RESUMEN
Chronic granulomatous disease (CGD) is an uncommon inherited disorder of phagocytic cells in which a defective respiratory burst leads to severe recurrent bacterial and fungal infections. The disease is a consequence of mutations in one of the four molecules that constitute the NADPH oxidase system of electron transport, whose most critical component is an unusual flavocytochrome b localized in the plasma and specific granule membranes. Mutations in the CYBB gene (localized in the short arm of the X chromosome) encoding the beta-subunit of this flavocytochrome (gp91-phox), which is are responsible for 60-65% of all cases of CGD. In this paper, we report the molecular characterization of seven unrelated kindreds native from Colombia and Brazil with CGD caused by gp91-phox deficiency. The exons with the possible mutation were identified by single-strand conformational polymorphism (SSCP) of genomic DNA and then confirmed by DNA sequencing. In one patient we found a substitution of A to G in the penultimate nucleotide of intron 12 (IVS12-2A-->G). In four other cases, four different nonsense mutations were detected: R91X, W106X, R157X, and R290X and the other two patients showed missense substitutions: E225V and C244Y. In six of these kindreds, all mothers were carriers but one that did not present any change in the gp91-phox gene, which indicates a de novo mutation in this kindred. Then, these family-specific mutations in gp91-phox produce different structural defects that alter the expression or function of an essential component of phagocyte oxidase.
Asunto(s)
Enfermedad Granulomatosa Crónica/genética , Glicoproteínas de Membrana/genética , Mutación Missense , NADPH Oxidasas , Adolescente , Brasil/etnología , Preescolar , Colombia/etnología , Análisis Mutacional de ADN , Cartilla de ADN , Ligamiento Genético , Humanos , Lactante , Masculino , Glicoproteínas de Membrana/deficiencia , NADPH Oxidasa 2 , Polimorfismo Conformacional Retorcido-Simple , Cromosoma XRESUMEN
The Latin American Group for Primary Immunodeficiencies, formed in 1993, presently includes 12 countries. One goal was to study the frequency of primary immunodeficiencies in various regions of the American continent and to enhance knowledge about these diseases among primary-care physicians, as well as allergist-immunologists. Important for this purpose was the development of a registry of primary immunodeficiencies using a uniform questionnaire and computerized database. To date, eight countries have collected information on a total of 1428 patients. Predominantly antibody deficiencies were reported in 58% of patients, followed by cellular and antibody immunodeficiencies associated with other abnormalities in 18%, immunodeficiency syndromes associated with granulocyte dysfunction in 8%, phagocytic disorders in 9%, combined cellular and antibody immunodeficiencies in 5%, and complement deficiencies in 2% of patients. The information gathered from this initial analysis of data will serve to expand the patient database to more areas within participating countries and to new countries and to increase collaboration toward better diagnosis and treatment of these diseases.
Asunto(s)
Síndromes de Inmunodeficiencia/epidemiología , Humanos , Síndromes de Inmunodeficiencia/clasificación , Síndromes de Inmunodeficiencia/inmunología , América Latina/epidemiología , Fenotipo , Sistema de RegistrosRESUMEN
The respiratory burst of phagocytes plays an important role in the tissue damage that accompanies the inflammatory response. One of these conditions is allergic bronchial asthma, therefore, to evaluate the activation state of peripheral granulocytes the generation of reactive oxygen metabolites was evaluated using Luminol-enhanced chemiluminescence (LCL) and reduction of cytochrome C by superoxide. The resting granulocytes of the asthmatic patients under crisis showed a higher LCL compared to the noncrisis patients and control subjects. The granulocytes stimulated with PMA presented a significant increase in the respiratory burst in both groups of asthmatics. The granulocytes of noncrisis asthmatics challenged with Ops-Zym and with fMLP + Ops-Zym showed a higher metabolic activity, whereas the asthmatics under crisis presented no difference between reactive oxygen generation and that of the control group. The quantitative analysis of superoxide generation by granulocytes of the same patients did not show differences among the groups. Our findings suggest that the granulocytes of crisis and noncrisis asthmatics seem to be in a hyperreactive state and with a higher metabolic response when compared to the control group. However, the patients present a different behavior depending on stimulus used to activate cells. This could indicate that in peripheral blood exist different granulocyte populations depending on the inflammatory response taking place in the respiratory tract.