Baker, K. F. et al. (2024) Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission. Nature Communications, 15, 1063. (doi: 10.1038/s41467-024-45213-2) (PMID:38316770) (PMCID:PMC10844292)
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Abstract
Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare – CD45RO+PD1hi CD4+ and CD8+ T cells, and CD27+CD86+CD21- B cells – further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+ memory T cells, memory CD8+CXCR5+ T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+ T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+ memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by grants from the Wellcome Trust (102595/Z/13/A to K.F.B.), National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BH136167/PD0045 to K.F.B.), British Society for Rheumatology (K.F.B.), Academy of Medical Sciences Starter Grant (supported by the Wellcome Trust, the Medical Research Council, the British Heart Foundation, Versus Arthritis, Diabetes UK and the British Thoracic Society Helen and Andrew Douglas bequest: SGL022\1074 to K.F.B.), Newcastle University Wellcome Trust Translational Partnership grant (K.F.B.), Newcastle Hospitals Charity grant (8033 to K.F.B.), Newcastle Health Innovation Partners Senior Clinical Fellowship (K.F.B.), and an NIHR Clinical Lectureship (CL-2017-01-004 to K.F.B.). Work in our laboratory is supported by the Research into Inflammatory Arthritis Centre Versus Arthritis (RACE) (grant number 20298), and Rheuma Tolerance for Cure (European Union Innovative Medicines Initiative 2, grant number 777357). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Preliminary data within this manuscript was previously published as an oral abstract at the 2022 EULAR Congress66. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | MacDonald, Dr Lucy |
| Authors: | Baker, K. F., McDonald, D., Hulme, G., Hussain, R., Coxhead, J., Swan, D., Schulz, A. R., Mei, H. E., MacDonald, L., Pratt, A. G., Filby, A., Anderson, A. E., and Isaacs, J. D. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Nature Communications |
| Publisher: | Nature Research |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Nature Communications 15:1063 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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