Secretory Immunoglobulin A

Abstract

Secretory immunoglobulin A (IgA) (SIgA) is the most abundant Ig produced at the surface of mucosal membranes in mammals. These very thin and sensitive barriers are challenged by occasional pathogenic microbes as well as by permanently residing commensal bacteria. Although not the unique guardian of mucosal epithelia, SIgA is an important component of the protective function guaranteeing maintenance of homoeostasis and wellness. Topics presented in this article include: (1) mechanisms involved in local induction of SIgA via T‐cell‐dependent and ‐independent pathways; (2) structure–function relationship in SIgA; (3) immunoregulatory role of SIgA vis‐à‐vis pathogens and commensals and (4) the unexpected contribution of SIgA in diseases. Because this is the most studied mucosal environment, most of the functional characteristics of SIgA are exemplified with respect to the gastrointestinal tract.

Key Concepts:

  • SIgA is the most abundant immunoglobulin produced at mucosal surfaces, and it exists in secretions in polymeric forms of high and low antigenic affinity/avidity.

  • The presence of secretory component in SIgA confers additional features including improved stability, proper anchoring in mucus and adequate localisation for optimal functions on the antibody.

  • Because epithelia in the gastrointestinal, respiratory and urogenital tracts are highly sensitive to invading environmental antigens, shielding of mucosal surfaces by SIgA is crucial to the process of protection and homoeostasis.

  • In addition to canonical immune exclusion, SIgA is endowed with the capacity to transport immune complexes via M‐cells to underlying dendritic cells, thus inducing attenuated mucosal and systemic immune responses.

  • Communication between natural polyreactive SIgA‐commensal bacteria complexes and the epithelial cells lining mucosal surfaces contributes to regulate the symbiotic host–commensal relationship.

  • SC, by itself, via multiple glycosylation sites, displays neutralising properties against pathogen‐associated molecules. This holds true when SC is bound to polymeric IgA in the SIgA molecule.

  • Increasing knowledge of the multiple modes of action of SIgA provides opportunities to investigate the potential of the antibody in passive immunisation against bacteria, viruses and toxins in the clinics.

Keywords: secretory IgA ; secretory component; mucosal immune responses; pathogens; commensals; dendritic cells; Peyer's patch; homoeostasis

Figure 1.

Induction of IgA production in the mouse GALT. T‐cell‐dependent IgA responses are triggered following receptor‐mediated uptake of antigens sampled by M‐cells and delivered to underlying DCs in the SED region (pathway 1) or by intra‐epithelial DCs extending their dendrites in the luminal environment (pathway 2). Subsequent activation of CD4+ T‐cells in the IFR of Peyer's patches will depend on the nature of the antigen, in particular the presence of associated danger signals. In the intestinal environment, local and epithelial cell‐derived conditioning (TGF‐β, thymic stromal lymphopoietin and retinoic acid (RA)) prompt DCs to differentiate T‐cells into dominating Th2 and Treg populations producing IL‐4, IL‐5, IL‐6, IL‐10 and TGF‐β, a bunch of cytokines important to the process of class switch recombination taking place after CD40L–CD40 cross‐linking between T‐ and B‐cells (pathway 3). Further differentiation of some regulatory T (Treg) cells into TFH contributes to CSR as well (pathway 3). In the Peyer's patch, inducible nitric oxide synthase (iNOS)+TNF‐α+DCs enhances CSR and production by upregulating the expression of the TGF‐β receptor on B‐cells via nitric oxide (NO) (pathway 4). On the influence of local RA, switched IgA+ B‐cells upregulate the surface markers α4β7 integrin and CCR9 chemokine receptor and migrate via the thoracic duct to proximal and distant mucosal sites where they terminally differentiate into plasma cells producing polymeric IgA (pIgA) (pathway 5). It is generally accepted that this T‐cell‐dependent pathway eventually generates high‐affinity IgA antibodies with a unique specificity that in secretions recognise pathogenic microbes and protein toxins. On TLR‐mediated sensing of bacteria, follicular DC in the Peyer's patch directly educate B‐cells to switch to IgA production, a mechanism that is independent of the canonical T–B cell interaction but requires the B‐cell‐activating factor of the TNF family BAFF, a proliferation‐inducing ligand (APRIL), and TGF‐β (pathway 6). Together with NO and IL‐6 released by intestinal epithelial cells, the same CSR factors secreted by lamina propria DCs having detected bacteria via TLRs contribute to T‐cell‐independent activation (pathway 7) of mostly peritoneal B1 cells prone to secrete low‐affinity, multireactive IgA antibodies involved in the control of the commensal microbiota.

Figure 2.

Schematic representation of the structure and the secretion pathway of SIgA. (a) Although structures of higher degree of polymerisation have been recovered in secretions, SIgA exists mostly as a dimer. Two IgA monomers containing canonical heavy and light chains with domains depicted in purple are linked together by the joining (J) chain (red) in a tail‐to‐tail arrangement. SC (green) comprises five Ig‐like domains and is covalently bound to the Fc portion of polymeric IgA (pIgA). IgA and SC display several glycosylation sites drawn for simplification as yellow spheres on half a monomer. (b) Once produced by plasma cells in the lamina propria, pIgA interacts with the pIgR in a J chain‐dependent manner and is transported through epithelial cells from the basal to the apical side, a mechanism referred to as transcytosis. Migration along successive intracellular compartments (ARE, apical recycling endosome; BEE, basolateral early endosome; CE, common endosome) ensures controlled basolateral to apical move of the antibody–pIgR complex. Following apical cleavage of pIgR, SIgA is released into the lumen in the form of SIgA, a complex made of pIgA and bound SC.

Figure 3.

Protective and immunomodulatory functions of SIgA. The multifaceted modes of action of SIgA are depicted. Although immune exclusion remains the primordial function of SIgA in the intestinal mucosae, the antibody is involved in several processes that participate in the maintenance of local homoeostasis vis‐à‐vis pathogenic and commensal bacteria. Many cellular and molecular immune and nonimmune partners are involved in the communication between SIgA and the epithelium, eventually ensuring the integrity of this fragile barrier.

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Bemark M , Boysen P and Lycke NY (2012) Induction of gut IgA production through T-cell dependent and T-cell independent pathways. Annals of the New York Academy of Sciences 1247: 97–116.

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Corthésy, Blaise(Sep 2013) Secretory Immunoglobulin A. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024227]