Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function

Blood. 2021 May 6;137(18):2450-2462. doi: 10.1182/blood.2020009620.


Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • B-Lymphocytes / pathology
  • Bone Marrow Failure Disorders / etiology
  • Bone Marrow Failure Disorders / metabolism
  • Bone Marrow Failure Disorders / pathology*
  • Cell Differentiation
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Female
  • Follow-Up Studies
  • Gain of Function Mutation*
  • Humans
  • Immunologic Deficiency Syndromes / etiology
  • Immunologic Deficiency Syndromes / metabolism
  • Immunologic Deficiency Syndromes / pathology*
  • Infant
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Lymphocyte Activation
  • Male
  • Mosaicism*
  • Pancytopenia / etiology
  • Pancytopenia / metabolism
  • Pancytopenia / pathology*
  • Pedigree
  • Prognosis
  • T-Lymphocytes / immunology
  • Toll-Like Receptor 8 / genetics*
  • Young Adult


  • Cytokines
  • TLR8 protein, human
  • Toll-Like Receptor 8