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Dissecting the contribution of innate and antigen-specific pathways to the breach of self-tolerance observed in a murine model of arthritis
  1. M B Nickdel1,
  2. P Conigliaro1,2,3,
  3. G Valesini3,
  4. S Hutchison1,
  5. R Benson1,
  6. R V Bundick4,
  7. A J Leishman4,
  8. I B McInnes2,
  9. J M Brewer1,
  10. P Garside1
  1. 1
    Centre for Biophotonics, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
  2. 2
    Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK
  3. 3
    Cattedra di Reumatologia, Dipartimento di Clinica e Terapia Medica Applicata, Università di Roma “La Sapienza”, Rome, Italy
  4. 4
    Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, UK
  1. Dr P Garside, Centre for Biophotonics Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK; paul.garside{at}strath.ac.uk

Abstract

Background: The relative roles of innate immunity and antigen-specific T cells in rheumatoid arthritis remain controversial. Previous studies demonstrated that T-helper type 1 cells of irrelevant antigen specificity (ovalbumin) induced a transient arthritis in BALB/c mice, which recapitulates many of the pre-articular and articular features of human disease and is associated with the emergence of autoreactive T and B-cell responses to joint-specific antigens. However, the mechanisms underlying this phenomenon were unclear.

Objectives: The aim of this study was to dissect the relative contribution of innate and heterologous antigen-specific pathways to the breach of self-tolerance and pathology observed in this model and how this may result from modified T and B-cell interactions.

Methods: To address this issue, experimental arthritis was elicited either by a non-specific inflammatory stimulus alone, by activation of T cells of an irrelevant specificity or a combination of both.

Results: The non-specific inflammatory response generated by lipopolysaccharide led to articular inflammation and cartilage erosion, but did not break tolerance to joint-specific antigens. In contrast, local activation of T cells of an irrelevant specificity produced a similar pathological picture but, in addition, induced T-cell responses to unrelated joint-specific antigens with associated activation of autoreactive B cells. These effects could be further potentiated by the addition of lipopolysaccharide.

Conclusion: These data demonstrate that non-specific inflammation alone is insufficient to breach self-tolerance. In contrast, T cells of an irrelevant specificity, when triggered locally in an antigen-specific manner, can breach self-tolerance leading to arthritis and autoantibody production, which can then be amplified in a non-specific manner.

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Footnotes

  • Competing interests: None.

  • Funding: This study received grant support from a BBSRC CASE award and AstraZeneca.

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