A novel toll-like receptor 8 (TLR8) gene mutation was discovered in male monozygotic twins leading to autoinflammation and severe autoimmune hemolytic anemia (AIHA) including cold agglutinin disease (CAD), as published in the American Journal of Hematology.

The results showed that the TLR8 mutation led to dysregulation between TLR8 and TLR7 protein signaling. The mutation, a germline c.1715G>T (p.G572V) on the X chromosome, resulted in impaired stability of the TLR8 molecule resulting in cross-reactivity with TLR7 ligands. The mutation also decreased the ability of TLR8 to reduce TLR7 signaling causing an increase in proinflammatory responses.

“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,” the authors said.

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The authors suggested that the dysregulation of the balance between TLR8 and TLR7 signaling could lead to a pathologically increased response to pathogens that ultimately cause autoinflammation in patients. This idea was supported by the fact that both twins would experience frequent enteritis and fevers as well as worsening of AIHA with infections.

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The twins in the study first experienced corticodependent AIHA at the ages of 6 and 2.5 years old for twin A and twin B, respectively. They both had increased levels of antierythrocyte antibodies with twin A having high titers of immunoglobulin while twin B had high titers of immunoglobulin. Both patients were prescribed rituximab and sirolimus to help control their AIHA.

Twin B continued to have attacks which eventually manifested as acute hemiparesis and aphasia due to a central nervous system hemorrhage at the age of 11 years that required hematopoietic stem cell transplantation. Twin A was eventually shifted to hydroxychloroquine as a therapeutic regimen which enabled the cessation of corticosteroid therapy.

“The disparity in the disease severity between twin A and B is intriguing. It may be explained by different spectrum of pathogens encountered by the siblings, which may have revealed diverse autoantigens driving the severity of autoinflammatory phenomena,” the authors concluded.


Fejtkova M, Sukova M, Hlozkova K, et al. TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins. Am J Hematol. Published online January 3, 2022. doi:10.1002/ajh.26452