Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

Jacinta Bustamante, Andres A. Arias, Guillaume Vogt, Capucine Picard, Lizbeth Blancas Galicia, Carolina Prando, Audrey V. Grant, Christophe C. Marchal, Marjorie Hubeau, Ariane Chapgier, Ludovic De Beaucoudrey, Anne Puel, Jacqueline Feinberg, Ethan Valinetz, Lucile Jannière, Céline Besse, Anne Boland, Jean Marie Brisseau, Stéphane Blanche, Olivier LortholaryClaire Fieschi, Jean François Emile, Stéphanie Boisson-Dupuis, Saleh Al-Muhsen, Bruce Woda, Peter E. Newburger, Antonio Condino-Neto, Mary C. Dinauer, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

Germline mutations in CYBB, the human gene encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.

Original languageEnglish
Pages (from-to)213-221
Number of pages9
JournalNature immunology
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

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