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

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 beta II-spectrin. Most patients with IgAN also have serum anti-beta II-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 beta II-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous beta II-spectrin exposed on the surface of em-bryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular me-sangial 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.

Automated summary

This study demonstrates that IgA nephropathy is the most common form of primary glomerulonephritis, characterized by the deposition of IgA in the glomerular mesangium. The researchers found that patients with IgA nephropathy and a spontaneous mouse model produce IgA antibodies against mesangial antigens, specifically beta II-spectrin. These antibodies have substantial V-region mutations and can bind to the surface of mesangial cells, indicating the presence of a tissue-specific autoimmune response in IgA nephropathy.