Origin and Homing of Intestinal IgA Antibody-secreting Cells

The fact that IgA comprises the body's major isotype of antibody on a biosynthetic basis is not widely appreciated because IgG, not IgA, is the predominant isotype in serum. Nevertheless, the bulk of the body's Ig-producing cells reside in the various mucosal and exocrine sites, especially along the intestinal tract, and most of them make IgA anti-bodies against environmental antigens, including the local microbial flora. These antibodies can then function in multiple ways as a first line of immune defense at boundaries with the external environment (1). It has long been recognized that a major source of the precursors of the IgA plasma cells in the intestine is the organized lymphoid tissue of the Peyer's patches (2). Here B cells in the germinal centers are thought to switch from IgM to IgA under the influence of T cells and cytokines, in particular TGF-␤ (3, 4). They then migrate from the Peyer's patches to the draining mesenteric lymph nodes, where they continue to divide and differentiate. Finally they exit the lymph nodes and pass via the thoracic duct lymph into the blood, which carries them to the lamina propria of the gut. Here they complete their differentiation into the mature IgA-secreting plasma cells so characteristic of this location (5, 6). During this process such Th2 cy-tokines as IL-5, IL-6, and IL-10 are thought to be important in inducing the switched B cells to make IgA for secretion (3, 4). With regard to this IgA cell cycle, two points are worth emphasizing. One, the precursors of the plasma cells become committed to producing IgA well before they reach the intestinal lamina propria, and two, trafficking to lamina propria is independent of specific antigen even though the presence of antigen in the lamina propria can enhance the proliferation of the newly arrived B cells. From a mechanistic viewpoint, what accounts for the attraction of circulating IgA B cells to the mucosa of the gut? The paradigm has been that the regional specificity of lymphocyte trafficking is governed by the net effect of sets of interacting local vascular endothelial receptors and their respective counterreceptors on circulating lymphocytes (7). These interactions are thought to account for the series of steps that begins with transient binding of the lymphocytes to endothelium and ends with their diapedesis across the vascular wall. For trafficking to the gut, the MAdCAM-1 addressin on local venules and the ␣ 4 ␤ …