Galactose-Deficient IgA1 B cells in the Circulation of IgA Nephropathy Patients Carry Preferentially Lambda Light Chains and Mucosal Homing Receptors.

Background: IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly light (L) chains, but the nature and origin of such IgA remains enigmatic.

Methods: We analyzed L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN).

Results: In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1 cells from IgAN patients express predominantly L chains. In contrast, total mb-IgA, mb-IgG, and mb-IgM cells were preferentially positive for kappa () L chains, in all analyzed groups. Although minor in comparison to L chains, L chain subsets of mb-IgG, mb-IgM, and mb-IgA cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with mb-Gd-IgA1, CCR10, and CCR9 cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1 cell populations comprise more CD138 cells and plasmablasts (CD38) in comparison to total mb-IgA cells.

Conclusions: Peripheral blood of IgAN patients is enriched with migratory mb-Gd-IgA1 B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.