Mucosal Immunoregulation: Environmental Lipopolysaccharide and GALT T Lymphocytes Regulate the IgA Response

In this review, we have emphasized: 1) bacterial lipopolysaccharide (LPS) involvement in IgA responses to orally administered thymic‐dependent (TD) antigens; 2) characterization of Peyer's patch (PP) lymphoreticular cells; and 3) gastrointestinal immunization with gram negative pathogens and anti‐LPS immunity to infection. Gut LPS, which interacts with PP lymphoreticular cells, is a major determinant for host responses to orally administered TD antigens. Bacteroides species are the principal microflora present in the gastrointestinal tract and our studies with phenol‐water LPS extracts from Bacteroides fragilis indicate that both polysaccharide and lipid A activate lymphoreticular cells. The B. fragilis lipid A moiety, like that derived from E. coli and Salmonella LPS, induces B cell mitogenic responses in cultures from LPS responsive mice, but does not stimulate C3H/HeJ B cells. The inability of lipid A to stimulate gut‐associated lymphoreticular tissue (GALT) cells of C3H/HeJ mice results in the induction of greater T helper cell activity in this tissue in response to orally administered TD antigens and ultimately results in an elevated IgA response pattern. Murine PP contain accessory cells (~1% dendritic cells and 6–8% macrophages) and lymphocytes T (35–38%) and B (40–42%). Recent studies with antigen‐specific T cell clones from C3H/HeJ PP have resulted in the isolation of IgA isotype‐specific T helper cells (PP Th A cells). PP Th A cells are antigen‐specific, bear Fcα receptors, and require H‐2 histocompatibility with B cells for helper activity. PP Th A cells most effectively collaborate with surface IgA (sIgA)‐bearing B cells (IgA committed B cells) for IgA isotype responses. Other studies have shown that PP dendritic cells and T cells form clusters when stimulated in vitro with sodium periodate and that these clusters promote polyclonal IgA responses in B cell cultures. Polyclonal IgA responses in cultures containing PP cell clusters from C3H/HeJ mice are considerably higher than those in identical cultures from LPS responsive mice. In other studies, the environmental influence on GALT B cells and their resultant commitment to IgA isotype is under investigation. CBA/N, X‐linked immuno‐deficient ( xid ) mice possess an immature splenic B cell population which cannot respond to thymic‐independent class‐2 (TI‐2) or certain TD antigens. However, GALT B cells of xid mice possess a mature Lyb‐5 + B cell subpopulation capable of both TI‐2 and TD responses. GALT T cells and environmental influences are responsible for the induction of mature B cells in PP of xid mice. The gastrointestinal route represents both a mode for induction of IgA responses and the major site of infection by pathogenic E. coli and Salmonella species. We have compared immune responses to the three major LPS regions in LPS non‐responsive, high IgA responsive C3H/HeJ mice and in LPS responsive C3H/HeN animals. Oral immunization of C3H/HeJ mice with smooth Salmonella cells induced elevated splenic IgA anti‐LPS PFC responses. In separate studies, we have produced monoclonal antibodies to antigenic determinants of Salmonella LPS. These monoclonal antibodies are being tested to determine the isotype and specificity of antibodies required for immunity to Salmonella typhimurium infection.