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

Martina Fejtkova, Martina Sukova, Katerina Hlozkova, Karolina Skvarova Kramarzova, Marketa Rackova, David Jakubec, Marina Bakardjieva, Marketa Bloomfield, Adam Klocperk, Zuzana Parackova, Anna Sediva, Jahnavi Aluri, Michaela Novakova, Tomas Kalina, Eva Fronkova, Ondrej Hrusak, Hana Malcova, Petr Sedlacek, Zuzana Liba, Martin KudrJan Stary, Megan A. Cooper, Michael Svaton, Veronika Kanderova

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)338-351
Number of pages14
JournalAmerican journal of hematology
Volume97
Issue number3
DOIs
StatePublished - Mar 1 2022

Fingerprint

Dive into the research topics of 'TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins'. Together they form a unique fingerprint.

Cite this