Interferon signature in giant cell arteritis aortitis. Issue 127 (February 2022) - Vieira, Matheus
Abstract: Objectives: Molecular mechanisms underlying large-vessel involvement in giant cell arteritis (LV-GCA) are largely unknown. Herein, we explore the critical involvement of pro-inflammatory signaling pathways in both aorta and T cells from patients with LV-GCA. Methods: We analyzed transcriptome and interferon gene signature in inflamed aortas from LV-GCA patients and compared them to non-inflammatory control aorta. Differential transcriptomic analyses of circulating CD4 + and CD8 + T cells were also performed between patients with active GCA (not under any immunosuppressants or corticosteroid doses higher than 10 mg/day by the time of blood collection) and healthy donors. Interferon-alpha serum levels were measured using ultra-sensitive technique (HD-X Simoa Planar Technology) in GCA patients according to disease activity status. Results: Transcriptomic analyses revealed 1042, 1479 and 2075 significantly dysregulated genes for aortas, CD4 + and CD8 + cells from LV-GCA patients, respectively, as compared to controls. A great enrichment for pathways linked to interferons (type I, II and III), JAK/STAT signaling, cytokines and chemokines was seen across aortas and circulating T cells. A type I interferon signature was identified as significantly upregulated in the aorta of patients with LV-GCA, notably regarding EPSTI1 and IFI44L genes. STAT3 was significantly upregulated in both aorta and T cells and appeared as central in related gene networks from LV-GCA patients. Interferon-alpha serum levels were higher in patients with active GCA when compared to those in remission (0.024 vs. 0.011 pg/mL; p = 0.028). Conclusion: LV-GCA presents a clear type I interferon signature in aortas, which paves the way for tailored therapeutical targeting. Highlights: Aortas from LV-GCA patients are enriched with type I interferon signature. JAK/STAT pathway seems key in disease mechanisms, notably regarding STAT3. Interferon-alpha serum levels may be associated with disease activity. Upregulated signaling pathways in LV-GCA paves the way for therapeutical targeting.