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Claire Fieschi¹, Stéphanie Dupuis¹, Emilie Catherinot¹, Jacqueline Feinberg¹, Jacinta Bustamante¹, Adrien Breiman¹, Frédéric Altare¹, Richard Baretto⁶, Françoise Le Deist², Samer Kayal³, Hartmut Koch⁷, Darko Richter⁸, Martin Brezina⁹, Guzide Aksu¹⁰, Phil Wood¹¹, Suliman Al-Jumaah¹², Miquel Raspall¹³, Alberto José da Silva Duarte¹⁴, David Tuerlinckx¹⁵, Jean-Louis Virelizier⁵, Alain Fischer^2,4, Andrea Enright¹⁶, Jutta Bernhöft¹⁷, Aileen M. Cleary¹⁶, Christiane Vermylen¹⁸, Carlos Rodriguez-Gallego¹⁹, Graham Davies²⁰, Renate Blütters-Sawatzki¹⁷, Claire-Anne Siegrist²¹, Mohammad S. Ehlayel²², Vas Novelli²⁰, Walther H. Haas^23,24, Jacob Levy²⁵, Joachim Freihorst²⁶, Sami Al-Hajjar¹², David Nadal²⁷, Dewton de Moraes Vasconcelos¹⁴, Olle Jeppsson²⁸, Necil Kutukculer¹⁰, Klara Frecerova⁹, Isabel Caragol¹³, David Lammas⁶, Dinakantha S. Kumararatne²⁹, Laurent Abel¹ and Jean-Laurent Casanova^1,4

¹ Laboratory of Human Genetics of Infectious Diseases, University René Descartes INSERM U550, Necker Medical School
² INSERM U429, Necker Hospital
³ INSERM U411, Necker Hospital
⁴ Pediatric Immunology and Hematology Unit, Necker Hospital
⁵ Department of Molecular Medicine, Institut Pasteur, 75015 Paris, France
⁶ MRC Center for Immune Regulation, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom
⁷ Department of Pediatrics, St. Marienhospital, D-49377 Vechta, Germany
⁸ Division of Allergy and Clinical Immunology, Department of Pediatrics, University Hospital Center, 10000 Zagreb, Croatia
⁹ Pediatric Pneumology and Phtiseology Clinic SPAM, National Institute of Tuberculosis and Respiratory Diseases, 82556 Bratislava, Slovak Republic
¹⁰ Division of Pediatric Immunology, Department of Pediatrics, The Medical School, Ege University, 35100 Izmir, Turkey
¹¹ Department of Clinical Chemistry and Immunology, Leeds General Infirmary, Leeds LS1 3EX, United Kingdom
¹² Department of Pediatrics, King Faycal Hospital and Research Center, 11211 Riyadh, Saudi Arabia
¹³ Pediatric Infectious Diseases Unit and Department of Immunology, Vall d'Hebron Hospital, 08035 Barcelona, Spain
¹⁴ Primary Immunodeficiency Unit, Department of Dermatology of the Clinical Hospital, and Laboratory of Clinical and Experimental Allergy and Immunology, University of Sao Paulo Medical School, 01246-903 Sao Paulo, Brazil
¹⁵ Departement of Pediatrics, Catholic University of Louvain at Mont-Godinne, 5530 Yvoir, Belgium
¹⁶ Department of Pediatrics, Stanford University Medical Center, Stanford, CA 94010
¹⁷ Department of Pediatric Hematology and Oncology, D35385 Giessen, Germany
¹⁸ Department of Pediatric Hematology, Cliniques Universitaires Saint Luc, Louvain Medical School, B-1200 Brussels, Belgium
¹⁹ Department of Immunology, Gran Canaria Dr Negrin Hospital, 35020 Las Palmas, Spain
²⁰ Division of Paediatric Infectious Diseases, Great Ormond Street Children's Hospital, London WC1N 3JH, United Kingdom
²¹ Department of Pediatrics, University Hospital of Geneva, 1211, Geneva 4, Switzerland
²² Hamad Medical Corporation, P.O. Box: 3050, Doha, Qatar
²³ Department of General Pediatrics, Children's Hospital, University of Heidelberg, D-69120 Heidelberg, Germany
²⁴ Center for Epidemiology of Infectious Diseases, Robert Koch Institute, D-10963 Berlin, Germany
²⁵ Division of Pediatrics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva 84101, Israel
²⁶ Pediatric Pulmonology and Neonatology, Hannover Medical School, D-30623 Hannover, Germany
²⁷ Division of Infectious Diseases, University Children's Hospital of Zürich, CH-8032 Zürich, Switzerland
²⁸ Children's Hospital, Huddinge University Hospital, 141 86 Huddinge, Sweden
²⁹ Departments of Clinical Immunology and Medicine, Addenbrookes Hospital NHS Trust, Hill Road, Cambridge CB2 2QQ, United Kingdom

Address correspondence to Jean-Laurent Casanova, Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes-INSERM U550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France. Phone: 33-1-40-61-56-87; Fax: 33-1-40-61-56-88; E-mail: casanova{at}necker.fr

The clinical phenotype of interleukin 12 receptor ß1 chain (IL-12Rß1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rß1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rß1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

Key Words: Mycobacteria • Salmonella • immunodeficiency • interleukin 12 receptor • interferon

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