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Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.
- Source :
-
Blood [Blood] 2021 May 06; Vol. 137 (18), pp. 2450-2462. - Publication Year :
- 2021
-
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.
- Subjects :
- Adolescent
Adult
B-Lymphocytes pathology
Bone Marrow Failure Disorders etiology
Bone Marrow Failure Disorders metabolism
Cell Differentiation
Child
Child, Preschool
Cytokines metabolism
Female
Follow-Up Studies
Humans
Immunologic Deficiency Syndromes etiology
Immunologic Deficiency Syndromes metabolism
Infant
Inflammation etiology
Inflammation metabolism
Lymphocyte Activation
Male
Pancytopenia etiology
Pancytopenia metabolism
Pedigree
Prognosis
T-Lymphocytes immunology
Young Adult
Bone Marrow Failure Disorders pathology
Gain of Function Mutation
Immunologic Deficiency Syndromes pathology
Inflammation pathology
Mosaicism
Pancytopenia pathology
Toll-Like Receptor 8 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 137
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 33512449
- Full Text :
- https://doi.org/10.1182/blood.2020009620