Glycoengineering IgA1 in IgA nephropathy

摘要

ABSTRACT IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and often progresses to end stage renal disease due to the absence of disease-specific modifying therapies. Unlike many other autoimmune diseases, an autoantigen in IgAN has been identified and characterized. Altered O-glycosylation in the heavy chain of IgA1 exposes antigenic determinants, which are targets of naturally occurring IgG1 and, to a lesser extent, IgA1 antibodies. The resulting circulating immune complexes together with complement deposit in the kidney to promote mesangial cell proliferation and matrix expansion, which in turn induce glomerular dysfunction. The objective of this proposal is to develop novel glycoengineering techniques to restore glycosylation of the IgA and thus inhibit its autoantigenicity. Successful completion of this proposal could lead to the development of a new disease-specific therapeutic strategy for the treatment of IgA. This is a high-risk proposal as there are conceivable pitfalls with developing the techniques for restoring glycosylation. The high-reward is the potential to normalize IgA1 glycan structures and thus avert the generation and subsequent deposition of pathogenic IgA1-anti-IgA1 immune complexes and associated glomerulonephritis.