the reuse of data. Data can be open access (publicly available) or controlled (restricted), also, sharing data encompasses both sharing of primary (in case of nucleotide sequences) and secondary data (already used or

**Figure 4** above illustrates that precision medicine data encompasses both hospital data (information), GIS and PGHD. Sharing of the Precision medicine information (clinical data) can be accessed openly or otherwise restricted, whereby authorization will be needed by an authorized person to access and use the specified

*2.3.8 Other database related to precision/personalized medicine*

**2.4 Genomic and personalized medicine data utilization**

data for therapeutic, diagnostic and research purpose.

#### *Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Innate Immunity in Health and Disease*

bioinformatics [18].

iedb.org/.

and medical-based questionnaire) and others [18].

**2.3 Genomic and personalized medicine database**

*2.3.2 Prostate cancer related lifestyle database (PCaLiStDB)*

link is http://www.sysbio.org.cn/pcalistdb/.

*2.3.3 Clinical genome resources (ClinGen)*

*2.3.4 Personal genome project (PGP)*

*2.3.1 Immune epitope database (IEDB)*

spectrometry), digital pathology data, biomedical instrument data (blood pressure, heart rate and insulin level) and clinical data (death/survival data, demographics

Some of the achievement in Precision medicine has led to solutions, such as the birth of personalized brain models for a patient with intractable epilepsy [19] and the success in epigenetics mechanism of hematopoiesis [20]. The combination and integration of these data types require a sound understanding of the different fields of informatics (data science, data management and data curation) and

A database is an ordered set of structured information or data usually controlled by the database management system (DBMS) in an electronic computer. The data, DBMS and the applications associated with them are called database system or database in short. Each database contains certain types of data; here, we will be introducing some of the database associated with personalized or precision medicine.

The IEDB is a free to use database that is very useful in vaccine and drug development, this database catalogs data such as experimental data on antibodies, Major histocompatibility complex (MHC) binding data from different antigenic sources, Helper T lymphocyte (HTL) and Cytotoxic T Lymphocytes (CTL) epitopes for human and other animal species. This database also aids in prediction and analysis of varieties of epitopes [21]. This database can be accessed through https://www.

Lifestyle medicine is the study of association between lifestyle, chronic and immune diseases. PCaLiStDB is a lifestyle database that is channeled towards precision in the prevention of prostate cancer and other diseases associated with lifestyle. The data found in this database are lifestyle associated genes, lifestyle type biomarkers and personalized lifestyle-disease associated predictors [22]. The database

ClinGen database provides data that are of clinical importance, this database is funded by the National Institute of Health (NIH), and it is aimed at collecting necessary data for use in precision medicine and research. Data such as clinically relevant gene and variants are retrieved from this database in making precise diagnosis and treatment [23]. This database is accessed via https://clinicalgenome.org/.

One of the breakthroughs of medical informatics is the personal genome project database. This is an open-access database that is channeled towards the development of a tool for personalized medicine and advancing research. The database provides a wide range of data for different regions (PGP-UK, PGP-AUSTRIA, PGP-CHINA, PGP-CANADA and PGP-UNITED STATE, etc.). Data such as Genome,

**336**

Methylome, transcriptome and phenotype data are retrieved from this database for use in the procedure of precise medicine [24]. The database can be linked through https://www.personalgenomes.org/.

#### *2.3.5 Online mendelian inheritance in man (OMIM)*

This database was initiated in the early 1960s, and the online version was created in 1985. OMIM is an open-access database that is mainly built for professionals concerned with genetic disorders, a genetics researcher and advance students in medicine. Data such as human gene, genetic disorders, clinical features, phenotype and genes are available [25, 26]. This database address is https://www. omim.org/.

#### *2.3.6 Human gene mutation database (HGMD)*

This is a variant-related database that collates already known gene lesion that is responsible for human inherited diseases. The database includes precision medicine data such as gene symbol, genomics coordinates, splicing, different disease, phenotype and mutations in the human genome [27, 28]. This database is accessible via http://www.hgmd.cf.ac.uk/ac/index.php.

#### *2.3.7 Clinical genome database (CGD)*

Clinical Genomic Database fills the critical niche in the field of clinical and genomic medicine; it also encompasses medically significant genetic data with available interventions. For each entry in the database, the CGD gives out data such as allelic conditions, gene symbol, clinical categorization (both manifestation and interventions), affected age groups mode of inheritance and pathogenic mutation for all diseases so far captured [27]. This database can be accessed via https:// research.nhgri.nih.gov/CGD/.

#### *2.3.8 Other database related to precision/personalized medicine*

There are other ongoing database projects to improve the existing ones, an example of this is The Human Variome Project [29]. Also, there are many websites and databases linked to precision medicine that this chapter cannot introduce all. **Table 1** below provides more of the database related to precision medicine in general and their links [30].

#### **2.4 Genomic and personalized medicine data utilization**

Data sharing is the potential inherent in the exchange of the same data resource with many applications or users; it encompasses the transferring of copies, accessing and enabling the reuse of data. Data can be open access (publicly available) or controlled (restricted), also, sharing data encompasses both sharing of primary (in case of nucleotide sequences) and secondary data (already used or analyzed data) [31].

**Figure 4** above illustrates that precision medicine data encompasses both hospital data (information), GIS and PGHD. Sharing of the Precision medicine information (clinical data) can be accessed openly or otherwise restricted, whereby authorization will be needed by an authorized person to access and use the specified data for therapeutic, diagnostic and research purpose.


#### **Table 1.**

*Database linked to precision medicine in general and their links [30].*

#### **2.5 Precision medicine of specific autoimmune diseases**

Autoimmune diseases are disease conditions where the immune system respond to self-antigens as a result of damage or dysfunction or disorder in the tissues. It is controlled by a whole lot of factors of which host gene and environment play a vital role. It could affect the entire body, selected systems or selected organs and an

**339**

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

interplay between genetic makeup with environmental factors and the self-antigen presented for recognition controls which organ or system of the body that will

*Semantic diagram of genomic and personalized medicine data sharing (LIS: Laboratory Information System; GIS: Genome Information System; EHR: Electronic Health Record; PGHD: Person Generated Health Data; PACS: Picture Archives and Communication System; CPOE: Computerized Physician Order Entry).*

Multiple sclerosis is an inflammatory/autoimmune disorder that selects the myelin in the central nervous system which is capable of affecting patients of all age and causing neurologic disability when not adequately managed [34, 35]. More than

The precision medicines of the following autoimmune diseases are

become the target of the immune system [32, 33].

discussed below:

**Figure 4.**

1.Multiple Sclerosis

2.Myasthenia Gravis

3.Pernicious Anemia

5.Sjogren Syndrome

7.Type 1 Diabetes

4.Rheumatoid Arthritis

6.Lupus Erythematosus

*2.5.1 Genomic assessment of multiple sclerosis*

#### **Figure 4.**

*Innate Immunity in Health and Disease*

VirusMINT (interaction between viral

Online Mendelian Inheritance in Man

National Institute of Neurological Disorders and Stroke (NINDS): Clinical

Database of Genotypes and Phenotypes

ENCODE Project: ENCyclopedia of

National Human Genome Research

Kyoto Encyclopedia of Genes and

European Proteomics Association

DNA Elements, NHGRI

Institute (NHGRI)

Genomes

(EuPA)

**Table 1.**

and Translational Resources

Pathogen Interaction Gateway ((host and pathogen interaction)

protein and human)

(OMIM)

(dbGaP)

