Sex differences in the percentage of IRF5 positive B cells are associated with higher production of TNF-α in women in response to TLR9 in humans

Biol Sex Differ. 2023 Feb 22;14(1):11. doi: 10.1186/s13293-023-00495-x.


Background: The clinical course and outcome of many diseases differ between women and men, with women experiencing a higher prevalence and more severe pathogenesis of autoimmune diseases. The precise mechanisms underlying these sex differences still remain to be fully understood. IRF5 is a master transcription factor that regulates TLR/MyD88-mediated responses to pathogen-associated molecular patterns (PAMPS) in DCs and B cells. B cells are central effector cells involved in autoimmune diseases via the production of antibodies and pro-inflammatory cytokines as well as mediating T cell help. Dysregulation of IRF5 expression has been reported in autoimmune diseases, including systemic lupus erythematosus, primary Sjögren syndrome, and rheumatoid arthritis.

Methods: In the current study, we analyzed whether the percentage of IRF5 positive B cells differs between women and men and assessed the resulting consequences for the production of inflammatory cytokines after TLR7- or TLR9 stimulation.

Results: The percentage of IRF5 positive B cells was significantly higher in B cells of women compared to men in both unstimulated and TLR7- or TLR9-stimulated B cells. B cells of women produced higher levels of TNF-α in response to TLR9 stimulation.

Conclusions: Taken together, our data contribute to the understanding of sex differences in immune responses and may identify IRF5 as a potential therapeutic target to reduce harmful B cell-mediated immune responses in women.

Keywords: B cells; Interferon regulatory factor 5; Sex differences; Toll-like receptor 7/9; Tumor necrosis factor-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes* / metabolism
  • Cytokines / metabolism
  • Female
  • Humans
  • Interferon Regulatory Factors* / metabolism
  • Male
  • Sex Characteristics
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / metabolism
  • Tumor Necrosis Factor-alpha* / metabolism


  • Cytokines
  • Interferon Regulatory Factors
  • IRF5 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha