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

• Published in: Nephrology, dialysis, transplantation Vol. 40; no. 3; pp. 505 - 515
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 28.02.2025
• Subjects: Adult; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Case-Control Studies; Female; Flow Cytometry; Follow-Up Studies; Glomerulonephritis, IGA - immunology; Glomerulonephritis, IGA - metabolism; Glomerulonephritis, IGA - pathology; Humans; Immunoglobulin A - immunology; Immunoglobulin Class Switching - immunology; Lymphocyte Activation; Male; Middle Aged; Original; Prognosis; Receptors, Complement 3d - immunology; Receptors, Complement 3d - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism; IgA-producing plasmablasts; antibodies; IgA nephropathy; B cells; disease mechanisms
• ISSN: 0931-0509; 1460-2385; 1460-2385
• DOI: 10.1093/ndt/gfae173

Immunoglobulin A nephropathy (IgAN) is characterized 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 IgAN 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 naïve 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 CD21+. IgAN patients furthermore have an expanded population of IgA+ antibody-secreting cells, which correlate with serum IgA levels. Both IgA+ plasmabalsts and CD27- B cells co-express GdIgA1. 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. We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA+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.