**Database Link**

Pathway Interaction Database http://pid.nci.nih.gov/

NetPath (signal transduction) http://www.netpath.org/

GeneCards http://www.genecards.org/

GeneCards http://www.genecards.org/

NIH Chemical Genomics Center http://www.ncgc.nih.gov/] Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo/

PubChem http://pubchem.ncbi.nlm.nih.gov/ PhenX Toolkit https://www.plienxtoolkit.org/ Human Genome Project, NHGRI http://www.genome.gov/10001772 NCBI BioSystems http://www.ncbi.nlm.nih.gov/biosystems/

HUPO Brain Proteome Project http://www.hbpp.org/5602.html

ExPASy Proteomics Server http://expasy.org/ HUPO: Human Proteome Organization http://www.hupo.org/

*Database linked to precision medicine in general and their links [30].*

AutDB (animal model resources) http://autism.mindspec.org/autdb/AMHome.do

Entrez – (encompasses sub-Databases) http://www.ncbi.nlm.nih.gov/sites/gquery

Ensembl Human Genome Browser http://www.ensembl.org/IIomo\_sapiens/Info/

Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene

http://molvis.vbi.vt.edu/ or http://pathogenportal.net/pig/

http://www.ncbi.nlm.nih.gov/omim/

http://www.genome.gov/ENCODE/

http://www.ninds.nih.gov/research/scientific\_resources/clinical/

http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap

Human Genome Resources http://www.ncbi.nlm.nih.gov/projects/genome/guide/human/

http://mint.bio.uniroma2.it/virusmint/Welcome.do

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**2.5 Precision medicine of specific autoimmune diseases**

Autoimmune diseases are disease conditions where the immune system respond to self-antigens as a result of damage or dysfunction or disorder in the tissues. It is controlled by a whole lot of factors of which host gene and environment play a vital role. It could affect the entire body, selected systems or selected organs and an

http://www.eupa.org/

http://genome.gov

http://www.genome.jp/kegg/

*Semantic diagram of genomic and personalized medicine data sharing (LIS: Laboratory Information System; GIS: Genome Information System; EHR: Electronic Health Record; PGHD: Person Generated Health Data; PACS: Picture Archives and Communication System; CPOE: Computerized Physician Order Entry).*

interplay between genetic makeup with environmental factors and the self-antigen presented for recognition controls which organ or system of the body that will become the target of the immune system [32, 33].

The precision medicines of the following autoimmune diseases are discussed below:


#### *2.5.1 Genomic assessment of multiple sclerosis*

Multiple sclerosis is an inflammatory/autoimmune disorder that selects the myelin in the central nervous system which is capable of affecting patients of all age and causing neurologic disability when not adequately managed [34, 35]. More than 200 loci have been identified as an independent contributor to the pathogenesis of multiple sclerosis [36]. Multiple sclerosis is usually diagnosed between age 30 and 50 in most patients and occurs more often in females than male. The best way to understand the pathogenesis of multiple sclerosis is to address it from a multifactorial perspective with a model that proposes the interaction among genetic, epigenetic, infectious, dietary, climatic, or other environmental effects, together with sunlight exposure, and smoking. These interacting factors leads to self-intolerance and depreciation of immune homeostasis in the central Nervous system [34]. The brain and spinal cord tissues get infiltrated by stimulating peripheral mononuclear cells, and this leads to the loss of myelin, gliosis, which often leads to neurological dysfunction. Two primary approach of treatment has been given to the patient with multiple sclerosis due to the autoimmune model of the pathogenesis of such disease [34]. The former treatment is the use of global immunosuppressive agents which are aggressive. At the same time, the latter is the use of more specific agents to target specific elements of the immune system.

The contribution of common variants to multiple sclerosis has been probed, and different HLA alleles variants have been modeled for their contribution to multiple sclerosis and were found to be almost as common in control as it is in the sample as it was observed that OR of the statistical analysis tends towards 1 with an increase in sample size [37]. Biomarkers are important in the genetic assessment of Multiple Sclerosis as they possess the ability to express diverse aspects of multiple sclerosis heterogeneity. They also help in the diagnosis, stratification, and disease course prediction, identification of beneficial therapies and development of a precise treatment based on the predicted treatment response. As of 2016, MRI has turned to the most appropriate tool in the diagnosis of MS. The recommendation for brain MRI is the use of 1.5 T field strength, but 3.0 T is deemed preferable. However, using 7 T field strength has been supported by recent evidence to detect central vein in brain lesion of MS patients, but this can also be depicted using T2-weighted sequences at 3 T which help in the differentiation from microangiopathic lesions. The use of MRI for the diagnosis of MS seems simplified but its complexity sets in the differentiation of MS from other disease conditions like neuromyelitis optical spectrum disorders (NMOSD) which also has short spinal cord lesion at the onset. T2-weighted and contrast-enhanced T1-weighted brain MRI are recommended for the monitoring of disease progression while MRI of the spinal cord is not encouraged. Other than the MRI biomarkers there exist a few body fluid biomarker which could mark different stages of MS disease and differentiate each step from other similar disease conditions [34].

Body fluid biomarkers can be divided into three main groups, including those marking the early phase of MS, those associated with disease course and those associated with treatment response. Low vitamin D level in Cerebrospinal fluid is a marker of the initial stage of MS. Astrocyte-derived chitinase 3-like 1 (CHI3L1) in the CSF is also a prognostic marker of which an increased level of CHI3L1 in the CSF is a significant independent risk factor connected with the progression of disability in multivariate Cox regression models. Utilizing a proteomic approach and verification of result with ELISA confirmed that CHI3L1 would be the best predictors of the conversion to MS in CIS patients. CSF CHI3L1 level with MRI and age were the best predictors of MS risk in a multivariable analysis. Neurofilaments (NF-L) has also been implicated as a biomarker in the early phase of MS [36, 37].

Transcriptional regulator high-mobility group box protein 1 help differentiates patients with relapse-onset MS from patients from primary progressive MS. Proteomic studies show that two isoforms of vitamin D-binding protein and apolipoprotein E permit discrimination between MS patients with aggressive and benign disease courses [36]. During the disease course, calcium-binding protein

**341**

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*2.5.2 Genomic assessment of myasthenia gravis*

*2.5.3 Genomic assessment of pernicious anemia*

*2.5.4 Genomic assessment of rheumatoid arthritis*

secretogranin-1 is decreased in the CSF when compared with the early phase of MS. Stable MS patients, when compared with relapsing patients, possess an increase in B cell activating factors in their plasma samples. Solute carrier family 9, subfamily A (SLC9A9) is a biomarker associated with the non-response to IFN beta. Upregulation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome is also a biomarker for non-responsive IFN beta treatment. Biomarkers of glatiramer acetate response are feedback gene to complement 32 (RGC-32), FasL, and IL-21. Up-regulated mRNA expression levels of RGC-32 and FasL and reduced expression of IL-21 seen in peripheral blood cells from responders in contrast to non-responders forms the basis for the use of these biomarkers [34, 36, 37].

