(IgAN) is characterized by mesangial IgA1 immune deposits. These deposits originate from circulating immune complexes that contain aberrantly-glycosylated IgA1, i.e., IgA1 that is galactose-deficient in the hinge region O-linked glycans. Several lines of evidence suggest a direct causal relationship between aberrant glycosylation, the formation of immune complexes containing aberrantly glycosylated IgA1, their deposition in the mesangium, and renal injury in IgAN. These data provide the basis for the central hypothesis that an O- glycosylation abnormality in the hinge region of IgA1 is a pivotal pathogenic feature of IgAN. The ability to translate these observations into clinically relevant non-invasive diagnostic tests and novel therapeutics has been frustrated, however, by the current inability to obtain sufficient, informative samples of the pathogenic aberrantly glycosylated IgA1 for molecular analysis. We hypothesize that immortalized IgA1-producing cell lines from patients with IgAN can be used for analysis of the O-glycosylation abnormality and the specific metabolic mechanisms that result in this defect. The goal of the proposed study is to establish immortalized IgA1-secreting cell lines from circulating B cells from patients with IgAN and controls and to evaluate the potential of this new tool for advancing the studies of IgAN pathogenesis. Specifically, we propose to determine the fine structure of the O-glycosylation abnormalities of the hinge region of IgA1 secreted by the immortalized cells from IgAN patients and to identify the enzymatic pathways that may lead to this defect. The feasibility of these studies is enhanced greatly by our development of high throughput methods of analysis, state-of-the-art techniques for analysis of glycopeptides, and our extensive basic and clinical collaborations that permit testing of the hypothesis by experimental manipulation as well as clinical correlations. Relevance: IgAN is the most common primary glomerulonephritis and leads to the loss of renal function in 20-40% patients. The current inability to describe the pathogenesis of IgAN at the molecular level is a major barrier to the development of IgA-specific treatments. The proposed studies will provide an essential new tool for studies of the molecular mechanisms of pathogenesis of IgAN and a key resource for the future development and testing of potential new therapeutic interventions. This would represent a major advance in the quality of care for IgAN patients. IgAN is the most common primary glomerulonephritis. It is characterized by aberrantly- glycosylated IgA1, which represents a pivotal pathogenic feature. The proposed development of cell lines from IgAN patients will provide a significant new tool for the identification of the defects underlying the abnormal glycosylation of IgA1 in patients with IgAN and, thus, lay the basis for the translation of the basic research into clinical applications. ? ? ?
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