Multi-omics analyses reveal the pathogenic role of terminal ileum-derived IgA⁺β7⁺ cells in IgA nephropathy.

Abstract

Galactose-deficient IgA1 (Gd-IgA1) plays a key role in IgA nephropathy (IgAN), but the location of the plasma cells responsible for its production remain unknown. To locate Gd-IgA1-producing cells, we profiled intestinal and circulating immune cells from three independent cohorts totaling 99 IgAN cases and 121 healthy controls. The IgA phenotypes-including total IgA, Gd-IgA1, IgA-IgG complexes, secretory IgA, and polymeric IgA levels were measured in paired ileocecal and blood samples. Bulk RNA sequencing, cell deconvolution, and spatial profiling of biopsies identified Gd-IgA1-producing cells in ileocecal samples and blood. Functional studies employed anti-integrin α4β7 monoclonal antibodies in vitro and in a humanized IgAN mouse model. We found significantly elevated levels of ileocecal IgA enriched for polymeric and Gd-IgA1 O-glycoforms in patients with IgAN. In parallel, terminal ileal rather than ascending colon IgA⁺ B cells were increased. Most of these cells expressed Gd-IgA1 and displayed dysregulation of enzymes involved in O-glycosylation. Furthermore, circulating IgA⁺ B cells in IgAN exhibited gene expression signatures more closely resembling that of terminal ileum-derived IgA⁺ B cells, rather than those from ascending colon or tonsil. Integrin β7 was identified as a biomarker for cells of terminal ileal origin, and there was an increase in IgA⁺β7⁺ plasmablasts/plasma cells, correlating with disease severity. In a mouse model of IgAN, anti-α4β7 monoclonal antibody reduced β7⁺ cells and Gd-IgA1 levels in vitro and induced attrition of Peyer's patches, decreased circulating β7⁺ plasmablasts/plasma cells, and prevented mesangial IgA deposition. Our study highlights the importance of dysregulated B cell responses in the terminal ileum in IgAN and suggests the α4β7-MAdCAM-1 axis as a potential therapeutic target.