Altered function and differentiation of age-associated B cells contribute to the female bias in lupus mice

Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7. Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c(+)T-bet(+) B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c(+) and CD11c(-) effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis.

Automated summary

This study demonstrates that age-associated B cells (ABC) play a crucial role in sex-specific autoimmune diseases, particularly in the development of lupus-like syndrome in females. The absence of certain guanine exchange factors in double-knock-out (DKO) mice leads to the accumulation of ABCs, which differentiate into pathogenic effector B cell populations with pro-inflammatory function. The upregulation of Tlr7 in DKO males further enhances the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality.