Trial reportBlood2015
Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.
Registry-linked trialOpen access · bronzeAbstract readClinical TrialMulticenter Study
In one paragraph
Trial report in Blood, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00001350 (Study of the Immunopathogenesis, Natural History, and Genetics of Autoimmune Lymphoproliferative Syndrome), which is not on this map. Cited by 296 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
296citing papers in PubMed, 2 pooled it
16.3field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Study of the Immunopathogenesis, Natural History, and Genetics of Autoimmune Lymphoproliferative Syndrome (ALPS) Associated With an Expansion of CD4-8-/TCR Alpha/Beta+ T Cells
Who cites it
296 citing papers in PubMed, 2 syntheses or guidelines pooled it, 547 citations in OpenAlex.
- Pooled it
- Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management.Frontiers in immunology · 2021Pooled it
- Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study.Frontiers in immunology · 2021Trial
- Advancements in Diagnosis and Care for Immune Dysregulation and Inborn Errors of Immunity in Pediatric Rheumatology: Our 50-Year Journey.Arthritis care & research · 2026Review
- Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function.JCI insight · 2026Article
- Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency.Clinical reviews in allergy & immunology · 2026Review
- Rare variants in genes related to inborn errors of immunity in patients with rheumatoid arthritis and secondary immunodeficiency.RMD open · 2026Article
- From CVID to PIRD: Genetic Testing Leading to Signal Transducer and Activator of Transcription 3 Gain-of-Function Diagnosis and Directed Therapy.The journal of allergy and clinical immunology. In practice · 2026Article
- Familial lymphoma and genetic predisposition: an updated review.BMC medical genomics · 2026Review
- Novel Partial Loss-of-function STAT3-variant as Cause of Hyper-IgE-Syndrome in a Danish Family with Variable Expressivity.Journal of clinical immunology · 2026Article
- Antigen Microarray Reveals Broad and Subclinical Autoimmunity in Patients with Inborn Errors of Immunity.Journal of clinical immunology · 2026Article
- JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities.International journal of oral science · 2026Review
- DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells.The Journal of experimental medicine · 2026Article
- Article
- Reduction in mucosal phosphorylated STAT3 under therapy with JAK inhibitor in STAT3 gain of function mutation - a case study.Virchows Archiv : an international journal of pathology · 2026Article
- A case report of ADMIO type 1 caused by aFrontiers in immunology · 2026Article
- STAT3 isoform dynamics reveal robust splice ratio maintenance across cytokine-activated human immune cells.Frontiers in immunology · 2026Article
- STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs.Journal of cellular and molecular medicine · 2026Article
- ALPS-like Disorder Linked with STAT3 Mutation:Endocrine, metabolic & immune disorders drug targets · 2026Review
- Divergent molecular pathways drive monomorphic epitheliotropic and enteropathy-associated intestinal T-cell lymphoma.Leukemia · 2026Article
236 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
44 authors at 13 institutions in 3 countries.
Joshua D MilnerLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Tiphanie P VogelDepartments of Pediatrics, Division of Rheumatology, and Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO;
Lisa ForbesDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
Chi A MaLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Asbjørg Stray-PedersenDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and Molecular and Human Genetics, Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;
Julie E NiemelaDepartment of Laboratory Medicine, National Institutes of Health, Bethesda, MD;
Jonathan J LyonsLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Karin R EngelhardtInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Yu ZhangLaboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Nermina TopcagicDepartments of Pediatrics, Division of Rheumatology, and.
Elisha D O RobersonInternal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO; Department of Genetics, Washington University School of Medicine, St. Louis, MO;
Helen MatthewsLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
James W VerbskyDepartments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and.
Trivikram DasuDepartments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and Clinical Immunodiagnostic & Research Laboratory, Medical College of Wisconsin, Milwaukee, WI;
Alexander Vargas-HernandezDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology.
Nidhy VargheseDepartment of Pediatrics, Baylor College of Medicine, Houston, TX;
Kenneth L McClainDepartment of Pediatrics, Baylor College of Medicine, Houston, TX;
Lina B KaramDepartment of Pediatrics, Baylor College of Medicine, Houston, TX;
Karen NahmodDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
George MakedonasDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
Emily M MaceDepartments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
Hanne S SorteDepartment of Medical Genetics, Oslo University Hospital, Oslo, Norway;
Gøri PerminowDepartment of Pediatrics, Oslo University Hospital, Oslo, Norway;
V Koneti RaoLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Michael P O'ConnellLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Susan PriceLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Helen C SuLaboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Morgan ButrickLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
Joshua McElweeMerck Research Laboratories, Boston, MA;
Jason D HughesMerck Research Laboratories, Boston, MA;
Joseph WilletInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
David SwanInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Yaobo XuInstitute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Mauro Santibanez-KorefInstitute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Voytek SlowikDepartment of Pediatrics, Section of Pediatric Gastroenterology and.
