B-Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy.

Key Points: Dysregulated IgA production plays a key role in the pathogenesis of IgA nephropathy. Increased 5-methylcytosine modification, an epigenetic regulatory mechanism, exaggerated IgA nephropathy phenotype in mice. Conversely, inhibition of 5-methylcytosine modification ameliorated progression of IgA nephropathy–like kidney disease in mice.

Background: IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is believed to play a key role in IgA nephropathy pathogenesis; however, little is known about the epigenetic mechanisms, such as RNA 5-methylcytosine (5mC) modification, in regulating IgA synthesis.

Methods: To decipher the role of RNA 5mC in regulation of IgA class switch, the microRNA (miR)-23b and (Chinese Industrial Microbial Culture Collection Center) cell wall extract–induced Kawasaki disease mice were treated with 5-azacytidine. and double / mice and mice or / mice were also used.

Results: We showed that downregulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 and consequently reduced 5mC (mC) RNA modification and IgA synthesis in B cells. Inhibition of mC RNA modification normalized serum IgA levels and ameliorated progression of the IgA nephropathy–like kidney disease in and Kawasaki disease mice, while mesangial IgA and C3 deposition failed to develop in mice. By contrast, increased mC RNA modification resulted in an exaggerated IgA nephropathy phenotype. regulation of serum IgA levels and the development of an IgA nephropathy–like kidney disease in and Kawasaki disease mice is likely mediated through TRDMT1-driven 5mC RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination.

Conclusions: This study revealed TRDMT1-induced RNA 5mC methylation regulated IgA class switch, and inhibition of RNA 5mC by 5-azacytidine ameliorated progression of IgA nephropathy.