Myasthenia gravis (MG) is an autoimmune disease treated with chronic immunosuppression due to the actions of autoantibodies against the diverse structure of the neuromuscular intersection [38]. The variation of the patient's response to treatment and the variation in side effects to such treatment is the justifying reason for the recognition of the biological markers to predict the effectiveness of each treatment in each patient. Presence of anti-AChR antibodies is a beneficial biomarker in the diagnosis of MG. Still, it cannot judge disease severity as no specific correlation was found between MG severity and anti-AChR antibodies level [39]. MiR-323b-3p, −409-3p, −485-3p, −181d-5p, and − 340-3p has been predicted and suggested as response biomarker to project immunosuppressive drug sensitivity in MG patients. The miRNAs can be tested in the blood, which would make it a potent response

biomarker for treatment response, and any patient detected not to respond as expected will be addressed to other treatments thereby increasing cost-effectiveness. MiR-323b-3p, −409-3p and − 485-3p were downregulated in Non-responding patients while miRNA-181d-5p, and − 340-3p were upregulated in the Nonresponding patients [39, 40]. A significant association has been identified between patient's response to azathioprine and two haplotypes, the TPMT3E haplotype in the thiopurine S-methyltransferase and a haplotype in the ATP-binding cassette sub-family C member 6 transporter. The glucocorticoid therapy non-responsive MG patients were found to possess a genetic variant in the secreted phosphoprotein 1 (SPP1) gene encoding osteopontin, which associates it with the non-responsive group [40].

Pernicious anemia (PA), is an autoimmune disease which results from a longstanding infection by *Helicobacter pylori* and the end-stage of atrophic body gastritis (ABG). The condition which is still active gradually phased out by an autoimmunity reaction that depletes the gastric mucosa irreversibly. The deficiency of vitamin B12 has been implicated in the etiology also. Therefore the goal of a clinician in treating pernicious anemia may be to avert the signs and symptoms of anemia itself, manage its complications such as damage to the nerve and heart tissues, and identifying the specific cause where precision medicine comes in [41]. The National Heart, Lung, and Blood Institute (NHLBI) are currently carrying out basic and clinical researches that could incorporate precision medicine and improve the treatment of the condition.

Rheumatoid arthritis (RA) is a heterogeneous disease which can range from mild, self-limiting arthritis to fast progressive joint damage. It is triggered by a complex interaction between the human genetic makeup and the environment. Still,

#### *Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Innate Immunity in Health and Disease*

specific elements of the immune system.

similar disease conditions [34].

200 loci have been identified as an independent contributor to the pathogenesis of multiple sclerosis [36]. Multiple sclerosis is usually diagnosed between age 30 and 50 in most patients and occurs more often in females than male. The best way to understand the pathogenesis of multiple sclerosis is to address it from a multifactorial perspective with a model that proposes the interaction among genetic, epigenetic, infectious, dietary, climatic, or other environmental effects, together with sunlight exposure, and smoking. These interacting factors leads to self-intolerance and depreciation of immune homeostasis in the central Nervous system [34]. The brain and spinal cord tissues get infiltrated by stimulating peripheral mononuclear cells, and this leads to the loss of myelin, gliosis, which often leads to neurological dysfunction. Two primary approach of treatment has been given to the patient with multiple sclerosis due to the autoimmune model of the pathogenesis of such disease [34]. The former treatment is the use of global immunosuppressive agents which are aggressive. At the same time, the latter is the use of more specific agents to target

The contribution of common variants to multiple sclerosis has been probed, and different HLA alleles variants have been modeled for their contribution to multiple sclerosis and were found to be almost as common in control as it is in the sample as it was observed that OR of the statistical analysis tends towards 1 with an increase in sample size [37]. Biomarkers are important in the genetic assessment of Multiple Sclerosis as they possess the ability to express diverse aspects of multiple sclerosis heterogeneity. They also help in the diagnosis, stratification, and disease course prediction, identification of beneficial therapies and development of a precise treatment based on the predicted treatment response. As of 2016, MRI has turned to the most appropriate tool in the diagnosis of MS. The recommendation for brain MRI is the use of 1.5 T field strength, but 3.0 T is deemed preferable. However, using 7 T field strength has been supported by recent evidence to detect central vein in brain lesion of MS patients, but this can also be depicted using T2-weighted sequences at 3 T which help in the differentiation from microangiopathic lesions. The use of MRI for the diagnosis of MS seems simplified but its complexity sets in the differentiation of MS from other disease conditions like neuromyelitis optical spectrum disorders (NMOSD) which also has short spinal cord lesion at the onset. T2-weighted and contrast-enhanced T1-weighted brain MRI are recommended for the monitoring of disease progression while MRI of the spinal cord is not encouraged. Other than the MRI biomarkers there exist a few body fluid biomarker which could mark different stages of MS disease and differentiate each step from other

Body fluid biomarkers can be divided into three main groups, including those marking the early phase of MS, those associated with disease course and those associated with treatment response. Low vitamin D level in Cerebrospinal fluid is a marker of the initial stage of MS. Astrocyte-derived chitinase 3-like 1 (CHI3L1) in the CSF is also a prognostic marker of which an increased level of CHI3L1 in the CSF is a significant independent risk factor connected with the progression of disability in multivariate Cox regression models. Utilizing a proteomic approach and verification of result with ELISA confirmed that CHI3L1 would be the best predictors of the conversion to MS in CIS patients. CSF CHI3L1 level with MRI and age were the best predictors of MS risk in a multivariable analysis. Neurofilaments (NF-L) has also been implicated as a biomarker in the early phase of MS [36, 37]. Transcriptional regulator high-mobility group box protein 1 help differentiates patients with relapse-onset MS from patients from primary progressive MS. Proteomic studies show that two isoforms of vitamin D-binding protein and apolipoprotein E permit discrimination between MS patients with aggressive and benign disease courses [36]. During the disease course, calcium-binding protein

**340**

secretogranin-1 is decreased in the CSF when compared with the early phase of MS. Stable MS patients, when compared with relapsing patients, possess an increase in B cell activating factors in their plasma samples. Solute carrier family 9, subfamily A (SLC9A9) is a biomarker associated with the non-response to IFN beta. Upregulation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome is also a biomarker for non-responsive IFN beta treatment. Biomarkers of glatiramer acetate response are feedback gene to complement 32 (RGC-32), FasL, and IL-21. Up-regulated mRNA expression levels of RGC-32 and FasL and reduced expression of IL-21 seen in peripheral blood cells from responders in contrast to non-responders forms the basis for the use of these biomarkers [34, 36, 37].

#### *2.5.2 Genomic assessment of myasthenia gravis*

Myasthenia gravis (MG) is an autoimmune disease treated with chronic immunosuppression due to the actions of autoantibodies against the diverse structure of the neuromuscular intersection [38]. The variation of the patient's response to treatment and the variation in side effects to such treatment is the justifying reason for the recognition of the biological markers to predict the effectiveness of each treatment in each patient. Presence of anti-AChR antibodies is a beneficial biomarker in the diagnosis of MG. Still, it cannot judge disease severity as no specific correlation was found between MG severity and anti-AChR antibodies level [39]. MiR-323b-3p, −409-3p, −485-3p, −181d-5p, and − 340-3p has been predicted and suggested as response biomarker to project immunosuppressive drug sensitivity in MG patients.

The miRNAs can be tested in the blood, which would make it a potent response biomarker for treatment response, and any patient detected not to respond as expected will be addressed to other treatments thereby increasing cost-effectiveness. MiR-323b-3p, −409-3p and − 485-3p were downregulated in Non-responding patients while miRNA-181d-5p, and − 340-3p were upregulated in the Nonresponding patients [39, 40]. A significant association has been identified between patient's response to azathioprine and two haplotypes, the TPMT3E haplotype in the thiopurine S-methyltransferase and a haplotype in the ATP-binding cassette sub-family C member 6 transporter. The glucocorticoid therapy non-responsive MG patients were found to possess a genetic variant in the secreted phosphoprotein 1 (SPP1) gene encoding osteopontin, which associates it with the non-responsive group [40].

