Nioosha Nekooie-Marnany1, Caroline Deswarte2,3, Vajiheh Ostadi1, Bahram Bagherpour1, Elaheh Taleby1, Mazdak Ganjalikhani-Hakemi1, Tom Le Voyer2,3, Hamid Rahimi4, Jérémie Rosain2,3,5, Zahra Pourmoghadas6, Saba Sheikhbahaei1, Razieh Khoshnevisan1, Daniel Petersheim7, Daniel Kotlarz7, Christoph Klein7, Stéphanie Boisson-Dupuis2,3,8, Jean-Laurent Casanova2,3,8,9,10, Jacinta Bustamante2,3,5,8, Roya Sherkat11. 1. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, EU, France. 3. Paris Descartes University, Paris, EU, France. 4. Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran. 5. Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, EU, France. 6. Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 7. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, EU, Germany. 8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 9. Howard Hughes Medical Institute, New York, NY, USA. 10. Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, EU, France. 11. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. sherkat@med.mui.ac.ir.
Abstract
PURPOSE: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). METHODS: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T cell blasts, and sequenced candidate genes. RESULTS: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations. CONCLUSIONS: IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.
PURPOSE:Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). METHODS: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T cell blasts, and sequenced candidate genes. RESULTS: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations. CONCLUSIONS: IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.
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