Modulation of adaptive and innate immune responses influence the risk and severity of murine ANCA GN.

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Glomerulonephritis (GN) caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) is the most common form of aggressive glomerulonephritis, especially in adults. Earlier cycles of this P01 titled ?ANCA Glomerulonephritis: from Molecules to Man? have produced compelling evidence that ANCA GN is caused by ANCA, and have provided an understanding of pathogenic mechanisms that have influenced diagnosis, prognostication and treatment of ANCA GN. One of the most impactful accomplishments has been the development and effective use of the first animal model of ANCA GN, which is induced in mice by ANCA with specificity for mouse myeloperoxidase (MPO). The current proposed project titled ?Modulation of both the adaptive and innate immune responses influence the risk, severity and clinicopathologic phenotype of ANCA glomerulonephritis? will use this animal model to build on this strong foundation of knowledge. Specific Aim 1 tests the hypothesis that not all ANCA are equally pathogenic because of differences in epitope specificity as well as differences in the structure and function of Fc regions and Fc receptors. Specific Aim 2 tests the hypothesis that genetically determined and acquired modulation of innate immunity determines the severity and clinicopathologic phenotype of ANCA GN. These aims will include studies of the pathogenic importance of IgG epitope specificity and Fc glycosylation, the role of complement regulation and kinins, and modulation of disease actiity by leukocyte gene expression. In additon to elucidating basic autoimmune pathogenic mechanisms, the knowledge gained from these aims is likely to identify biomarkers that could provide more accurate and sensitive diagnosis, more useful monitoring of disease activity and response to therapy, and possible novel targets for more effective treament. In some patients, ANCA GN is accompanied by a destructive extravascular inflammatory process called granulomatosis. Specific Aim 3 tests the innovative hypothesis that ANCA IgG-induced neutrophil and monocyte activation (in the absence of antigen-specific T cells) mediates the necrotizing granulomatous inflammation of ANCA GN. To our knowledge, our animal model of ANCA granulomatosis will be the first ever reported, and will provide new understanding of the pathogenesis of ANCA granulomatosis that could facilitate design of effective preventive or treatment strategies for this destructive process that complicates the care of patients with ANCA GN.