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

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

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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.

Original languageEnglish
Article number4813
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 1 Dec 2021
Externally publishedYes

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