IgA class-switched CD27-CD21+B cells in IgA nephropathy

Abstract

Background: Immunoglobulin A nephropathy (IgAN) is characterized by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA secretion remain unknown. Methods: We carried out flow cytometry analysis of peripheral blood B cells in patients with IgAN and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. Results: In addition to global changes in the B cell landscape - expansion of naïve and reduction in memory B cells - IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21+. IgAN patients furthermore have an expanded population of IgA+ antibody-secreting cells, which correlate with serum IgA levels. Both IgA+ plasmabalsts and CD27- B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27- B cell frequency. Conclusion: We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA+CD27- B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow further investigation of this pathway to uncover biomarkers and develop therapeutic interventions.