TLR8 gain-of-function syndrome

Toll-like receptor 8 (TLR8) is an endosomal pattern recognition receptor highly expressed in myeloid cells that senses RNA degradation fragments. Monogenic gain-of-function (GOF) variants in TLR8 cause an inborn error of immunity (IEI) with a spectrum of immune-mediated pathology ranging from severe lymphoproliferation with neutropenia and bone marrow failure to anemia and autoimmunity. Half of identified patients have mosaic disease-causing variants, with variant allele fractions as low as 7% sufficient to drive systemic immune dysregulation. This, along with immunologic profiling of patients, demonstrates a dominant mechanism of disease, likely mediated by inflammatory cytokines. Disease-causing variants in TLR8 are enriched at or near agonist and antagonist binding sites in the encoded protein. As a spectrum of disease and genotypes emerges, identifying sensitivity to agonism and resistance to antagonism may provide insight into molecular mechanisms and therapeutic targets. Here, we review the genetics and clinical features of 19 reported cases of TLR8 GOF diseases, and future areas of investigation for this IEI.