TLR8 gain-of-function: on the highway to the danger zone

In this issue of Blood Advances, Arnold et al 1 expand the inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by toll-like receptor 8 (INFLTR8) cohort to 10 patients and focus on therapeutic outcomes, particularly medical management and allogeneic hematopoietic cell transplantation (HCT).Extending the initial 2021 report of 6 male patients with germ line or somatic variants, 2 they report the first female patient with full disease due to a germ line heterozygous variant and expresses both alleles, establishing X-linked dominant inheritance.All harbor gain-of-function (GOF) TLR8 mutations that drive disease refractory to immunomodulation and fatal in nearly all cases without HCT.