ArticleBlood2021
Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 98 citations in OpenAlex.
- Mosaic TLR8 gain-of-function in an elderly female treated with JAK inhibitor and adjunctive therapy.Journal of human immunity · 2026Article
- Advancements in Diagnosis and Care for Immune Dysregulation and Inborn Errors of Immunity in Pediatric Rheumatology: Our 50-Year Journey.Arthritis care & research · 2026Review
- TLR7 in systemic lupus erythematosus: genetics and emerging therapies.Nature reviews. Rheumatology · 2026Review
- Clinical relevance of mosaic variants detected by exome sequencing.The Journal of allergy and clinical immunology · 2026Article
- Targeted deep sequencing identifies mosaicism in patients with immune dysregulation.The Journal of allergy and clinical immunology · 2026Article
- 2'-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity.Nature immunology · 2026Article
- Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function.Blood advances · 2026Article
- TLR8 gain-of-function: on the highway to the danger zone.Blood advances · 2026Article
- Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.JCI insight · 2026Article
- Anti-human TLR7 antibody for therapeutic intervention in systemic lupus erythematosus.International immunology · 2026Article
- Autoimmune myelofibrosis with aLeukemia research reports · 2026Article
- A truncatingFrontiers in immunology · 2026Article
- Molecular diagnostics 101: how to use genetic tests in classical hematology.Hematology. American Society of Hematology. Education Program · 2025Review
- Addressing gaps in the diagnoses of genetic errors of immunity.Nature immunology · 2025Article
- Review
- Incomplete penetrance in inborn errors of immunity: A skeleton in the closet-The sequel.Journal of human immunity · 2025Review
- Recent insights into the role of innate immunity in lupus.Human molecular genetics · 2025Review
- Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.Journal of human immunity · 2025Article
- Identifying genetic errors of immunity due to mosaicism.The Journal of experimental medicine · 2025Review
- Somatic mosaicism in genetic errors of immunity.The Journal of allergy and clinical immunology · 2025Review
Corrections and comments
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Authors and funding
36 authors at 14 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.