Gonzalez-Martin Alicia, Adams Brian D, Lai Maoyi, Shepherd Jovan, Salvador-Bernaldez Maria, Salvador Jesus M, Lu Jun, Nemazee David, Xiao Changchun
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University, New Haven, Connecticut, USA.
Nat Immunol. 2016 Apr;17(4):433-40. doi: 10.1038/ni.3385. Epub 2016 Feb 22.
Autoreactive B cells have critical roles in a large diversity of autoimmune diseases, but the molecular pathways that control these cells remain poorly understood. We performed an in vivo functional screen of a lymphocyte-expressed microRNA library and identified miR-148a as a potent regulator of B cell tolerance. Elevated miR-148a expression impaired B cell tolerance by promoting the survival of immature B cells after engagement of the B cell antigen receptor by suppressing the expression of the autoimmune suppressor Gadd45α, the tumor suppressor PTEN and the pro-apoptotic protein Bim. Furthermore, increased expression of miR-148a, which occurs frequently in patients with lupus and lupus-prone mice, facilitated the development of lethal autoimmune disease in a mouse model of lupus. Our studies demonstrate a function for miR-148a as a regulator of B cell tolerance and autoimmunity.
自身反应性B细胞在多种自身免疫性疾病中起关键作用，但控制这些细胞的分子途径仍知之甚少。我们对淋巴细胞表达的microRNA文库进行了体内功能筛选，并确定miR-148a是B细胞耐受性的有效调节因子。miR-148a表达升高通过抑制自身免疫抑制因子Gadd45α、肿瘤抑制因子PTEN和促凋亡蛋白Bim的表达，促进未成熟B细胞在B细胞抗原受体结合后存活，从而损害B细胞耐受性。此外，miR-148a表达增加在狼疮患者和狼疮易感小鼠中很常见，在狼疮小鼠模型中促进了致死性自身免疫疾病的发展。我们的研究证明了miR-148a作为B细胞耐受性和自身免疫调节因子的功能。
