Autoimmunity

Transcription factor

Biology

Gene

IRF4

Antibody

Autoantibody

Immunology

IRF5

Cell biology

Genetics

Interferon regulatory factors

Nature Immunology

Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase–regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity. A unique subset of T-bet-expressing B cells accumulates with aging and in autoimmunity. Pernis and colleagues show that dysregulation of the transcription factor IRF5 occurs after loss of the Rho GTPase–regulatory proteins DEF6 and SWAP-70 and leads to the premature generation of age-associated B cells.

Regulation of age-associated B cells by IRF5 in systemic autoimmunity