Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies
- 1Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
Abstract
Rationale & Objective: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1), predominantly with {lambda} light chains and Gd-IgA1 glycans-recognizing antibodies. Disease exacerbations are frequently linked to mucosal infections, underscoring the role of dysregulated mucosal immunity. Whereas current therapeutic strategies targeting Gd-IgA1-producing cells are largely evaluated based on clinical endpoints, a critical gap remains in understanding how these therapies influence Gd-IgA production and whether targeting mucosal immunity represents an effective therapeutic strategy. Here, we provide a mechanistic insight into Gd-IgA1+ B cell behavior within inflammatory mucosal-like microenvironment. Study Design: Case-control study with ex vivo functional analysis. Setting & Participants: Peripheral blood mononuclear cells from patients with biopsy-proven IgAN and healthy controls. Exposure(s): Stimulation with a cytokine combination mimicking mucosal immune activation (IL-6, IL-21, BAFF, APRIL). Outcome(s): Differentiation of B cell subsets involved in IgAN and production of IgA, Gd-IgA1, and IgG. Analytical Approach: Flow cytometry, ELISA, cytometric bead array, and Western blotting. Results: Mucosal cytokine stimulation induced robust differentiation of B cells into CD38high plasmablasts and CD138high plasma cells, with a disproportionate expansion of Gd-IgA1 populations in IgAN. Compared with controls, PBMCs from IgAN patients demonstrated markedly increased production of Gd-IgA1, predominantly in polymeric form and strongly enriched for {lambda} light chains (~90% vs ~51%). This response was accompanied by selective expansion of Gd-IgA1{lambda} plasma cells, identifying a disease-specific, highly responsive B cell compartment. Limitations: The cytokine combination was selected to reflect key signals present in mucosal immune environments, although in vivo conditions are more complex. Conclusions: Mucosal cytokine signals directly amplify pathogenic B cell responses in IgAN, driving production of polymeric, {lambda}-enriched Gd-IgA1. These findings provide mechanistic validation for therapies targeting the mucosal-systemic axis and offer a biologic explanation for the clinical efficacy of gut-directed corticosteroids and BAFF/APRIL inhibition.
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BibTeX
@misc{zachova2026mucosal,
title = {{Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies}},
author = {K. Zachova and A. Cutkova and P. Kosztyu and Y. Ohyama and K. Takahashi and J. Zadrazil and J. Orsag and N. Petejova and D. Galuszkova and J. Mestecky and M. Raska},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.759132},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies
AU - K. Zachova
AU - A. Cutkova
AU - P. Kosztyu
AU - Y. Ohyama
AU - K. Takahashi
AU - J. Zadrazil
AU - J. Orsag
AU - N. Petejova
AU - D. Galuszkova
AU - J. Mestecky
AU - M. Raska
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.759132
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1
AB - Rationale & Objective: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1), predominantly with {lambda} light chains and Gd-IgA1 glycans-recognizing antibodies. Disease exacerbations are frequently linked to mucosal infections, underscoring the role of dysregulated mucosal immunity. Whereas current therapeutic strategies targeting Gd-IgA1-producing cells are largely evaluated based on clinical endpoints, a critical gap remains in understanding how these therapies influence Gd-IgA production and whether targeting mucosal immunity represents an effective therapeutic strategy. Here, we provide a mechanistic insight into Gd-IgA1+ B cell behavior within inflammatory mucosal-like microenvironment. Study Design: Case-control study with ex vivo functional analysis. Setting & Participants: Peripheral blood mononuclear cells from patients with biopsy-proven IgAN and healthy controls. Exposure(s): Stimulation with a cytokine combination mimicking mucosal immune activation (IL-6, IL-21, BAFF, APRIL). Outcome(s): Differentiation of B cell subsets involved in IgAN and production of IgA, Gd-IgA1, and IgG. Analytical Approach: Flow cytometry, ELISA, cytometric bead array, and Western blotting. Results: Mucosal cytokine stimulation induced robust differentiation of B cells into CD38high plasmablasts and CD138high plasma cells, with a disproportionate expansion of Gd-IgA1 populations in IgAN. Compared with controls, PBMCs from IgAN patients demonstrated markedly increased production of Gd-IgA1, predominantly in polymeric form and strongly enriched for {lambda} light chains (~90% vs ~51%). This response was accompanied by selective expansion of Gd-IgA1{lambda} plasma cells, identifying a disease-specific, highly responsive B cell compartment. Limitations: The cytokine combination was selected to reflect key signals present in mucosal immune environments, although in vivo conditions are more complex. Conclusions: Mucosal cytokine signals directly amplify pathogenic B cell responses in IgAN, driving production of polymeric, {lambda}-enriched Gd-IgA1. These findings provide mechanistic validation for therapies targeting the mucosal-systemic axis and offer a biologic explanation for the clinical efficacy of gut-directed corticosteroids and BAFF/APRIL inhibition.
ER -