DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B cell activation and differentiation.

Abstract

Systemic lupus erythematosus (SLE) is characterized by the overproduction of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Studies have shown that DNA damage responses play a role in B cell activity in SLE. However, the exact role of DNA damage-induced transcript 3 (DDIT3) in humoral immune response and SLE pathogenesis remains unknown. We observed increased expression of DDIT3 in B cells of SLE patients and this expression was positively correlated with disease activity. In DDIT3-knockout mice, we observed disturbances in B cell development and differentiation, inhibition of B cell activation, and BCR signaling. In addition, DDIT3 deficiency leads to a reduction in T-cell-dependent humoral immune responses. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Finally, we found that DDIT3 deficiency attenuated lupus autoimmunity and reduced germinal center responses. In conclusion, our study reveals for the first time the role of DDIT3 in adaptive immune responses, especially in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for therapeutic intervention in SLE.