Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function PMID: 33512449

Target-related Cytokines

2026-09-23

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

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.

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.