Evidence from multicenter clinical studies and humanized mouse models indicates that glomerular mesangial IgA2 deposition contributes to the pathogenesis of IgA nephropathy.

Abstract

While IgA1 is well established as pathogenic in IgA nephropathy (IgAN), IgA2's role remains controversial. The most notable difference between IgA1 and IgA2 lies in the hinge region: IgA2 lacks a 13-amino acid segment unique in IgA1, which contains nine serine and threonine residues that can be O-glycosylated. Here, we investigated the role of IgA2 in the development of IgAN. To characterize glomerular IgA2 deposition in IgAN, we performed laser capture microdissection coupled with mass spectrometry (LCM/MS) on kidney biopsies from 14 patients with IgAN and 10 healthy donors. Additionally, multicenter immunofluorescence analysis was conducted using validated subclass-specific antibodies on 161 biopsy-proven IgAN cases from three Chinese clinical centers. To establish IgA2's pathogenicity, we generated humanized IgA1/IgA2 mouse models and induced IgAN via intraperitoneal administration of Lactobacillus casei cell wall extract with complete Freund's adjuvant. LCM/MS detected both IgA2(m1) and IgA2(m2) in IgAN glomeruli, confirming IgA2 deposition despite lower abundance than IgA1. Multicenter kidney immunofluorescence staining revealed mesangial IgA2 in over 98% of IgAN cases, with significant intensity correlating with chronic lesions (Oxford T lesion: ρ of 0.237) and significant kidney dysfunction (eGFR: r of -0.272). The humanized IgA2 model exhibited IgA2 mesangial deposition and developed tubular atrophy (16%-22% area), absent in humanized IgA1 mice. IgA2 mice also exhibited stronger glomerular complement C3 activation and interstitial macrophage infiltration compared with IgA1 mice. Our study highlights the role of IgA2 in IgAN development, demonstrating its capacity for glomerular deposition, complement activation, and induction of distinct histopathological injury patterns. These findings extend the IgA1-centric paradigm, indicating that IgA2 should be incorporated into future investigations of IgAN.