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TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins.
- Source :
-
American journal of hematology [Am J Hematol] 2022 Mar 01; Vol. 97 (3), pp. 338-351. Date of Electronic Publication: 2022 Jan 28. - Publication Year :
- 2022
-
Abstract
- 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.<br /> (© 2022 Wiley Periodicals LLC.)
- Subjects :
- Anemia, Hemolytic, Autoimmune immunology
Cytokines genetics
Cytokines immunology
Female
HEK293 Cells
Humans
Inflammation genetics
Inflammation immunology
Male
Patient Acuity
Toll-Like Receptor 7 immunology
Toll-Like Receptor 8 immunology
Twins, Monozygotic
Anemia, Hemolytic, Autoimmune genetics
Mutation
Toll-Like Receptor 7 genetics
Toll-Like Receptor 8 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1096-8652
- Volume :
- 97
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of hematology
- Publication Type :
- Academic Journal
- Accession number :
- 34981838
- Full Text :
- https://doi.org/10.1002/ajh.26452