TY - JOUR
T1 - Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function
AU - Aluri, Jahnavi
AU - Bach, Alicia
AU - Kaviany, Saara
AU - Chiquetto Paracatu, Luana
AU - Kitcharoensakkul, Maleewan
AU - Walkiewicz, Magdalena A.
AU - Putnam, Christopher D.
AU - Shinawi, Marwan
AU - Saucier, Nermina
AU - Rizzi, Elise M.
AU - Harmon, Michael T.
AU - Keppel, Molly P.
AU - Ritter, Michelle
AU - Similuk, Morgan
AU - Kulm, Elaine
AU - Joyce, Michael
AU - de Jesus, Adriana A.
AU - Goldbach-Mansky, Raphaela
AU - Lee, Yi Shan
AU - Cella, Marina
AU - Kendall, Peggy L.
AU - Dinauer, Mary C.
AU - Bednarski, Jeffrey J.
AU - Bemrich-Stolz, Christina
AU - Canna, Scott W.
AU - Abraham, Shirley M.
AU - Demczko, Matthew M.
AU - Powell, Jonathan
AU - Jones, Stacie M.
AU - Scurlock, Amy M.
AU - De Ravin, Suk See
AU - Bleesing, Jack J.
AU - Connelly, James A.
AU - Rao, V. Koneti
AU - Schuettpelz, Laura G.
AU - Cooper, Megan A.
N1 - Funding Information:
Research support was provided by The Children's Discovery Institute at Washington University and St. Louis Children's Hospital, Center for Pediatric Immunology and St. Louis Children's Hospital Foundation, The Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children's Hospital, The Immune Deficiency Foundation, and the Washington University Rheumatic Diseases Research Resource-Based Center through National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant P30AR073752 (M.A.C.). Support was provided by the Genome Engineering and iPSC Center at Washington University, the Bursky Center for Human Immunology and Immunotherapy Programs (CHiiPs), and the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases. Support was provided for the Immunomonitoring Laboratory and immunoassay service by the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, supported in part by a National Institutes of Health, National Cancer Institute cancer center support grant P30 CA091842. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Support was provided by the Centralized Sequencing Initiative, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases of the National Institutes of Health. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E and 75N910D00024, task order 75N91019F00131.
Funding Information:
The authors would like to dedicate this article to Joseph and his family. The authors also wish to thank Joie Davis and Susan Price for their contributions toward clinical evaluation and care of patients. Research support was provided by The Children's Discovery Institute at Washington University and St. Louis Children's Hospital, Center for Pediatric Immunology and St. Louis Children's Hospital Foundation, The Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children's Hospital, The Immune Deficiency Foundation, and the Washington University Rheumatic Diseases Research Resource-Based Center through National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant P30AR073752 (M.A.C.). Support was provided by the Genome Engineering and iPSC Center at Washington University, the Bursky Center for Human Immunology and Immunotherapy Programs (CHiiPs), and the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases. Support was provided for the Immunomonitoring Laboratory and immunoassay service by the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, supported in part by a National Institutes of Health, National Cancer Institute cancer center support grant P30 CA091842. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Support was provided by the Centralized Sequencing Initiative, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases of the National Institutes of Health. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E and 75N910D00024, task order 75N91019F00131. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/5/6
Y1 - 2021/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104836098&partnerID=8YFLogxK
U2 - 10.1182/blood.2020009620
DO - 10.1182/blood.2020009620
M3 - Article
C2 - 33512449
AN - SCOPUS:85104836098
SN - 0006-4971
VL - 137
SP - 2450
EP - 2462
JO - Blood
JF - Blood
IS - 18
ER -