artículo
IRF8 Mutations and Human Dendritic-Cell Immunodeficiency
Fecha
2011Registro en:
10.1056/NEJMoa1100066
0028-4793
MEDLINE:21524210
WOS:000292685500009
Autor
Hambleton, Sophie
Salem, Sandra
Bustamante, Jacinta
Bigley, Venetia
Boisson Dupuis, Stephanie
Azevedo, Joana
Fortin, Anny
Haniffa, Muzlifah
Ceron Gutierrez, Lourdes
Bacon, Chris M.
Menon, Geetha
Trouillet, Celine
McDonald, David
Carey, Peter
Ginhoux, Florent
Alsina, Laia
Zumwalt, Timothy J.
Kong, Xiao Fei
Kumararatne, Dinakantha
Butler, Karina
Hubeau, Marjorie
Feinberg, Jacqueline
Al Muhsen, Saleh
Cant, Andrew
Abel, Laurent
Chaussabel, Damien
Doffinger, Rainer
Talesnik, Eduardo
Grumach, Anete
Duarte, Alberto
Abarca, Katia
Moraes Vasconcelos, Dewton
Burk, David
Berghuis, Albert
Geissmann, Frederic
Collin, Matthew
Casanova, Jean Laurent
Gros, Philippe
Institución
Resumen
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-Guerin (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.)