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.

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 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.

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.