Dissecting the contribution of innate and antigen-specific pathways to the breach of self-tolerance observed in a murine model of arthritis

Nickdel, M.B. and Valesini, G. and Hutchison, S. and Benson, R. and Bundick, R.V. and Leishman, A.J. and McInnes, I.B. and Brewer, J.M. and Garside, P. (2008) 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. ISSN 0003-4967 (https://doi.org/10.1136/ard.2008.089300)

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Abstract

The relative roles of innate immunity and antigen-specific T cells in rheumatoid arthritis remain controversial. Previous studies demonstrated that Th1 cells of irrelevant antigen (Ag)-specificity (ovalbumin; OVA) 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 emergence of autoreactive T and B cell responses to joint specific antigens. However, the mechanisms underlying this phenomenon were unclear. 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. 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. The non-specific inflammatory response generated by LPS 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 Ags with associated activation of autoreactive B cells. These effects could be further potentiated by addition of LPS. 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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