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Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy

2023; American Association for the Advancement of Science; Volume: 9; Issue: 12 Linguagem: Inglês

10.1126/sciadv.add6734

2375-2548

Yoshihito Nihei, Kei Haniuda, Mizuki Higashiyama, Shohei Asami, Hiroyuki Iwasaki, Yusuke Fukao, Maiko Nakayama, Hitoshi Suzuki, Mika Kikkawa, Saiko Kazuno, Yoshiki Miura, Yusuke Suzuki, Daisuke Kitamura,

Chronic Kidney Disease and Diabetes

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti-βII-spectrin IgA. As in patients with IgAN, IgA+ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.