Abstract
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-Icoshi 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.
Highlights
Systemic lupus erythematosus (SLE or lupus) is a systemic autoimmune disease characterized by an abundance of antibodies (Abs) against nuclear self-antigens[1]
Bach[2] deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2deficient 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-Icoshi helper T cells
The Bach2-deficient mice did not form any germinal center (GC) in their spleens, while substantial numbers of GCs were present in their WT littermates (Fig. 1b)
Summary
Systemic lupus erythematosus (SLE or lupus) is a systemic autoimmune disease characterized by an abundance of antibodies (Abs) against nuclear self-antigens[1]. Among the diverse isotypes of anti-nuclear Abs (ANAs), only IgG class-switched ANAs are considered pathogenic since they are deposited in tissues as immune complexes, leading to inflammation and end-stage organ damage in the kidneys, skin, and additional organs. IgM class-unswitched ANAs elicit protective effects against autoimmunity by assisting in the clearance of cellular debris and interfering with the responses mediated by IgG ANAs2–4. There are models in which T cell-independent Ab responses contribute to lupus in mice[5], the majority of studies with lupus-prone mice and SLE patients indicate that T cell-dependent Ab responses are the main drivers of the disease. The EF and GC responses are instructed by specialized subsets of helper T (Th) effector cells, known as EF Th (Tefh) and follicular Th (Tfh) cells, Official journal of the Korean Society for Biochemistry and Molecular Biology
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