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).
Highlights
The existence of an external antibody system was proposed by Alexandre Besredka at the Pasteur Institute, Paris, when he in 1919 showed that rabbits, after oral immunization with killed Shigella, were protected against fatal dysentery irrespective of the serum antibody titer [1]
Some studies have concluded that the predominance of IgA2+ plasmablasts/plasma cells (PCs) in the distal intestine can be explained by in situ switching to this subclass in the lamina propria [80], we have found by molecular methods that such a contribution must be negligible or absent; the IgA-subclass profile seems, instead, to be imprinted in mucosa-associated lymphoid tissue (MALT) structures before the homing of activated B cells to secretory effector sites takes place (Lin et al, in revision)
Live attenuated vaccines or adequate combinations of non-replicating vaccines and mucosal adjuvants administered by the oral route to target gut-associated lymphoid tissue (GALT), give rise to secretory immunoglobulin A (SIgA) antibodies and to longstanding serum IgG and IgA responses [199]
Summary
The existence of an external antibody system was proposed by Alexandre Besredka at the Pasteur Institute, Paris, when he in 1919 showed that rabbits, after oral immunization with killed Shigella, were protected against fatal dysentery irrespective of the serum antibody titer [1]. As alluded to previously (Figure 2), evaluation of IgA+ PCs at secretory effector sites for J-chain expression and in vitro cytoplasmic affinity for free SC (marker of pIgA production), has indicated that almost 90% of them are variably involved in production of polymers [45] These pIgA molecules are immediately available for the unique pIgR-driven epithelial transport system which generates both free SC and the hybrid SIgA molecule (Figures 1 and 2), where the bound SC in a changed conformational shape covers most of the J chain, according to recent modeling studies [41, 46]. There is normally no enrichment of pIgA in thoracic duct lymph and portal vein blood [50]
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