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

Bustamante, Jacinta
Arias, Andres A.
Vogt, Guillaume
Picard, Capucine
Galicia, Lizbeth Blancas
Prando, Carolina
Grant, Audrey V.
Marchal, Christophe C.
Hubeau, Marjorie
Chapgier, Ariane
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Abstract

Germline mutations in CYBB, the human gene encoding the gp91(phox) 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.

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Nat Immunol. 2011 Mar;12(3):213-21. Epub 2011 Jan 30. Link to article on publisher's website

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10.1038/ni.1992
PubMed ID
21278736
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