Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies

Rationale & Objective: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1), predominantly with λ 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-IgA1 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.