EAF2 deficiency attenuates autoimmune disease in Faslpr mice by modulating B cell activation and apoptosis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents significant challenges to human health. MRL/lpr mice, which develop SLE-like autoimmunity due to defective apoptosis in activated B and T cells, were used to study the role of apoptosis in autoimmunity. 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 autoantibody production and reducing immune complex deposition in the kidneys. Additionally, EAF2 deficiency markedly reduced accumulation of activated B cells, GC B cells, and plasma cells in Faslpr mice. Moreover, the abnormal B220+CD3+ T cells typically observed in Faslpr mice were substantially reduced by EAF2 deficiency. 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.