(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.
| Eison, T Matthew; Hastings, M Colleen; Moldoveanu, Zina et al. (2012) Association of IgG co-deposition with serum levels of galactose-deficient IgA1 in pediatric IgA nephropathy. Clin Nephrol 78:465-9 |
| Novak, Jan; Julian, Bruce A; Mestecky, Jiri et al. (2012) Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin Immunopathol 34:365-82 |
| Takahashi, Kazuo; Smith, Archer D; Poulsen, Knud et al. (2012) Naturally occurring structural isomers in serum IgA1 o-glycosylation. J Proteome Res 11:692-702 |
| Schoeb, Trenton R; Jarmi, Tambi; Hicks, M John et al. (2012) Endothelial nitric oxide synthase inhibits the development of autoimmune-mediated vasculitis in mice. Arthritis Rheum 64:4114-24 |
| Suzuki, Hitoshi; Kiryluk, Krzysztof; Novak, Jan et al. (2011) The pathophysiology of IgA nephropathy. J Am Soc Nephrol 22:1795-803 |
| Kiryluk, Krzysztof; Moldoveanu, Zina; Sanders, John T et al. (2011) Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis. Kidney Int 80:79-87 |
| McCarthy, Douglas D; Kujawa, Julie; Wilson, Cheryl et al. (2011) Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J Clin Invest 121:3991-4002 |
| Novak, Jan; Moldoveanu, Zina; Julian, Bruce A et al. (2011) Aberrant glycosylation of IgA1 and anti-glycan antibodies in IgA nephropathy: role of mucosal immune system. Adv Otorhinolaryngol 72:60-3 |
| Herzenberg, Andrew M; Fogo, Agnes B; Reich, Heather N et al. (2011) Validation of the Oxford classification of IgA nephropathy. Kidney Int 80:310-7 |
| Novak, Jan; Raskova Kafkova, Leona; Suzuki, Hitoshi et al. (2011) IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol Dial Transplant 26:3451-7 |
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