Background: 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. Methods: 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. Results: 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. Conclusion: 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.

The authors have declared no competing interest.

This work was funded by the Latvian Council of Science, project Nr. lzp-2019/1-0139.

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