#### *2.5.3 Genomic assessment of pernicious anemia*

Pernicious anemia (PA), is an autoimmune disease which results from a longstanding infection by *Helicobacter pylori* and the end-stage of atrophic body gastritis (ABG). The condition which is still active gradually phased out by an autoimmunity reaction that depletes the gastric mucosa irreversibly. The deficiency of vitamin B12 has been implicated in the etiology also. Therefore the goal of a clinician in treating pernicious anemia may be to avert the signs and symptoms of anemia itself, manage its complications such as damage to the nerve and heart tissues, and identifying the specific cause where precision medicine comes in [41]. The National Heart, Lung, and Blood Institute (NHLBI) are currently carrying out basic and clinical researches that could incorporate precision medicine and improve the treatment of the condition.

#### *2.5.4 Genomic assessment of rheumatoid arthritis*

Rheumatoid arthritis (RA) is a heterogeneous disease which can range from mild, self-limiting arthritis to fast progressive joint damage. It is triggered by a complex interaction between the human genetic makeup and the environment. Still, both environmental influence and genetics cannot exhaustively account for the heterogenic clinical features of the disease condition. It is also characterized by synovial hyperplasia and joint destruction, which can lead to joint deformity or [42].

Currently, the treatment of RA is based on the control of inflammation with which an effective therapy that comes early ensures a drastic reduction in the risk of joint damage, mortality and disability. As of 2017, major researches has focused on the identification of biomarkers that can predict patient's response to only Methotrexate (MTX) which is the first non-biologic therapeutic agent administered. Also, TNF inhibitors (TNFi) has been established to be ineffective in about 30% of patients but remains the first choice of available biologic therapeutic agents. Solute carrier family 19 member 1 (SLC19A1) gene possess the most consistent and relevant evidence. It is one of the many transport carriers that allow the transport of MTX into the cell [43].

Anti- CCP antibodies a genomic marker associated with poor prognosis as it relates to the severity of disease and the extent of damage caused on the joint, HLA-DRB1 alleles coding for shared epitope is another marker for severity in RA [44].

#### *2.5.5 Genomic assessment of sjogren syndrome*

Sjögren's syndrome (SS) is a form of B cell hypersensitivity which is manifested in the formation of excess autoantibodies and a strong propensity for NHL of B cell emergence [45]. About 5% of patients of primary SS are at risk of lymphoma development. However, it is vital to have a specific biomarker to identify such patient early to be able to monitor and detect early and select appropriate therapy. The diagnostic biomarkers will guide in the diagnosis, and the predictive biomarkers are meant to show another aspect of clinical decision. Cytopenias is an established prognostic biomarker for the development of lymphoma [46]. A lot of proposed biomarkers in the assessment of SS are yet to be confirmed in more extensive studies before adoption into clinical use [47].

#### *2.5.6 Genomic assessment of systemic lupus erythematosus*

The systemic lupus erythematosus (SLE) has a broad spectrum of signs and symptoms which varies among patients and involves numerous organs with skin, joints, kidneys, lungs and CNS included. It is a chronic inflammatory autoimmune disease [48]. An association has been established between SLE and human leukocyte antigen (HLA) haplotypes (HLA-DR3; DR9; DR15; DQA1\*0101 especially). The extensive association has also been found between vitamin D matching up with serum concentrations and vitamin D-receptor genomic binding domains [49].

#### *2.5.7 Genomic assessment of type 1 diabetes*

The type 1 diabetes (T1D) takes place as a result of autoimmune beta-cell destruction, which leads to insufficient production of insulin and results in hyperglycemia [50]. Although the role of precision medicine in type 1 diabetes is not well defined, patient with T1D severity varies with difference in their pancreatic autoantibodies profile and the rate at which their beta cells destroy [51].

In genetic studies (an important feature of precision medicine), identification of over 50 genetic signals in notably HLA region has been found to influence T1D predisposition [52]. The diagnostic biomarkers (serum biomarkers) use in the diagnosis of T1D includes the combination of glucose, C-peptide, glycated molecules and autoantibodies established for T1D. Still, these molecules often mark the late stage of the disease [53].

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diabetes.

researches to the bedside.

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

sclerosis and new treatment strategies.

**2.6 Future perspectives**

So far, advance in genomic research introduces the administration of islet autoantigens or peptides into a recipient with the risk of T1D; these studies suggest promising changes in immune regulation of islet autoimmunity. The challenges remain dosing frequency, dosage, route of administration, and adjuvants use.

i.A systemic follow up of variant genes like the TNFRSF1A that is connected with multiple sclerosis risk should be closely investigated by researchers. This gene could give an essential perception of the etiology of multiple

ii.Myasthenia gravis-related loci may display their involvement in the pathogenesis of immune disease by increasing immune response, repression of the mechanism involved in immune suppression, alteration of procedure that differentiates between autologous and heterologous molecular configuration through immune tolerance, therefore investigations into Single nucleotide polymorphisms (SNPs) in the general population that is associated with Myasthenia gravis will improve diagnosis, therapy and its outcome.

iii.Genome editing technologies have been used with a degree of success in the treatment of sickle cell disease and β-thalassemia, this could be introduced into the precise treatment of pernicious anemia with proper study of the

iv.Rheumatoid arthritis research should focus on discovering more associated genes and their resultant effects. Transcriptomic and epigenomic strategies should also be used in discovering biomarkers of response to treatments and pathways that are related to therapies. Integration of genetic, clinical and environmental data are also crucial in achieving the aim of precision medi-

v.Selection of novel treatments could be achieved for sjogren syndrome by identification of genetic risk factors like that of profound interferon signal-

vi.Prevention of systemic lupus erythematosus by assaying genetic profile, developing new biomarkers of immune activation and alteration is the

vii.Investigations into genes and pathways of type 1 diabetes may reveal on time the pathogenic role of the destruction of β-cell and production of clinical disease by the innate and adaptive immune system. Type 1 Diabetes Genetics Consortium (T1DGC) international have resources that could help in diagnosis, interventions, and monitoring outcomes of treatment of type 1

As the era of 'Big Health Data' continues, it is essential for the diagnosis, prognosis and treatment monitoring efforts on autoimmune diseases to take advantage of the data and different machine learning and deep learning algorithms to establish patterns and clusters within the disease groups. This will help in the identification of more relevant biomarkers and also help in the easy transition of biomarker

gene encoding for mitochondrial transport of vitamin B12.

cine in the treatment of rheumatoid arthritis.

ing pathway by IRF5 and STAT 4 genes.

precise future treatment of this condition.

So far, advance in genomic research introduces the administration of islet autoantigens or peptides into a recipient with the risk of T1D; these studies suggest promising changes in immune regulation of islet autoimmunity. The challenges remain dosing frequency, dosage, route of administration, and adjuvants use.

#### **2.6 Future perspectives**

*Innate Immunity in Health and Disease*

MTX into the cell [43].

*2.5.5 Genomic assessment of sjogren syndrome*

ies before adoption into clinical use [47].

*2.5.7 Genomic assessment of type 1 diabetes*

*2.5.6 Genomic assessment of systemic lupus erythematosus*

both environmental influence and genetics cannot exhaustively account for the heterogenic clinical features of the disease condition. It is also characterized by synovial

Currently, the treatment of RA is based on the control of inflammation with which an effective therapy that comes early ensures a drastic reduction in the risk of joint damage, mortality and disability. As of 2017, major researches has focused on the identification of biomarkers that can predict patient's response to only Methotrexate (MTX) which is the first non-biologic therapeutic agent administered. Also, TNF inhibitors (TNFi) has been established to be ineffective in about 30% of patients but remains the first choice of available biologic therapeutic agents. Solute carrier family 19 member 1 (SLC19A1) gene possess the most consistent and relevant evidence. It is one of the many transport carriers that allow the transport of

Anti- CCP antibodies a genomic marker associated with poor prognosis as it relates to the severity of disease and the extent of damage caused on the joint, HLA-DRB1 alleles coding for shared epitope is another marker for severity in RA [44].

