title: The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gonzalez-Martin
authors.affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Brian D
authors.identifier: http://orcid.org/0000-0001-8372-2970
authors.initials: BD
authors.lastname: Adams
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Maoyi
authors.initials: M
authors.lastname: Lai
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jovan
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Department of Immunology and Oncology, National Biotechnology Center, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Salvador-Bernaldez
authors.affiliation: Department of Immunology and Oncology, National Biotechnology Center, Madrid, Spain.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Salvador
authors.affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Changchun
authors.identifier: http://orcid.org/0000-0001-8754-3208
authors.initials: C
authors.lastname: Xiao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D015151:Immunoblotting; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D000097642:GADD45 Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D011518:Proto-Oncogene Proteins; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C554644:Mirn148 microRNA, mouse; C487757:Pten protein, mouse