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¹ Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes-Institut National de la Santé et de la Recherche Médicale (INSERM) U 550, Necker Medical School; ² Laboratory of Enzymatic Regulation of Cellular Activities, URA 2185 Centre National de la Recherche Scientifique (CNRS), Pasteur Institute; ³ Laboratory of Normal and Pathologic Development of the Immune System, INSERM U768, ⁴ Center for the Study of Primary Immunodeficiencies, ⁵ Laboratory of Confocal Microscopy, ⁶ Dermatology Unit, and ⁷ Pediatric Hematology-Immunology Unit, Necker Hospital; ⁸ Laboratory of Molecular Signaling and Cellular Activation, URA 2582 CNRS, Pasteur Institute; and ⁹ INSERM, Laboratory of Mononuclear Phagocyte Biology, Avenir Team, Necker Enfants Malades Institute, 75015 Paris, France
¹⁰ Laboratory of Clinical Infectious Diseases, National Institutes of Health and ¹¹ Laboratory of Cell Biology, Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
¹² Department of Infectious Diseases, Leiden University Medical Center, 2300 Leiden, Netherlands
¹³ Laboratory of Immunology, Saint Louis Hospital, 75010 Paris, France
¹⁴ Department of Pediatrics, Sahloul Hospital, 4054 Sousse, Tunisia
¹⁵ National Center for Bone Marrow Transplantation and ¹⁶ Department of Immunology, Pasteur Institute, 1002 Tunis, Tunisia
¹⁷ Second Department of Pediatrics, University of Athens School of Medicine, P. and A. Kyriakou Children's Hospital, 115 27 Athens, Greece
¹⁸ Department of Pediatrics, Ege University, 35100 Izmir, Turkey
¹⁹ Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, 25121 Brescia, Italy
²⁰ Department of Pediatric Pulmonology and Immunology, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany
²¹ Department of Pediatrics, St. Vincent de Paul Hospital, 75014 Paris, France

CORRESPONDENCE Jean-Laurent Casanova: casanova{at}necker.fr

Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-–mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)–MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-B essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell–dependent IL-12 production, resulting in defective IFN- secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-B/c-Rel–mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-B activators, such as tumor necrosis factor-, IL-1ß, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell– and CD40L-triggered, CD40-, and NEMO/NF-B/c-Rel–mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.

Abbreviations used: EM, environmental mycobacteria; LZ, leucine zipper; MDDC, monocyte-derived dendritic cell; MSMD, Mendelian susceptibility to mycobacterial diseases; NEMO, NF-B essential modulator; XR, X-linked recessive.

O. Filipe-Santos and J. Bustamante contributed equally to this work.

S.M. Holland and J.-L. Casanova contributed equally to this work.

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