X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Orchidée Filipe-Santos; Jacinta Bustamante; Margje H Haverkamp; Emilie Vinolo; Cheng-Lung Ku; Anne Puel; David M Frucht; Karin Christel; Horst von Bernuth; Emmanuelle Jouanguy; Jacqueline Feinberg; Anne Durandy; Brigitte Senechal; Ariane Chapgier; Guillaume Vogt; Ludovic de Beaucoudrey; Claire Fieschi; Capucine Picard; Meriem Garfa; Jalel Chemli; Mohamed Bejaoui; Maria N Tsolia; Necil Kutukculer; Alessandro Plebani; Luigi Notarangelo; Christine Bodemer; Frédéric Geissmann; Alain Israël; Michel Véron; Maike Knackstedt; Mohamed-Ridha Barbouche; Laurent Abel; Klaus Magdorf; Dominique Gendrel; Fabrice Agou; Steven M Holland; Jean-Laurent Casanova

doi:10.1084/jem.20060085

Journal articles

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Orchidée Filipe-Santos ¹ Jacinta Bustamante ¹ Margje H Haverkamp ^{2, 3} Emilie Vinolo ⁴ Cheng-Lung Ku ¹ Anne Puel ¹ David M Frucht ⁵ Karin Christel ¹ Horst von Bernuth ¹ Emmanuelle Jouanguy ¹ Jacqueline Feinberg ¹ Anne Durandy ⁶ Brigitte Senechal ⁷ Ariane Chapgier ¹ Guillaume Vogt ¹ Ludovic de Beaucoudrey ¹ Claire Fieschi ^{1, 8} Capucine Picard ¹ Meriem Garfa ⁹ Jalel Chemli ¹⁰ Mohamed Bejaoui ¹¹ Maria N Tsolia ¹² Necil Kutukculer ^{7, 13} Alessandro Plebani ¹⁴ Luigi Notarangelo ¹⁴ Christine Bodemer ¹⁵ Frédéric Geissmann ⁷ Alain Israël ¹⁶ Michel Véron ⁴ Maike Knackstedt ¹⁷ Mohamed-Ridha Barbouche ¹⁸ Laurent Abel ¹ Klaus Magdorf ¹⁷ Dominique Gendrel ¹⁹ Fabrice Agou ⁴ Steven M Holland ² Jean-Laurent Casanova ^{1, 20, *}

* Corresponding author

1 Inserm U980 - Génétique Humaine des Maladies Infectieuses

2 Laboratory of clinical infectious diseases

3 Department of Infectious Diseases

4 Régulation Enzymatique des Activités Cellulaires

5 Laboratory of Cell Biology

6 Developpement Normal et Pathologique du Système Immunitaire

7 Système des phagocytes mononucléés et immunopathologie

8 Laboratoire d'immunologie

9 Laboratoire de Microscopie confocale

10 Departement de Pediatrie

11 CNGMO - Centre National de Greffe de la Moëlle osseuse Tunis

12 Second Department of Pediatrics

13 Department of Pediatrics

14 Università degli Studi di Brescia [Brescia]

15 Service de dermatologie [CHU Necker]

16 SMAC - Signalisation Moléculaire et Activation Cellulaire

17 Department of Pediatric Pulmonology and Immunology,

18 Laboratoire d'immunologie clinique [Institut Pasteur de Tunis]

19 Département de Pédiatrie

20 Service d'immuno-hématologie pédiatrique [CHU Necker]

Abstract : Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-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-kappaB 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-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/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-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, 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-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Biochemistry, Molecular Biology

Complete list of metadata

Cited literature [54 references] Display Hide Download

https://hal-pasteur.archives-ouvertes.fr/pasteur-00162856
Contributor : Marie-Dominique Aytac Connect in order to contact the contributor
Submitted on : Saturday, February 27, 2010 - 4:31:16 PM
Last modification on : Tuesday, December 7, 2021 - 5:58:33 PM
Long-term archiving on: : Thursday, September 16, 2010 - 11:17:21 AM

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

File

Identifiers

Collections

Citation

Export

Metrics

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

File

Identifiers

Collections

Citation

Export

Share

Metrics