Immune checkpoints in autoimmune vasculitis.

Area of Science:

• Immunology
• Autoimmunity
• Vascular Biology

Background:

• Giant cell arteritis (GCA) is an autoimmune disease targeting medium and large arteries, causing inflammation and potential ischemia.
• Pathology involves CD4+ T cells and macrophages, indicating innate and adaptive immune system roles.
• While antigen-specific T cell expansion occurs, non-specific pathways regulate pathogenic immunity.

Purpose of the Study:

• To investigate the role of immune co-stimulatory and co-inhibitory pathways in GCA pathogenesis.
• To elucidate the
• lost inhibition concept
• in GCA by examining specific immune checkpoints.
• To understand how defective co-inhibition contributes to sustained autoimmune responses in GCA.

Main Methods:

• Analysis of patient-derived CD4+ T cells for co-stimulatory (NOTCH1, CD28/CD80-CD86) and co-inhibitory pathway function.
• Investigation of the Programmed death-1 (PD-1)/Programmed cell death ligand 1 (PD-L1) and CD96/CD155 checkpoints in GCA.
• Subcellular and molecular analysis of antigen-presenting cells and checkpoint ligand expression.

Main Results:

• Patient T cells exhibit strong co-stimulation via NOTCH1 and CD28 pathways.
• Defective co-inhibition is observed at the PD-1/PD-L1 and CD96/CD155 checkpoints.
• Checkpoint ligands are trapped in the endoplasmic reticulum, resulting in low PD-L1 and CD155 on antigen-presenting cells.
• Uninhibited T cells produce Interleukin-9 (IL-9) and differentiate into long-lived effector memory cells.

Conclusions:

• GCA is characterized by nonfunctional inhibitory checkpoints, leading to "lost inhibition" and sustained autoimmune responses.
• This contrasts with cancer, where excessive inhibition causes immune paralysis.
• Defective immune checkpoints in GCA permit unopposed CD4+ T cell activation and contribute to disease pathogenesis.