4. Function of autoantibodies; mechanism of protection and cause of diseases?

The antibodies' Fab regions bind to antigens and can block/stimulate the effects of them and the Fc regions can bind to many cells of immune system as phagocytes and complement and activate diverse effector mechanisms to eliminate these antigens; Fcγ-R (for IgG), Fcα-R (for IgA), Fcα/μ-R (for IgA and IgM), Fcε-R (for IgE). The effective binding of antigen-antibody occurs after recognization several IgG molecules. The affinity of the binding is too low with a single, free antibody. Bigger immune complexes by antigen and several Fc parts of antibodies causes to rapid internalization for phagocytosis and antigen clearance. Heavy chain class switching and affinity maturation enhance the protective functions of antibodies. There is an exception to this rule in mast cells and eosinophils, just binding a free (meaning non-antigencomplexed) IgE is enough because of their high-affinity Fc-ε-receptors [4, 17].

#### 4.1. Some examples for the functions of antibodies and autoantibodies

1. Neutralization of foreign and self-antigens: Antibodies bind to block, or neutralize the activity of foreign or self-antigens [4].

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

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

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

5. Mucosal immunity.

diseases (Table 4), involve a single organ or tissue. Almost all organs can be affected by either

Primary biliary cirrhosis Bile ducts Dihydrolipoamide acyltransferase and other antigens b

Thyroglobulin

intrinsic factor

insulin islet cell antigens

The antibodies' Fab regions bind to antigens and can block/stimulate the effects of them and the Fc regions can bind to many cells of immune system as phagocytes and complement and activate diverse effector mechanisms to eliminate these antigens; Fcγ-R (for IgG), Fcα-R (for IgA), Fcα/μ-R (for IgA and IgM), Fcε-R (for IgE). The effective binding of antigen-antibody occurs after recognization several IgG molecules. The affinity of the binding is too low with a single, free antibody. Bigger immune complexes by antigen and several Fc parts of antibodies causes to rapid internalization for phagocytosis and antigen clearance. Heavy chain class switching and affinity maturation enhance the protective functions of antibodies. There is an exception to this rule in mast cells and eosinophils, just binding a free (meaning non-antigen-

1. Neutralization of foreign and self-antigens: Antibodies bind to block, or neutralize the

4. Function of autoantibodies; mechanism of protection and cause of

complexed) IgE is enough because of their high-affinity Fc-ε-receptors [4, 17].

4.1. Some examples for the functions of antibodies and autoantibodies

activity of foreign or self-antigens [4].

systemic or organ-specific autoimmune disease [5].

Table 4. Some organ-specific autoimmune diseases.

Disease Organ(s) involved Autoantibodies Hashimoto's thyroiditis Thyroid Thyroid peroxidase

Addison's disease Adrenal glands 2I-hydroxylase

Pemphigus vulgaris Skin Desmoglein 3

Goodpasture's syndrome Kidneys, lungs Type VII collagen Myasthenia gravis Nervous system Acetylcholine receptor Multiple sclerosis Nervous system Unknown myelin antigens Pernicious anemia Gastric parietal cells Parietal cell antigens,

Graves' disease Thyroid Thyroid-stimulating hormone receptor

Type I diabetes Pancreatic islet cells Glutamic acid dehydrogenase,

Bullous pemphigoid Skin 230 kDa hemidesmosomal antigen Vitiligo Skin melanocytes Unknown melanocyte antigens

Autoimmune hepatitis Liver Smooth muscle antigens (F-actin)

diseases?

26 Autoantibodies and Cytokines

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/ sialylation pattern.

Testing of autoantibodies is diagnostic criteria in many diseases. But, also autoantibodies could be detected in healthy individuals [79]. Since isotype/subclass and glycosylation pattern is critical for the pathogenic potential of a particular antibody, it could be helpful for the diagnostic analysis. Pathogenic autoantibodies could be produced either by continuous formation of short-lived plasma cells or through the formation of long-lived plasma cells, or both [80]. Therapeutic treatment available nowadays could suppress B cell activation and short-lived plasma cell, while do nothing to long-lived plasma cells [81].

2. Type III (caused by immune complexes):

complex mediated diseases are given.

examples of T cell-mediated diseases are given.

Table 6. Immune complex mediated diseases.

Author details

Neval Yurttutan Uyar

Table 7. T cell-mediated diseases.

Address all correspondence to: nevaluyar@gmail.com

Mehmet Ali Aydınlar Acibadem University, Istanbul, Turkey

3. Type IV (delayed-type hypersensitivity, mediated by T cells):

Disease Target antigen Mechanism

Autoantibodies can bind to circulating antigens and form immune complexes that deposit in vessels, tissues and cause tissue injury. Injury is mainly due to leukocyte recruitment and inflammation [4]. Autoantibodies can cause disease by forming immune complexes with the circulating antigens. Immune complex formation is a normal process to remove antigens and to phagocyte through Fc or complement receptors so are prevented their deposition. The efficiency of uptake of immune complexes by either Fc receptors or CR1 is proportional to the number of IgG molecules associated in the complex [5]. At Table 6, some examples of immune

Structure, Physiology, and Functions of Autoantibodies http://dx.doi.org/10.5772/intechopen.76020 29

T cell-mediated disease is caused by CD4 T lymphocytes or by killing of host cells by CD8 CTLs [4]. T cells recognize protein antigen-presenting cells in the context of class II major histocompatibility complex (MHC) molecules and produce the cytokines interferon γ (IFN-γ), interleukin 3 (IL-3), tumor necrosis factor (TNF) α, TNF-β, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Elaboration of "TH1 (a subset of helper T cells) cytokines" leads to macrophage recruitment and activation, enhanced expression of adhesion molecules, and increased production of monocytes by the bone marrow [5]. At Table 7, some

Systemic lupus erythematosus DNA, nucleoproteins Complement and Fc region mediated Polyarteritis nodosa Hepatitis B surface antigen Complement and Fc region mediated Poststreptococcal glomerulonephritis Streptococcal cell wall antigen Complement and Fc region mediated

Disease Target antigen Mechanism Rheumatoid arthritis Antigen in joint synovium T cell mediated Type I diabetes mellitus Islet cell antigen T cell mediated

By contrast, mice with FcγRIIb knocked out spontaneously develop a lupus like disease [71]. Different isotypes antibodies have different affinities for the four FcγRs. IgG2a has higher affinity for FcγRIV, leading to inflammatory responses, whereas IgG1 selectively engages FcγRIIb, leading to inhibitory responses [30]. There is a similar relationships with human FcγRs and that the ability to protect or induce inflammation will change according to the isotype of the autoantibody and FcγR engaged.

7. Removal of cell debris: Natural autoantibodies takes role in the removal of cell debris during inflammation, and autoantibodies to inflammatory cytokines have protective functions against inflammation [82].
