Enhanced differentiation of IgA+ class-switched CD27-CD21+ B cells in patients with IgA nephropathy

BackgroundIgA nephropathy (IgAN) is characterised by the production of galactose-deficient IgA1 (Gd-IgA1) 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. MethodsWe 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. ResultsIn 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. ConclusionWe 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. Key learning pointsO_ST_ABSWhat was knownC_ST_ABSO_LIPatients with IgA nephropathy (IgAN) have aberrant production of galactose-deficient IgA1 (Gd-IgA1) and antibodies against it, which together form immune complexes that are deposited in the renal mesangium and lead to kidney damage; this is known as the multi-hit model of IgAN pathogenesis. C_LIO_LIThe multi-hit model centrally implicates B cells as they produce both Gd-IgA1 and antibodies against it, yet B cell activation pathways that lead to aberrant antibody production are absent from the model. C_LIO_LIOnly isolated reports exist describing specific features of B cells that are altered in patients with IgAN, including a reduction in regulatory B cells, increase in toll-like receptor 7 expression in total peripheral blood B cells and elevated frequency of circulating CCR9+IgA+ B cells. C_LI This study addsO_LIIn addition to changes in the overall circulating B cell landscape, differentiation of IgA+ plasmablasts is enhanced in patients with IgAN and their levels correlate with serum IgA. C_LIO_LIIgA-expressing plasmablast frequency correlates with that of IgA+CD21+ B cells, that lack the classical memory B cell marker CD27. C_LIO_LIBoth IgA+ plasmablasts and IgA-expressing CD27- B cells co-express GdIgA1 receptors. C_LIO_LIIgA+CD27-CD21+ B cell frequency correlates with serum lipopolysaccharide (LPS) levels, implicating mucosa in their activation. C_LI Potential impactO_LIWe uncover the previously unknown B cell activation pathway that appears to be associated with pathogenic IgA secretion in IgAN and integrate this into the multi-hit model of IgAN pathogenesis. C_LIO_LIThis pathway holds potential for further investigation to identify biomarkers and therapeutic targets in IgAN. C_LI