Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome - 13/08/11

Doi : 10.1016/j.jaci.2009.10.059

Cristina Woellner, MSc ^a, E. Michael Gertz, PhD ^b, Alejandro A. Schäffer, PhD ^b, Macarena Lagos, MD ^d, Mario Perro, MSc ^a, Erik-Oliver Glocker, MD ^a, Maria C. Pietrogrande, MD ^e, Fausto Cossu, MD ^f, José L. Franco, MD, PhD ^g, Nuria Matamoros, MD ^h, Barbara Pietrucha, MD, PhD ⁱ, Edyta Heropolitańska-Pliszka, MD ⁱ, Mehdi Yeganeh, MD ^j, Mostafa Moin, MD ^j, Teresa Español, MD, PhD ^k, Stephan Ehl, MD ^l, Andrew R. Gennery, MD ^m, Mario Abinun, MD, PhD ^m, Anna Bręborowicz, MD ⁿ, Tim Niehues, MD ^o, Sara Sebnem Kilic, MD ^p, Anne Junker, MD ^q, Stuart E. Turvey, MD, PhD ^q, Alessandro Plebani, MD ^r, Berta Sánchez, PhD ^s, Ben-Zion Garty, MD ^t, Claudio Pignata, MD ^u, Caterina Cancrini, MD ^v, Jiri Litzman, MD ^w, Özden Sanal, MD ^x, Ulrich Baumann, MD ^y, Rosa Bacchetta, MD ^z, Amy P. Hsu, BA ^c, Joie N. Davis, CRNP ^c, Lennart Hammarström, MD ^aa, E. Graham Davies, MD ^bb, Efrem Eren, MD ^cc, Peter D. Arkwright, MD, PhD ^dd, Jukka S. Moilanen, MD, PhD ^ee, Dorothee Viemann, MD ^ff, Sujoy Khan, MRCP ^gg, László Maródi, MD ^hh, Andrew J. Cant, MD ^m, Alexandra F. Freeman, MD ^c, Jennifer M. Puck, MD ⁱⁱ, Steven M. Holland, MD ^c, Bodo Grimbacher, MD ^a,^⁎
^a Department of Immunology and Molecular Pathology, Royal Free Hospital, University College London, London, United Kingdom
^b National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
^c Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
^d Cátedra de Inmunología Escuela de Medicina, Universidad de Valparaíso, Valparaíso, Chile
^e Department of Pediatrics, University of Milan, Fondazione Policlinico IRCCS, Milan, Italy
^f Bone Marrow Transplant Unit, Ospedale Microcitemico, Cagliari, Italy
^g Group of Primary Immunodeficiencies, University of Antioquia, Medellín, Colombia
^h Immunology Service, Son Dureta Hospital, Palma de Mallorca, Spain
ⁱ Gastroenterology, Hepatology and Immunology Clinic, Children’s Memorial Health Institute, Warsaw, Poland
^j Immunology, Asthma and Allergy Research Institute, Children Medical Centre, Tehran University of Medical Sciences, Tehran, Iran
^k Immunology Unit, Hospital Vall d’Hebron, School of Medicine, Barcelona, Spain
^l Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
^m Children’s Bone Marrow Transplant Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
ⁿ Department of Pediatric Pulmonology, Allergy and Clinical Immunology, 3rd Department of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
^o Immunodeficiency and Pediatric Rheumatology Centre, HELIOS Klinikum Krefeld, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
^p Department of Pediatric Immunology, Faculty of Medicine, Uludag University, Bursa, Turkey
^q Department of Pediatrics, British Columbia’s Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada
^r Department of Pediatrics and Institute of Molecular Medicine A. Novicelli, University of Brescia, Brescia, Italy
^s Immunology Service, University Hospital, Virgen del Rocıo, Sevilla, Spain
^t Department of Pediatrics, Schneider Children’s Medical Center, Petah Tiqva, Israel
^u Department of Pediatrics, “Federico II” University of Naples, Naples, Italy
^v Division of Immunology and Infectious Disease, Bambino Gesù Children’s Hospital, University of Rome Tor Vergata, Rome, Italy
^w Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, St Anne’s University Hospital, Brno, Czech Republic
^x Immunology Division, Hacettepe University Children’s Hospital, Ankara, Turkey
^y Department of Pediatric Pulmonology and Neonatology, Medical School Hannover, Hannover, Germany
^z San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
^aa Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at the Karolinska University Hospital, Stockholm, Sweden
^bb Department of Immunology, Great Ormond Street Hospital, London, United Kingdom
^cc Immunology Department, Southampton General Hospital, Southampton, United Kingdom
^dd Paediatric Immunology, University of Manchester, Manchester, United Kingdom
^ee Department of Clinical Genetics, University of Oulu and Medical School, University of Tampere, Tampere, Finland
^ff Institute of Immunology and Department of Pediatrics, University of Münster, Münster, Germany
^gg Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, United Kingdom
^hh Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
ⁱⁱ Department of Pediatrics, University of California, San Francisco, Calif

