IRF8 mutations and human dendritic-cell immunodeficiency

Sophie Hambleton, Sandra Salem, Jacinta Bustamante, Venetia Bigley, Stéphanie Boisson-Dupuis, Joana Azevedo, Anny Fortin, Muzlifah Haniffa, Lourdes Ceron-Gutierrez, Chris M. Bacon, Geetha Menon, Céline Trouillet, David McDonald, Peter Carey, Florent Ginhoux, Laia Alsina, Timothy J. Zumwalt, Xiao Fei Kong, Dinakantha Kumararatne, Karina ButlerMarjorie Hubeau, Jacqueline Feinberg, Saleh Al-Muhsen, Andrew Cant, Laurent Abel, Damien Chaussabel, Rainer Doffinger, Eduardo Talesnik, Anete Grumach, Alberto Duarte, Katia Abarca, Dewton Moraes-Vasconcelos, David Burk, Albert Berghuis, Frédéric Geissmann, Matthew Collin, Jean Laurent Casanova, Philippe Gros

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483 Scopus citations


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 stemcell 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.)

Original languageEnglish (US)
Pages (from-to)127-138
Number of pages12
JournalNew England Journal of Medicine
Issue number2
StatePublished - Jul 14 2011
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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