3.3.1. Immunologic tolerance

The T cell activation by B cell requires antigen recognition and co-stimulation:

peptides of that protein to T lymphocyte.

also stimulated by helper T lymphocytes [4, 5, 19].

class switching and affinity increase [17, 19].

3.2. Stimuli for generation of autoantibody

rheumatoid arthritis but not everyone [5, 6].

chemicals, and infectious agents [5].

produce immunoglobulins. The two advantages of memory cells;

1. Shorter reaction day: instead of five or more days, it takes one or two.

by B cells.

18 Autoantibodies and Cytokines

1. Antigen recognition: B lymphocytes work as antigen-presenting cells (APCs); B lymphocytes may bind, internalize and process the antigen protein, and present multiple different

2. Co-stimulation: The helper T cells are stimulated by B7 molecules as co-stimulator expressed

CD40 ligand (CD40) and cytokines are expressed by CD4+ helper T lymphocytes after activation. CD40 ligand; a surface protein delivers the co-stimulatory signal in B cells and interacts with CD40 on the surface of B lymphocytes. Attachment of CD40 and cytokines stimulate B cell clonal expression and antibody production. Class switching and affinity maturation are

After B lymphocytes proliferation and differentiation into antibody-secreting plasma cells, the antibodies enter the blood through lymphoid follicle. Some plasma cells move to bone marrow, live at the bone marrow for months or years and continue to produce antibodies afterwards antigen is removed. These antibodies supply a rapid response when they meet with same antigen. The humoral immune response decreases physiologically by time because of programmed B cell death. But a small number of activated cells differentiate into memory cells, which "freeze" in a state for a very long time [4, 18, 19]. When the body encounter with the same antigen, the memory cells quickly change into antibody-secreting plasma cells and

2. B memory cells differentiate with class switch and somatic hypermutation so in case of reinfection, only memory cells with higher affinities and class switch are selected which are completely same with the B cell receptors of the original infection. Recurring antigen stimulation causes to helper T lymphocytes increase consecutively antibody increase with heavy chain

Failure of immunologic tolerance can cause the development of autoimmunity. With a genetic background, intolerance can be triggered by environmental factors as sunlight, drugs,

1. Genetic factors: Immunologic tolerance failure is multifactorial and genetic factors are just one of the cause. For example, the relative risk of having autoimmune disease is 5–50 times higher in siblings of affected individuals than in unrelated ones. Multiple genes; mostly MHC predispose to autoimmune disease and genetic predisposition is detected in many autoimmune diseases. For example, individual with HLA-DR4 gene can be suffered from

2. Environmental factors: İnfections can cause the autoimmune diseases by activating selfreactive lymphocytes. The mechanism is like that an infection lead to a local immune response and activation of APCs. Activated APCs secretes co-stimulators - cytokines and The immune system can differentiate self from non-self [5]. Immunologic tolerance is lack of response to self-antigens that encounter with lymphocytes [6]. The recognition of self is a special set of immune events that all constituents of the organism take a role and may be interrupted by environmental and genetic factors [25–29]. There are three possible immune responses according to antigen type, after antigen encounter with the lymphocytes which has the receptors for a specific antigen;



Table 2. Infections related with autoimmune diseases.

3. Ignorance: The antigen cannot either stimulate immunity or induce tolerance. This situation is called as ignorance. For example, self-antigens [4, 5].

3. Immune suppression: Autoreactive mature T lymphocytes that encounter with self-antigen may develop into regulatory cells which suppress the self-reactive lymphocytes response

Structure, Physiology, and Functions of Autoantibodies http://dx.doi.org/10.5772/intechopen.76020 21

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

When immature B cells encounter with self-antigens in the bone marrow, the B cells are killed

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

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].

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

[4, 18, 19].

3.3.2.3. B cell tolerance

3.4. Central B cell tolerance

follicular regulatory T cells [30–33].

3.5. Role of natural autoantibody

3.4.1. Peripheral B cell tolerance

processes occur at the every stage of B cell [30, 31].

and the process is called as negative selection [4].

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

