Targeting JAK/STAT pathway in Takayasu's arteritis.

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• Takayasu's arteritis (TAK) is a large vessel vasculitis involving T cell infiltration in the aorta.
• The exact etiology of TAK remains unknown, prompting investigation into underlying molecular mechanisms.
• The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is implicated in T cell differentiation and inflammatory processes.

Purpose of the Study:

• To explore the role of the JAK/STAT signaling pathway in T cell differentiation within TAK.
• To investigate the involvement of the JAK/STAT pathway in the disease activity of Takayasu's arteritis.
• To evaluate the therapeutic potential of JAK inhibitors (JAKinibs) in TAK patients.

Main Methods:

• Transcriptome analysis of fluorescence-activated cell sorting (FACS)-sorted CD4+ and CD8+ T cells from healthy donors (HD) and TAK patients.
• Analysis of interferon gene signatures in T cells from HD and TAK.
• In vitro and in vivo testing of JAK inhibitors (JAKinibs) on T cell populations and disease markers in TAK.

Main Results:

• Significant dysregulation of genes, particularly those related to type I/II interferons and JAK/STAT signaling, was observed in TAK T cells.
• JAKinibs reduced CD25 expression, decreased T helper 1 (Th1) and T helper 17 (Th17) cells, and increased regulatory T cells (Tregs) in TAK.
• JAKinibs treatment led to decreased C-reactive protein levels, improved NIH scores, and reduced corticosteroid dosage in TAK patients.

Conclusions:

• The JAK/STAT signaling pathway plays a critical role in the pathogenesis of Takayasu's arteritis.
• JAK inhibitors demonstrate potential as a promising therapeutic strategy for managing TAK disease activity and inflammation.