Background/Purpose: AIRE is a transcriptional regulator of tissue specific antigens in medullary thymic epithelial cells (mTEC). AIRE orchestrates the negative selection of self-reactive T cells as well as the induction of regulatory T cells in the thymus. AIRE was recently identified as a risk gene in rheumatoid arthritis (RA) by GWAS. Integrative analysis using omics data on fibroblast-like synoviocytes (FLS) from RA patients and controls points to a role of AIRE in RA-FLS. Activated FLS are key effector cells in RA, mediating persistent inflammation and tissue destruction. In addition, MHC class II is induced on FLS in the RA joint suggesting a role in antigen presentation. Our aim was to investigate if AIRE is expressed and can regulate gene transcription in primary RA-FLS and if AIRE is present in synovial tissue in RA.

Methods:

Primary FLS were stimulated by proinflammatory cytokines for 12-24 hours before qPCR, confocal microscopy and ImageStreamX flow cytometry for AIRE expression. Stimulated or unstimulated control or AIRE-silenced RA-FLS samples were subjected to RNA seq. Differential gene expression and pathway analyses were performed. Synovial tissues from RA and control osteoarthritis (OA) patients were subjected to confocal microscopy.

Results: No AIRE expression was detected in unstimulated FLS. However, AIRE mRNA expression was induced up to 222±102 fold by IL-1β in RA-FLS compared with unstimulated (p=0.009, n=3). In OA-FLS AIRE was induced 39±9 fold (p<0.0001, n=6) by IL-1β and 10±5 fold (p=0.011) by TNF compared with unstimulated. A synergistic effect was seen using IL-1β + TNF (66±33 fold, p=0.009). The AIRE induction was significantly higher in RA than OA-FLS (p=0.035). AIRE protein expression was detected in stimulated RA-FLS. RNAseq analysis identifyed 55 (adjP-value<0,05) genes regulated by AIRE in RA-FLS of which 33 are annotated as interferon-γ response genes. The top-ranked network by pathway analysis was ”Dermatological diseases and conditions, organismal injury and abnormalities, connective tissue disorders” with a score of 38. AIRE expressing cells were present in lining and sublining in RA but not in OA synovium.

Conclusion:

AIRE is induced by TNF and IL-1β in primary RA-FLS and regulates the expression of interferon-γ response genes suggesting an immune-modulatory role in these cells. AIRE is expressed in the RA synovium supporting a role of AIRE in arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cytokine-induced-aire-activity-in-rheumatoid-arthritis-fibroblast-like-synoviocytes-regulates-expression-of-interferon-%ce%b3-response-genes/