3.3.2.3. B cell tolerance

3. Ignorance: The antigen cannot either stimulate immunity or induce tolerance. This situa-

Immune tolerance is set of immune events, operating both at central immune organs and

1. Central tolerance happens at immature T and B lymphocytes encounter self-antigens in the

2. Peripheral tolerance happens at mature lymphocytes encounter self-antigens in peripheral

The immature T cells die by apoptosis, whenever encounter with self-high avidity protein antigens in the thymus. The immature lymphocytes in the thymus can recognize both self and non-self-antigens. If a self-antigen high in concentration and avidity meet with immature lymphocyte, lymphocytes receives signals that trigger apoptosis, finally dies. This is known as negative selection. Since the self-protein antigens are expressed mainly in thymus because of transcription factor responsible called AIRE (for autoimmune regulator), they are high in

Some lymphocytes which escape from negative selection, mature to dangerous self-reactive T cells with CD4+ T and CD8+ T. They recognize self-antigens through class I and II MHC

And some other develop into regulatory T cells which regulate mostly suppress both naïve and memory T cell responses by a cell to cell contact and by down-regulating the expression of cytokines and co-stimulatory molecules on the antigen-presenting cells. Unfortunately this is

1. Anergy: Anergy is the functional inactivation of T lymphocytes occurs whenever level of the co-stimulators (second signals) is not enough for T cell activation. If level is enough, the co-stimulatory signal which is taken by CD80 and CD86; interaction of molecules expressed on the surface of APC or B cells, reacts with CD28 (or other receptors) on the T cell surface. If T cells with receptors for the self-antigens encounter with sufficient level of self-antigens (signal 1) but do not receive sufficient signal 2, they may induce long-lived T

2. Deletion: Activation-induced cell death: Repeated activation of mature T lymphocytes by repeated encountering with the same antigen cause apoptosis and this is called deletion or

tion is called as ignorance. For example, self-antigens [4, 5].

peripheral ones.

20 Autoantibodies and Cytokines

tissues [4, 5].

concentration [4, 19].

molecules [4, 18, 19].

3.3.2. T lymphocyte tolerance

thymus and bone marrow.

3.3.2.1. Central T lymphocyte tolerance

not antigen specific reaction [4, 5, 18, 19].

3.3.2.2. Peripheral T lymphocytes tolerance

cell anergy [4, 5, 18, 19].

activation-induced cell death [4, 18].

If the self-antigens are in structure of polysaccharides, lipids and nucleic acids antigens, they must induce tolerance in B cell and prevent autoantibody production [4]. The B cell tolerance is a set of actions and finally ends with the depletion of or inactive autoreactive B cells. These processes occur at the every stage of B cell [30, 31].

### 3.4. Central B cell tolerance

When immature B cells encounter with self-antigens in the bone marrow, the B cells are killed and the process is called as negative selection [4].

When immature B cells recognize self-antigens in the bone marrow, they may activate their genes of antibodies and start to express a new light chain. These light chains bind to the previously produced Ig heavy chain to produce a new antigen receptor. This process is called receptor editing. The mechanisms of B cell tolerance are multifaceted and may involve receptor editing, controlled migration, and limited availability of BAFF, CD22, Siglec-G, miRNA, and follicular regulatory T cells [30–33].

#### 3.4.1. Peripheral B cell tolerance

When mature B lymphocytes encounter with high concentration of self-antigens and B cells producing antibodies that bind with high affinity to self-antigens in peripheral lymphoid tissues, they become anergic; functionally inactivation. T cell-independent antigens can trigger strong signals in the B cell. If it is not strong, the B lymphocytes become anergic [30, 34, 35].

#### 3.5. Role of natural autoantibody

Roles of self-reactive B cells are changing according to binding affinities to self-antigens. If selfreactive B cells produce antibodies with high affinity, they undergo elimination or anergy. But if self-reactive B cells produce antibodies with medium or low affinity, they may escape from anergy, even in non-autoimmune individuals [30, 34, 35].Therefore, a significant proportion of immunoglobulins in healthy individuals are made by these autoantibodies. Most of the medium/ low affinity antibodies are multireactive and recognize both self and non-self-antigens [30, 35]. They are called as natural antibodies or natural autoantibodies [16, 17, 36]. Because of their multireactivity, the natural antibodies take an important role in the first part of defense against infections [16, 37] and natural autoantibodies in the development of the B cell repertoire [38].

