Among the infiltrating leukocytes present in inflamed human gingiva, monocytes/macrophages, neutrophils, and eosinophils express surface receptors for the Fc part of immunoglobulin (Ig) A (FcalphaR) and of IgG (FcgammaR). However, the physiological and pathological significance of the signals transduced by FcalphaR are incompletely understood, especially in comparison with FcgammaR-mediated inflammatory processes. IgA, including IgA antibodies to periodontal pathogens, is produced by plasma cells in inflamed gingiva, and possesses anti-inflammatory properties with respect to inhibition of complement activation. Conversely, stimulation of eosinophils with IgA induces degranulation which may lead to tissue damage. This component of the Research Center for Oral Biology, in collaboration with other Center Projects and Cores, proposes to examine the hypothesis that human IgA antibodies modulate inflammatory processes mediated by infiltrating leukocytes relevant to human periodontal disease. The presence and regulation of FaclphaR on leukocytes in inflamed gingival tissue will be examined by immunofluorescence and flow cytometry. As gingival leukocytes are derived from the circulating pool, the up-regulation of FcalphaR on peripheral blood monocytes, neutrophils, and eosinophils, and model promonocytic and promyelocytic cell lines by exposure to various molecular forms, subclasses, immune complexes, and fragments (generated by bacterial IgA proteases) of human IgA, and by relevant cytokines (IL- 1, IL-6, and TNF-alpha for monocytes and neutrophils; IL-3, IL-5, and GM- CSF for eosinophils) will be investigated in vitro. The techniques will include flow cytometry for FcalphaR surface expression and analysis of FcalphaR-mRNA transcription. the consequences of stimulating these cells through he FcalphaR, in comparison with receptors for IgG and/or complement, will be examined with respect to: (i) the generation of inflammatory cytokines (IL-1, IL-6, and TNF-alpha) by monocytes and neutrophils, and of TGF-alpha by eosinophils; (ii) the release of proteases by monocytes and neutrophils; and (iii) the release of cytotoxic granule proteins by eosinophils. The potential for inflammatory gingival tissue damage caused by factors released from IgA- stimulated leukocytes will be assessed by determining: (i) the presence of released eosinophil granule proteins in inflamed gingival tissue; (ii) cytotoxicity of IgA-stimulated leukocytes and their products towards oral mucosal fibroblasts; and (iii) the development of tissue-destructive properties (induction of matrix metalloproteinases) in cultured oral mucosal fibroblasts exposed to IgA-stimulated eosinophils and their products. The fundamental question that these studies seek to address is whether IgA acts antagonistically to or synergistically with IgG in inflammatory lesions. The answer will not only help to elucidate the immunopathogenesis of human periodontal disease, but also advance knowledge of the physiology of human IgA and its role in modulating inflammatory processes.
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