RESUMEN
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.
Asunto(s)
Genes Ligados a X , Predisposición Genética a la Enfermedad , Macrófagos/inmunología , Glicoproteínas de Membrana/genética , NADPH Oxidasas/genética , Tuberculosis/genética , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Mutación , NADPH Oxidasa 2 , NADPH Oxidasas/inmunologíaRESUMEN
The chronic granulomatous disease is a primary immunodeficiency with a defect of the phagocytosis process; its main alteration resides in the incapacity of the NADPH oxidase system to produce reactive oxygen species capable of destruct pathogenic organisms such as bacteria, fungus and mycobacteria. Patients are susceptible to severe and mild infections, mainly pneumonias, linfadenitis and gastroenteritis that tend to be repetitive; in addition, they presented granulomatous inflammation and autoimmunity. We presented the case of two brothers with X-linked chronic granulomatous disease with alteration in the sub-unit gp91Phox; heredofamilial background was endogamy and consanguinity. Both patients suffered severe infections, frequent abscesses and a poor growth. Diagnosis was confirmed with nitroblue tetrazolium test. During their evolution, the patients presented also BCGitis, BCGosis and septic shock. They began prophylactic treatment with trimetoprim sulfametoxazole and itraconazole, as well as gamma interferon, with favorable response, presenting a lower amount of infectious episodes, as well as a recovery of their weight and height. The early diagnosis of the patients has improved their prognosis.