Propensity of IgA to self-aggregate via tailpiece cysteine-471 and treatment of IgA nephropathy using cysteamine

Abstract

IgA nephropathy is caused by deposition of circulatory IgA1 in the kidney. Hypo-galactosylated IgA1 has the propensity to form poly-IgA aggregates that are prone to deposition. We purified poly-IgA from the plasma of IgAN patients and showed the complex being susceptible to reducing condition, suggesting intermolecular disulfide connections between IgA units. We sought to find the cysteine residue(s) in forming intermolecular disulfide. Naturally assembled dimeric IgA, also known as secretory IgA, involves a J-chain subunit connected with two IgA1 molecules via their penultimate cysteine-471 residue on '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 disulfide bond in poly-IgA formation. Mutagenesis confirmed cysteine-471 capable of promoting IgA aggregation. These discoveries prompted us to test thiol-based drugs for stabilizing cysteine. Specifically, cystine-reducing drug cysteamine used for treatment of cystinosis showed a remarkable potency in preventing IgA from selfaggregation. When administrated to rat and mouse models of IgA nephropathy, cysteamine significantly reduced glomerular IgA deposition. Collectively, our results revealed a novel molecular mechanism for aberrant formation of IgA aggregates, to which repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.

mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection

“…This was validated by chromatography, where there was a predominance of d IgA2 over m IgA2 upon JC coexpression, as compared to m IgA2 or aggregates of IgA2 that assembled in the absence of the JC ( Fig. 1C ) ( 22 ). Notably, size exclusion chromatography retention times of the d IgA2 and m IgA2 peaks were nearly identical between IgA2 mRNA and IgA2 R ( Fig.…”

Effects of N-glycans on the structure of human IgA2

“…The absence of the N-glycan in the tailpiece is known to cause the formation of larger oligomers (Xie et al, 2021;Pan et al, 2024). Lombana et al (2019) previously observed this phenomenon during dimeric IgA2 (m2) production when coexpressing heavy chain (HC), light chain (LC), and the joining chain (JC).…”

Advances in IgA glycosylation and its correlation with diseases

“…In addition, there is a conserved tail structure consisting of 18 amino acids at the C-terminal of the CH3 region on the IgA heavy chain. This kind of tail is essential for the formation of divalent and multivalent structures of IgA ( Xie et al, 2021 ).…”

“…Half of the glycans found at this site are core-fucosylated ( Huang et al, 2015 ). The N -glycans at this site are required for the correct conformation of J chain, deletion of them can prevent the dimeric IgA formation and inhibit the pIgR-mediated epithelial transport of IgA ( Xie et al, 2021 ).…”