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TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins
M. Fejtkova, M. Sukova, K. Hlozkova, K. Skvarova Kramarzova, M. Rackova, D. Jakubec, M. Bakardjieva, M. Bloomfield, A. Klocperk, Z. Parackova, A. Sediva, J. Aluri, M. Novakova, T. Kalina, E. Fronkova, O. Hrusak, H. Malcova, P. Sedlacek, Z. Liba,...
American journal of hematology.
2022 ;
97 (3) :
338-351.
[pub] 20220128
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, studie na dvojčatech
Perzistentní odkaz
https://www.medvik.cz/link/bmc22010805
Online
Plný text
NLK
Free Medical Journals
od 1998 do Před 1 rokem
Wiley Free Content
od 1996 do Před 1 rokem
PubMed
34981838
DOI
10.1002/ajh.26452
Knihovny.cz E-zdroje
- MeSH
- autoimunitní hemolytická anemie genetika imunologie MeSH
- cytokiny genetika imunologie MeSH
- dvojčata monozygotní MeSH
- HEK293 buňky MeSH
- lidé MeSH
- mutace * MeSH
- posouzení stavu pacienta MeSH
- toll-like receptor 7 genetika imunologie MeSH
- toll-like receptor 8 genetika imunologie MeSH
- zánět genetika imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- studie na dvojčatech MeSH
Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.
Citace poskytuje Crossref.org
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