IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

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.)

Medical Research Council[G0701897]

Medical Research Council[G0800358]

Medical Research Council[G0900867]

National Institutes of Health (NIH)[AI035237]

National Institutes of Health (NIH)[AI089970]

Canadian Institutes of Health Research[MOP106424]

Agence Nationale de la Recherche (ANR)

St. Giles Foundation

Jeffrey Modell Foundation

Talecris Biotherapeutics

Rockefeller University Center for Clinical and Translational Science[5UL1RR024143-03]

European Union[HOMITB-CEE E08153KK]

European Union[NEOTIM 018736]

March of Dimes[RO5050KK]

Wellcome Trust[WT088555MA]

Leukaemia and Lymphoma Research Fund[LRF060169]

Arthritis Research UK Chair in Inflammation Biology

Medical Research Council

European Research Council[ERC 2010-StG 261299]

Fundacao Calouste Gulbenkian

Fundacao Champalimaud

Ministerio da Saude e Fundacao para a Ciencia e Tecnologia, Portugal