ArticleThe journal of allergy and clinical immunology. In practice
Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency.
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49 citing papers in PubMed, 76 citations in OpenAlex.
- Rubella-associated granuloma in a patient with a compound heterozygous RAG1 defect and review of the literature.Immunologic research · 2025Review
- Thrombocytopenia in patients with inborn errors of immunity.BMC immunology · 2025Article
- Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.Journal of clinical immunology · 2025Article
- Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.Science immunology · 2025Article
- Building alliances for early detection of immunodeficiencies: from primary care to hematology.Frontiers in immunology · 2025Review
- Review
- Approach to diagnosing and managing granulomatous-lymphocytic interstitial lung disease.EClinicalMedicine · 2024Review
- Clinical, immunological features, treatments, and outcomes of autoimmune hemolytic anemia in patients with RAG deficiency.Blood advances · 2024Article
- Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.Clinical and experimental immunology · 2024Article
- Case report: Identification of a Chinese patient withFrontiers in immunology · 2024Article
- Separating the Wheat From the Chaff in Asthma and Bronchiectasis: The Saga Trajectory of a Patient With Adult-Onset RAG1 Deficiency.The journal of allergy and clinical immunology. In practice · 2023Article
- [Principles of the diagnostics of inborn errors of immunity].Zeitschrift fur Rheumatologie · 2023Review
- Refractory, fatal autoimmune hemolytic anemia due to ineffective thymic-derived T-cell reconstitution following allogeneic hematopoietic cell transplantation for hypomorphic RAG1 deficiency.Pediatric blood & cancer · 2023Article
- Article
- Granulomatous inflammation in inborn errors of immunity.Frontiers in pediatrics · 2023Review
- B cell abnormalities and autoantibody production in patients with partial RAG deficiency.Frontiers in immunology · 2023Review
- Editorial: Mechanisms of dysregulated antibody responses in inborn errors of immunity.Frontiers in immunology · 2023Article
- Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-betNature immunology · 2022Article
- SARS-CoV-2 infection in patients with inborn errors of immunity due to DNA repair defects.Acta biochimica et biophysica Sinica · 2022Review
- Adapted guideline for the diagnosis and treatment of primary immune thrombocytopenia for Chinese children (2021).Pediatric investigation · 2022Article
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Authors and funding
75 authors at 20 institutions in 20 countries.
Jocelyn R FarmerMassachusetts General Hospital, Harvard Medical School, Boston, Mass.
Zsofia FoldvariDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
Boglarka UjhaziUniversity of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla.
Suk See De RavinLaboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Md.
Karin ChenDivision of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
Jack J H BleesingDivision of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Catharina SchuetzDepartment of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Waleed Al-HerzFaculty of Medicine, Pediatrics Department, Kuwait University, Kuwait City, Kuwait; Allergy and Clinical Immunology Unit, Pediatrics Department, Alsabah Hospital, Kuwait City, Kuwait.
Roshini S AbrahamDepartment of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn.
Avni Y JoshiDivision of Pediatric Allergy/Immunology, Mayo Clinic Children's Center Rochester, Rochester, Minn.
Beatriz T Costa-CarvalhoDepartment of Pediatrics, UNIFESP-EPM, São Paulo, Brazil.
David BuchbinderPediatrics/Hematology, CHOC Children's Hospital - UC Irvine, Irvine, Calif.
Claire BoothDepartment of Paediatric Immunology, Great Ormond Street Hospital, London, United Kingdom.
Andreas ReiffDivision of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, Calif.
Polly J FergusonDepartment of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
Asghar AghamohammadiResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Hassan AbolhassaniResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Jennifer M PuckDepartment of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, Calif.
Mehdi AdeliSidra Medicine, Weill Cornell Medicine, and Hamad Medical Corporation, Doha, Qatar.
Caterina CancriniAcademic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Paolo PalmaAcademic Department of Pediatrics (DPUO), Research Unit in Congenital and Perinatal Infection, Children's Hospital Bambino Gesù, Rome, Italy.
Alice BertainaDepartment of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, Italy.
Franco LocatelliDepartment of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, Italy; Department of Pediatrics, Sapienza, University of Rome, Rome, Italy.
Gigliola Di MatteoAcademic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Raif S GehaImmunology Division, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Maria G KanariouDepartment of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
Lilia Lycopoulou1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, Greece.
Marianna TzanoudakiDepartment of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
John W SleasmanDivision of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC.
Suhag ParikhDivision of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NC.
Gloria PineroDivision of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC.
Bernard M FischerDivision of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC.
Ghassan DbaiboDepartment of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.
Ekrem UnalDivision of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Turkan PatirogluDivision of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey; Division of Pediatric Immunology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Musa KarakukcuDivision of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Khulood Khalifa Al-SaadSalmanyia Medical Complex, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Manama, Bahrain.
Meredith A DilleyDepartment of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Sung-Yun PaiDivision of Hematology-Oncology, Boston Children's Hospital, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass; Harvard Medical School, Boston, Mass.
Cullen M DutmerDivision of Allergy & Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colo.
Erwin W GelfandDepartment of Pediatrics, National Jewish Health, Denver, Colo.
Christoph B GeierImmunology Outpatient Clinic, Vienna, Austria.
Martha M EiblImmunology Outpatient Clinic, Vienna, Austria; Biomedizinische Forschungs GmbH, Vienna, Austria.
Hermann M WolfImmunology Outpatient Clinic, Vienna, Austria; Sigmund Freud Private University-Medical School, Vienna, Austria.
