2. Academic Validation
  3. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function

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.
Jahnavi Aluri 1,  Alicia Bach 2,  Saara Kaviany 3,  Luana Chiquetto Paracatu 2,  Maleewan Kitcharoensakkul 1 4,  Magdalena A Walkiewicz 5,  Christopher D Putnam 6 7,  Marwan Shinawi 8,  Nermina Saucier 1,  Elise M Rizzi 9,  Michael T Harmon 1,  Molly P Keppel 1,  Michelle Ritter 1,  Morgan Similuk 5,  Elaine Kulm 10,  Michael Joyce 11,  Adriana A de Jesus 12,  Raphaela Goldbach-Mansky 12,  Yi-Shan Lee 13,  Marina Cella 14,  Peggy L Kendall 9 14,  Mary C Dinauer 2,  Jeffrey J Bednarski 2,  Christina Bemrich-Stolz 15,  Scott W Canna 16,  Shirley M Abraham 17,  Matthew M Demczko 18,  Jonathan Powell 19,  Stacie M Jones 20,  Amy M Scurlock 20,  Suk See De Ravin 21,  Jack J Bleesing 22,  James A Connelly 3,  V Koneti Rao 21,  Laura G Schuettpelz 2,  Megan A Cooper 1
Affiliations

Affiliations

  • 1 Division of Rheumatology/Immunology and.
  • 2 Division of Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
  • 3 Pediatric Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN.
  • 4 Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
  • 5 Centralized Sequencing Initiative, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 6 Department of Medicine, University of California School of Medicine, San Diego, La Jolla, CA.
  • 7 San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA.
  • 8 Division of Genetics and Genomic Medicine, Department of Pediatrics and.
  • 9 Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
  • 10 Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD.
  • 11 Nemours Children's Specialty Care, Jacksonville, FL.
  • 12 Translational Autoinflammatory Diseases Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 13 Division of Anatomic and Molecular Pathology and.
  • 14 Division of Immunology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
  • 15 Division of Hematology and Oncology, Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL.
  • 16 Division of Pediatric Rheumatology and RK Mellon Institute, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA.
  • 17 Division of Hematology and Oncology, Department of Pediatrics, University of New Mexico, Albuquerque, NM.
  • 18 Division of Diagnostic Referral and.
  • 19 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Nemours Alfred I. DuPont Hospital for Children, Wilmington, DE.
  • 20 Division of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR.
  • 21 Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.
  • 22 Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
PMID: 33512449 DOI: 10.1182/blood.2020009620
Abstract

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.

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