Most of natural autoantibodies are IgM isotype, polyreactive with moderate and low affinity. Therefore, they bind to several unrelated antigens. Also there are natural mono-reactive antibodies [16, 36, 39, 40]. Natural autoantibodies are expressed mostly by CD5+ B1 cell which is the most common B lymphocytes in the neonatal period and in marginal zone B cells [41, 42]. These B1 lymphocytes actively present antigens [43] and also play an important role in the pathogenic autoantibodies production of some autoimmune diseases, as rheumatoid arthritis, Sjögren syndrome, primary antiphospholipid syndrome and systemic lupus [44].

Changing from preclinical to clinical autoantibody has certain steps. In genetic predisposed individuals, autoantibodies are produced by autoreactive cells. These preclinical autoantibodies can stay for months or even years in these individuals. Under proper environmental conditions, the autoreactive cells would be activated and proliferated. Then, they produce large amounts of autoantibodies and inflammatory cytokines, which lead to tissue injury and

Structure, Physiology, and Functions of Autoantibodies http://dx.doi.org/10.5772/intechopen.76020 23

Natural autoantibodies can provide the templates for the higher-affinity and class-switched

1. Somatic hypermutation: Each antibody can bind at least 2 (IgG, IgD and IgE isotypes) – maximum 10 epitopes (IgM isotype) of an antigen, which has identical epitopes and are close enough. If the multiple antigen-antibody bind each other, the total strength of the bond is much greater than a single one. This is called the avidity of the interaction. The molar concentration of an antigen needed to occupy half the available antibody molecules in a solution is the dissociation constant (Kd) and used for expression of affinity. The lower the Kd means the higher the affinity. In a primary immune response, produced antibodies have a Kd in the range

–10<sup>9</sup> M and after encountering with repeated antigens, the affinity can rises up to 10–

11 M. This increase in antigen-binding strength is called affinity maturation or somatic hypermutation [4]. Mostly point mutations in the genes responsible for variable regions of antibody are detected [16]. They happen in the germinal centers of secondary follicles and AID

2. Class switching: The membrane bound IgM and IgD the antigen receptors of naïve B lymphocytes. After stimulation, the antigen specific clone B lymphocytes may proliferate and differentiate into antibody-secreting cells. Some of these B cells may secrete IgM, and some others may produce antibodies of other heavy chain classes. The change in Ig isotype production is called heavy chain class switching. The V regions remains same, specificity of B cells

The exons encoding the constant regions of all antibody classes on chromosome 14, are placed with μ (for IgM) nearest to variable region segments, followed by γ (IgG), α (IgA) and ε (IgE). By a successful VDJ rearrangement, first the nearest constant region which is μ is used, resulting in the production of IgM [17]. Unmutated or minimally mutated recombined VDJ gene sequences encode the multi and monoreactive natural IgM antibodies/autoantibodies [56]. AID deaminates cytidines in immunoglobulin VDJ and switch-region DNA, then ssDNA nicks, gaps or double-strand breaks are generated. Repair of these lesions involving errorprone translesion DNA polymerases are made by the B cell DNA and this results in insertions of point mutations or resolution of double-strand breaks, and hence, class-switch DNA recombination [57]. After class switch with the same variable region, these cells can express IgG if the exons encoding the γ constant region; IgA if it is α constant region; and IgE if it is ε constant region. T-lymphocytes and other cells release cytokines influence isotype of class switch [17]. Unmutated natural IgM autoantibodies expressed by B1 cells provide the 'templates' for the high-affinity and class-switched IgG and/or IgA autoantibodies which can cause autoimmune diseases [49, 58, 59]. Anti-DNA, anti-insulin and anti-IgG (RF) autoantibodies are pathogenic

the clinical symptoms are observed [6].

Production of pathogenic autoantibody:

enzyme that initiate them [17].

of 10<sup>6</sup>

maintains [4].

pathogenic autoantibodies, under appropriate conditions [16].

