Kidney Week

Abstract: TH-PO0448

Functional Evidence Linking Mucosal Immune Activation to Polymeric λ-Gd-IgA1 Production in IgAN

Session Information

• Glomerular Diseases: Autoimmune Diseases
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Zachova, Katerina, Fakultni nemocnice Olomouc, Olomouc, Olomouc Region, Czechia

Katerina Zachova, MS, PhD

• Cutkova, Alica, Univerzita Palackeho v Olomouci, Olomouc, Olomouc Region, Czechia

Alica Cutkova

• Mestecky, Jiri F., The University of Alabama at Birmingham, Birmingham, United States

Jiri F. Mestecky, MD, PhD

• Raska, Milan, Fakultni nemocnice Olomouc, Olomouc, Olomouc Region, Czechia

Milan Raska, PhD

Background

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of nephritogenic immune complexes composed of polymeric galactose-deficient IgA1 (Gd-IgA1), predominantly enriched for λ light chains and antiglycan autoantibodies, leading to glomerular injury. Although mucosal immune activation is strongly implicated in disease pathogenesis, the mechanisms underlying the effects of mucosal cytokine signaling on pathogenic B cell responses remain incompletely understood. Emerging therapies targeting the mucosal–systemic axis, including gut-directed corticosteroids and BAFF/APRIL inhibition, have shown favorable clinical outcomes, but their effects on primary Gd-IgA1⁺ B cells remain poorly defined.

Methods

Peripheral blood mononuclear cells (PBMCs) from patients with biopsy-proven IgAN (n=13) and healthy controls (n=10) were stimulated ex vivo using a cytokine combination mimicking mucosal immune activation (IL-6, IL-21, BAFF, APRIL). Changes in proportion of IgA⁺, Gd-IgA1⁺ and IgG⁺ B cell subsets were analyzed by multidimesional spectral flow cytometry and fluorescence microscopy. Production and composition of IgA, Gd-IgA1, and IgG were assessed by ELISA, cytometric bead array, and Western blotting under non-reducing conditions.

Results

Mucosal cytokine stimulation induced differentiation of B cells into CD38^high plasmablasts and CD138^high plasma cells in both groups. However, PBMCs from IgAN patients demonstrated disproportionate expansion of Gd-IgA1⁺ populations and significantly increased secretion of Gd-IgA1 compared with controls. Produced Gd-IgA1 was predominantly polymeric and showed marked λ light chain enrichment (~90% in IgAN vs ~51% in controls), consistent with key features of nephritogenic immune complexes detected in circulation and mesangial deposits. Stimulation also selectively increased Gd-IgA1⁺λ⁺CD138⁺ plasma cells in IgAN patients, identifying a disease-specific B-cell compartment highly responsive to mucosal cytokine signaling.

Conclusion

These findings provide functional evidence linking mucosal immune activation to differentiation of pathogenic Gd-IgA1⁺ plasma cells in IgAN. The results support the concept that mucosal inflammatory signals contribute to generation of polymeric, λ-enriched nephritogenic IgA and provide mechanistic support for therapies targeting the mucosal–systemic axis.

Acknowledgment

Supported by a grant from the Ministry of Health, Conceptual Development of Research Organization, Czech Republic (MHCZ-DRO, FNOL, 00098892) , grants from the Ministry of School, Youth, and Sport, Czech Republic (CZ.02.1.01/0.0/0.0/16_025/0007397 and CZ.02.01.01/00/23_021/0009224), a grant from Palacky University Olomouc, Czech Republic (IGA_LF_2025_014 and IGA_LF_2026_13) ), and a grant from the National Institutes of Health, United States of America (AI 168754) .

Funding

• Other NIH Support