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 l light (L) chains, but the nature and origin of such IgA remains enigmatic. Methods We analyzed l 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-IgA11 cells from IgAN patients express predominantly l L chains. In contrast, total mb-IgA1, mb- IgG1, and mb-IgM1 cells were preferentially positive for kappa (k) L chains, in all analyzed groups. Although minor in comparison to k L chains, l L chain subsets of mb-IgG1, mb-IgM1, and mb-IgA1 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 l1 mb-Gd-IgA11, CCR101, and CCR91 cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA11 cell populations comprise more CD1381 cells and plasmablasts (CD381) in comparison to total mb-IgA1 cells. Conclusions Peripheral blood of IgAN patients is enriched with migratory l1 mb-Gd-IgA11 B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.