Secretory IgA: Designed for Anti-Microbial Defense

Abstract

Prevention of infections by vaccination remains a compelling goal to improve public health. Mucosal vaccines would make immunization procedures easier, be better suited for mass administration, and most efficiently induce immune exclusion – a term coined for non-inflammatory antibody shielding of internal body surfaces, mediated principally by secretory immunoglobulin A (SIgA). The exported antibodies are polymeric, mainly IgA dimers (pIgA), produced by local plasma cells (PCs) stimulated by antigens that target the mucose. SIgA was early shown to be complexed with an epithelial glycoprotein – the secretory component (SC). A common SC-dependent transport mechanism for pIgA and pentameric IgM was then proposed, implying that membrane SC acts as a receptor, now usually called the polymeric Ig receptor (pIgR). From the basolateral surface, pIg-pIgR complexes are taken up by endocytosis and then extruded into the lumen after apical cleavage of the receptor – bound SC having stabilizing and innate functions in the secretory antibodies. Mice deficient for pIgR show that this is the only receptor responsible for epithelial export of IgA and IgM. These knockout mice show a variety of defects in their mucosal defense and changes in their intestinal microbiota. In the gut, induction of B-cells occurs in gut-associated lymphoid tissue, particularly the Peyer’s patches and isolated lymphoid follicles, but also in mesenteric lymph nodes. PC differentiation is accomplished in the lamina propria to which the activated memory/effector B-cells home. The airways also receive such cells from nasopharynx-associated lymphoid tissue but by different homing receptors. This compartmentalization is a challenge for mucosal vaccination, as are the mechanisms used by the mucosal immune system to discriminate between commensal symbionts (mutualism), pathobionts, and overt pathogens (elimination).

Reconstituted Human Polyclonal Plasma-derived Secretory-like IgM and IgA Maintain the Barrier Function of Epithelial Cells Infected with an Enteropathogen

“…Both secretory Abs result from the transport across the epithelium of J chain-containing polymeric IgA (mostly dimeric) and pentameric IgM by the polymeric immunoglobulin receptor and exert a role of neutralizing Abs (1,2). The role of specific SIgA at mucosal surfaces has been studied extensively, and its multiple functional facets extend from immune exclusion to homeostatic control of epithelial integrity (3,4). As the most conserved Ab among vertebrate species, the importance of IgM has been appreciated for several decades.…”

Novel Monoclonal Antibodies for Studies of Human and Rhesus Macaque Secretory Component and Human J-Chain

“…(1)(2)(3) IgA plays protective roles against both infectious bacteria (4)(5)(6)(7) and viruses (8)(9)(10)(11)(12) at gastrointestinal, genital, and respiratory mucosal surfaces and also important roles in interactions with commensal microbiota. (1,13) IgA antibodies have been reported to be a correlate of infection risk in the ALVAC/AIDSVAX Ò HIV vaccine efficacy trial, wherein HIV-1 envelope IgA antibodies were inversely correlated with infection risk and found to inhibit IgG in antibodydependent cellular cytotoxicity (ADCC) responses. (14) Both IgA antibody subclasses, IgA1 and IgA2, exist as monomeric and polymeric (mainly dimeric [d]) forms comprising two or more monomeric (m) IgA units covalently linked by a 15-kD joining ( J) chain.…”

“…(2) This dIgA-pIgR/SC complex is transported to the epithelial apical surface, where the antibodybinding domain of the pIgR is cleaved off from the membrane domain, resulting in SIgA with bound SC covalently complexed to dIgA. (1,(17)(18)(19) Depending on the level of J-chain expression, mIgA and dIgA antibodies can be produced in various proportions by a single plasmablast or plasma cell. (1,20) Dimeric IgA has enhanced antigen binding compared to mIgA because of better avidity; SIgA is therefore a key component of antibody immunity at mucosal surfaces.…”

“…(14) Both IgA antibody subclasses, IgA1 and IgA2, exist as monomeric and polymeric (mainly dimeric [d]) forms comprising two or more monomeric (m) IgA units covalently linked by a 15-kD joining ( J) chain. (1,15,16) IgA dimers bind to a membrane epithelial glycoprotein termed the ''polymeric immunoglobulin receptor'' (pIgR), (1,(17)(18)(19) also called ''membrane secretory component'' (SC). (2) This dIgA-pIgR/SC complex is transported to the epithelial apical surface, where the antibodybinding domain of the pIgR is cleaved off from the membrane domain, resulting in SIgA with bound SC covalently complexed to dIgA.…”

“…(1,(17)(18)(19) Depending on the level of J-chain expression, mIgA and dIgA antibodies can be produced in various proportions by a single plasmablast or plasma cell. (1,20) Dimeric IgA has enhanced antigen binding compared to mIgA because of better avidity; SIgA is therefore a key component of antibody immunity at mucosal surfaces. (1,21,22) SIgA plays a critical role in protection against mucosal pathogens.…”