title: Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells.
abstract: By inhibiting target gene expression, microRNAs (miRNAs) play major roles in various physiological and pathological processes. miR-146a, a miRNA induced upon lipopolysaccharide (LPS) stimulation and virus infection, is also highly expressed in patients with immune disorders such as rheumatoid arthritis, Sjögren's syndrome, and psoriasis. Whether the high level of miR-146a contributes to any of these pathogenesis-related processes remains unknown. To elucidate the function of miR-146a in vivo, we generated a transgenic (TG) mouse line overexpressing miR-146a. Starting at an early age, these TG mice developed spontaneous immune disorders that mimicked human autoimmune lymphoproliferative syndrome (ALPS) with distinct manifestations, including enlarged spleens and lymph nodes, inflammatory infiltration in the livers and lungs, increased levels of double-negative T cells in peripheral blood, and increased serum immunoglobulin G levels. Moreover, with the adoptive transfer approach, we found that the B-cell population was the major etiological factor and that the expression of Fas, a direct target of miR-146a, was significantly dampened in TG germinal center B cells. These results indicate that miR-146a may be involved in the pathogenesis of ALPS by targeting Fas and may therefore serve as a novel therapeutic target.
authors: Institute of Immunology, People's Liberation Army, Third Military Medical University, Chongqing, China.
authors: Qiuye
authors: Q
authors: Guo
authors: Jinjun
authors: J
authors: Zhang
authors: Jingyi
authors: J
authors: Li
authors: Liyun
authors: L
authors: Zou
authors: Jinyu
authors: J
authors: Zhang
authors: Zunyi
authors: Z
authors: Xie
authors: Xiaolan
authors: X
authors: Fu
authors: Shan
authors: S
authors: Jiang
authors: Gang
authors: G
authors: Chen
authors: Qingzhu
authors: Q
authors: Jia
authors: Fei
authors: F
authors: Li
authors: Ying
authors: Y
authors: Wan
authors: Yuzhang
authors: Y
authors: Wu
mesh_terms: D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C491899:Fas protein, mouse; D007074:Immunoglobulin G; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D019014:fas Receptor