TLR7 escapes X chromosome inactivation in immune cells
| Autor: | Solange Grunenwald, Jean-Charles Guéry, Astrid Canivet, Pascal Azar, Julie Chaumeil, Claire Cenac, José E. Mejía, Catherine Pienkowski, Danièle Daviaud, Mélanie Souyris |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lupus erythematosus biology Immunology virus diseases General Medicine TLR7 medicine.disease Immunoglobulin G X-inactivation 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system medicine.anatomical_structure medicine biology.protein Klinefelter syndrome X chromosome B cell 030215 immunology |
| Zdroj: | Science Immunology. 3 |
| ISSN: | 2470-9468 |
| DOI: | 10.1126/sciimmunol.aap8855 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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