Nickdel, M.B., Conigliaro, P., Valesini, G., Hutchison, S., Benson, R. , Bundick, R.V., Leishman, A.J., McInnes, I. , Brewer, J.M. and Garside, P. (2009) Dissecting the contribution of innate and antigen-specific pathways to the breach of self-tolerance observed in a murine model of arthritis. Annals of the Rheumatic Diseases, 68(6), pp. 1059-1066. (doi: 10.1136/ard.2008.089300) (PMID:18635595)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | McInnes, Professor Iain and Conigliaro, Dr Paola and Garside, Professor Paul and Brewer, Professor James and Benson, Dr Robert and Hutchison, Dr Sharon |
Authors: | Nickdel, M.B., Conigliaro, P., Valesini, G., Hutchison, S., Benson, R., Bundick, R.V., Leishman, A.J., McInnes, I., Brewer, J.M., and Garside, P. |
Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Annals of the Rheumatic Diseases |
Publisher: | B M J Group |
ISSN: | 0003-4967 |
ISSN (Online): | 1468-2060 |
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