Evidence map›Paper›PMID 26162572›Full record

ArticleThe Journal of allergy and clinical immunology2015

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

Cindy S Ma, Natalie Wong, Geetha Rao, Danielle T Avery, James Torpy, Thomas Hambridge, Jacinta Bustamante, Satoshi Okada, Jennifer L Stoddard, Elissa K Deenick and 40 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of allergy and clinical immunology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers.

0numbers the graph read from it
0cells of the map it votes in
134citing papers in PubMed
8.3field-weighted citation impact, top 2% of its field
1 · What the graph read from it

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

134 citing papers in PubMed, 186 citations in OpenAlex.

  1. Trial
  2. The Antigen Presenting Potential of CD21Frontiers in immunology · 2020
    Trial
  3. Trial
  4. Trial
  5. Trial
  6. Trial
  7. Article
  8. Human CD21Journal of human immunity · 2026
    Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. T follicular helper cells in primary immune regulatory disorders.The Journal of allergy and clinical immunology · 2025
    Review
  14. Article
  15. Article
  16. Pathogenic Role of Cytokines in Rheumatoid Arthritis.Journal of clinical medicine · 2025
    Review
  17. Article
  18. Review
  19. Article
  20. Article

74 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

50 authors at 20 institutions in 12 countries.

Cindy S MaImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. Electronic address: c.ma@garvan.org.au.
Natalie WongImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Geetha RaoImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Danielle T AveryImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
James TorpyImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Thomas HambridgeImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Jacinta BustamanteLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
Satoshi OkadaDepartment of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
Jennifer L StoddardClinical Center, National Institutes of Health, Bethesda, Md.
Elissa K DeenickImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
Simon J PelhamImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
Kathryn PayneImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Stéphanie Boisson-DupuisLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France.
Masao KobayashiDepartment of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
Peter D ArkwrightUniversity of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
Sara Sebnem KilicDepartment of Pediatric Immunology, Uludag University Medical Faculty, Görükle, Bursa, Turkey.
Jamila El BaghdadiGenetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
Shigeaki NonoyamaDepartment of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan.
Yoshiyuki MinegishiDivision of Molecular Medicine, Institute for Genome Research, University of Tokushima, Tokushima, Japan.
Seyed Alireza MahdavianiPediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Davood MansouriPediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Aziz BousfihaClinical Immunology Unit, Pediatric Infectious Diseases Department, Averroes University Hospital, King Hasan II University, Casablanca, Morocco.
Annaliesse K BlincoeStarship Children's Hospital, Auckland, New Zealand.
Martyn A FrenchDepartment of Clinical Immunology, Royal Perth Hospital, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
Peter HsuChildren's Hospital at Westmead, Westmead, Australia.
Dianne E CampbellChildren's Hospital at Westmead, Westmead, Australia.
Michael O StormonChildren's Hospital at Westmead, Westmead, Australia.
Melanie WongChildren's Hospital at Westmead, Westmead, Australia.
Stephen AdelsteinClinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia.
Joanne M SmartDepartment of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, Australia.
David A FulcherDepartment of Immunology, Westmead Hospital, University of Sydney, Westmead, Australia.
Matthew C CookAustralian National University Medical School, Australian National University, Acton, Australia; John Curtin School of Medical Research, Australian National University, Acton, Australia; Department of Immunology, Canberra Hospital, Canberra, Australia.
Tri Giang PhanImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
Polina StepenskyPediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Kaan BoztugCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Aydan KansuDepartment of Pediatric Gastroenterology, Ankara University Medical School, Ankara, Turkey.
Aydan İkincioğullariDepartment of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara, Turkey.
Ulrich BaumannPaediatric Pulmonology, Allergy and Neonatology, Hanover Medical School, Hannover, Germany.
Rita BeierPediatric Haematology and Oncology, University Hospital Essen, Essen, Germany.
Tony RoscioliSt Vincent's Clinical School, UNSW Australia, Melbourne, Australia; Kinghorn Centre for Clinical Genomics, Victoria St Darlinghurst, Darlinghurst, Australia; Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia.
John B ZieglerSydney Children's Hospital, Randwick, and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
Paul GraySydney Children's Hospital, Randwick, and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
Capucine PicardLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
Bodo GrimbacherCenter for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Klaus WarnatzCenter for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Steven M HollandLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
Jean-Laurent CasanovaLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, NY.
Gulbu UzelLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
Stuart G TangyeImmunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. Electronic address: s.tangye@garvan.org.au.
Garvan Institute of Medical Research · AUChildren's Hospital at Westmead · AUSt Vincent's Clinic · AUAnkara University · TRHiroshima University · JPInserm · FRShahid Beheshti University of Medical Sciences · IRSydney Children's Hospital · AUUniversité Paris Cité · FRAustralian National University · AUBursa Uludağ Üni̇versi̇tesi̇ · TREssen University Hospital · DEHadassah Medical Center · ILHôpital Militaire Moulay Ismail · MAInstitut des Maladies Génétiques Imagine · FRMedical University of Vienna · ATMedizinische Hochschule Hannover · DENational Defense Medical College · JPNational Institute of Allergy and Infectious Diseases · USNational Institutes of Health · US

Funding

TRANSFORMING TRANSLATIONAL SCIENCE AND EDUCATION TO BENEFIT HUMAN HEALTHUL1RR024143 · NCRR · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY · 2006 to 2011
$49.1M
Transgenic Animal Models Of Human Immune DefectsZIAAI000646 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI HOLLAND, STEVEN · 2009 to 2025
$22.2M
Howard Hughes Medical InstituteNCRR NIH HHS 5UL1RR024143NCRR NIH HHS UL1 RR024143
6 · The paper itself

Abstract

backgroundFollicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.

objectiveWe sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.

methodsHuman primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.

resultsLoss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.

conclusionSpecific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

Indexed as

Agammaglobulinaemia Tyrosine KinaseB-LymphocytesCD40 LigandCell DifferentiationCell ProliferationCells, CulturedHumansI-kappa B KinaseImmunity, HumoralImmunologic Deficiency SyndromesImmunologic MemoryInducible T-Cell Co-Stimulator ProteinInterferon-gammaLymphocyte ActivationMutationProtein-Tyrosine KinasesAgammaglobulinaemia Tyrosine KinaseBTK protein, humanCD40 LigandICOS protein, humanI-kappa B KinaseIKBKG protein, humanInducible T-Cell Co-Stimulator ProteinInterferon-gammaProtein-Tyrosine KinasesReceptors, CytokineSTAT1 protein, humanSTAT1 Transcription FactorSTAT3 protein, humanSTAT3 Transcription Factorcytokine signalingFollicular helper T cellshumoral immunityprimary immunodeficiencies

Identifiers

PMID26162572
PMCPMC5042203
OpenAlexW2130988038

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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.