Abstract
The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1β by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.
Highlights
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease pre-dominantly affecting joints [1]
In the search for novel important pathways in RA, we investigated the transcriptome of cytokine-activated compared to untreated control RA fibroblast-like synoviocytes (FLS) using RNA sequencing
It has been reported that genetic variations of AIRE pre-dispose for RA, and multiple omics analysis [13] have pointed to a role for this autoimmune regulator in FLS
Summary
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease pre-dominantly affecting joints [1]. The disease is characterized by persistent inflammation and formation of a hyperplastic invasive synovium Key players in these processes are activated fibroblast-like synoviocytes (FLS), which possess tumor cell-like features such as increased cell proliferation and the ability to invade and destroy surrounding tissue [3]. RA FLS continue their aggressive tissue destructive behavior without the need of further stimulation from the immune system. This might contribute to the fact that only 20–40% of RA patients achieve sustained clinical remission by the currently available immunosuppressive anti-rheumatic therapies [7]. It demonstrates the urgent need for novel drugs targeting the RA FLS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
