The objectives of this R01 application are to elucidate the role of immunoglobulin A (IgA) in human periodontal disease, which afflicts significant numbers of adults with increasing age, and is a major cause of tooth loss in the elderly. Recent advances in understanding the physiological role of IgA suggest that it functions as a non-inflammatory regulator of immune processes. It is hypothesized that circulating (serum) IgA antibodies have, in contrast to IgG antibodies, a suppressive effect on the inflammatory responses of gingival mononuclear phagocytes to lipopolysaccharide (LPS) and other antigens of periodontal pathogens, especially Porphyromonas gingivalis (Pg). Gingival mononuclear phagocytes and peripheral blood monocytes will be stimulated with Pg LPS in the presence of IgA or IgG antibodies to Pg LPS, and their responses will be assessed in terms of the production of inflammatory cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor-necrosis factor-alpha (TNF-alpha), and of IL-1 receptor antagonist. Secretion of these molecules into the culture fluid will be measured immunochemically, and their intracellular expression will be determined in terms of the transcription of messenger RNA. The mechanisms and conditions under which the postulated suppression of inflammatory cytokine production occurs will be investigated. It is further hypothesized that IgA antibodies to Pg LPS and other antigens down-regulate the antigen-presenting cell activities of both gingival mononuclear phagocytes and B lymphocytes, which are responsible for the perpetuation of immune responses to periodontal pathogens. It is postulated that such dysregulated responses contribute to the continuation of chronic destructive inflammation, instead of eliminating the pathogens. The IgA-mediated modulating on the antigen-presenting capabilities of gingival mononuclear phagocytes, blood monocytes, and B lymphocytes will be assessed in terms of the expression of important 'second signal' surface molecules (B7.1, B7.2, and CD$)) by which thee cells communicate with T lymphocytes in primary and secondary immune responses. The ability of T cells to respond to Pg antigens presented by these cells under the influence of IgA antibodies will also be determined. If IgA antibodies are found to have ameliorating effects on inflammatory responses and the perpetuation of immune responses, then measures to enhance the serum IgA antibody response to periodontal pathogens might constitute a novel therapeutic approach.
