INTESTINAL IMMUNOGLOBULIN A: ROLE IN HOST DEFENSE

The major source of stimulation of the entire immune system is the external environment, comprising potentially pathogenic microorganisms, many species of the commensal mucosal microbiota, food antigens, and allergens, all of which are encountered primarily at mucosal surfaces that cover an enormous surface area. Majority of antibodies are produced in mucosal lymphoid tissues, particularly in the intestine, rather than in the spleen, lymph nodes, or bone marrow, and more than half of total antibodies produced appear in the secretions of mucosal tissues and their associated glands. Quantitative studies of the origin of immunoglobulin A (IgA) in the human intestinal lumen have convincingly demonstrated that ~99% is of local origin and only trace amounts are derived from the circulation. The constant regions of IgA2 heavy chains each contain four or five N-linked glycan chains compared to two in IgA1, and the hinge region of each IgA1 heavy chain also contains three to five short O-linked glycan chains. The most widely recognized protective mechanism of S-IgA antibodies against pathogens at mucosal surfaces is inhibition of adherence. Several medically important bacteria produce highly specialized proteases that cleave human IgA1 at one of the Pro-Ser or Pro-Thr bonds in the hinge region, yielding Fabα and Fcα fragments. The predominant isotype of Ig found in this location, both at the surface and within the mucosal tissues, is IgA, and its essentially noninflammatory nature is of great importance for the maintenance of the integrity of the mucosae.