In the infantile periods as an evolutionary process, proteins participate mainly in the building and protection of the organism from non-self and self-antigens. During evolution period, these proteins are highly preserved as the autopolyreactive IgM natural autoantibodies (Nabs) produced mainly by B-1 CD5þ cells [25, 41] and also after class switch, polymeric and monomeric IgG isotype antibodies are produced by mostly B2 cells [25, 45].

Natural antibodies take critical roles; such as:


During cell death, some multiple intracellular enzymes as nucleases and proteases are activated which cause the numerous cellular molecules cleavage; as a consequence, some hidden antigens are exposed and called as 'neoepitopes' or neodeterminants. Most of the neoepitopes are undergo to tolerance, but some undergo modification; as cleavage, phosphorylation and oxidation. The self-antigens released by dying cells can be changed by ultraviolet light, oxidation or cleavage by granzyme B [53] delivered by cytotoxic T cells and this change can lead to autoimmune responses. In rheumatoid arthritis, cyclic citrullinated peptides autoantibodies (anti-CCP antibodies) are one of a neoepitope secondary to inflammation [54]. Citrulline is formed by deamination of the arginine amino acid during inflammation/oxidative stress or apoptosis.

### 3.6. Generation of pathogenic autoantibody

In specific autoimmune diseases, some of autoantibodies could be detected before beginning of the disease. For example; in SLE, rheumatoid arthritis, type I diabetes, limbic encephalitis and primary biliary cholangitis [55].

Changing from preclinical to clinical autoantibody has certain steps. In genetic predisposed individuals, autoantibodies are produced by autoreactive cells. These preclinical autoantibodies can stay for months or even years in these individuals. Under proper environmental conditions, the autoreactive cells would be activated and proliferated. Then, they produce large amounts of autoantibodies and inflammatory cytokines, which lead to tissue injury and the clinical symptoms are observed [6].

Natural autoantibodies can provide the templates for the higher-affinity and class-switched pathogenic autoantibodies, under appropriate conditions [16].

Production of pathogenic autoantibody:

the most common B lymphocytes in the neonatal period and in marginal zone B cells [41, 42]. These B1 lymphocytes actively present antigens [43] and also play an important role in the pathogenic autoantibodies production of some autoimmune diseases, as rheumatoid arthritis,

In the infantile periods as an evolutionary process, proteins participate mainly in the building and protection of the organism from non-self and self-antigens. During evolution period, these proteins are highly preserved as the autopolyreactive IgM natural autoantibodies (Nabs) produced mainly by B-1 CD5þ cells [25, 41] and also after class switch, polymeric and mono-

Sjögren syndrome, primary antiphospholipid syndrome and systemic lupus [44].

4. First line defense against non-self-antigens; bacterial and viral infections [46].

5. Regulate the immune system protect the system against tolerance breakdown and the

6. Maintain tissue balance [47]: Up or down regulation of immunotolerance leads to susceptibility/ progressive or protective role in disease as chronic inflammatory disease [48], cancer [49], cardiovascular disease [50], and certain neurodegenerative conditions [33, 34].

7. Clearance of tissue and cell debris after degradation [51]; Most diseases is resulting the destruction of tissues/cells which leads to the continuous antigens release. Natural autoantibody recognizes antigens in cell debris and can react with specific antigens of target tissues. In case of chronic inflammation, more natural autoantibody can be stimulated and some autoantigens can mutate to xenoantigens; after these mutations, more specific path-

During cell death, some multiple intracellular enzymes as nucleases and proteases are activated which cause the numerous cellular molecules cleavage; as a consequence, some hidden antigens are exposed and called as 'neoepitopes' or neodeterminants. Most of the neoepitopes are undergo to tolerance, but some undergo modification; as cleavage, phosphorylation and oxidation. The self-antigens released by dying cells can be changed by ultraviolet light, oxidation or cleavage by granzyme B [53] delivered by cytotoxic T cells and this change can lead to autoimmune responses. In rheumatoid arthritis, cyclic citrullinated peptides autoantibodies (anti-CCP antibodies) are one of a neoepitope secondary to inflammation [54]. Citrulline is formed by deamination of the arginine amino acid during inflammation/oxidative stress or apoptosis.

