Mammalian immune systems must provide whole body protection against a plethora of antigens that can gain access to the host via differing portals. Direct contact between the animal and pathogen is the most basic route of inoculation. Intact skin provides a substantial and usually highly effective barrier to such invasion. However the skin represents a relatively small surface of the animal directly exposed to the outside environment. The mucosal surfaces of the respiratory, gastrointestinal, salivary, genitourinary, and mammary tracts collectively represent a huge area of potential exposure to the environment, with varying degrees of risk for pathogen exposure and invasion. Mucosal immunity at these sites provides a coordinated system of defense against this invasion.15,16
Development of the orally administered polio vaccine demonstrated practical evidence of gut immune function decades ago. The GI tract provided both a convenient route for delivery of the antigen and an instrument to initiate the desired immune response. Distinct recognition of secretory immunoglobulin A and specialized immune function to protect mucosal sites was first written about in the 1960’s.17
Experimental evidence of the mucosal immune system as we know it currently advanced in the 1970’s as several investigators showed that exposure to antigen at one mucosal surface generated immunity to the same pathogen at other, non-exposed, mucosal sites.18, 19
Further investigations led to the development of the ‘common mucosal immune hypothesis’ that generally describes the anatomic, immunologic and mechanistic framework responsible for providing immunity at mucosal sites throughout the body.19
Mechanistically, the mucosal immune system is composed of inductive and effector sites.20
While anatomically there is some overlap between such them, they will be considered as distinct entities for simplicity ().
Figure 1 Schematic representation of a typical mucosal immune response. The process begins with antigen sampling and recognition at inductive sites and ends with the generation of antigen specific secretory immunoglobulin A at effector sites which is actively (more ...)
Peyer’s patches serve as the inductive site for antigen absorption and immunologic processing for sensitization of mucosal immunity.21, 22
Peyer’s patches are anatomically distinct (more so in rodents than humans) collections of immune cells found on the anti-mesenteric border of the small intestine throughout its length. Peyer’s patches display follicular architecture, similar to lymph nodes, with distinct areas rich in T and B lymphocytes.23
The luminal surface overlying Peyer’s patches contain specialized epithelia termed M cells that function to sample, capture and shuttle antigens to the underlying Peyer’s patch components.24
Simultaneously, naïve lymphocytes migrate out of the circulation into PP for activation if exposed to their cognate antigen.25
From the PP, activated lymphocytes travel via efferent lymph channels to the mesenteric lymph nodes and through the thoracic duct into the systemic circulation.26
Homing of such activated lymphocytes back to mucosal immune effector sites occurs by a specific process likely regulated in combination by factors including cellular adhesion molecules, cytokines and chemokines.
Once returned to an effector site (generally regarded as the lamina propria underlying a mucosal surface and the lymphatic cells therein), T and B lymphocytes work in conjunction for IgA production by terminally differentiated B cells termed plasma cells.27
T cells, predominated by Th-2 type cells, enrich the milieu with IgA production stimulating Th-2 cytokines such as interleukin-4 (IL-4), and IL-10. The end product of this process is dimeric IgA consisting of 2 IgA monomers structurally linked at the constant region by a small peptide called J-chain.28
Transepithelial transport from the lamina propria to the mucosal surface occurs actively via a specific membrane bound protein transporter called polymeric immunoglobulin receptor (pIgR).29
pIgR is a 7 domain membrane spanning protein present on the basolateral surface of epithelial cells capable of binding, transporting and releasing immunoglobulin onto the apical cell surface.30
Five of the seven pIgR domains (termed secretory component, SC) remain attached to the antibody yielding an IgA + J-chain + SC complex referred to as secretory IgA (SIgA, ).30
SIgA provides the principle antigen-specific immunologic defense against potential pathogens at all mucosal surfaces.31–33
Figure 2 The relationship between pIgR and dimeric IgA. Dimeric IgA generated in the lamina propria is bound, and transported across the epithelium, by pIgR. As the pIgR/IgA complex is released into the lumen, a portion of the pIgR protein remains with the IgA (more ...)
This model provides the classic description of the pathway to mucosal immune response activation but variations on the theme exist. For example, “extra-follicular” pathways appear to exist where lamina propria B cells can be induced by local factors to undergo class switch recombination to IgA+.34
T-cell independent pathways also yield IgA plasmablasts able to produce antigen-specific IgA. In the mouse, naïve B cell populations are generated in both the pleuro-peritoneal (B1) and bone marrow (B2) spaces: the former is able to mature independently of T cell help and ultimately contribute ~50% of intestinal IgA production.35, 36
In humans the bone marrow appears to be the sole source of naïve B cells.
This discussion of the interplay between type/route of nutrition and gut immunity uses the classically described mucosal immune pathway.