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

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.

• Authors: 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 Kudr, Jan Stary, Megan A Cooper, Michael Svaton, Veronika Kanderova
• Journal: American journal of hematology (Am J Hematol) Vol. 97 Issue 3 Pg. 338-351 (03 01 2022) ISSN: 1096-8652 [Electronic] United States
• PMID: 34981838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Twin Study)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Cytokines
• TLR7 protein, human
• TLR8 protein, human
• Toll-Like Receptor 7
• Toll-Like Receptor 8

Topics

• Anemia, Hemolytic, Autoimmune (genetics, immunology)
• Cytokines (genetics, immunology)
• Female
• HEK293 Cells
• Humans
• Inflammation (genetics, immunology)
• Male
• Mutation
• Patient Acuity
• Toll-Like Receptor 7 (genetics, immunology)
• Toll-Like Receptor 8 (genetics, immunology)
• Twins, Monozygotic