Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis

Area of Science:

• Immunology
• Vascular Biology
• Rheumatology

Background:

• Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large arteries, leading to serious complications like blindness and stroke.
• Pathogenic mechanisms are unclear, particularly the role of immune checkpoints in GCA pathogenesis.
• CD4+ T cells and macrophages contribute to arterial wall damage and luminal occlusion via granulomatous inflammation and intimal hyperplasia.

Purpose of the Study:

• To investigate the role of the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint in GCA pathogenesis.
• To determine if impaired PD-1/PD-L1 signaling contributes to the unopposed immune activation observed in GCA.

Main Methods:

• Transcriptome analysis of GCA-affected temporal arteries.
• Analysis of PD-L1 expression on dendritic cells (DCs) and PD-1 expression on T cells from GCA patients.
• Assessment of vascular inflammation in human artery-SCID chimeras following PD-1 blockade.

Main Results:

• GCA arteries showed low PD-L1 expression and high PD-1 expression, indicating a deficient PD-1/PD-L1 checkpoint.
• Dendritic cells from GCA patients were PD-L1(lo), while T cells were PD-1(hi).
• PD-1 blockade in human artery-SCID chimeras worsened vascular inflammation, increased effector T cells, and amplified pro-inflammatory cytokine production, leading to arterial remodeling.

Conclusions:

• A breakdown in the PD-1/PD-L1 immune checkpoint contributes to GCA pathogenesis.
• This checkpoint deficiency unleashes vasculitic immunity and drives pathogenic remodeling of the arterial wall in GCA.
• Targeting this checkpoint may offer therapeutic strategies for GCA.