Reprint requests: Bodo Grimbacher, MD, Dept of Immunology and Molecular Pathology, Royal Free Hospital and University College London, Pond Street, London NW3 2QG, United Kingdom.

Abstract

Background

The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T_H17 cells.

Objective

To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients.

Methods

We collected clinical data, determined T_H17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation.

Results

In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T_H17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T_H17 cells but were distinct by markedly reduced IFN-γ–producing CD4⁺T cells.

Conclusion

We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T_H17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Le texte complet de cet article est disponible en PDF.

Key words : Hyper-IgE syndrome, HIES, Job syndrome, T_H17 cells, STAT3 mutations, diagnostic guidelines

Abbreviations used : HIES, NIH, SEB, SH2, STAT3, SVM, UPN

Plan

Methods

Patients and controls

PCR and sequencing

Cell culture and TNF-⍺ ELISA

Lymphocyte stimulation and flow cytometry

Statistical analysis

Results

STAT3 mutations

Evaluating the value of the NIH-HIES clinical scoring system

Set of clinical features best predicting the genotype

Using T_H17 cells in HIES as a diagnostic marker: IL-17 and IFN-γ production by CD4⁺T cells in HIES

Discussion

Proposed set of diagnostic features for STAT3-mutant HIES

Supported by in part by the European grant MEXT-CT-2006-042316 to B.G., a grant of the Primary Immunodeficiency Association provided by GSK, the European consortium grant EURO-PADnet HEALTH-F2-2008-201549, the grant OTKA49017 to L.M., the foundation C. Golgi from Brescia to A.P., the Intramural Research Program of the National Institutes of Health, NLM (E.M.G., A.A.S.), the National Institute of Allergy and Infectious Diseases (A.P.H., A.F.F., J.N.D., S.M.H.), and federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Disclosure of potential conflict of interest: B. Grimbacher has received research support from the European Union and the Primary Immunodeficiency Association, and is secretary of the European Society for Immunodeficiencies. J. L. Franco is vice president of Fundación Diana García de Olarte. T. Niehues has received consulting fees from Talecris Biotherapeutics, Octapharma, Behring ZLB, and Baxter. S. S. Kilic has received research support from Uludag University. A. Junker has received research support from the BS Children’s Hospital Foundation, the Michael Smith Foundation, and the Canadian Institutes of Health Research. L. Hammarström has received research support from the National Institutes of Health, the European Union, and the Swedish Research Council. J. S. Moilanen has received research support from the Academy of Finland. A. J. Cant has received research support from the Bubble Foundation, UK, and the Medical Research Council, and has served as an expert witness on cases of bacterial meningitis and herpes simplex encephalitis. J. M. Puck has received research support from the National Institutes of Health, NICHD, and the Jeffrey Modell Foundation, and is on the Steering Committee of the Immune Deficiency Foundation and the Expert Committee on Primary Immunodeficiencies for IUIS. The rest of the authors have declared that they have no conflict of interest.

Export

Vol 125 - N° 2

P. 424 - février 2010 Retour au numéro

Article précédent

Voluntarily reported unintentional injections from epinephrine auto-injectors
F. Estelle R. Simons, Eric S. Edwards, Edward J. Read, Sunday Clark, Erica L. Liebelt

| Article suivant

Early-life EBV infection protects against persistent IgE sensitization
Shanie Saghafian-Hedengren, Eva Sverremark-Ekström, Annika Linde, Gunnar Lilja, Caroline Nilsson

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome - 13/08/11

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL