**2. The human immune system and manifestations of RA**

#### **2.1. Primary and secondary lymphoid organs and defense mechanism**

The immune system is responsible for protecting the human body from external and potentially pathogenic organisms. It is made up of a series of cells, tissues, and organs distributed widely throughout the body. From the point of view of its structural characteristics, there are organs such as the thymus, spleen, and lymph nodes and tubular structures such as the lymphatic vessels that are intercommunicated. If the functions performed are taken into account, they can be classified into primary and secondary lymphoid organs. The primary lymphoid organs (thymus and bone marrow) produce T and B lymphocytes, while secondary lymphoid organs include lymph nodes (LNs), spleen, Peyer's patches (PPs), and mucosal tissues, nasal-associated lymphoid tissue (NALT), adenoids, and tonsils, which also harbor perifollicular areas [6].

The immune system has two lines of defense, specific and nonspecific (adaptive and innate), which are responsible for keeping the body free from pathogens or, if present, can eliminate them as well as their residue [7, 8]. The innate, nonspecific antigen response destroys microorganisms and triggers an inflammatory process that blocks the spread of infection. If microorganisms get past this first barrier, antigen-specific adaptive immunity composed of T and B lymphocytes can produce antibodies and killer cells that destroy infected cells [9]. The innate immunity is constituted of external barriers such as mucous and skin; the inflammatory process; cells such as macrophages, natural killer (NK) cells, and phagocytic cells; and chemicals. In relation to adaptive immunity, this is generated only after exposure of inducing agents, and two distinct responses are generated, the cellular response, in which T lymphocytes are responsible for generating this reaction and the humoral response, carried out by B lymphocytes, which in turn are responsible for producing antibodies against the agents that cause damage [10].

#### **2.2. Autoimmune disease as an imbalance in immunoregulation**

**Keywords:** autoimmune disease, rheumatoid arthritis, animal models, biomarkers,

Traditionally the immune system has been considered as a set of structures (molecules, cells, and specialized tissues) and biological processes responsible for the defense against aggression by a variety of infectious agents, chemicals, and tumor cells. One of the fundamental characteristics of the immune system is its ability to discriminate foreign antigens [1]. Autoimmunity is a multifactorial condition in which the host organizes an immune response against its own antigens [2]. Autoimmunity is associated with genetic, immunological, hormonal, and environmental factors, with it being classified as organ-specific and systemic, of which RA is one of the most representative. RA has an incidence of 5 per 100,000 adults and occurs in 0.5–1% of the population in industrialized countries [3]. The RA can manifest as pain, stiffness, swelling, and loss of mobility. There are different strategies for the study of RA, including experimental animal models that help elucidate different aspects of the disease, as well as evaluate compounds that can reduce the inflammation that triggers the disease. An ideal animal model for RA should reproduce as close as possible the complex pathogenesis and symptoms that underlie the disease, including the presence of chronic inflammatory infiltrates, the development of destructive arthropathy, bone erosion, and degradation of the articular cartilage and subchondral bone [4]. Current RA animal models are highly reproducible and of short duration, having similar patterns to those occurring in human disease although they present some differences, such as (1) faster progression of the disease, characterized by an acute inflammatory response and (2) rodents have a tendency to marked resorption and bone formation (especially of the periosteum/endosteum) in response to joint inflammation. The use of animal models has contributed significantly to the knowledge of processes and mediators that generate inflammation and bone and cartilage damage and, in this sense, can be used as an intermediary to provide knowledge and for the evaluation of therapeutic molecules to correct these disorders [5]. There are numerous therapeutic alternatives for RA; however, the duration of these therapies and the side effects associated with some of these drugs mean that until now, there is no effective therapy for this disease.

**2. The human immune system and manifestations of RA**

**2.1. Primary and secondary lymphoid organs and defense mechanism**

The immune system is responsible for protecting the human body from external and potentially pathogenic organisms. It is made up of a series of cells, tissues, and organs distributed widely throughout the body. From the point of view of its structural characteristics, there are organs such as the thymus, spleen, and lymph nodes and tubular structures such as the lymphatic vessels that are intercommunicated. If the functions performed are taken into account, they can be classified into primary and secondary lymphoid organs. The primary lymphoid organs

therapeutic alternative

258 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

**1. Introduction**

Autoimmune diseases have been classified according to the organ and tissues affected by the impaired immune response. Nearly 80 autoimmune diseases have been reported to date, and a prevalence of 5–6% worldwide has been stated [11].

An autoimmune manifestation is triggered by antigens that are generated naturally in an individual, and most of the time, these autoimmune events are devoid of pathological character. A large number of people worldwide have autoantibodies to different parts of the body, which are activated when a viral or pathogen infection is present. These diseases are usually the result of an imbalance of immunoregulation [12].

The process by which autoimmune disease is triggered follows different pathways including infection with viruses or bacteria, the use of drugs, the use of irritant chemicals, and environmental factors that damage health. The infection is capable of generating enzymatic changes which in turn alter cell membranes exposed to hidden antigens or may expose new antigenic sites [13]. Also the viral infection can induce new antigens that are released or expressed on its cell surface [14].

Among the first signs of autoimmune disease are pain, swelling, heat, and inflammation [15]. The affection of these diseases will depend on the target organ, since any part of the body, such as the eyes, heart, joints, or brain, can be attacked [16].

Aging and molecular haptens are also associated with the formation of new antigens or the appearance of those that are hidden; in the haptens a response is triggered both against them and the protein to which they bind [17]. Such antigens may be obtained from diet or generated from virus cross reactions with antigens that are present in the individual which force the immune system to react against them.

There are several theories which consider that these types of autoimmunity are due to the loss of tolerance of T lymphocytes or their inability to effectively suppress the reaction that is generated against their own antigens or harmless agents [18].

Autoimmunity is triggered when the response is persistent and leads to the development of uncontrolled cells that react aggressively against any component of the body [19]. These processes require the entry of effector cells into the target organ, whereby there are changes in blood vessels due to the inflammatory substances that are released into the blood [20]. There are different associated factors that trigger an autoimmune disease such as those shown in **Figure 1**.

After the onset of the disease, the synovial membrane of patients with RA, which is generally hypocellular, becomes hyperplastic, containing a large number of cells, such as polymorpho-

Animal Models of Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.72554 261

Chronic inflammation in hypertrophic synovium is maintained by activated cell groups such as synovial fibroblasts and macrophages, as well as an area containing a clear cell infiltrate: mast cells, CD4+ and CD8+ T lymphocytes, NK cells, B lymphocytes, and plasma cells (the latter produce RF against altered IgGs), along with invasive mesenchymal cells. This accumu-

Once the presence of inflammatory arthritis is recognized, a preliminary diagnosis is made; other diagnoses of arthritis (lupus, psoriatic arthritis, spondyloarthritis, among others) are ruled out. Finally, the risk of developing persistent and/or erosive arthritis is assessed. Patients with early RA develop symmetrical polyarthritis, and its appearance is associated with the presence of positive rheumatoid factor (RF) and/or anti-citrullinated (anti-CCP) antibodies. RF corresponds to antibodies that are directed against immunoglobulins IgG, IgM, and IgA and are usually present in 80% of the patients who suffer this disease [27]. In RA, the inflammatory process is mediated primarily by the action of pro-inflammatory cytokines. In addition to enhancing the activity of IL-1 and TNF-α, IL-17 has a direct effect on the evolution of the disease, since it stimulates osteoclast differentiation and promotes the destruction of the cartilage and bone [28]. Until a few years ago, Th1 cells were considered to be the main cause of tissue damage in autoimmune diseases, but Th17 is currently considered to be the major inducer of autoimmune disease. It migrates more rapidly than Th1 to the areas of lesion. Once there, it stimulates the inflammatory response and is able to recruit other complementary cells, including Th1, which is necessarily associated with Th17 for inflammation and tissue destruction [29]. The onset of RA involves certain components such as T cells (CD4+), monocytes, fibroblasts, B cells, dendritic cells, mast cells, and neutrophils [30]. The synovium of patients with RA usually presents a certain red coloration due to the strong inflammation that is present. Chemokines are usually very important in the pathogenesis of the disease, being the most

representative of the CXC family which is a strong promoter of angiogenesis [31].

pro-inflammatory role in arthritis are TNFα, IL-1β, IL-6, and IL-17 [32].

**3. In vivo models for RA**

and the manifestation of clinical symptoms [34].

Cytokines are implicated in the pathogenesis of RA, which triggers and perpetuates autoimmunity, maintaining chronic inflammatory synovitis and directing the destruction of connective tissue. Therefore, they integrate the regulatory immune events and destruction of the tissues that are observed in the clinical progression of RA. Cytokines that play an important

RA is a cosmopolitan disease that affects 60 million people, making it a big problem for the health sector [33]. The etiology and pathophysiology of RA remain poorly understood, but it is generally accepted that genetic, immunological, hormonal, and environmental factors could lead to chronic inflammatory infiltrates, the development of destructive arthropathy,

nuclear leukocytes surrounding immune complexes and complement molecules [26].

lation of complexes and cells forms what is called pannus [26].

