Joint damage without antigen

The development of various autoimmune diseases, including rheumatoid arthritis, is thought to be due to a breakdown in CD4⁺ T cell tolerance for a tissue-specific antigen. However, several lines of evidence have suggested that cognate antigen recognition by CD4⁺ T cells may not always be necessary. Murakami et al. now show that initiation of CD4⁺ T cell-dependent arthritis in gp130^F759/F759 mice involves the local accumulation of activated T helper 17 (T_H17) cells in the absence of cognate antigen recognition. This triggers an interleukin-17A (IL-17A)-dependent IL-6 amplification loop, which the authors termed the 'IL-6 amplifier'.

gp130^F759/F759 mice have enhanced IL-6 receptor-mediated signalling and spontaneously develop a rheumatoid arthritis-like disease as they age. In this study, the authors found that gp130^F759/F759 mice engineered to express a single T cell receptor that recognizes a non-joint antigen also develop arthritis, indicating that cognate antigen recognition was not involved. These mice had a higher number of T_H17 cells in lymphoid tissues, and the concentrations of IL-6 and IL-17A in the blood were increased.

The authors hypothesized that local events in the joint (such as microbleeding) may contribute to joint inflammation by triggering the accumulation of activated T_H17 cells, so they transferred in vitro differentiated T_H17 cells to gp130^F759/F759 or control C57BL/6 mice that had undergone experimental microbleeding in one leg. Arthritis developed in the leg in which microbleeding was induced (but not the other leg) in gp130^F759/F759 mice following T_H17 cell transfer, but did not occur in control mice, suggesting that the enhanced sensitivity to IL-6 in gp130^F759/F759 mice is required for disease. Microbleeding in the joint induced the localized expression of CC-chemokine ligand 20 (CCL20), which is a chemoattractant for CC-chemokine receptor 6 (CCR6)⁺ T_H17 cells. In addition, IL-6-mediated signalling in type I collagen-expressing cells and local IL-17A production by T_H17 cells were shown to be important for disease pathogenesis in this mouse model.

So, putting these observations together, the following model emerges. A local event in the joint, such as microbleeding, induces the accumulation of T_H17 cells through increased CCL20 expression, resulting in the activation of the IL-6 amplifier and disease development. The authors propose that in humans, the availability of T_H17 cells for such a model could be due to the known age-dependent increase in memory or activated phenotype T cells. Also, several factors, such as infection, may increase sensitivity to IL-6 in the tissue.