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

Abstract

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 <i>λ</i> light (L) chains, but the nature and origin of such IgA remains enigmatic. We analyzed <i>λ</i> 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). In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1⁺ cells from IgAN patients express predominantly <i>λ</i> L chains. In contrast, total mb-IgA⁺, mb-IgG⁺, and mb-IgM⁺ cells were preferentially positive for kappa (<i>κ</i>) L chains, in all analyzed groups. Although minor in comparison to <i>κ</i> L chains, <i>λ</i> 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 <i>λ</i>⁺ 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. Peripheral blood of IgAN patients is enriched with migratory <i>λ</i>⁺ 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.