ORCID Profile
0000-0002-2208-8870
Current Organisation
INSERM
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Publisher: Springer Science and Business Media LLC
Date: 10-2018
DOI: 10.1007/S00281-018-0712-Y
Abstract: Women develop stronger immune responses than men, with positive effects on the resistance to viral or bacterial infections but magnifying also the susceptibility to autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, the dosage of the endosomal Toll-like receptor 7 (TLR7) is crucial. Murine models have shown that TLR7 overexpression suffices to induce spontaneous lupus-like disease. Conversely, suppressing TLR7 in lupus-prone mice abolishes SLE development. TLR7 is encoded by a gene on the X chromosome gene, denoted TLR7 in humans and Tlr7 in the mouse, and expressed in plasmacytoid dendritic cells (pDC), monocytes/macrophages, and B cells. The receptor recognizes single-stranded RNA, and its engagement promotes B cell maturation and the production of pro-inflammatory cytokines and antibodies. In female mammals, each cell randomly inactivates one of its two X chromosomes to equalize gene dosage with XY males. However, 15 to 23% of X-linked human genes escape X chromosome inactivation so that both alleles can be expressed simultaneously. It has been hypothesized that biallelic expression of X-linked genes could occur in female immune cells, hence fostering harmful autoreactive and inflammatory responses. We review here the current knowledge of the role of TLR7 in SLE, and recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in pDCs, monocytes, and B lymphocytes from women and Klinefelter syndrome men. Female B cells where TLR7 is thus biallelically expressed display higher TLR7-driven functional responses, connecting the presence of two X chromosomes with the enhanced immunity of women and their increased susceptibility to TLR7-dependent autoimmune syndromes.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-01-2018
DOI: 10.1126/SCIIMMUNOL.AAP8855
Abstract: Biallelic TLR7 expression in immune cells may contribute to increased autoimmune disease risk in women.
Publisher: Cold Spring Harbor Laboratory
Date: 13-08-2023
DOI: 10.1101/2023.08.08.23293823
Abstract: Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are encoded by the adjacent X-linked genes, TLR7 and TLR8 . We previously established that TLR7 evades X chromosome inactivation in female immune cells, and that mononuclear blood cells express more TLR7 protein in women than in men. Using RNA fluorescence in situ hybridization, we now show that TLR8 likewise evades X chromosome inactivation in CD14 + monocytes and CD4 + T lymphocytes, and that cells harboring TLR7 or TLR8 transcript foci are more frequent in women than in men. In parallel, we found TLR7 and TLR8 simultaneous transcription to be disproportionally frequent in female monocytes and T cells, and disproportionally scarce in the male cells, resulting in a 7-fold difference in frequency. These transcriptional biases were again observable when comparing the single X of XY males with the active X of female cells. Among (47,XXY) Klinefelter syndrome males, both TLR7 and TLR8 escape X chromosome inactivation, and co-transcription frequencies on the active X of monocytes were intermediate overall between those for XY males and XX females, and encompassed both male- and female-like in idual patterns. These findings indicate that the TLR7 and TLR8 genes form a co-regulated gene cluster, which we have called the X-linked Toll-like receptor locus, with different sex- and sexual karyotype-dependent modes of transcription. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in the male cells. Thus, co-dependent transcription from the active X chromosome and escape from inactivation could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases. TLR8 , like TLR7 , escapes X chromosome inactivation in immune cells from women and 47,XXY Klinefelter syndrome (KS) men. The frequency of cells double-positive for TLR7 and TLR8 primary transcripts is 7-fold higher in women than in men. TLR7 and TLR8 form a co-regulated gene cluster on the human X chromosome, with sex-specific, ergent transcriptional patterns observable in monocytes and CD4 + T lymphocytes. Co-dependent transcription of the TLR7 and TLR8 genes on the active X was observed in women and KS men, contrasting with mutually exclusive transcription in euploid men. Blood mononuclear cells, including monocyte subsets, expressed higher levels of TLR8 protein in females than in males.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
DOI: 10.1097/GOX.0000000000002110
Abstract: Presented is the case of an obese, 72 year-old diabetic man with a dorsal foot de-gloving injury. Whilst the tendons of extensor hallucis longus, extensor digitorum longus to all digits, and extensor digitorum brevis to hallux and second toe were intact after surgical debridement, none had any covering paratenon. The joint between the medial cuneiform and first metatarsal was open. Reconstructive options were limited by his age and co-morbidities. A novel, completely synthetic dermal matrix (NovoSorb BTM) was applied, after which the patient was discharged home to attend for dressings and review of integration progress as an outpatient. He was allowed to mobilise without limitation. Because of the poor quality of the wound bed (and patient), the material integrated slowly over 9 weeks. Delamination of the matrix, and definitive closure by application of sheet split skin autograft, produced a robust, soft, mobile and excellent aesthetic result, over which he could wear footwear immediately. Clinically, the paratenon-denuded tendons glided under the neo-dermis without tethering to the overlying integrated matrix, allowing a full range of digital movement. This was confirmed on ultrasound examination, which also demonstrated no inflammation or oedema. Already proven in extensive burns, necrotising fasciitis and complex surgical wounds, BTM represents a useful addition to the reconstructive surgeon’s toolbox.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for José Enrique Mejía.