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IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

Lookup NU author(s): Professor Sophie Hambleton, Dr Venetia BigleyORCiD, Professor Muzlifah Haniffa, Dr Christopher Bacon, Professor Andrew Cant, Professor Matthew CollinORCiD


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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.ResultsWe 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.)

Publication metadata

Author(s): Hambleton S, Salem S, Bustamente J, Bigley V, Boisson-Dupuis S, Azevedo J, Fortin A, Haniffa M, Ceron-Gutierrez C, Bacon CM, Menon G, Trouillet C, McDonald D, Carey P, Ginhoux F, Alsina L, Zumwalt TJ, Kong X, Kumararatne D, Butler K, Hubeau M, Feinberg J, Al-Muhsen S, Cant A, Abel L, Chaussabel D, Doffinger R, Talesnik E, Grumach A, Duarte A, Abarca K, Moraes-Vasconcelos D, Burk D, Berghuis A, Geissmann F, Collin M, Casanova J-L, Gros P

Publication type: Article

Publication status: Published

Journal: New England Journal of Medicine

Year: 2011

Volume: 365

Issue: 2

Pages: 127-138

Print publication date: 27/04/2011

ISSN (print): 0028-4793

ISSN (electronic): 1533-4406

Publisher: Massachusetts Medical Society


DOI: 10.1056/NEJMoa1100066


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Funder referenceFunder name
Arthritis Research UK Chair in Inflammation Biology
Ministerio da Saude e Fundacao para a Ciencia e Tecnologia, Portugal
Agence Nationale de la Recherche (ANR)
Fundacao Calouste Gulbenkian
Fundacao Champalimaud
Jeffrey Modell Foundation
Medical Research Council
St. Giles Foundation
Talecris Biotherapeutics
AI035237National Institutes of Health
AI089970National Institutes of Health
5UL1RR024143-03Rockefeller University Center for Clinical and Translational Science
ERC 2010-StG 261299European Research Council
G0701897Medical Research Council
G0900867Medical Research Council
HOMITB-CEE E08153KKEuropean Union
G0800358Medical Research Council
LRF060169Leukaemia and Lymphoma Research Fund
MOP106424Canadian Institutes of Health Research
NEOTIM 018736European Union
RO5050KKMarch of Dimes
WT088555MAWellcome Trust