Recognition of the major histocompatibility complex (MHC) II by the T-lymphocyte receptor (TCR) will produce a clustering with other surface receptors that activate a signaling cascade, which in turn alters the T-lymphocyte transcriptional program. These events produce tissue destruction and loss of function of affected organs during the course of the autoimmune disease. There is evidence that CD4+ T cells are active in local inflammation and cell infiltration that result in inflammation [21].

#### **2.3. Rheumatoid arthritis, its causes and prognosis**

RA is a chronic inflammatory disease characterized by synovitis with a symmetrical distribution that causes severe joint destruction [22]. RA is a common autoimmune systemic inflammatory disease that affects approximately 1% of the worldwide population and its incidence is 0.5–1% [3]. Cohort studies have shown that people with arthritis are 54% more likely to die than a healthy person, and there are data that indicate that this frequency is directly associated with the severity of the disease [23]. The process was reported in 1909 by Nichols and Richardson, and among the symptoms of RA are a prodromal period preceded by overt asthenia, general malaise, diffuse myalgia, fever, and anorexia, weight loss, pain, stiffness, and swelling in affected joints [24].

RA initiates as an inflammation of synovial fluid, in which rheumatoid factor (RF), IgM and IgG, and anti-CCP antibodies are present in serum and joints. Complement is activated within the synovial fluid, with C3a and C5a being the most important components found [9]. The disease is perpetuated by the production of cytokines and the action of extracellular matrix metalloproteinases (MMP) [25].

**Figure 1.** Factors associated with the development of autoimmunity. There are several important factors that are considered the trigger of an autoimmune disease, since the true etiology is not currently known. These include hormonal, immunological, environmental, or genetic factors (susceptibility).

After the onset of the disease, the synovial membrane of patients with RA, which is generally hypocellular, becomes hyperplastic, containing a large number of cells, such as polymorphonuclear leukocytes surrounding immune complexes and complement molecules [26].

Chronic inflammation in hypertrophic synovium is maintained by activated cell groups such as synovial fibroblasts and macrophages, as well as an area containing a clear cell infiltrate: mast cells, CD4+ and CD8+ T lymphocytes, NK cells, B lymphocytes, and plasma cells (the latter produce RF against altered IgGs), along with invasive mesenchymal cells. This accumulation of complexes and cells forms what is called pannus [26].

Once the presence of inflammatory arthritis is recognized, a preliminary diagnosis is made; other diagnoses of arthritis (lupus, psoriatic arthritis, spondyloarthritis, among others) are ruled out. Finally, the risk of developing persistent and/or erosive arthritis is assessed. Patients with early RA develop symmetrical polyarthritis, and its appearance is associated with the presence of positive rheumatoid factor (RF) and/or anti-citrullinated (anti-CCP) antibodies. RF corresponds to antibodies that are directed against immunoglobulins IgG, IgM, and IgA and are usually present in 80% of the patients who suffer this disease [27]. In RA, the inflammatory process is mediated primarily by the action of pro-inflammatory cytokines. In addition to enhancing the activity of IL-1 and TNF-α, IL-17 has a direct effect on the evolution of the disease, since it stimulates osteoclast differentiation and promotes the destruction of the cartilage and bone [28].

Until a few years ago, Th1 cells were considered to be the main cause of tissue damage in autoimmune diseases, but Th17 is currently considered to be the major inducer of autoimmune disease. It migrates more rapidly than Th1 to the areas of lesion. Once there, it stimulates the inflammatory response and is able to recruit other complementary cells, including Th1, which is necessarily associated with Th17 for inflammation and tissue destruction [29].

The onset of RA involves certain components such as T cells (CD4+), monocytes, fibroblasts, B cells, dendritic cells, mast cells, and neutrophils [30]. The synovium of patients with RA usually presents a certain red coloration due to the strong inflammation that is present. Chemokines are usually very important in the pathogenesis of the disease, being the most representative of the CXC family which is a strong promoter of angiogenesis [31].

Cytokines are implicated in the pathogenesis of RA, which triggers and perpetuates autoimmunity, maintaining chronic inflammatory synovitis and directing the destruction of connective tissue. Therefore, they integrate the regulatory immune events and destruction of the tissues that are observed in the clinical progression of RA. Cytokines that play an important pro-inflammatory role in arthritis are TNFα, IL-1β, IL-6, and IL-17 [32].
