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 λ light (L) chains, but the nature and origin of such IgA remains enigmatic.

Methods: We analyzed λ 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 λ L chains. In contrast, total mb-IgA⁺, mb-IgG⁺, and mb-IgM⁺ cells were preferentially positive for kappa (κ) L chains, in all analyzed groups. Although minor in comparison to κ L chains, λ 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 λ⁺ 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 λ⁺ 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.