Glomerulonephritis mediated by antibodies (Ab) to the glomerular basement membrane (GBM) is the prototype of human glomerular disease produced by pathogenic Ab to intrinsic glomerular components. Although there has been intense investigation into identification of the target basement membrane antigen (Ag) and inflammatory mediators of this disease, less attention has been devoted to the structural features, immunobiology and genes encoding pathogenic human anti-GBM autoAb. Recent technical advances, however, make the selection and large scale production of human autoAb feasible. These advances, coupled with the identification, cloning, expression and availability of the major target autoAg (alpha3 type IV collagen, (alpha3 (IV) for human anti-GBM Ab, provide the ideal circumstances, necessary methodologies and molecular reagents to define the genetic and structural features of human anti-GBM Ab. In the past project period, we have utilized these and other approaches to examine human antiGBM Ab, and the results have defined autoAb, from different patients, as having high affinity and with shared structural features. Furthermore, a new model of anti-GBM disease was developed in Xenomouse II, a novel murine strain that expresses human, but not murine, immunoglobulins. Following immunization with (alpha3(IV), the mice develop crescentic glomerulonephritis mediated by human autoAb that share structural features with autoAb produced by patients. Further-more a pathogenic monoclonal Ab have been identified and characterized. In parallel genetic and structural analysis of Fab derived from nephritic patients has been initiated. Our goal is to extend these studies to examine autoAb from both patients and Xenomouse II to pursue the following Specific Aims: i) To define the structural properties of pathogenic human anti-alpha3 (IV) collagen Ab.and use this information ii) To develop small molecules with high affinity and specificity for human anti-GBM Ab. Our working hypothesis is that molecular and structural analysis of pathogenic autoAb, together with existing information pertaining to the relevant pathogenic epitopes of alpha3(IV) will lead to a more precise understanding of this particular autoAb-autoAg interaction, and that this information, coupled with an established model of nephritis mediated by human anti-GBM Ab, will be useful in the design and evaluation of specific inhibitors of autoAb deposition or/and autoAb production. The results also have the potential to provide insight into the origins of pathogenic human autoAb. Furthermore, since the autoAb response in patients with anti-GBM disease is focused on a specific and will defined autoAg (alpha3(IV), this condition represent the ideal situation, where evaluation of therapy directed against a specific subset of soluble and surface receptors on immunoreactive cells, to alter disease activity, can be evaluated. If successful, the strategy has the potential for application in the development of therapeutic strategies in other Ab-mediated diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Flessner, Michael Francis
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Meyers, Kevin E C; Christensen, Mette; Madaio, Michael P (2009) Modeling of human anti-GBM antibody-alpha3(IV)NC1 interactions predicts antigenic cross-linking through contact of both heavy chains with repeating epitopes on alpha3(IV)NC1. Am J Nephrol 30:474-80
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