TLR7 escapes X chromosome inactivation in immune cells
- PMID: 29374079
- DOI: 10.1126/sciimmunol.aap8855
TLR7 escapes X chromosome inactivation in immune cells
Abstract
Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. SLE prevalence is also elevated in individuals with Klinefelter syndrome, who carry one or more supernumerary X chromosomes, suggesting that the X chromosome complement contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and we examined here whether the TLR7 gene evades silencing by X chromosome inactivation in immune cells from women and Klinefelter syndrome males. Single-cell analyses of TLR7 allelic expression demonstrated that substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells not only in women but also in Klinefelter syndrome males express TLR7 on both X chromosomes. Biallelic B lymphocytes from women displayed greater TLR7 transcriptional expression than the monoallelic cells, correlated with higher TLR7 protein expression in female than in male leukocyte populations. Biallelic B cells were preferentially enriched during the TLR7-driven proliferation of CD27+ plasma cells. In addition, biallelic cells showed a greater than twofold increase over monoallelic cells in the propensity to immunoglobulin G class switch during the TLR7-driven, T cell-dependent differentiation of naive B lymphocytes into immunoglobulin-secreting cells. TLR7 escape from X inactivation endows the B cell compartment with added responsiveness to TLR7 ligands. This finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with Klinefelter syndrome.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Comment in
-
Autoimmunity: TLR7 evades silencing in human immune cells.Nat Rev Nephrol. 2018 Apr;14(4):214. doi: 10.1038/nrneph.2018.13. Epub 2018 Feb 12. Nat Rev Nephrol. 2018. PMID: 29430014 No abstract available.
-
Autoimmunity: TLR7 evades silencing in human immune cells.Nat Rev Rheumatol. 2018 Apr;14(4):183. doi: 10.1038/nrrheum.2018.28. Epub 2018 Feb 22. Nat Rev Rheumatol. 2018. PMID: 29467454 No abstract available.
Similar articles
-
Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation.Semin Immunopathol. 2019 Mar;41(2):153-164. doi: 10.1007/s00281-018-0712-y. Epub 2018 Oct 1. Semin Immunopathol. 2019. PMID: 30276444 Review.
-
TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells.Biol Sex Differ. 2023 Sep 18;14(1):60. doi: 10.1186/s13293-023-00544-5. Biol Sex Differ. 2023. PMID: 37723501 Free PMC article.
-
Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.Front Immunol. 2019 Oct 21;10:2160. doi: 10.3389/fimmu.2019.02160. eCollection 2019. Front Immunol. 2019. PMID: 31695690 Free PMC article.
-
B cell autophagy mediates TLR7-dependent autoimmunity and inflammation.Autophagy. 2015;11(7):1010-24. doi: 10.1080/15548627.2015.1052206. Autophagy. 2015. PMID: 26120731 Free PMC article.
-
Emerging roles of TLR7 and TLR9 in murine SLE.J Autoimmun. 2009 Nov-Dec;33(3-4):231-8. doi: 10.1016/j.jaut.2009.10.001. Epub 2009 Oct 21. J Autoimmun. 2009. PMID: 19846276 Review.
Cited by
-
Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus.Nat Immunol. 2024 Jun;25(6):969-980. doi: 10.1038/s41590-024-01846-5. Epub 2024 Jun 3. Nat Immunol. 2024. PMID: 38831104 Free PMC article.
-
Tissue-specific sex differences in pediatric and adult immune cell composition and function.Front Immunol. 2024 May 15;15:1373537. doi: 10.3389/fimmu.2024.1373537. eCollection 2024. Front Immunol. 2024. PMID: 38812520 Free PMC article.
-
Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus.Int J Mol Sci. 2024 May 14;25(10):5351. doi: 10.3390/ijms25105351. Int J Mol Sci. 2024. PMID: 38791389 Free PMC article. Review.
-
Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.J Exp Med. 2024 Aug 5;221(8):e20232005. doi: 10.1084/jem.20232005. Epub 2024 May 23. J Exp Med. 2024. PMID: 38780621 Free PMC article.
-
LncRNAs, nuclear architecture and the immune response.Nucleus. 2024 Dec;15(1):2350182. doi: 10.1080/19491034.2024.2350182. Epub 2024 May 13. Nucleus. 2024. PMID: 38738760 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials