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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,...

. 2022 ; 97 (3) : 338-351. [pub] 20220128

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't, Twin Study

Persistent link   https://www.medvik.cz/link/bmc22010805

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.

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$a TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins / $c M. Fejtkova, M. Sukova, K. Hlozkova, K. Skvarova Kramarzova, M. Rackova, D. Jakubec, M. Bakardjieva, M. Bloomfield, A. Klocperk, Z. Parackova, A. Sediva, J. Aluri, M. Novakova, T. Kalina, E. Fronkova, O. Hrusak, H. Malcova, P. Sedlacek, Z. Liba, M. Kudr, J. Stary, MA. Cooper, M. Svaton, V. Kanderova
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$a 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.
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$a Sukova, Martina $u Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Rackova, Marketa $u CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic $1 https://orcid.org/0000000229918873
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$a Jakubec, David $u Bioinformatics Group, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic $u Department of Software Engineering, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic
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$a Bloomfield, Marketa $u Department of Paediatrics, First Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czech Republic $u Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic $1 https://orcid.org/0000000153309341
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$a Malcova, Hana $u Department of Paediatric and Adult Rheumatology, University Hospital Motol, Prague, Czech Republic
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$a Sedlacek, Petr $u Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Liba, Zuzana $u Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Kudr, Martin $u Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Stary, Jan $u Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Cooper, Megan A $u Division of Rheumatology/Immunology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
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