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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
IRF8 mutations and human dendritic-cell immunodeficiency
New England Journal of Medicine, Volume 365, No. 2, Year 2011
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Description
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.) Copyright © 2011 Massachusetts Medical Society.
Authors & Co-Authors
Hambleton, Sophie
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Salem, Sandra
Canada, Montreal
Université Mcgill
Bustamante, Jacinta Cecilia
France, Paris
L'institut Des Maladies Génétiques Imagine
Bigley, Venetia
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Boisson-Dupuis, Stéphanie
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Azevedo, Joana
United Kingdom, London
King's College London
Fortin, Anny
Canada, Montreal
Université Mcgill
Haniffa, Muzlifah A.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
France, Paris
L'institut Des Maladies Génétiques Imagine
Ceron-Gutierrez, Lourdes
United Kingdom, Cambridge
Addenbrooke's Hospital
Bacon, Chris M.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Menon, Geetha
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Trouillet, Céline
United Kingdom, London
King's College London
McDonald, David
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Carey, P.
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Ginhoux, Florent
United Kingdom, London
King's College London
Alsina, Laia
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
United States, Dallas
Baylor Institute for Immunology Research
Spain, Barcelona
Universitat de Barcelona
Zumwalt, Timothy J.
United States, Dallas
Baylor Institute for Immunology Research
United States, Waco
Baylor University
Kong, Xiao Fei
United States, New York
Rockefeller University
Kumararatne, Dinakantha S.
United Kingdom, Cambridge
Addenbrooke's Hospital
Butler, Karina M.
Ireland, Dublin
Our Lady's Hospital for Sick Children
Hubeau, Marjorie
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
France, Paris
L'institut Des Maladies Génétiques Imagine
Feinberg, Jacqueline
France, Paris
L'institut Des Maladies Génétiques Imagine
Al-Muhsen, Saleh Zaid
Saudi Arabia, Riyadh
College of Medicine
Cant, Andrew James
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Abel, Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
United States, Dallas
Baylor Institute for Immunology Research
Spain, Barcelona
Universitat de Barcelona
Chaussabel, Damien
United States, Dallas
Baylor Institute for Immunology Research
Döffinger, Rainer
United Kingdom, Cambridge
Addenbrooke's Hospital
Talesnik, Eduardo
Chile, Santiago
Pontificia Universidad Católica de Chile
Grumach, Anete Sevciovic G.
Brazil, Sao Paulo
Universidade de São Paulo
Duarte, Alberto
Brazil, Sao Paulo
Universidade de São Paulo
Abarca, Katia
Chile, Santiago
Pontificia Universidad Católica de Chile
Moraes-Vasconcelos, Dewton
Brazil, Sao Paulo
Universidade de São Paulo
Burk, David
Canada, Montreal
Université Mcgill
Berghuis, Albert
Canada, Montreal
Université Mcgill
Geissmann, Frédéric
Singapore, Singapore City
A-star, Singapore Immunology Network
Collin, Matthew P.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Casanova, Jean Laurent
France, Paris
L'institut Des Maladies Génétiques Imagine
United States, New York
Rockefeller University
Saudi Arabia, Riyadh
College of Medicine
Gros, Philippe
Canada, Montreal
Université Mcgill
Statistics
Citations: 564
Authors: 38
Affiliations: 15
Identifiers
Doi:
10.1056/NEJMoa1100066
ISSN:
00284793
e-ISSN:
15334406
Research Areas
Genetics And Genomics
Maternal And Child Health