In specific autoimmune diseases, some of autoantibodies could be detected before beginning of the disease. For example; in SLE, rheumatoid arthritis, type I diabetes, limbic encephalitis and

meric IgG isotype antibodies are produced by mostly B2 cells [25, 45].

ogenic or protective antibodies can be produced [52].

3.6. Generation of pathogenic autoantibody

primary biliary cholangitis [55].

Natural antibodies take critical roles; such as:

3. At evolution period, autopolyreactivity

1. Differentiation self from foreign

autoimmune diseases.

2. Recognition of self

22 Autoantibodies and Cytokines

1. Somatic hypermutation: Each antibody can bind at least 2 (IgG, IgD and IgE isotypes) – maximum 10 epitopes (IgM isotype) of an antigen, which has identical epitopes and are close enough. If the multiple antigen-antibody bind each other, the total strength of the bond is much greater than a single one. This is called the avidity of the interaction. The molar concentration of an antigen needed to occupy half the available antibody molecules in a solution is the dissociation constant (Kd) and used for expression of affinity. The lower the Kd means the higher the affinity. In a primary immune response, produced antibodies have a Kd in the range of 10<sup>6</sup> –10<sup>9</sup> M and after encountering with repeated antigens, the affinity can rises up to 10– 11 M. This increase in antigen-binding strength is called affinity maturation or somatic hypermutation [4]. Mostly point mutations in the genes responsible for variable regions of antibody are detected [16]. They happen in the germinal centers of secondary follicles and AID enzyme that initiate them [17].

2. Class switching: The membrane bound IgM and IgD the antigen receptors of naïve B lymphocytes. After stimulation, the antigen specific clone B lymphocytes may proliferate and differentiate into antibody-secreting cells. Some of these B cells may secrete IgM, and some others may produce antibodies of other heavy chain classes. The change in Ig isotype production is called heavy chain class switching. The V regions remains same, specificity of B cells maintains [4].

The exons encoding the constant regions of all antibody classes on chromosome 14, are placed with μ (for IgM) nearest to variable region segments, followed by γ (IgG), α (IgA) and ε (IgE). By a successful VDJ rearrangement, first the nearest constant region which is μ is used, resulting in the production of IgM [17]. Unmutated or minimally mutated recombined VDJ gene sequences encode the multi and monoreactive natural IgM antibodies/autoantibodies [56]. AID deaminates cytidines in immunoglobulin VDJ and switch-region DNA, then ssDNA nicks, gaps or double-strand breaks are generated. Repair of these lesions involving errorprone translesion DNA polymerases are made by the B cell DNA and this results in insertions of point mutations or resolution of double-strand breaks, and hence, class-switch DNA recombination [57]. After class switch with the same variable region, these cells can express IgG if the exons encoding the γ constant region; IgA if it is α constant region; and IgE if it is ε constant region. T-lymphocytes and other cells release cytokines influence isotype of class switch [17].

Unmutated natural IgM autoantibodies expressed by B1 cells provide the 'templates' for the high-affinity and class-switched IgG and/or IgA autoantibodies which can cause autoimmune diseases [49, 58, 59]. Anti-DNA, anti-insulin and anti-IgG (RF) autoantibodies are pathogenic high-affinity autoantibodies that undergo somatic hypermutation, class-switch DNA recombination and antigen driven clonal selection detected at systemic lupus, type 1 diabetes and rheumatoid arthritis patients [60]. Somatic hypermutation and class-switching [56, 60, 61] including the expression of activation-induced cytidine deaminase (AID) [62] are associated with the expansion of B-2 cells.

MFG-E8 deficiency, apoptotic cells accumulate in germinal centers and in C1q-deficiency, apoptotic cells accumulate in the kidney. These deficiencies cause lupus-like diseases [16].

c. Breakdown in the regulation of B cell or T cell activation threshold: If threshold regulators of cbl-b, PD-1 and Zap-70 and the SLAM cluster in T cells, and Lyn and FcγRIIb in B cells change genetically, failure of peripheral immune system could happens. If lymphocytes are more easily activated, they produce more auto-antibodies as in systemic lupus. Mutations of Zap-70 lead to production of RFs as in rheumatoid arthritis [16, 65]. PD-1-defi-

There is some signature autoantibodies cause autoimmune diseases as anti-endomysial antibodies (EMA), anti-gliadin antibodies (AGA). But there is not a specific antibody detected yet

Lymphocytes and APC are strongly activated by type I interferons (interferon-α and β) [66]. Patients with systemic lupus have elevated levels of interferon and autoantibodies as anti-DNA and Sm/RNP. By binding to chromatin which contains DNA or to Sm/RNP which contain small nuclear RNAs, they enter cells through the FcγR or B cell receptor. The intracellular Toll-like receptor is activated by nucleic acid which leads to production of interferon and activation of immune system. The protein antigen stimulates T cells, probably are responsible

Autoimmune disease can be classified as systemic or organ specific. Systemic autoimmune diseases (Table 3), involve multiple organs or tissues, whereas organ specific autoimmune

> Anti dsDNAb Anti Sm b Anti ribosomal P b Anti RNA helicase

Structure, Physiology, and Functions of Autoantibodies http://dx.doi.org/10.5772/intechopen.76020 25

Rheumatoid factor

Anti Ro60 (SS-A) Anti Ro52 Anti La (SS-B)

etc.) b

Anti fi brillarin (U3 RNP) b Anti RNA polymerase I b Anti RNA polymerase III b

(Histidyl, alanyl, threonyl, glycyl,

Signal recognition particle b

for the specificity of the immune response. These are called Toll hypothesis [67].

Disease Organ(s) involved Autoantibodies

Joints, skin, nervous system, kidneys, blood cells, heart,

Rheumatoid arthritis Joints, blood, vessels, lungs Anti citrullinated peptides b

Scleroderma Skin, blood vessels, GI tract, lungs, kidneys Anti topoisomerase I b

Polymyositis Muscles, lungs tRNA synthetases

ciency causes lupus in C57BL/6 and myocarditis in BALB/c.

in several autoimmune diseases, as psoriasis [6].

3.7. Systemic versus organ-specific autoimmune disease

Sjögren's syndrome Exocrine glands (salivary and lacrimal glands), kidneys, nerves

lungs

Table 3. Some systemic autoimmune diseases.

Systemic lupus erythematosus

Class switch and somatic hypermutation are initiated by the same enzyme, AID, in the germinal centers of secondary follicles parallelly [17].

3. Somatic diversity: Somatic recombination: Antibodies are capable of binding a wide variety of antigen, since variable region of antibody molecules forms a flat surface field into different shapes. The epitopes or determinants are the parts of antigens that are recognized by antibodies based on sequence (linear determinants) or shape (conformational determinants). Some hidden antigen molecules are exposed after a physicochemical change, called as neodeterminants [4].

Diversity of antibodies is generated by the genetics arrangement of antibody production; unique molecular random generator. The variable region of an immunoglobulin is formed by both the heavy and the light chain which are carried on different chromosomes [5]. The variable portion of the heavy chain is encoded in separated gene segments of three types, V (variable; the number of gene segments is 65), D (diversity; 27) and J (joining; 6). A complete heavy chain variable region exon is randomly cobbled together by juxtaposing one V, one D and one J segment by a cut and paste process at the DNA level by an enzyme complex containing RAG-proteins (recombination activating gene) which excises intervening DNA, and normal DNA repair proteins directly rejoin the segments. Light chain genes have just V and J segments, not D [17]. In summary, the diversity of antigen binding is achieved by mostly V genes and their combination with different D and J genes. Different antibodies are produced by four different mechanisms as; randomly combining V-(D)-J segments, randomly combining heavy and light chain, imprecise joining and somatic hypermutation [4, 17]. Somatic diversity is performed during central B cell intolerance.

4. Genetic abnormalities: Some genetic alterations results clinical autoimmune disease but some alterations are influenced by environmental factors. For example; single gen knockout and overexpression lead to clinical autoimmune disease while most of the autoimmune disorders are polygenic. Three examples of spontaneous or induced genetic alterations lead to clinical diseases [16].


MFG-E8 deficiency, apoptotic cells accumulate in germinal centers and in C1q-deficiency, apoptotic cells accumulate in the kidney. These deficiencies cause lupus-like diseases [16].

c. Breakdown in the regulation of B cell or T cell activation threshold: If threshold regulators of cbl-b, PD-1 and Zap-70 and the SLAM cluster in T cells, and Lyn and FcγRIIb in B cells change genetically, failure of peripheral immune system could happens. If lymphocytes are more easily activated, they produce more auto-antibodies as in systemic lupus. Mutations of Zap-70 lead to production of RFs as in rheumatoid arthritis [16, 65]. PD-1-deficiency causes lupus in C57BL/6 and myocarditis in BALB/c.

