IgA is found in both serum and mucosal secretions and is the most abundant human Ig isotype overall, as well as the principal mucosal antibody (Kerr 1990). Indeed, more IgA is produced in adult humans per day than all other antibody isotypes combined (Monteiro and van de Winkel 2003). IgA in mucosal secretions has been described as the "first line of defense" of the immune system against pathogens, and serum IgA forms a "second line of defense" against those pathogens that have penetrated the epithelial barrier (van Egmond et al. 2000). Serum IgA is predominantly found in the so-called monomeric form (actually a heterotetramer of two heavy and two light chains), although approximately five to ten percent of serum IgA is polymeric. Polymeric IgA (pIgA) is composed of two or more IgA monomers linked by disulfide bonds between a small protein called J ("joining") chain and C-ter-minal extensions called the tailpieces on each IgA monomer. Polymeric IgA is delivered to mucosal secretions by pIgR, a receptor that actively transcy-toses J chain-containing pIgs from the basolateral side to the apical surface of epithelial cells (Mostov 1994). Once in secretions, SIgA binds pathogens and their toxins and prevents their attachment to, and invasion of, the host. SIgA can neutralize pathogens by directly blocking interactions between bacterial adhesins and their cellular receptors or by inhibiting the movement of the bacteria by cross-linking them or interacting with their flagella (reviewed in Lamm 1997). Binding can occur specifically to defined antigens by the IgA antigen-binding site (Outlaw and Dimmock 1990; Armstrong and Dimmock 1992; Lamm 1997) or nonspecifically to bacterial lectins by carbohydrate moieties in the hinge region of IgA1 or on pIgR (Wold et al. 1990). In addition to its barrier function in mucosal secretions, SIgA is also a major component in human breast milk and provides passive immunization to newborns (reviewed in Brandtzaeg 2003; van de Perre 2003; Cleary 2004).
IgA has long been considered noninflammatory because it does not bind and activate complement by the classic pathway (Russell et al. 1989; Kaet-zel et al. 1991). However, many studies have now shown that aggregated serum IgA triggers cellular functions similar to IgG such as phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation, and respiratory burst after binding to its receptor, FcaRI (reviewed in Monteiro and van de Winkel 2003). Intracellular signaling by IgA, IgG, and IgE receptors is transduced via the same coreceptor, the FcR y chain, which contains a cytoplasmic immunoreceptor tyrosine activation motif (ITAM) that recruits SH2-containing signaling molecules (Monteiro and van de Winkel 2003). Monomeric and dimeric forms of IgA, but not SIgA, can elicit strong inflammatory responses via FcaRI; however, SIgA is unable to trigger FcaRI except in the presence of an integrin coreceptor (van Egmond et al. 2000; van Spriel et al. 2001; Vidarsson et al. 2001). As described above, the main function of SIgA is immune exclusion at mucosal surfaces, where the body is in constant contact with antigens from pathogens but also commensal bacteria and ingested food. Therefore, it would actually be disadvantageous for SIgA to elicit inflammatory signals to foreign substances because the body would be in a constant state of mucosal inflammation, which would eventually damage the protective barrier of the epithelial lining. However, the ability of serum IgA to trigger these cellular functions when pathogens have breached the epithelium provides additional protection in the serum. Recent work has indicated that FcaRI itself is able to mediate both inflammatory and noninflammatory responses, depending on the extent of receptor clustering. Transient cross-linking of FcaRI leads to recruitment of the tyrosine phosphatase SHP-1 and inhibition of FcyR and FceRI signaling, whereas prolonged FcaRI clustering due to multivalent interactions with antigen-bound IgA recruits the Syk ki-nase, displacing SHP-1 and triggering downstream inflammatory responses (Pasquier et al. 2005). The structural basis for the ability of monomeric and dimeric IgA but not SIgA to initiate phagocytosis is described below.
IgM, the first antibody produced in the humoral response to infection, is present in both serum and mucosal secretions (Janewayetal. 1999). Although SIgA is the primary Ig in secretions, SIgM is also present at lower concentrations and clears pathogens via similar mechanisms (Norderhaug et al. 1999). Serum IgM is able to activate the classic complement pathway very effectively, whereas SIgM in mucosal secretions does not (Davis et al. 1988; Randall et al. 1990; Wiersma et al. 1998). In patients with IgA deficiency, IgM is thought to substitute for the function of IgA (Brandtzaeg et al. 1987). A small percentage of plasma cells in the lamina propria secrete IgG. Although there is no known active transport of IgG to mucosal secretions in humans, damage to the epithelial layer can result in passively transferred IgG molecules, particularly at mucosal surfaces with low proteolytic activity such as the respiratory and reproductive tracts. Therefore, IgG provides some, albeit minimal, protection at mucosal surfaces (Lamm 1997; Norderhaug et al. 1999).
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