EAF2 deficiency attenuates autoimmune disease in Faslpr mice by modulating B cell activation and apoptosis
Yingying Luan,
Qing Min,
Runyun Zhang,
Zichao Wen,
Xin Meng,
Ziying Hu,
Xiaoqian Feng,
Meiping Yu,
Lulu Dong,
Ji-Yang Wang
Affiliations
Yingying Luan
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Qing Min
Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China
Runyun Zhang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Zichao Wen
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Xin Meng
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Ziying Hu
Department of Microbiology and Immunology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
Xiaoqian Feng
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Meiping Yu
Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
Lulu Dong
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Ji-Yang Wang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China; Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China; Corresponding author
Summary: MRL/lpr mice develop systemic lupus erythematosus-like autoimmunity due to defective FAS-mediated apoptosis. We generated Faslpr mice deficient in EAF2, a transcription elongation-associated factor known to promote apoptosis in germinal center (GC) B cells and crucial for preventing autoimmunity. Contrary to expectations, EAF2 deficiency significantly reduced lymphadenopathy and splenomegaly, extended lifespan, and alleviated nephritis by decreasing renal immune complex deposition. Additionally, EAF2 deficiency markedly reduced accumulation of activated B cells, GC B cells, plasma cells, and the abnormal B220+CD3+ T cells in Faslpr mice. Further analysis revealed that Eaf2−/−Faslpr B cells showed hyperactivation upon various stimulations, followed by increased death. RNA sequencing of the B220+CD3+ cells revealed a downregulation in survival-promoting genes such as Bcl-2 and Akt and an upregulation of proapoptotic genes. We conclude that the combined deficiency in FAS- and EAF2-mediated apoptotic pathways leads to B cell hyperactivation and subsequent death, thereby ameliorating systemic autoimmunity in this model.
