Malcolm, J. et al. (2023) C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance. Journal of Autoimmunity, 135, 102994. (doi: 10.1016/j.jaut.2023.102994) (PMID:36706535)
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Abstract
In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by grants from Versus Arthritis (20823), European commission FP7 - Gums and Joints (261460), Marie Curie ITN RAPID (290246), a Jules Thorne PhD Scholarship and an EPSRC grant (EP/H024891/1). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McInnes, Professor Iain and Butcher, Mr John and Malcolm, Dr Jennifer and Nyirenda, Dr Mukanthu and Brown, Dr Jason and Piela, Dr Krystyna and Culshaw, Professor Shauna and Adrados Planell, Miss Ana and Goodyear, Professor Carl |
| Authors: | Malcolm, J., Nyirenda, M.H., Brown, J.L., Adrados-Planell, A., Campbell, L., Butcher, J.P., Glass, D.G., Piela, K., Goodyear, C.S., Wright, A.J., McInnes, I.B., Millington, O.R., and Culshaw, S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| Journal Name: | Journal of Autoimmunity |
| Publisher: | Elsevier |
| ISSN: | 0896-8411 |
| ISSN (Online): | 1095-9157 |
| Published Online: | 25 January 2023 |
| Copyright Holders: | Copyright © 2023 Crown Copyright |
| First Published: | First published in Journal of Autoimmunity 135: 102994 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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