There is some signature autoantibodies cause autoimmune diseases as anti-endomysial antibodies (EMA), anti-gliadin antibodies (AGA). But there is not a specific antibody detected yet in several autoimmune diseases, as psoriasis [6].

Lymphocytes and APC are strongly activated by type I interferons (interferon-α and β) [66]. Patients with systemic lupus have elevated levels of interferon and autoantibodies as anti-DNA and Sm/RNP. By binding to chromatin which contains DNA or to Sm/RNP which contain small nuclear RNAs, they enter cells through the FcγR or B cell receptor. The intracellular Toll-like receptor is activated by nucleic acid which leads to production of interferon and activation of immune system. The protein antigen stimulates T cells, probably are responsible for the specificity of the immune response. These are called Toll hypothesis [67].

#### 3.7. Systemic versus organ-specific autoimmune disease

high-affinity autoantibodies that undergo somatic hypermutation, class-switch DNA recombination and antigen driven clonal selection detected at systemic lupus, type 1 diabetes and rheumatoid arthritis patients [60]. Somatic hypermutation and class-switching [56, 60, 61] including the expression of activation-induced cytidine deaminase (AID) [62] are associated

Class switch and somatic hypermutation are initiated by the same enzyme, AID, in the

3. Somatic diversity: Somatic recombination: Antibodies are capable of binding a wide variety of antigen, since variable region of antibody molecules forms a flat surface field into different shapes. The epitopes or determinants are the parts of antigens that are recognized by antibodies based on sequence (linear determinants) or shape (conformational determinants). Some hidden antigen molecules are exposed after a physicochemical change, called as neodeterminants [4].

Diversity of antibodies is generated by the genetics arrangement of antibody production; unique molecular random generator. The variable region of an immunoglobulin is formed by both the heavy and the light chain which are carried on different chromosomes [5]. The variable portion of the heavy chain is encoded in separated gene segments of three types, V (variable; the number of gene segments is 65), D (diversity; 27) and J (joining; 6). A complete heavy chain variable region exon is randomly cobbled together by juxtaposing one V, one D and one J segment by a cut and paste process at the DNA level by an enzyme complex containing RAG-proteins (recombination activating gene) which excises intervening DNA, and normal DNA repair proteins directly rejoin the segments. Light chain genes have just V and J segments, not D [17]. In summary, the diversity of antigen binding is achieved by mostly V genes and their combination with different D and J genes. Different antibodies are produced by four different mechanisms as; randomly combining V-(D)-J segments, randomly combining heavy and light chain, imprecise joining and somatic

hypermutation [4, 17]. Somatic diversity is performed during central B cell intolerance.

lymphoproliferative syndrome/Canale Smith syndrome in humans [16, 63],

4. Genetic abnormalities: Some genetic alterations results clinical autoimmune disease but some alterations are influenced by environmental factors. For example; single gen knockout and overexpression lead to clinical autoimmune disease while most of the autoimmune disorders are polygenic. Three examples of spontaneous or induced genetic alterations lead to clinical

a. Abnormal survival of autoreactive lymphocytes: Mutations in Fas/CD95 causes over expression of the B cell stimulator BLyS; BAFF and the antiapoptotic regulator Bcl-2 which leads the abnormal survival of autoreactive lymphocytes. It causes an autoimmune

b. Defective removal of apoptotic cells: A group of proteins as Mer and serum opsonins (e.g., natural IgM antibodies, C1q, serum amyloid P component [SAP] and milk fat globulin epithelial growth factor-8 [MFGE8]) [64] take role in the removal of apoptotic cells. In Mer deficiency, macrophages take a proinflammatory signal not an anti-inflammatory one for ingestion of apoptotic cells. If there is a defective clearance of apoptotic cells in surface IgM, C1q, SAP and MFGE8, clearance of apoptotic cells leads to postapoptotic necrosis and/or through lack of engagement with specific inhibitory receptors on the phagocyte. In

with the expansion of B-2 cells.

