The mechanism of intestinal IgA class switching regulated by TRIM21 through down-regulation of AID in IgA nephropathy.

Aberrant mucosal IgA production is central to IgA nephropathy (IgAN), yet the regulatory mechanisms remain poorly understood. TRIM21 has been identified as a key gene in IgAN, but its functional contribution to disease pathogenesis is unclear. In this study, we investigated whether TRIM21 regulates mucosal IgA synthesis and disease progression. TRIM21 expression was significantly reduced in peripheral blood mononuclear cells from IgAN patients and correlated inversely with serum IgA levels. In Trim21-/- mice subjected to oral mucosal immunization, TRIM21 deficiency exacerbated disease phenotypes, including increased urinary protein-to-creatinine ratio and serum creatinine, impaired intestinal barrier integrity, and expansion of IgA+ B cells in gut-associated lymphoid tissues. Mechanistically, TRIM21 may directly bind IκBα and promote its ubiquitination, thereby restraining NF-κB activation and downstream AID expression. Loss of TRIM21 relieved this suppression, leading to enhanced IgA class switching. Collectively, these findings demonstrate that TRIM21 negatively regulates intestinal IgA biosynthesis by ubiquitinating IκBα and inhibiting the NF-κB-AID axis, identifying the TRIM21-IκBα-NF-κB pathway as a potential therapeutic target in IgAN.