Background/Purpose: Autoimmune diseases, such as autoimmune inflammatory arthritis, result through breakdown of immune tolerance and development of self-reactive T cells, or autoantibody-producing B cells. Tolerance breakdown and progression to autoimmune disease is multifactorial and usually involves a complex interplay between both genetic and external environmental factors. While past studies have extensively studied genetic associations, less attention has been paid to defining environmental factors that precipitate disease, or flares. For autoimmune inflammatory arthritis strong links have been reported for intestinal inflammation, bronchial stress and various infections. Nevertheless underlying molecular pathways whereby such remote challenges precipitate arthritis or flares remain unclear.

Methods: Here, we used a transfer model of self-reactive arthritis-inducing CD4⁺ cells from KRNtg mice that, upon transfer, induce a very mild form of auto-inflammatory arthritis in recipient animals. Transfer of gene-deficient KRNtg CD4⁺ cells and manipulation of the recipient animals allowed us to identify external factors that aggravated disease and to examine underlying mechanisms.

Results: We show that several distinct challenges precipitated full-blown arthritis, including intestinal inflammation through DSS-induced colitis, and bronchial stress through Influenza infection. Both challenges result in locally increased IL-1β levels what triggers strong IL-17 expression primarily in self-reactive CD4⁺ cells in local lymph nodes draining the site of inflammation. Moreover, treatment of mice with IL-1β greatly exacerbated arthritis, while transfer of KRNtg CD4⁺ cells lacking IL-1R significantly reduced disease and IL-17 expression. Thus, the results of this study suggest that IL-1β enhances the autoaggressive potential of self-reactive CD4⁺ cells, through increased Th17 differentiation, and this influences inflammatory events in the joints. As IL-17⁺ autoreactive CD4 T cells express high levels of CCR6 we speculate this may drive their migration to the joints, enriched in the chemokine ligand CCL20. In addition to that, our results suggest that IL-1β may exert direct inflammatory effects to the joints. In search of common downstream mechanisms for IL-1β production, we could demonstrate that Caspase-1/NLRP3 activation did not impact on inflammation-induced Th17 differentiation of autoreactive KRNtg CD4⁺ cells, nor influence arthritis in our model. We therefore speculate that e.g. serine proteases secreted by locally infiltrating neutrophils, may be able to trigger Caspase-1-/NLRP3-independent IL-1β activation. Alternatively, Caspase-8 (possibly in concert with Caspase-1) may induce non-canonical IL-1β maturation.

Conclusion: We propose that diverse challenges including intestinal inflammation and bronchial stress/infection, result in IL-1β-driven Th17 differentiation, and this precipitates arthritis in genetically susceptible individuals. Thus the etiology of autoimmune inflammatory arthritis likely involves numerous challenges, that ultimately converge on a common pathway involving IL-1β/Th17. This may also explain why a single etiological factor for arthritis has been difficult to identify.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/remote-inflammation-triggers-autoimmune-arthritis-through-th17-distribution/