Lauren A HendersonDivision of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Melissa M HazenDivision of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Carmem BonfimHospital Infantil Pequeno Principe, Curitiba, Brazil.
Beata Wolska-KuśnierzImmunology Department, Children's Memorial Health Institute, Warsaw, Poland.
Manish J ButteDivision of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Los Angeles, Calif.
Joseph D HernandezDepartment of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif.
Sarah K NicholasSection of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.
Polina StepenskyDepartment of Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Shanmuganathan ChandrakasanDivision of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga.
Maurizio MianoHaematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Emma Westermann-ClarkDepartment of Internal Medicine, Division of Allergy/Immunology, University of South Florida Morsani College of Medicine, Tampa, Fla.
Vera GodaDepartment for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, Hungary.
Gergely KrivánDepartment for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, Hungary.
Steven M HollandLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Md.
Olajumoke FadugbaDivision of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
Sarah E HenricksonAllergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Institute for Immunology, the University of Pennsylvania, Philadelphia, Pa.
Ahmet OzenMarmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey.
Elif Karakoc-AydinerMarmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey.
Safa BarisMarmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey.
Ayca KiykimMinistry of Health, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey.
Robbert BrediusDepartment of Pediatrics, Section Pediatric Immunology, Infections and Stem Cell Transplantation, Leiden University Medical Center, Leiden, the Netherlands.
Birgit HoegerLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Kaan BoztugLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; St Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Olga PashchenkoDepartment of Immunology, Pirogov Russian National Research Medical University, Russian Clinical Children's Hospital, Moscow, Russia.
Benedicte NevenParis Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory "Immunogenetics of Pediatric Autoimmune Diseases", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
Despina MoshousParis Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory "Genome Dynamics in The Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
Jean-Pierre de VillartayLaboratory "Genome Dynamics in The Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
Ahmed Aziz BousfihaLaboratoire d'Immunologie Clinique, d'Inflammation et d'Allergie LICIA, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco; Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, Hassan II University, Casablanca, Morocco.
Harry R HillDivision of Clinical Immunology, Departments of Pathology, Pediatrics and Medicine, University of Utah, Salt Lake City, Utah.
Luigi D NotarangeloHaematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Jolan E WalterUniversity of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla; Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, Mass. Electronic address: jolanwalter@health.usf.edu.
Harvard University · USDuke University · USMarmara University · TRBambino Gesù Children's Hospital · ITErciyes University · TRChildren's Hospital Agia Sophia · GRDélégation Paris 5 · FRJohns Hopkins University · USNational Institute of Allergy and Infectious Diseases · USTehran University of Medical Sciences · IRUniversity of Utah · USAmerican University of Beirut · LBAustrian Academy of Sciences · ATBio Forschung Austria · ATBoston Children's Hospital · USChildren's Center · USChildren's Hospital of Los Angeles · USChildren's Hospital of Philadelphia · USChildren's Memorial Health Institute · PLCincinnati Children's Hospital Medical Center · US
Funding
Genes And Gene Products As ImmunoadjuvantsZIAAI000647 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI HOLLAND, STEVEN · 2009 to 2025
$22.6MTransgenic Animal Models Of Human Immune DefectsZIAAI000646 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI HOLLAND, STEVEN · 2009 to 2025
$22.2MCharacterization of the cellular and molecular bases of inborn errors of immunityZIAAI001222 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2017 to 2025
$15.2MDevelopment and Clinical Application of Gene and Cell therapies for Patients with Immune DeficienciesZIAAI000645 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI DE RAVIN, SUK SEE · 2009 to 2025
$10.1MResearch Training in Pulmonary Immunology and Allergy at MGHT32HL116275 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI David C Christiani, ANDREW D LUSTER · 2013 to 2026
$8.6MPediatric Scholars ProgramK12HD043245 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI ST. GEME, JOSEPH W. · 2003 to 2022
$7.4MModeling and correcting human SCID using patient-derived iPS cellsR01AI100887 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI MANIS, JOHN P · 2012 to 2020
$4.5MGenetic & immunologic etiology of chronic recurrent multifocal osteomyelitis-CRMOR01AR059703 · NIAMS · UNIVERSITY OF IOWA · PI BASSUK, ALEXANDER G, FERGUSON, POLLY J · 2010 to 2019
$3.5MAutoimmunity in Rag Deficiency: A Nexus of Immunodeficiency and DysregulationK08AI103035 · NIAID · UNIVERSITY OF SOUTH FLORIDA · PI WALTER, JOLAN ESZTER · 2012 to 2016
$683kNHLBI NIH HHS T32 HL116275NIAID NIH HHS K08 AI103035NIAID NIH HHS R01 AI100887NIAMS NIH HHS R01 AR059703NICHD NIH HHS K12 HD043245
Abstract
backgroundAlthough autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series.
objectiveUnderstand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.
methodsIn reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology.
resultsDiagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients.
conclusionsAutoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
Indexed as
Homeodomain ProteinsImmunologic Deficiency SyndromesAdolescentAdultAutoimmunityChildChild, PreschoolFemaleHematopoietic Stem Cell TransplantationHumansImmunosuppressive AgentsInfantInflammationMaleMiddle AgedTreatment OutcomeHomeodomain ProteinsImmunosuppressive AgentsRAG-1 proteinAutoimmune cytopeniasHematopoietic stem cell transplantation (HSCT)Immune dysregulationRecombination activating gene (RAG)Severe combined immunodeficiency (SCID)
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