GdIgA+ B cell Differentiation in IgA Nephropathy

Objectives:
IgA nephropathy (IgAN) is the most common primary glomerulonephritis and a frequent cause of end-stage renal disease. The pathogenesis of IgAN is conceptualised by the multi-hit model. It integrates observations from studies of IgAN patients showing increased production of galactose deficient IgA1 (GdIgA1, hit 1), the generation of antibodies against it (hit 2), immune complex formation (hit 3), and the mechanisms of immune-complex-mediated kidney injury (hit 4). As the source of the pathogenic antibodies B cells are central to IgAN development, yet they have been absent from the multi-hit model.

Materials and Methods:
We combine flow cytometry, confocal microscopy of mucosa-associated lymphoid tissue (MALT) and in vitro Peyer’s patch modelling to characterise GdIgA1+ B cells in IgAN and uncover the molecular requirements and developmental niches for their differentiation.

Results:
We identify a GdIgA1+ B cell population that is increased in the peripheral blood of IgAN patients. IgAN patients further have an expanded population of GdIgA+ antibody-secreting cells (ASCs), which correlate with serum IgA levels. 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. These B cells are the putative precursors of GdIgA1-producing ASCs.

Conclusions:
This provides mechanistic insight into the B cell source and differentiation pathways that are central to IgAN pathogenesis. We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to GdIgA+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.