Absence of glomerular IgA1 deposition despite overexpression of galactose-deficient IgA1 in the B cell c1galt1 knockout mouse

INTRODUCTION: Aberrant O-linked glycosylation of the IgA hinge segment resulting in galactose-deficient IgA1 (Gd-IgA1) is frequently observed in patients with IgA nephropathy (IgAN), and it is hypothesized to be pathogenic. Here, we genetically disrupted the expression of galactosyltransferase 1 (C1galt1) to elevate Gd-IgA1 levels in mice and examine its role in glomerular deposition. METHODS: We previously established a mouse model expressing the human IgA1 heavy chain via an IGHA1-knock-in allele. To investigate the role of aberrant glycosylation, we introduced a B cell-specific deletion of c1galt1 into this model. Circulating Gd-IgA1 levels were measured, and kidney phenotypes were evaluated under physiological conditions and following inflammatory stimulation. Furthermore, using a passive mouse model, we compared the glomerular deposition potential of IgA1 derived from various human sources, including serum, ileocecal mucus, as well as from patients with myeloma. RESULTS: B cell-specific deletion of c1galt1 resulted in markedly elevated circulating Gd-IgA1 levels under both physiological conditions and inflammatory stimulation (Lactobacillus casei cell wall extract and complete Freund's adjuvant), and these mice exhibited impaired B cell development and reduced IgA production in both systemic circulation and intestinal mucosa. Correspondingly, glomerular IgA deposition remained limited under physiological conditions and was not substantially enhanced following inflammatory stimulation. In contrast, mucosa-derived IgA1 from patients with IgAN induced significantly stronger mesangial deposition than serum- or myeloma-derived IgA1, despite having a similar or lower Gd-IgA1 content. CONCLUSIONS: Our findings support Gd-IgA1 as a correlate of mucosal immune activation rather than a direct pathogenic driver. Instead, tissue origin and immune context are likely key determinants of IgA1 deposition and pathogenic potential.