title: IRF8 mutations and human dendritic-cell immunodeficiency.
abstract: BACKGROUND
  The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained.
  
  
  METHODS
  We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease.
  
  
  RESULTS
  We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells.
  
  
  CONCLUSIONS
  These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Sophie
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authors.lastname: Hambleton
authors.forename: Sandra
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authors.lastname: Salem
authors.forename: Jacinta
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authors.lastname: Bustamante
authors.forename: Venetia
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authors.lastname: Bigley
authors.forename: Stéphanie
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authors.lastname: Boisson-Dupuis
authors.forename: Joana
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authors.lastname: Azevedo
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authors.forename: Muzlifah
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authors.forename: Lourdes
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authors.forename: Chris M
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authors.forename: Céline
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authors.lastname: Trouillet
authors.forename: David
authors.initials: D
authors.lastname: McDonald
authors.forename: Peter
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authors.lastname: Carey
authors.forename: Florent
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authors.lastname: Ginhoux
authors.forename: Laia
authors.initials: L
authors.lastname: Alsina
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Zumwalt
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Kong
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.forename: Karina
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authors.lastname: Butler
authors.forename: Marjorie
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authors.lastname: Hubeau
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Andrew
authors.initials: A
authors.lastname: Cant
authors.forename: Laurent
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authors.lastname: Abel
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Eduardo
authors.initials: E
authors.lastname: Talesnik
authors.forename: Anete
authors.initials: A
authors.lastname: Grumach
authors.forename: Alberto
authors.initials: A
authors.lastname: Duarte
authors.forename: Katia
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authors.lastname: Abarca
authors.forename: Dewton
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authors.lastname: Moraes-Vasconcelos
authors.forename: David
authors.initials: D
authors.lastname: Burk
authors.forename: Albert
authors.initials: A
authors.lastname: Berghuis
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Philippe
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authors.lastname: Gros
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics*; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D011487:Protein Conformation; D016415:Sequence Alignment; D000099185:Interferon Regulatory Factor-8
chemical_list: D001500:BCG Vaccine; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D000099185:Interferon Regulatory Factor-8