Abstract
IgA nephropathy is caused by deposition of circulatory IgA1 in the kidney. Hypogalactosylated IgA1 has the propensity to form poly-IgA aggregates that are prone to deposition. Herein, we purified poly-IgA from the plasma of patients with IgA nephropathy and showed that the complex is susceptible to reducing conditions, suggesting intermolecular disulfide connections between IgA units. We sought to find the cysteine residue(s) that form intermolecular disulfide. Naturally assembled dimeric IgA, also known as secretory IgA, involves a J chain subunit connected with 2 IgA1 molecules via their penultimate cysteine-471 residue on a “tailpiece” segment of IgA heavy chain. It is plausible that, with the absence of J chain, the cysteine residue of mono-IgA1 might aberrantly form a disulfide bond in poly-IgA formation. Mutagenesis confirmed that cysteine-471 is capable of promoting IgA aggregation. These discoveries prompted us to test thiol-based drugs for stabilizing cysteine. Specifically, the cystine-reducing drug cysteamine used for treatment of cystinosis showed a remarkable potency in preventing self-aggregation of IgA. When administrated to rat and mouse models of IgA nephropathy, cysteamine significantly reduced glomerular IgA deposition. Collectively, our results reveal a potentially novel molecular mechanism for aberrant formation of IgA aggregates, to which the repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.
Highlights
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a leading cause of end-stage kidney disease (ESKD) [1]
Our study investigated structural features of IgA that could potentially make it susceptible to forming high-order complexes and causing IgA nephropathy
We discovered poly-IgA complexes isolated from patient plasma disassembled by reducing agents, suggesting that IgA and possibly its nonIgA constituents interconnected via disulfide bridges
Summary
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a leading cause of end-stage kidney disease (ESKD) [1]. The disease is characterized by chronic deposition of poly-IgA complexes in the glomerular mesangium, which causes inflammatory injuries to the kidney. Glycoforms with reduced galactose contents are associated with higher incidence of IgAN [2,3,4]. It was suggested that these aberrant glycoforms, referred to as galactose-deficient IgA1 (Gd-IgA1), are antigenic. In patients with IgAN, anti–Gd-IgA1 autoantibodies against IgG or IgM can be detected, and these IgG-IgA1 and IgM-IgA1 antibody-antigen pairs may lead to the formation of poly-IgA immune complexes in circulation that are susceptible to renal deposition [7]
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