Role of dendritic cells and TSLP in rheumatoid arthritis and primary Sjögren’s syndrome

Summary

Rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) are rheumatic autoimmune diseases of the joints and excretory glands respectively. We have studied the role of dendritic cells (DCs) and the cytokine thymic stromal lymphopoietin (TSLP), which is a strong activator of DCs and increased in RA, in these diseases. In RA, we examined the additive effects of TSLP and interleukin (IL)-7, which use the same receptor subunit to signal. We show that TSLP and IL-7 can additively contribute to disease, which makes their mutual receptor subunit an attractive target for therapy. Furthermore, we examined the role of thymus and activation-regulated chemokine (TARC). This chemokine is produced at high levels by DCs that are activated with TSLP. We show that TARC is increased in the RA joints and is involved in the attraction of pro-inflammatory T-cells. In pSS, we examined the presence of TSLP in the salivary glands. TSLP is decreased in pSS patients, in contrast to RA, and is inversely correlated with disease markers. This may be explained by previous data showing that TSLP contributes to tolerance at mucosal sites, indicating that TSLP plays a different role in the local environment of the joints and the salivary glands. Furthermore, we performed miRNA analysis on isolated type-1 classical DCs and plasmacytoid DCs from the blood of pSS patients and compared expression to healthy controls (HC). We found several differentially expressed miRNAs in both subsets, which is the first data on the molecular dysregulation of these cells in pSS patients. The findings in this thesis contribute to a better understanding of the role that DCs and TSLP play in autoimmune diseases. In addition, several new leads for research have been identified, which may result in novel therapeutic targets in the future.

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