Darrell L DinwiddieCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Department of Pediatrics and Clinical Translational Science Center, University of New Mexico Health Sciences Center, Albuquerque, NM;
Christina E CiaccioDepartments of Pediatrics, Division of Allergy and Immunology, and.
Carol J SaundersCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Pathology, Children's Mercy Hospital and Clinics Kansas City, MO; School of Medicine, University of Missouri-Kansas City, Kansas City, MO;
Seth SepterDepartment of Pediatrics, Section of Pediatric Gastroenterology and.
Stephen F KingsmoreCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Pathology, Children's Mercy Hospital and Clinics Kansas City, MO; School of Medicine, University of Missouri-Kansas City, Kansas City, MO;
Andrew J WhiteDepartments of Pediatrics, Division of Rheumatology, and.
Andrew J CantInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; and.
Sophie HambletonInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; and.
Megan A CooperDepartments of Pediatrics, Division of Rheumatology, and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
National Institutes of Health · USNewcastle University · GBCenter for Rheumatology · USNational Institute of Allergy and Infectious Diseases · USBaylor College of Medicine · USOslo University Hospital · NOTexas Children's Hospital · USENT and Allergy · USMerck & Co., Inc., Rahway, NJ, USA (United States) · USPediatrics and Genetics · USUniversity of Missouri–Kansas City · USWashington University in St. Louis · USChildren's Mercy Hospital · US
Funding
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MWashington University Center for Cellular ImagingP30CA091842 · NCI · WASHINGTON UNIVERSITY · PI TIMOTHY J. EBERLEIN · 2001 to 2026
$128.0MWashington University Institute of Clinical and Translational SciencesUL1TR000448 · NCATS · WASHINGTON UNIVERSITY · PI EVANOFF, BRADLEY A · 2012 to 2016
$41.4MDefining New Human Immunodeficiency and Immunodysregulation DisordersZIAAI001059 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI SU, HELEN CHUN-HUI · 2009 to 2025
$20.5MUniversity of New Mexico Center for Metals in Biology and Medicine - equipment supplementP20GM130422 · NIGMS · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI Sebastian Medina · 2020 to 2026
$20.4MBaylor-Johns Hopkins Center for Mendelian GeneticsU54HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2012 to 2015
$15.6MTranslational studies in allergic reactions and inflammationZIAAI001192 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI LYONS, JONATHAN · 2014 to 2023
$12.7MClinical, Immunological and Genetic Analyses of ALPS and Related Immunedysregulatory DisordersZIAAI000732 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI RAO, V KONETI · 2009 to 2025
$10.5MViral Discovery in Rheumatoid ArthritisP30AR048335 · NIAMS · WASHINGTON UNIVERSITY · PI WEIHL, CONRAD C · 2001 to 2015
$8.9MGenetic and Pathophysiologic Study of Atopic DiseaseZIAAI001183 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI MILNER, JOSHUA · 2013 to 2019
$8.7MConProject-001U19HD077693 · NICHD · RADY PEDIATRIC GENOMICS & SYSTEMS MEDICINE INSTITUTE · PI KINGSMORE, STEPHEN FRANCIS · 2013 to 2018
$6.2MTRAINING IN THE IMMUNOLOGY OF RHEUMATIC DISEASEST32AR007279 · NIAMS · WASHINGTON UNIVERSITY · PI Megan Anne Cooper, Deborah J Lenschow · 1986 to 2026
$6.0MIntramural NIH HHSNCATS NIH HHS KL2 TR001448NCATS NIH HHS UL1 TR000448NCI NIH HHS P30 CA091842NHGRI NIH HHS U54 HG003273NHGRI NIH HHS U54 HG006542NIAMS NIH HHS P30 AR048335NIAMS NIH HHS T32 AR007279NICHD NIH HHS U19 HD077693NIGMS NIH HHS P20 GM130422
Abstract
Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.
Indexed as
AdolescentAdultAutoimmune DiseasesChildChild, PreschoolFemaleGenetic Diseases, InbornHumansInfantLymphoproliferative DisordersMaleMutationPhosphorylationSTAT1 Transcription FactorSTAT3 Transcription FactorSTAT5 Transcription FactorSTAT1 protein, humanSTAT1 Transcription FactorSTAT3 protein, humanSTAT3 Transcription FactorSTAT5 Transcription Factor
Identifiers
What OpenQuestion holds
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Registered trials
NCT00001350ClinicalTrials.gov
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.