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Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus
  1. Erica Moore1,
  2. Sushma Bharrhan2,
  3. Deepak A Rao3,4,
  4. Fernando Macian5,
  5. Chaim Putterman1,6
  1. 1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
  2. 2Department of Microbiology and Immunology, Louisiana State University Shreveport, Shreveport, Louisiana, USA
  3. 3Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  4. 4Harvard Medical School, Boston, Massachusetts, USA
  5. 5Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
  6. 6Azrieli Faculty of Medicine of Bar-Ilan University, Safed, Israel
  1. Correspondence to Dr Chaim Putterman, Azrieli Faculty of Medicine, Bar-Ilan University, Zefat, Israel; chaim.putterman{at}einsteinmed.edu

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.

  • Lupus Erythematosus, Systemic
  • Therapeutics
  • T-Lymphocyte subsets

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @deepakarao, @ChaimPutterman

  • Contributors EM, SB, FM and CP conceptualised the study. EM performed the single-cell preparation and animal models. EM performed the computational analysis with supervision from DAR. The original draft of the manuscript was written by EM and CP. CP is the author acting as guarantor. All authors have reviewed and approved the manuscript. Please note: Unfortunately, FM passed away after the initial submission of the manuscript.

  • Funding The study was supported by the Gini M. Finzi Summer Fellowship and the Albert Einstein MSTP Grant (T32-GM007288).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.