TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins

0552900 - ÚOCHB 2023 RIV US eng J - Journal Article
Fejtkova, M. - Sukova, M. - Hložková, K. - Škvárová Kramarzová, K. - Rackova, M. - Jakubec, Dávid - Bakardjieva, M. - Bloomfield, M. - Klocperk, A. - Parackova, Z. - Šedivá, A. - Aluri, J. - Novaková, M. - Kalina, T. - Froňková, E. - Hrušák, O. - Malcova, H. - Sedláček, P. - Liba, Z. - Kudr, M. - Starý, J. - Cooper, M. A. - Svaton, M. - Kanderová, V.
TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins.
American Journal of Hematology. Roč. 97, č. 3 (2022), s. 338-351. ISSN 0361-8609. E-ISSN 1096-8652
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : toll-like receptor 7 * recognition * RNA
OECD category: Biochemistry and molecular biology
Impact factor: 12.8, year: 2022
Method of publishing: Limited access
https://doi.org/10.1002/ajh.26452

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-kappa B (NF-kappa B) activation and production of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF alpha. 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.
Permanent Link: http://hdl.handle.net/11104/0327975