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

TitleAltered function and differentiation of age-associated B cells contribute to the female bias in lupus mice.
Publication TypeJournal Article
Year of Publication2021
AuthorsRicker E, Manni M, Flores-Castro D, Jenkins D, Gupta S, Rivera-Correa J, Meng W, Rosenfeld AM, Pannellini T, Bachu M, Chinenov Y, Sculco PK, Jessberger R, Prak ETLuning, Pernis AB
JournalNat Commun
Volume12
Issue1
Pagination4813
Date Published2021 08 10
ISSN2041-1723
KeywordsAge Factors, Aging, Animals, B-Lymphocytes, CD11c Antigen, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Female, Guanine Nucleotide Exchange Factors, Kaplan-Meier Estimate, Lupus Erythematosus, Systemic, Male, Mice, Inbred C57BL, Mice, Knockout, Minor Histocompatibility Antigens, Nuclear Proteins, Sex Factors, T-Box Domain Proteins
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 CD11cT-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.

DOI10.1038/s41467-021-25102-8
Alternate JournalNat Commun
PubMed ID34376664
PubMed Central IDPMC8355159
Grant ListP30 CA016520 / CA / NCI NIH HHS / United States
R01 AR064883 / AR / NIAMS NIH HHS / United States
R01 AR070146 / AR / NIAMS NIH HHS / United States
S10 OD019986 / OD / NIH HHS / United States
Related Faculty: 
Tania Pannellini, M.D., Ph.D.

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