Sjögren's syndrome (SS) is a form of B cell hypersensitivity which is manifested in the formation of excess autoantibodies and a strong propensity for NHL of B cell emergence [45]. About 5% of patients of primary SS are at risk of lymphoma development. However, it is vital to have a specific biomarker to identify such patient early to be able to monitor and detect early and select appropriate therapy. The diagnostic biomarkers will guide in the diagnosis, and the predictive biomarkers are meant to show another aspect of clinical decision. Cytopenias is an established prognostic biomarker for the development of lymphoma [46]. A lot of proposed biomarkers in the assessment of SS are yet to be confirmed in more extensive stud-

The systemic lupus erythematosus (SLE) has a broad spectrum of signs and symptoms which varies among patients and involves numerous organs with skin, joints, kidneys, lungs and CNS included. It is a chronic inflammatory autoimmune disease [48]. An association has been established between SLE and human leukocyte antigen (HLA) haplotypes (HLA-DR3; DR9; DR15; DQA1\*0101 especially). The extensive association has also been found between vitamin D matching up with serum concentrations and vitamin D-receptor genomic binding domains [49].

The type 1 diabetes (T1D) takes place as a result of autoimmune beta-cell destruction, which leads to insufficient production of insulin and results in hyperglycemia [50]. Although the role of precision medicine in type 1 diabetes is not well defined, patient with T1D severity varies with difference in their pancreatic autoan-

In genetic studies (an important feature of precision medicine), identification of over 50 genetic signals in notably HLA region has been found to influence T1D predisposition [52]. The diagnostic biomarkers (serum biomarkers) use in the diagnosis of T1D includes the combination of glucose, C-peptide, glycated molecules and autoantibodies established for T1D. Still, these molecules often mark the late

tibodies profile and the rate at which their beta cells destroy [51].

hyperplasia and joint destruction, which can lead to joint deformity or [42].

**342**

stage of the disease [53].


As the era of 'Big Health Data' continues, it is essential for the diagnosis, prognosis and treatment monitoring efforts on autoimmune diseases to take advantage of the data and different machine learning and deep learning algorithms to establish patterns and clusters within the disease groups. This will help in the identification of more relevant biomarkers and also help in the easy transition of biomarker researches to the bedside.

Indeed, the application of precision medicine in autoimmune diseases depends on the progress of next-generation sequencing program, which at the same time will strive to provide not only a whole-exome, or transcriptome, but at an exact process that is cost-efficient.

## **3. Conclusions**

The information provided by the Genomics data is an indispensable component of precision medicine as it holds the key to the explanation in individual variability and evolution [54]. But, the clinical use of genomic data still needs to be improved on to overcome challenges stated by Kim et al. [55] like:


Also, there is no international validation for biomarkers in use; there is a need for international collaboration to validate biomarkers presently in existence.

Overcoming these challenges will open up more opportunities for the use of genomic data in clinical practices.

#### **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Ayodeji Ajayi\*, Oluwadunsin Adebayo and Emmanuel Adebayo Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

\*Address all correspondence to: aajayi22@lautech.edu.ng

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**345**

*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

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[11] Akira S, Takeda K, Kaisho T. Toll-like receptors : critical proteins.

[12] Doolan DL, Dobaño C, Baird JK. Acquired immunity to Malaria. Clin Microbiol Rev. 2009;22(1):13-36. doi:10.1128/CMR.00025-08

O'Shea JJ. Molecular and cellular basis of immunity and immunological diseases. Prim Rheum Dis Thirteen Ed. Published online 2008:94-107. doi:10.1007/978-0-387-68566-3\_4

[14] Galli SJ. Toward precision medicine

challenges in allergic diseases. J Allergy Clin Immunol. 2016;137(5):1289-1300.

Chester. "Personalised cancer medicine." International journal of cancer vol. 137,2 (2015): 262-6. doi:10.1002/ijc.28940

and health: Opportunities and

doi:10.1016/j.jaci.2016.03.006

[15] Jackson, Sarah E, and John D

[16] Cirillo D, Valencia A. Big data analytics for personalized medicine. Curr Opin Biotechnol. 2019 Aug;58:161- 167. doi: 10.1016/j.copbio.2019.03.004. Epub 2019 Apr 6. PMID: 30965188.

[17] Dinov ID. Volume and Value of Big Healthcare Data. J Med Stat Inform. 2016;4:3. doi: 10.7243/2053- 7662-4-3. PMID: 26998309; PMCID:

[18] Hulsen T, Jamuar SS, Moody AR, Karnes JH, Varga O, Hedensted S, Spreafico R, Hafler DA, McKinney EF. From Big Data to Precision Medicine. Front Med (Lausanne). 2019 Mar 1;6:34.

doi: 10.3389/fmed.2019.00034.

PMC4795481.

cell.2006.02.015

[13] Elias K, Siegel R,

2001;2(8).

[3] Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783-801.

[4] Shurin MR, Smolkin YS. Immunemediated diseases II congress: Summary. J Immunotoxicol. 2008;5(2):159-162. doi:10.1080/15476910802129604

Bousfiha A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64. doi:10.1007/

[6] Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125(2 SUPPL. 2):S195-S203. doi:10.1016/j.jaci.2009.08.040

[7] Delhalle S, Bode SFN, Balling R, Ollert M, He FQ. A roadmap towards personalized immunology. npj Syst Biol Appl. 2018;4(1). doi:10.1038/

Matthews PM. Personalised medicine

doi:10.1016/j.cell.2006.02.015

[5] Tangye SG, Al-Herz W,

s10875-019-00737-x

s41540-017-0045-9

[8] Gafson A, Craner MJ,

for multiple sclerosis care. Mult Scler. 2017;23(3):362-369. doi:10.1177/1352458516672017

[9] Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20(2):197- 216. doi:10.1146/annurev. immunol.20.083001.084359

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*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

#### **References**

*Innate Immunity in Health and Disease*

process that is cost-efficient.

tional processing [55, 56].

parallel to the clinical plan [57].

before medical analysis [58].

genomic data in clinical practices.

**3. Conclusions**

**344**

**Author details**

**Conflict of interest**

Nigeria

Ayodeji Ajayi\*, Oluwadunsin Adebayo and Emmanuel Adebayo

\*Address all correspondence to: aajayi22@lautech.edu.ng

provided the original work is properly cited.

The authors declare no conflict of interest.

Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Indeed, the application of precision medicine in autoimmune diseases depends on the progress of next-generation sequencing program, which at the same time will strive to provide not only a whole-exome, or transcriptome, but at an exact

The information provided by the Genomics data is an indispensable component of precision medicine as it holds the key to the explanation in individual variability and evolution [54]. But, the clinical use of genomic data still needs to be improved

a.The incongruity between the form of genomic and clinical information: as a result of extensive (several tens of gigabytes of sequence) data in the genomic data, clinical data cannot be processed in the clinical practice without addi-

b.The difference in the properties of genomic data and observational data used in the clinical settings: given that the genomic workflows hold a large number of data, data obtained from this workflows is undoubtedly different from systems

c.Difficulty in mapping the genomic and clinical data for medical interpretation: as seen in the case of targeted sequencing, where most data are processed

Also, there is no international validation for biomarkers in use; there is a need

for international collaboration to validate biomarkers presently in existence. Overcoming these challenges will open up more opportunities for the use of

on to overcome challenges stated by Kim et al. [55] like:

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[4] Shurin MR, Smolkin YS. Immunemediated diseases II congress: Summary. J Immunotoxicol. 2008;5(2):159-162. doi:10.1080/15476910802129604

[5] Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64. doi:10.1007/ s10875-019-00737-x

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[18] Hulsen T, Jamuar SS, Moody AR, Karnes JH, Varga O, Hedensted S, Spreafico R, Hafler DA, McKinney EF. From Big Data to Precision Medicine. Front Med (Lausanne). 2019 Mar 1;6:34. doi: 10.3389/fmed.2019.00034.

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[20] José María Fernández, Victor de la Torre, David Richardson, Romina Royo, Montserrat Puiggròs, Valentí Moncunill, Stamatina Fragkogianni, Laura Clarke, Paul Flicek, Daniel Rico, David Torrents, Enrique Carrillo de Santa Pau, Alfonso Valencia. The BLUEPRINT Data Analysis Portal, Cell Systems, 2016, ISSN 2405-4712, doi:10.1016/j. cels.2016.10.021.

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[22] Yalan Chen, Xingyun Liu, Yijun Yu, Chunjiang Yu, Lan Yang, Yuxin Lin, Ting Xi, Ziyun Ye, Zhe Feng, Bairong Shen, PCaLiStDB: a lifestyle database for precision prevention of prostate cancer, Database, Volume 2020, 2020, baz154, doi:10.1093/database/baz154

[23] Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE. ClinGen the clinical genome resource. New England Journal of Medicine. 2015 Jun 4;372(23):2235-42. DOI: 10.1056/ NEJMsr1406261

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Thomas Nalpathamkalam, Wilson W.L. Sung, Zhuozhi Wang, Rohan V. Patel, Giovanna Pellecchia, John Wei, Lisa J. Strug, Sherilyn Bell, Barbara Kellam, Melanie M. Mahtani, Anne S. Bassett, Yvonne Bombard, Rosanna Weksberg, Cheryl Shuman, Ronald D. Cohn, Dimitri J. Stavropoulos, Sarah Bowdin, Matthew R. Hildebrandt, Wei Wei, Asli Romm, Peter Pasceri, James Ellis, Peter Ray, M. Stephen Meyn, Nasim Monfared, S. Mohsen Hosseini, Ann M. Joseph-George, Fred W. Keeley, Ryan A. Cook, Marc Fiume, Hin C. Lee, Christian R. Marshall, Jill Davies, Allison Hazell, Janet A. Buchanan, Michael J. Szego, Stephen W. Scherer. The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. CMAJ 2018, 190 (5) E126-E136; doi: 10.1503/ cmaj.171151

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*Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

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[29] (HVP) Human Variome Project retrieved on 15/10/2020 from https:// www.humanvariomeproject.org/

[30] Stimson, Nancy F. "Personalized medicine: selected web resources." Dialogues in clinical neuroscience vol.

[31] Alessandro Blasimme, Marta Fadda, Manuel Schneider, and Effy Vayena. Data Sharing For Precision Medicine: Policy Lessons And Future Directions, Health Affairs, 2018;37(5):702-709,

[32] Marrack P, Kappler J, Kotzin BL. Autoimmune disease: why and where it occurs. Nat Med. 2001;7(8):899-905.

pnas.1302575110

cf.ac.uk/ac/index.php

2009;11(4):464-9.

doi: 10.1038/90935.

[33] Ngo, S. T., Steyn, F. J., & McCombe, P. A. Gender differences in autoimmune disease. Frontiers in Neuroendocrinology, 2014;35(3):347- 369. doi:10.1016/j.yfrne.2014.04.004

[34] Bose G, Freedman MS.

Precision medicine in the multiple sclerosis clinic: Selecting the right patient for the right treatment. Mult Scler J. 2020;26(5):540-547. doi:10.1177/1352458519887324

[35] Baranzini SE, Oksenberg JR. The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years. Trends Genet. 2017;33(12):960-970. doi:10.1016/j.

[36] Chitnis T, Prat A. A roadmap to precision medicine for multiple *Precision Medicine of Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.95248*

*Innate Immunity in Health and Disease*

Bartolomei, Maxime Guye, Viktor K. Jirsa, Individual brain structure and modelling predict seizure propagation, Brain, Volume 140, Issue 3, March 2017, Pages 641-654, doi: 10.1093/brain/

Thomas Nalpathamkalam, Wilson W.L. Sung, Zhuozhi Wang, Rohan V. Patel, Giovanna Pellecchia, John Wei, Lisa J. Strug, Sherilyn Bell, Barbara Kellam, Melanie M. Mahtani, Anne S. Bassett, Yvonne Bombard, Rosanna Weksberg, Cheryl Shuman, Ronald D. Cohn, Dimitri J. Stavropoulos, Sarah Bowdin, Matthew R. Hildebrandt, Wei Wei, Asli Romm, Peter Pasceri, James Ellis, Peter Ray, M. Stephen Meyn, Nasim Monfared, S. Mohsen Hosseini, Ann M. Joseph-George, Fred W. Keeley, Ryan A. Cook, Marc Fiume, Hin C. Lee, Christian R. Marshall, Jill Davies, Allison Hazell, Janet A. Buchanan, Michael J. Szego, Stephen W. Scherer. The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. CMAJ 2018, 190 (5) E126-E136; doi: 10.1503/

cmaj.171151

[25] Madeleine P. Ball, Joseph V. Thakuria, Alexander Wait Zaranek, TomClegg, AbrahamM. Rosenbaum, Xiaodi Wu, Misha Angrist, Jong Bhak, Jason Bobe, MatthewJ. Callow, Carlos Cano, MichaelF. Chou, Wendy K.Chung, Shawn M. Douglas, Preston W. Estep, Athurva Gore, Peter Hulick, Alberto Labarga, Je-Hyuk Lee, Jeantine E. Lunshof, Byung Chul Kim, Jong-Il Kim, Zhe Li, Michael F. Murray, Geoffrey B. Nilsen, Brock A. Peters, Anugraha M. Raman, Hugh Y. Rienhoff, Kimberly Robasky, Matthew T.Wheeler, Ward Vandewege, Daniel B. Vorhaus, Joyce L. Yang, LuhanYang, John Aach, Euan A. Ashley, Radoje Drmanac, Seong-Jin Kim, Jin Billy Li, Leonid Peshkin, Christine E. Seidman, Jeong-Sun Seo, Kun Zhang, Heidi L. Rehm, George M. Church. A public resource for clinical use of genomesSciences. 2012, 109 (30) 11920- 11927; doi:10.1073/pnas.1201904109

[26] (OMIM) Online Mendelian Inheritance in Man An Online Catalog of Human Genes and Genetic Disorders Updated October 14, 2020. (Retrieved from https://omim.org/ on 15th of

October 2020)

[20] José María Fernández, Victor de la Torre, David Richardson, Romina Royo, Montserrat Puiggròs, Valentí Moncunill, Stamatina Fragkogianni, Laura Clarke,

Torrents, Enrique Carrillo de Santa Pau, Alfonso Valencia. The BLUEPRINT Data Analysis Portal, Cell Systems, 2016, ISSN 2405-4712, doi:10.1016/j.

