Glycoengineering IgA1 in IgA nephropathy

摘要 IgA肾病(IgAN)是全世界最常见的原发性肾小球肾炎，通常进展为 终末期肾脏疾病，因缺乏针对疾病的调整疗法。与许多其他人不同 自身免疫性疾病是IgAN中的一种自身抗原，已被鉴定和鉴定。O-糖基化修饰 在IgA1的重链中暴露了抗原决定簇，这些决定簇是自然产生的IgG1的靶标 在较小程度上，还有IgA1抗体。由此产生的循环免疫复合体与 补体在肾脏中沉积，促进系膜细胞增殖和基质扩张，进而 导致肾小球功能障碍。这项建议的目标是开发新的糖工程 恢复免疫球蛋白A糖基化从而抑制其自身抗原性的技术。成功完成 这一建议可能导致开发一种新的针对疾病的治疗策略。 免疫球蛋白A。这是一个高风险的建议，因为在开发以下技术时存在可以想象的陷阱 恢复糖基化。最大的回报是有可能使IgA1糖链结构正常化，从而避免 致病性IgA1-抗-IgA1免疫复合体的产生和随后的沉积 肾小球肾炎。

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.