24 Autoantibodies and Cytokines

diseases [16].

germinal centers of secondary follicles parallelly [17].

Autoimmune disease can be classified as systemic or organ specific. Systemic autoimmune diseases (Table 3), involve multiple organs or tissues, whereas organ specific autoimmune


Table 3. Some systemic autoimmune diseases.


2. Opsonization and phagocytosis: Complex of antibodies with foreign and self-antigens promote their ingestion by phagocytes (opsonization). When IgG1 and IgG3 isotype antibodies bind to a foreign or self-antigen, their Fc regions bind to a high affinity receptors called FcγRI (CD64), which are on neutrophils and macrophages. The binding of antibody Fc tails to FcγRI results in opsonization of antigenic molecules into a vesicle called a phagosome, where fuse with lysosomes and activates the neutrophil or phagocytes. The activated ones produces in their lysosomes, large amounts of reactive oxygen intermediates, nitric oxide, and proteo-

Structure, Physiology, and Functions of Autoantibodies http://dx.doi.org/10.5772/intechopen.76020 27

3. Antibody-dependent cellular cytotoxicity (ADCC): Natural killer (NK) cells produce an Fc receptor called FcγRIII, which binds to IgG antibodies. The activated NK cells discharge their

4. Activation of the complement system: Antigens without antibody, as part of innate immune response to infection, and antigens with antibody, as part of adaptive immunity can activate the complement system. The complement system takes role in the elimination of opsonized antigens [4]. Examples; activation of complement causes diseases at kidneys of systemic lupus and lupus nephritis patients, fetal loss associated with the antiphospholipid syndrome [68, 69], autoantibody administration into the transgenic K/BxN mouse of rheumatoid arthritis [70], in glucose-6-phosphate isomerase patient. In the NZB/W F1 murine model of immune-complexmediated lupus nephritis, mice lacking the FcγRγ chain were protected from nephritis, indi-

6. Pro-inflammatory and anti-inflammatory effect: natural polyautoreactive IgM antibodies can protect from autoimmune diseases [30]. Also IgG isotype autoantibodies has an antiinflammatory capacities, according to their IgG subclass and the extent of glycosylation/ sialylation of the Fc glycan linked to Asn297 [71, 72]. These properties regulate the binding of antibody to a different Fc-receptors [72]. The receptors as FcγRI (CD64), FcγRIIIA (CD16a), and FcγRIIIB (CD16b) mediate activating signals, but also FcγRIIA and FcγRIIB (CD32) mediate inhibiting signals. Glycosylated/ sialylated different IgG isotypes antibodies bind to Fc-receptors for activating and inhibiting with different affinities [72]. According to glycosylation/sialylation patterns and IgG subclass determine, an autoantibody produces FcγRmediated either pro- or anti-inflammatory functions [73]. So glycosylation of autoantibody can be an important regulator of autoimmune disorders [74]. While IgG isotypes produced with T cell-dependent reactions were poorly sialylated causes pro- inflammatory, a high degree of sialylation that mediates anti-inflammatory properties [75]. Activated B cells and plasma cells regulate both T cell differentiation into follicular helper T cells and cytokine profiles [76]. By stimulation of TLR, B lymphocytes produce different cytokines to dendritic cells [77]. Dendritic cells are the most important antigen-presenting cells to T cell. B cell also present the antigen to T cell and so promote the proliferation of activated T lymphocytes, the development of robust T effector responses, and normal T cell memory compartments [78]. TLR-signals in murine B cells promote IFN-γ production from T cells and control antibody isotype switching to IgG2 in vivo [77]. The cowork of activated B and T cells is crucial for the antibody responses and their outcome as pathogenic potential, that is, the antibody class and glycosylation/

lytic enzymes, all of them together destroy the ingested antigenic cells [4].

granules, which contains proteins that kill the opsonized targets [4]

cating a critical role for FcγRs in tissue inflammation [71].

5. Mucosal immunity.

sialylation pattern.

Table 4. Some organ-specific autoimmune diseases.

diseases (Table 4), involve a single organ or tissue. Almost all organs can be affected by either systemic or organ-specific autoimmune disease [5].
