TY - JOUR
T1 - TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins
AU - Fejtkova, Martina
AU - Sukova, Martina
AU - Hlozkova, Katerina
AU - Skvarova Kramarzova, Karolina
AU - Rackova, Marketa
AU - Jakubec, David
AU - Bakardjieva, Marina
AU - Bloomfield, Marketa
AU - Klocperk, Adam
AU - Parackova, Zuzana
AU - Sediva, Anna
AU - Aluri, Jahnavi
AU - Novakova, Michaela
AU - Kalina, Tomas
AU - Fronkova, Eva
AU - Hrusak, Ondrej
AU - Malcova, Hana
AU - Sedlacek, Petr
AU - Liba, Zuzana
AU - Kudr, Martin
AU - Stary, Jan
AU - Cooper, Megan A.
AU - Svaton, Michael
AU - Kanderova, Veronika
N1 - Publisher Copyright:
© 2022 Wiley Periodicals LLC.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123750903&partnerID=8YFLogxK
U2 - 10.1002/ajh.26452
DO - 10.1002/ajh.26452
M3 - Article
C2 - 34981838
AN - SCOPUS:85123750903
SN - 0361-8609
VL - 97
SP - 338
EP - 351
JO - American journal of hematology
JF - American journal of hematology
IS - 3
ER -