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

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IgA nephropathy (IgAN) is characterised 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. We carried out flow cytometry analysis of peripheral blood B cells in patients with IgA nephropathy 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. In addition to global changes in the B cell landscape - expansion of naive 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 CD21pos. IgAN patients further have an expanded population of IgApos antibody-secreting cells, which correlate with serum IgA levels. Both IgApos plasmabalsts and CD27neg B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide (LPS) in the serum and IgAposCD27neg B cell frequency. We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgAposCD27neg B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow to further investigate this pathway to uncover biomarkers and develop therapeutic interventions.