Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus.
| Autor: | Moore E; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Bharrhan S; Department of Microbiology and Immunology, Louisiana State University Shreveport, Shreveport, Louisiana, USA., Rao DA; Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Macian F; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA., Putterman C; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA chaim.putterman@einsteinmed.edu.; Azrieli Faculty of Medicine of Bar-Ilan University, Safed, Israel. |
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| Jazyk: | angličtina |
| Zdroj: | Annals of the rheumatic diseases [Ann Rheum Dis] 2024 Jul 15; Vol. 83 (8), pp. 1006-1017. Date of Electronic Publication: 2024 Jul 15. |
| DOI: | 10.1136/ard-2023-224689 |
| Abstrakt: | Objective: Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease. Method: Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression. Results: We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype. Conclusion: Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.) |
| Databáze: | MEDLINE |
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