Epigenetic Modulation of Class-switch DNA Recombination to IgA by miR- 146a through Downregulation of Smad2, Smad3 and Smad4

Abstract IgA is the predominant isotype at intestinal mucosae, where it plays a critical role in homeostasis and first line of immune protection. Class-switch DNA recombination (CSR) to directed by TGF-b which induces activation Smad2 Smad3 transcription factors. Activated Smad2/Smad3 dimers are recruited with Smad4 IgH α locus Iα promoter activate germline Iα-Cα transcription, step CSR IgA. Epigenetic factors, such as microRNAs, regulate cells and, we have shown, modulate antibody response B cell- intrinsic fashion. We found that miR-146a targets Smad2, mRNA 3’UTRs, keeps check resting cells. Enforced expression aborted decreasing Smad levels. Induction IgA, TGF-b, downregulated cell miR-146a, thereby reversing silencing Smad4, which, once expressed, led recruitment for transcription. miR- 146a−/− mice significantly increased circulating levels total but not IgM, IgG or IgE, heightened specific OVA. In miR-146a−/− mice, this was associated IgA+ amounts fecal free bacteria-bound kidney deposition nephropathy. The cell-intrinsic repression confirmed −/− vitro vivo mixed bone marrow μMT/miR-146a−/− chimeric mice. Thus, inhibition expression, an important modulation response. Supported NIH grants AI 079705, 105813, AAI 167416 LRA grant 641363 PC.