An in vivo functional screen identifies miR-148a as a critical regulator of B cell tolerance and autoimmunity

Abstract

Autoreactive B cells are major contributors to autoimmune disease pathogenesis, but the molecular pathways responsible for the break of B cell tolerance in these patients remain largely unknown. In this study, we performed an in vivo functional screen of a lymphocyte-expressed miRNA library and identified miR-148a as a key regulator of this process. Elevated miR-148a expression impaired B cell tolerance by protecting immature B cells from BCR engagement-induced apoptosis, through downregulation of its targets Gadd45a, Bcl2l11, and Pten. Moreover, increased expression of miR-148a, which has been consistently found in lupus patients and lupus-prone mice, accelerated the development of lethal autoimmunity in a lupus mouse model. These results demonstrate that miR-148a functions as an important regulator of B cell tolerance and autoimmunity.