Enhanced differentiation of IgA+class-switched CD27-CD21+B cells in patients with IgA nephropathy
Authors: Popova Anna , Slisere Baiba , Racenis Karlis , Kuzema Viktorija , Karklins Roberts , Saulite Mikus , Seilis Janis , Saulite Anna Jana , Vasilvolfa Aiga , Vaivode Kristine , Pjanova Dace , Kroica Juta , Cernevskis Harijs , Lejnieks Aivars , Petersons Aivars , Oleinika Kristine 
Published: May 2024

Background

IgA 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.

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 IgAposantibody-secreting cells, which correlate with serum IgA levels. Both IgAposplasmabalsts and CD27negB 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 IgAposCD27negB cell frequency.

Conclusion

We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgAposCD27negB 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 points

What was known

Patients 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.

The 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.

Only 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.

This study adds

In 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.

IgA-expressing plasmablast frequency correlates with that of IgA+CD21+B cells, that lack the classical memory B cell marker CD27.

Both IgA+plasmablasts and IgA-expressing CD27-B cells co-express GdIgA1 receptors.

IgA+CD27-CD21+B cell frequency correlates with serum lipopolysaccharide (LPS) levels, implicating mucosa in their activation.

Potential impact

We 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.

This pathway holds potential for further investigation to identify biomarkers and therapeutic targets in IgAN.