Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus.
Ann Rheum Dis
; 83(8): 1006-1017, 2024 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-38531610
ABSTRACT
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Plexo Corióideo
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Vasculite Associada ao Lúpus do Sistema Nervoso Central
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Modelos Animais de Doenças
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article