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

Abstract

Introduction: 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.

Methods: 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.

Results: 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 to IgA1 mice.

Conclusions: 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.

Keywords: IgA nephropathy; IgA2; LCM/MS; Lactobacillus casei cell wall extract; mouse model.