Mechanism of Intestinal IgA Class Switching Regulated by TRIM21 through Downregulation of AID (Activation-Induced Cytidine Deaminase) in IgA Nephropathy

Background: IgA nephropathy (IgAN) is the most common primary glomerular disease and the leading cause of end-stage renal disease (ESRD). At present, the ‘multi-hit hypothesis’ is a generally recognized pathogenesis of IgAN. However, the mechanism that initially triggers abnormal IgA synthesis has not been fully elucidated, specific treatment options are still lacking. Studies have shown that aberrant class switching of IgA antibodies in B cells within intestinal peyer patches plays a central role in generating pathogenic IgA. TRIM21 (Ro52/SS-A1) is an E3 ubiquitin ligase that participates in cellular immune response and antibody production. This study aims to elucidate the underlying mechanism of TRIM21 in regulating intestinal IgA class switching. Methods: IgA deposition in the Intestinal tract was detected by immunofluorescence. The expression level of AID in peyer patches was detected by immunohistochemical staining and Western Blot. The mRNA levels of IgA transcripts in peyer patches were detected by RT-qPCR. To investigate the mechanism of TRIM21 influencing the down-regulation of IgA-switching enzyme AID by inhibiting NF-κB pathway. The interaction of TRIM21 with IκBα was analyzed by CO-IP. The change of protein ubiquitination was analyzed by Western Blot. Results: Upon knocking out TRIM21, there was an increase in AID expression and IgA class switch. Additionally, the NF-κB pathway was activated, leading to increased AID expression in B cell lines Following the administration of an NF-κB pathway inhibitor, the AID expression in TRIM21 knockdown cells was restricted, and there were alterations in the overall protein ubiquitination levels. TRIM21 was identified to interact with IκBα, an inhibitory protein of NF-κB. Conclusion: The findings of this study reveal that TRIM21 acts as a negative regulator of AID expression, and IgA class switching. Through ubiquitination of IκBα, TRIM21 exerts a negative effect on the NF-κB pathway, thereby upregulating AID expression. Our study provides a promising aspect of TRIM21 in IgAN through the NF-κB signaling pathway. Our study reveals the role of TRIM21 in immune response and the development of IgAN. Funding: Other NIH Support - This work was supported by the National Natural Science Foundation of China (82270752)