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

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.

Institut National de la Sante et de la Recherche Medicale

Institut National de la Santé et de la Recherche Médicale (Inserm)

European Union[NEOTIM EEA05095KKA]

European Union

European Union[HEALTH-F3-2008-200732]

European Union

March of Dimes

March of Dimes[RO5050KK]

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CNPq Conselho Nacional de Desenvolvimento Cientifico e Tecnologico

Fondation BNP-Paribas

Fondation BNP-Paribas

Fondation Schlumberger

Fondation Schlumberger

Institut Universitaire de France

Institut Universitaire de France

Agence Nationale de Recherche

Agence Nationale de la Recherche de la France (ANR)

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

Rockefeller University Center for Clinical and Translational Science

Rockefeller University

Rockefeller University

National Institutes of Health (NIH)[AI 079788]

U.S. National Institutes of Health (NIH)

National Institutes of Health (NIH)[DK54369]

U.S. National Institutes of Health (NIH)

National Institutes of Health (NIH)[HL045635]

U.S. National Institutes of Health (NIH)

Riley Children`s Foundation

Riley Children`s Foundation

Howard Hughes Medical Institute

Howard Hughes Medical Institute