[22] Yalan Chen, Xingyun Liu, Yijun Yu, Chunjiang Yu, Lan Yang, Yuxin Lin, Ting Xi, Ziyun Ye, Zhe Feng, Bairong Shen, PCaLiStDB: a lifestyle database for precision prevention of prostate cancer, Database, Volume 2020, 2020, baz154, doi:10.1093/database/baz154

[23] Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE. ClinGen the clinical genome resource. New England Journal of Medicine. 2015 Jun 4;372(23):2235-42. DOI: 10.1056/

[24] Miriam S. Reuter, Susan Walker, Bhooma Thiruvahindrapuram, Joe Whitney, Iris Cohn, Neal Sondheimer,

Ryan K.C. Yuen, Bret.t Trost, Tara A. Paton, Sergio L. Pereira, Jo-Anne Herbrick, Richard F. Wintle, Daniele Merico, Jennifer Howe, Jeffrey R. MacDonald, Chao Lu,

Paul Flicek, Daniel Rico, David

[21] Yan Q. Immunoinformatics and Systems Biology Methods for Personalized Medicine. In: Yan Q. (eds) Systems Biology in Drug Discovery and Development. Methods in Molecular Biology (Methods and Protocols), 2010, vol 662. Humana Press, Totowa, NJ. doi:10.1007/978-1-60761-800-3\_10

[19] Timothée Proix, Fabrice

awx004.

cels.2016.10.021.

**346**

NEJMsr1406261

[27] Benjamin D. Solomon, Anh-Dao Nguyen, Kelly A. Bear, and Tyra G. Wolfsberg PNAS June 11, 2013;110(24):9851-9855; doi:10.1073/ pnas.1302575110

[28] (HGMD) The Human Gene Mutation Database, at the Institute of Medical Genetics in Cardiff retrieved on 15/10/2020 from http://www.hgmd. cf.ac.uk/ac/index.php

[29] (HVP) Human Variome Project retrieved on 15/10/2020 from https:// www.humanvariomeproject.org/

[30] Stimson, Nancy F. "Personalized medicine: selected web resources." Dialogues in clinical neuroscience vol. 2009;11(4):464-9.

[31] Alessandro Blasimme, Marta Fadda, Manuel Schneider, and Effy Vayena. Data Sharing For Precision Medicine: Policy Lessons And Future Directions, Health Affairs, 2018;37(5):702-709,

[32] Marrack P, Kappler J, Kotzin BL. Autoimmune disease: why and where it occurs. Nat Med. 2001;7(8):899-905. doi: 10.1038/90935.

[33] Ngo, S. T., Steyn, F. J., & McCombe, P. A. Gender differences in autoimmune disease. Frontiers in Neuroendocrinology, 2014;35(3):347- 369. doi:10.1016/j.yfrne.2014.04.004

[34] Bose G, Freedman MS. Precision medicine in the multiple sclerosis clinic: Selecting the right patient for the right treatment. Mult Scler J. 2020;26(5):540-547. doi:10.1177/1352458519887324

[35] Baranzini SE, Oksenberg JR. The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years. Trends Genet. 2017;33(12):960-970. doi:10.1016/j. tig.2017.09.004

[36] Chitnis T, Prat A. A roadmap to precision medicine for multiple sclerosis. Mult Scler J. 2020;26(5):522- 532. doi:10.1177/1352458519881558

[37] Comabella M, Sastre-Garriga J, Montalban X. Precision medicine in multiple sclerosis: Biomarkers for diagnosis, prognosis, and treatment response. Curr Opin Neurol. 2016;29(3):254-262. doi:10.1097/ WCO.0000000000000336

[38] Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475-490. doi:10.1016/ S1474-4422(09)70063-8

[39] Cavalcante P, Mizrachi T, Barzago C, et al. MicroRNA signature associated with treatment response in myasthenia gravis: A further step towards precision medicine. Pharmacol Res. 2019;148(June). doi:10.1016/j. phrs.2019.104388

[40] Mantegazza R, Cavalcante P. Diagnosis and treatment of myasthenia gravis. Curr Opin Rheumatol. 2019;31(6):623-633. doi:10.1097/ BOR.0000000000000647

[41] Annibale B, Lahner E, Fave GD. Diagnosis and management of pernicious anemia. Curr Gastroenterol Rep. 2011;13(6):518-524. doi:10.1007/ s11894-011-0225-5

[42] Guo S, Xu L, Chang C, Zhang R, Jin Y, He D. Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis. Front Genet. 2020;11(August):1-9. doi:10.3389/ fgene.2020.00811

[43] Bluett J, Barton A. Precision Medicine in Rheumatoid Arthritis. Rheum Dis Clin North Am. 2017;43(3):377-387. doi:10.1016/j.rdc.2017.04.008

[44] Kaneko Y, Takeuchi T. Targeted antibody therapy and relevant novel biomarkers for precision medicine for rheumatoid arthritis. Int Immunol. 2017;29(11):511-517. doi:10.1093/ intimm/dxx055

[45] Goules A V., Tzioufas AG. Lymphomagenesis in Sjögren's syndrome: Predictive biomarkers towards precision medicine. Autoimmun Rev. 2019;18(2):137-143. doi:10.1016/j.autrev.2018.08.007

[46] Retamozo S, Brito-Zerón P, Ramos-Casals M. Prognostic markers of lymphoma development in primary Sjögren syndrome. Lupus. 2019;28(8):923-936. doi:10.1177/0961203319857132

[47] Baldini C, Ferro F, Elefante E, Bombardieri S. Biomarkers for Sj ogren ' s syndrome. Published online 2018.

[48] Chen L, Wang YF, Liu L, Bielowka A, Ahmed R, Zhang H, Tombleson P, Roberts AL, Odhams CA, Cunninghame Graham DS, Zhang X, Yang W, Vyse TJ, Morris DL. Genomewide assessment of genetic risk for systemic lupus erythematosus and disease severity. Hum Mol Genet. 2020 Jun 27;29(10):1745-1756. doi: 10.1093/ hmg/ddaa030. PMID: 32077931; PMCID: PMC7322569.

[49] Lever E, Alves MR, Isenberg DA. Towards precision medicine in systemic lupus erythematosus. Pharmgenomics Pers Med. 2020;13:39-49. doi:10.2147/ PGPM.S205079

[50] Kalra, S., Das, A.K., Bajaj, S. et al. Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel. Diabetes Ther 2020;11:411-422 . doi:10.1007/s13300-019-00753-5

[51] Mohan V, Unnikrishnan R. Precision diabetes: Where do we stand today?. Indian J Med Res. 2018;148(5):472-475. doi:10.4103/ijmr.IJMR\_1628\_18

[52] Miriam S Udler, Mark I McCarthy, Jose C Florez, Anubha Mahajan, Genetic Risk Scores for Diabetes Diagnosis and Precision Medicine, Endocrine Reviews, 40 (6) 2019, Pages 1500-1520, doi:10.1210/er.2019-00088

[53] Yi L, Swensen AC, Qian WJ. Serum biomarkers for diagnosis and prediction of type 1 diabetes. Transl Res. 2018 Nov;201:13-25. doi: 10.1016/j. trsl.2018.07.009.

