Immunoglobulins (Igs) are produced from differentiated B lymphocytes. They bind antigens and inactivate or remove offending toxins, microbial agents and other foreign substances hostile to the body. Initially, precursor cells transition through several developmental stages, then produce IgM. At this stage, further differentiation involves cytokine facilitated class switching. Structurally, all Ig classes (IgG, IgM, IgA, IgD and IgE) consist of two heavy and two light chains, however, their functional characteristics vary widely.

The mucosal immune system is comprised of the lymphoid tissue associated with epithelial surfaces of the gastrointestinal, respiratory and urogenital tracts. This system is different from the systemic immune system in that it evolves under constant exposure to environmental antigens. The distinctive features of this system include predominance of the mucosa-related immunoglobulin (IgA), mucosa-specific regulatory effector T cells and a mucosa-oriented lymphocyte-homing system which allows antigen-activated lymphocytes to migrate selectively from the mucosal follicles to the diffuse subepithelial lymphoid tissue [1], Thus, the mucosal immune system is relatively segregated from the systemic immune system and functions somewhat as a distinct immunological entity. However, both systems are quite complex with effector mechanisms influenced by cytokines, T cells, macrophages, agents and toxins.

Although IgA comprises only 7-15% of the total serum immunoglobulins, it is the predominant immunoglobulin in body secretions such as gastrointestinal tract secretions, saliva, tears, nasal secretions and human milk. The first step in isotype switching to IgA in humans is induction by transforming growth factor pi (TGF-/31). It has been proposed that TGF-fi \ binds to IgM cell surface receptors resulting in signaling and subsequent activation of IA-region.

There are two subclasses of IgA in humans, al and «2 [2], IgAl is the predominant circulating subclass in serum while IgA2 is primarily found in body secretions. Secretory IgA (slgA) is a dimer consisting of two monomers of IgA joined by a "J" chain and a glycoprotein called secretory protein. IgAl fixes complement by the alternate pathway and has potent antiviral properties. IgA also prevents the binding of virus to epithelial cells of the respiratory and the gas trointestinal tract. IgA has a special role in "immunological exclusion", a process by which it provides a barrier to macromolecular absorption at the mucosal level by binding antigens, leading to their entrapment and subsequent degradation by proteases. This protects the immune system from unnecessary, excessive and potentially harmful antigenic stimulation. Antigen bound IgA interferes with complement fixation which is necessary for cell-mediated tumor lysis [3],

Two lineages of intestinal IgA have been defined, B1 and B2. B1 cells are self-renewing cells of the peritoneal cavity that are directed against bacterial antigens. B2 cells account for the majority of IgA producing cells in mucosa and respond to proteins. B2 cells are IL-6 dependent and IL-5 independent while B1 cells are IL-5 dependent and IL-6 independent [4].

Cytokines are intimately involved in Ig class switching and reciprocal regulation of T-helper cell (Th) subsets occurs. In IFNy/IL-4 double knockout mice, IgA differentiation is normal, however, induction of specific antibody response is impaired [5]. Various external stimuli, such as LPS and toxins, mediated by intestinal macrophages, induce increased IL-6 production and elevated IgA levels. A co-stimulatory role for intestinal macrophages is suggested [6]. Dendritic cells recruit antigen specific T cells and induce the production of Igs by increasing B-cell growth and differentiation to IgA producing cells by induced isotype switching [7]. Mature B cells secrete IL-10, which inhibits cell-mediated immunity and inflammation, thereby promoting the humoral limb. The Epstein-Barr virus (EB V) infection induces high levels of human IL-10 in EBV expressing cells. Neutralizing antibody studies suggest that IL-10 acts as a B-cell growth factor in EBV infected B cells, with IL-6 acting synergistically. Overexpression of B cell derived IL-10 may contribute to humoral disorders [8], IL-12 alters helper T-cell subsets when administered orally, triggering Thl-type responses and subsequent decreased secretory IgA responses [9],

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