title: Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors.
abstract: Inborn errors of interferon-gamma (IFN-γ)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate interleukin (IL)-12 and IFN-γ ex vivo production stimulated with BCG and BCG + IFN-γ or BCG + IL-12, respectively, in BCG osteitis survivors.
  
  
  
  Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-γ or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing.
  
  
  
  By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-γ concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients.
  
  
  
  These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.
authors.affiliation: From the *Center for Child Health Research, University of Tampere and University Hospital and †School of Health Sciences, University of Tampere, Tampere, Finland; ‡Department of Pediatrics, University Hospital, Kuopio, Finland; §Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, ¶Department of Pediatrics, University of Turku and University Hospital, and ‖Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland; **St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University and ††Howard Hughes Medical Institute, New York, NY; and ‡‡Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, §§Paris Descartes University, Imagine Institute, ¶¶Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, and ‖‖Center for the Study of Primary Immunodeficiencies, Paris AP-HP, Necker-Enfants Malades Hospital, Paris, France, EU.
authors.forename: Laura
authors.initials: L
authors.lastname: Pöyhönen
authors.forename: Liisa
authors.initials: L
authors.lastname: Kröger
authors.forename: Heini
authors.initials: H
authors.lastname: Huhtala
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäkinen
authors.forename: Jussi
authors.initials: J
authors.lastname: Mertsola
authors.forename: Ruben
authors.initials: R
authors.lastname: Martinez-Barricarte
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Qiushui
authors.initials: Q
authors.lastname: He
authors.forename: Matti
authors.initials: M
authors.lastname: Korppi
mesh_terms: D000328:Adult; D001500:BCG Vaccine / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005387:Finland; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000276:immunology*; D010000:Osteitis / Q000139:chemically induced* / Q000276:immunology*; D017741:Survivors; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D007155:Immunologic Factors; D018664:Interleukin-12; D007371:Interferon-gamma