[54] Collins, F. S. & Varmus, H. A new initiative on precision medicine. New England Journal of Medicine 372, 793-795 (2015). DOI: 10.1056/ NEJMp1500523

[55] Kim, H.J., Kim, H.J., Park, Y. et al. Clinical Genome Data Model (cGDM) provides Interactive Clinical Decision Support for Precision Medicine. Sci Rep 2020;10:1414. doi:10.1038/ s41598-020-58088-2

[56] Lubin Ira M., Nazneen Aziz, Lawrence J. Babb, Dennis Ballinger, Himani Bisht, Deanna M. Church, Shaun Cordes, Karen Eilbeck, Fiona Hyland, Lisa Kalman, Melissa Landrum, Edward R. Lockhart, Donna Maglott, Gabor Marth, John D. Pfeifer, Heidi L. Rehm, Somak Roy, Zivana Tezak, Rebecca Truty, Mollie Ullman-Cullere, Karl V. Voelkerding, Elizabeth A. Worthey, Alexander W. Zaranek, Justin M. Zook. Principles and Recommendations for Standardizing the Use of the Next-Generation Sequencing Variant File in Clinical Settings. 2017, ISSN 1525-1578, doi:10.1016/j. jmoldx.2016.12.001.

[57] Kho, A., Rasmussen, L., Connolly, J. et al. Practical challenges in integrating genomic data into the electronic health record. Genet Med 2013;15, 772-778. doi:10.1038/gim.2013.131

[58] Roukos, D. H. Next-generation, genome sequencing-based biomarkers: concerns and challenges for medical practice. Biomarkers in medicine 2010;4:583-586. doi:10.2217/bmm.10.70.

**349**

**Chapter 15**

**Abstract**

analytes

**1. Introduction**

Multiplex Technology for

Biomarker Immunoassays

The simultaneous measurement of different substances from a single sample is an emerging area for achieving efficient and high-throughput detection in several applications. Although immunoanalytical techniques are established and advantageous over alternative screening analytical platforms, one of the challenges for immunoassays is multiplexing. While ELISA is still commonly used to characterise a single analyte, laboratories and organisations are moving towards multiplex immunoassays. The validation of novel biomarkers and their amalgamation into multiplex immunoassays confers the prospects of simultaneous measurement of multiple analytes in a single sample, thereby minimising cost, time and sample. Therefore, the technological advancement in clinical sciences is helpful in the identification of analytes or biomarkers in test samples. However, the analytical bioanalysers are expensive and capable of detecting only a small amount or type of analytes. The simultaneous measurement of different substances from a single sample called multiplexing has become increasingly important for the quantification of pathological or toxicological samples. Although multiplex assays have many advantages over conventional assays, there are also problems that may cause apprehension among clinicians and researchers. Hence, many challenges still remain for these multiplex-

**Keywords:** biomarkers, multiplex assays, immunoassays, autoantibodies, ELISA,

An early and accurate diagnosis of a specific disease plays an important role in its effective treatment, especially in an emergency where an immediate decision needs to be made (such as in stroke or sepsis) for the treatment of patient, and the rapid and precise identification of the pathological condition is vital. However, in many instances, the clinical evidence based on a single analyte or biomarker is not adequate for an appropriate diagnosis of a disease or monitoring of its treatment. The biomarkers have a pathophysiological significance and clinical application which may have a profound impact on the diagnosis and treatment of the patient. While contemporary singleplex techniques such as enzyme-linked immunosorbent assay (ELISA) and biomarker kits are able to accurately analyse a single analyte, the monitoring of more complex, multifactorial diseases such as cancer and autoimmune and neurodegenerative diseases requires the analysis of multiple biomarkers in order to implement optimised therapeutic regimen [1]*.* In addition, it is advantageous to screen various analytes simultaneously for a rapid, cost-effective and

*Haseeb Ahsan and Rizwan Ahmad*

ing systems which are at early stages of development.

#### **Chapter 15**

*Innate Immunity in Health and Disease*

rheumatoid arthritis. Int Immunol. 2017;29(11):511-517. doi:10.1093/

Risk Scores for Diabetes Diagnosis and Precision Medicine, Endocrine Reviews, 40 (6) 2019, Pages 1500-1520,

[53] Yi L, Swensen AC, Qian WJ. Serum biomarkers for diagnosis and prediction of type 1 diabetes. Transl Res. 2018 Nov;201:13-25. doi: 10.1016/j.

[54] Collins, F. S. & Varmus, H. A new initiative on precision medicine. New England Journal of Medicine 372, 793-795 (2015). DOI: 10.1056/

[55] Kim, H.J., Kim, H.J., Park, Y. et al. Clinical Genome Data Model (cGDM) provides Interactive Clinical Decision Support for Precision Medicine. Sci Rep 2020;10:1414. doi:10.1038/

[56] Lubin Ira M., Nazneen Aziz, Lawrence J. Babb, Dennis Ballinger, Himani Bisht, Deanna M. Church, Shaun Cordes, Karen Eilbeck, Fiona Hyland, Lisa Kalman, Melissa Landrum, Edward R. Lockhart, Donna Maglott, Gabor Marth, John D. Pfeifer, Heidi L. Rehm, Somak Roy, Zivana Tezak, Rebecca Truty, Mollie Ullman-Cullere, Karl V. Voelkerding, Elizabeth A. Worthey, Alexander W. Zaranek, Justin M. Zook. Principles and Recommendations for Standardizing the Use of the Next-Generation Sequencing

Variant File in Clinical Settings. 2017, ISSN 1525-1578, doi:10.1016/j.

[57] Kho, A., Rasmussen, L., Connolly, J. et al. Practical challenges in integrating genomic data into the electronic health record. Genet Med 2013;15, 772-778.

[58] Roukos, D. H. Next-generation, genome sequencing-based biomarkers: concerns and challenges for medical practice. Biomarkers in medicine 2010;4:583-586. doi:10.2217/bmm.10.70.

jmoldx.2016.12.001.

doi:10.1038/gim.2013.131

doi:10.1210/er.2019-00088

trsl.2018.07.009.

NEJMp1500523

s41598-020-58088-2

Autoimmun Rev. 2019;18(2):137-143. doi:10.1016/j.autrev.2018.08.007

[46] Retamozo S, Brito-Zerón P, Ramos-Casals M. Prognostic markers

of lymphoma development in primary Sjögren syndrome. Lupus. 2019;28(8):923-936. doi:10.1177/0961203319857132

[47] Baldini C, Ferro F, Elefante E, Bombardieri S. Biomarkers for Sj ogren ' s syndrome. Published online 2018.

[48] Chen L, Wang YF, Liu L, Bielowka A, Ahmed R, Zhang H, Tombleson P, Roberts AL, Odhams CA, Cunninghame Graham DS, Zhang X, Yang W, Vyse TJ, Morris DL. Genomewide assessment of genetic risk for systemic lupus erythematosus and disease severity. Hum Mol Genet. 2020 Jun 27;29(10):1745-1756. doi: 10.1093/ hmg/ddaa030. PMID: 32077931;

PMCID: PMC7322569.

PGPM.S205079

[49] Lever E, Alves MR, Isenberg DA. Towards precision medicine in systemic lupus erythematosus. Pharmgenomics Pers Med. 2020;13:39-49. doi:10.2147/

[50] Kalra, S., Das, A.K., Bajaj, S. et al. Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel. Diabetes Ther 2020;11:411-422 . doi:10.1007/s13300-019-00753-5

[51] Mohan V, Unnikrishnan R. Precision diabetes: Where do we stand today?. Indian J Med Res. 2018;148(5):472-475.

[52] Miriam S Udler, Mark I McCarthy, Jose C Florez, Anubha Mahajan, Genetic

doi:10.4103/ijmr.IJMR\_1628\_18

[45] Goules A V., Tzioufas AG. Lymphomagenesis in Sjögren's syndrome: Predictive biomarkers towards precision medicine.

intimm/dxx055

**348**
