Immune checkpoints in autoimmune vasculitis.
Best Pract Res Clin Rheumatol
; 38(2): 101943, 2024 05.
Article
en En
| MEDLINE
| ID: mdl-38599937
ABSTRACT
Giant cell arteritis (GCA) is a prototypic autoimmune disease with a highly selective tissue tropism for medium and large arteries. Extravascular GCA manifests with intense systemic inflammation and polymyalgia rheumatica; vascular GCA results in vessel wall damage and stenosis, causing tissue ischemia. Typical granulomatous infiltrates in affected arteries are composed of CD4+ T cells and hyperactivated macrophages, signifying the involvement of the innate and adaptive immune system. Lesional CD4+ T cells undergo antigen-dependent clonal expansion, but antigen-nonspecific pathways ultimately control the intensity and duration of pathogenic immunity. Patient-derived CD4+ T cells receive strong co-stimulatory signals through the NOTCH1 receptor and the CD28/CD80-CD86 pathway. In parallel, co-inhibitory signals, designed to dampen overshooting T cell immunity, are defective, leaving CD4+ T cells unopposed and capable of supporting long-lasting and inappropriate immune responses. Based on recent data, two inhibitory checkpoints are defective in GCA the Programmed death-1 (PD-1)/Programmed cell death ligand 1 (PD-L1) checkpoint and the CD96/CD155 checkpoint, giving rise to the "lost inhibition concept". Subcellular and molecular analysis has demonstrated trapping of the checkpoint ligands in the endoplasmic reticulum, creating PD-L1low CD155low antigen-presenting cells. Uninhibited CD4+ T cells expand, release copious amounts of the cytokine Interleukin (IL)-9, and differentiate into long-lived effector memory cells. These data place GCA and cancer on opposite ends of the co-inhibition spectrum, with cancer patients developing immune paralysis due to excessive inhibitory checkpoints and GCA patients developing autoimmunity due to nonfunctional inhibitory checkpoints.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arteritis de Células Gigantes
Límite:
Humans
Idioma:
En
Revista:
Best Pract Res Clin Rheumatol
Asunto de la revista:
REUMATOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos