Introduction: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and a leading cause of end-stage renal disease.While IgA1 has been recognized as the primary pathogenic subclass in IgAN, the role of IgA2 has remained controversial and less explored due to methodological limitations in past studies.This study was designed to comprehensively investigate the potential involvement of IgA2 in the pathogenesis of IgAN and its clinical implications.Methods: To characterize glomerular IgA2 deposition in IgAN, we performed laser capture microdissection coupled with mass spectrometry (LCM/MS) on renal biopsies from 14 IgAN patients 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 (PK, XA, SC).To establish IgA2's independent pathogenicity, we generated humanized IgA1/IgA2 mouse models and induced IgAN via intraperitoneal administration of Lactobacillus casei cell wall extract (LCWE) with complete Freund's adjuvant (CFA).Results: Through LCM/MS analysis, we detected both IgA2(m1) and IgA2(m2) subtypes in the glomerular mesangium of IgAN patients (Figure A), although their levels were significantly lower than those of IgA1.Quantification of relative peptide abundance clearly showed elevated levels of IgA subclasses in IgAN patients compared to donors.Multicenter immunofluorescence staining across the three Chinese cohorts demonstrated consistent mesangial deposition of IgA2 in over 98% of the cases (Figure B).Moreover, the intensity of IgA2 deposition was significantly correlated with chronic histological damage (such as Oxford classification M/S/T lesions) and a decline in estimated glomerular filtration rate (eGFR).In the humanized IgA2 mice treated with LCWE exhibited IgA2 mesangial deposition and developed characteristic tubular atrophy, which was not observed in the humanized IgA1 mice (Figure C).Additionally, humanized IgA2 mice showed stronger glomerular C3 activation and interstitial macrophage infiltration compared to humanized IgA2 mice. Conclusion:This study provides strong evidence the role of IgA2 in the development of IgAN, demonstrating its capacity for glomerular deposition, complement activation, and induction of distinct histopathological injury patterns.These findings necessitate the incorporation of IgA2-specific targeting in future therapeutic strategies for IgAN.
Li et al. (Wed,) studied this question.