Intestinal IgA: novel views on its function in the defence of the largest mucosal surface.

The intestine is undoubtedly the most misunderstood and under-appreciated lymphoid organ in the body. Yet, in the eyes of mucosal immunologists, the gut exemplifies finely tuned, extensively interacting populations of cells and their products involved in innate and specific defence of the body’s largest surface area, a surface exposed to the heaviest burden of environmental antigens. As the largest lymphoepithelial organ, it contains cells that absorb, process, and present antigen, B and T cells of various types, and antibody producing cells. Every day intestinal plasma cells produce more antibodies than do all other lymphoid organs (spleen, lymph nodes, and the bone marrow) combined. Although the remarkable dominance of IgA producing cells in the intestine and of IgA in the intestinal fluid has been known for decades, fine details of the migration or “homing” of IgA plasma cell precursors, their terminal diVerentiation, the mechanisms mediating and regulating the selective transepithelial transport of IgA, and the functional advantages of this molecule in the gut continue to emerge with impressive rapidity. One feature unique to the mucosal immune system is the crucial role of epithelial cells of various morphological forms and phenotypes in mucosal defences. Functional interdependence of epithelial and lymphoid cells in the intestine has been amply documented. In addition to production of inflammatory cytokines (e.g. interleukin (IL) 8 and macrophage inflammatory protein (MIP) 1á and antiinflammatory cytokines (e.g. transforming growth factor (TGF) â and IL-10), epithelial cells are also a source of cytokines that regulate the terminal diVerentiation of arriving lymphocytes into IgA producing plasma cells (e.g. TGF-â, IL-6, IL-10). Lymphocytes resident in the lamina propria and in the intraepithelial compartment, mostly of T cell lineage, participate directly and indirectly in the protection of the mucosa, and provide stimuli (e.g. interferon (IFN) ã) for the maintenance of epithelial health and expression of the epithelial receptor that selectively transports locally produced polymeric IgA (pIgA) into the intestinal lumen. Due to this intimate epithelial– lymphoid cell collaboration, the final product—secretory IgA (S-IgA)—is delivered onto the mucosal surfaces of the human gut in huge quantities, 3–5 g of S-IgA/day! IgA is the most heterogeneous of human immunoglobulins, as it occurs in multiple molecular forms (monomeric (m), polymeric, and secretory) and subclasses (IgA1 and IgA2) which are distributed diVerently between the circulatory and mucosal immune systems. 9 10 IgA antibodies may therefore have diVerent functional properties depending upon their molecular form as well as their location. Functional advantages of S-IgA over other immunoglobulin isotypes include its multi-valency (4–8 antigen binding sites) which enhances its eVectiveness over mIgA by at least an order of magnitude. Furthermore, S-IgA is characteristically resistant to proteolytic enzymes due to the unique primary structure of its á chains and a putatively protective eVect of the epithelial polymeric immunoglobulin receptor (pIgR), whose major extracellular fragment, secretory component (SC), remains covalently associated with pIgA after its transcytosis through epithelial cells. Most importantly, IgA displays strong anti-inflammatory properties mediated by several mechanisms (see later). The protective eVect of antigen specific S-IgA in the intestinal lumen depends on its ability to inhibit the absorption of soluble and particulate antigens by forming intraluminal immune complexes, to neutralise biologically active antigens (e.g. toxins and viruses) and to interfere with microbial adherence to epithelial cells. In addition to this specific antibody dependent function, abundant glycans on the Fc region of the molecule can aggregate enterobacteria carrying type 1 fimbriae, due to interaction of mannose binding fimbrial lectin and high mannose type glycan side chains of IgA. As a result, IgA coated bacteria are prevented from adhering to epithelial cells expressing analogous mannose rich glycans on their luminal surfaces without the need for specific antibody activity. However, commensal microorganisms endogenous to the intestinal lumen are also coated with IgA. The apparent contradiction between the earlier described role of S-IgA in immune exclusion of pathogenetic microorganisms, and the fact that the normal intestinal microbiota remains relatively stable despite the IgA coating, may be reconciled by the existence of two functionally distinct “types” of S-IgA antibodies, produced by two separate B cell populations. The so called B-1 (formerly Ly1+ or CD5+) lymphocytes whose origin has been traced, in the mouse, to the peritoneal cavity and which contribute importantly to the lamina propria IgA plasma cells, produce less specific, perhaps polyreactive, “natural” antibodies which may actually play a role in the maintenance of the normal intestinal microbiota. Pathogenetic microorganisms, however, which stimulate the immune system after invasion through the Peyer’s patch M cells, stimulate locally present conventional B-2 cells that are then disseminated to the lamina propria of the gut, mature into IgA plasma cells, and produce specific IgA antibodies with high aYnity for the pathogen, thereby leading to its exclusion. The existence of a similar functional dichotomy of S-IgA antibodies in humans has not been investigated. Nevertheless, the presence of IgA1 and IgA2 subclasses with subtle structural and functional diVerences 10 including sensitivity to bacterial proteases and notable differences in the distribution of mannose rich glycan chains, should provide fertile ground for such studies. Indeed, it is tempting to speculate that IgA2 antibodies, which are associated with specificity for common structural microbial antigens (e.g. lipopolysaccharides (LPS) and polysaccharides), are resistant to bacterial proteases, carry mannose rich glycans,