Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.
IRF5
Macrophage activation syndrome
Perforin
Systemic juvenile idiopathic arthritis
Journal
Advances in experimental medicine and biology
ISSN: 0065-2598
Titre abrégé: Adv Exp Med Biol
Pays: United States
ID NLM: 0121103
Informations de publication
Date de publication:
2024
2024
Historique:
medline:
9
8
2024
pubmed:
9
8
2024
entrez:
8
8
2024
Statut:
ppublish
Résumé
Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far most common in systemic juvenile idiopathic arthritis (SJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure seen in MAS. Whole exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with SJIA-associated MAS demonstrated increased "burden" of rare protein-altering variants affecting the cytolytic pathway compared to healthy controls, suggesting that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state, their presence partially reduces cytolytic activity that may lead to increased cytokine production.
Identifiants
pubmed: 39117811
doi: 10.1007/978-3-031-59815-9_9
doi:
Substances chimiques
Cytokines
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
121-126Informations de copyright
© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.
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