Shokouh Azam Sarrafzadeh1, Maryam Nourizadeh1, Maryam Mahloojirad1, Mohammad Reza Fazlollahi1, Raheleh Shokouhi Shoormasti1, Mohsen Badalzadeh1,2, Caroline Deswarte3,4, Jean-Laurent Casanova3,4,5,6,7, Zahra Pourpak1, Jacinta Bustamante8,9,10,11, Mostafa Moin12. 1. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, 4th Floor, Building no.3, Children's Medical Center, Gharib St, Keshavarz Blvd, 14185-863, Tehran, IR, 14194, Iran. 2. Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran. 3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, EU, France. 4. Imagine Institute, Paris Descartes University, Paris, EU, France. 5. Howard Hughes Medical Institute, New York, NY, USA. 6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA. 7. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, EU, France. 8. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, EU, France. jacinta.bustamante@inserm.fr. 9. Imagine Institute, Paris Descartes University, Paris, EU, France. jacinta.bustamante@inserm.fr. 10. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA. jacinta.bustamante@inserm.fr. 11. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, EU, France. jacinta.bustamante@inserm.fr. 12. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, 4th Floor, Building no.3, Children's Medical Center, Gharib St, Keshavarz Blvd, 14185-863, Tehran, IR, 14194, Iran. mmoin@sina.tums.ac.ir.
Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). METHODS: We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. RESULTS: Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. CONCLUSIONS: We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). METHODS: We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. RESULTS: Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. CONCLUSIONS: We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.
Authors: Davood Mansouri; Parisa Adimi; Mehdi Mirsaedi; Nahal Mansouri; Payam Tabarsi; Majid Amiri; Hamid R Jamaati; Masoud Motavasseli; Noushin Baghaii; Ali Cheraghvandi; Reza Rouhi; Navid A Roozbahany; Soheila Zahirifard; Forouzan Mohammadi; Mohammad R Masjedi; Ali A Velayati; Jean L Casanova; David P Speert; R Kevin Elwood; Robert Schellenberg; Stuart E Turvey Journal: J Clin Immunol Date: 2005-07 Impact factor: 8.317
Authors: A C Hesseling; H Rabie; B J Marais; M Manders; M Lips; H S Schaaf; R P Gie; M F Cotton; P D van Helden; R M Warren; N Beyers Journal: Clin Infect Dis Date: 2006-01-11 Impact factor: 9.079
Authors: Aileen M Cleary; Wenwei Tu; Andrea Enright; Thierry Giffon; Rene Dewaal-Malefyt; Kathleen Gutierrez; David B Lewis Journal: J Immunol Date: 2003-01-01 Impact factor: 5.422
Authors: Claire Fieschi; Stéphanie Dupuis; Emilie Catherinot; Jacqueline Feinberg; Jacinta Bustamante; Adrien Breiman; Frédéric Altare; Richard Baretto; Françoise Le Deist; Samer Kayal; Hartmut Koch; Darko Richter; Martin Brezina; Guzide Aksu; Phil Wood; Suliman Al-Jumaah; Miquel Raspall; Alberto José Da Silva Duarte; David Tuerlinckx; Jean-Louis Virelizier; Alain Fischer; Andrea Enright; Jutta Bernhöft; Aileen M Cleary; Christiane Vermylen; Carlos Rodriguez-Gallego; Graham Davies; Renate Blütters-Sawatzki; Claire-Anne Siegrist; Mohammad S Ehlayel; Vas Novelli; Walther H Haas; Jacob Levy; Joachim Freihorst; Sami Al-Hajjar; David Nadal; Dewton De Moraes Vasconcelos; Olle Jeppsson; Necil Kutukculer; Klara Frecerova; Isabel Caragol; David Lammas; Dinakantha S Kumararatne; Laurent Abel; Jean-Laurent Casanova Journal: J Exp Med Date: 2003-02-17 Impact factor: 14.307
Authors: Paula T Lyra; Edvaldo Souza; Ana Carla A Moura; Marina C Matta; Leuridan C Torres; Antonio Victor Campos Coelho; Maria Ângela W Rocha; Luiz Arraes; João Bosco Oliveira Journal: J Clin Immunol Date: 2022-07-30 Impact factor: 8.542