Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway

Class-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2 −/− mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4 + T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2 - Icos hi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4 + T cells are required to maintain self-tolerance against SLE. Autoimmune disease: Bach2 orchestrates immune function Bach2, a protein that regulates gene expression, is required in the B cells and T cells of the immune system to protect against autoimmune disease. Bach2 deficiency has previously been associated with systemic lupus erythematosus (SLE), but the mechanisms through which it contributes to the development of an immune response against healthy tissue in many parts of the body were unclear. Jeehee Youn at Hanyang University in Seoul, South Korea, and colleagues showed that B cells from mice lacking Bach2 produce self-reactive antibodies and express SLE-related genes. Furthermore, when they specifically deleted Bach2 in T cells, they found that it triggered differentiation into a type of T cell which promoted the maturation of self-reactive B cells. The authors conclude that Bach2 activity in both B cells and T cells is key to maintaining immune self-t