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

Katerina Zachova; Jana Jemelkova; Petr Kosztyu; Yukako Ohyama; Kazuo Takahashi; Josef Zadrazil; Jiri Orsag; Karel Matousovic; Dana Galuszkova; Nadezda Petejova; Jiri Mestecky; Milan Raska

doi:10.1681/ASN.2021081086

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Significance Statement

IgA nephropathy (IgAN) is associated with mesangial deposition of aberrantly glycosylated IgA1 containing λ light chains and the association of upper respiratory or digestive tract infection with macroscopic hematuria. We found that peripheral blood Gd-IgA1⁺ cells from IgAN patients express predominantly λ light chains and CCR9 and CCR10, compared with healthy controls. Furthermore, Gd-IgA1⁺ cell populations in peripheral blood are enriched with plasmablasts/plasma cells. Therefore, IgAN is associated with an increased number of migratory Gd-IgA1-λ⁺ cells predestined for homing to upper respiratory and digestive tract mucosal tissues, where their final maturation and Gd-IgA1-λ secretion may be stimulated during upper respiratory or digestive tract infections.

Abstract

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.

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