Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Abstract

Sex differences characterize immune responses to viruses like SARS-CoV2 and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c− effector populations with pathogenic and proinflammatory potential. 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 contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

Double Negative (DN) B cells: A connecting bridge between rheumatic diseases and COVID-19?

“…Of note, TLR7 gene, which is of high importance for DN2 activation, 13 is a chromosome X-linked gene, thus explaining (at least in part) the sex-bias that accompanies SLE immunopathogenesis. 55 , 56 As far as genetic burden is concerned, it is well known that ethnicity -among other factors- is linked to the severity of SLE manifestations. 57 A better understanding of the differences among the various ethnic groups could probably enable better management of SLE patients.…”