Paper

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

Meng, Wenzhao, Rivera-Correa, Juan, Flores-Castro, Danny, Jessberger, Rolf, Jenkins, Daniel, Ricker, Edd, Chinenov, Yurii, Gupta, Sanjay, Rosenfield, Aaron M, Sculco, Peter K, Eline T Luning Prak, Manni, Michela, Pernis, Alessandra B, Pannellini, Tania

2021

Overview

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. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Autoimmune diseases / CD11c antigen / Cell fate / Fate maps / Immunology / Immunopathogenesis / Inflammation / Lymphocytes B / Pathogenicity / Severe acute respiratory syndrome coronavirus 2 / Sex / Sex differences / Sexual dimorphism / Systemic lupus erythematosus / TLR7 protein / Toll-like receptors