Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

[Clinical and molecular inflammatory alterations in chronic granulomatous disease]. / Alteraciones inflamatorias clínicas y moleculares en enfermedad granulomatosa crónica.

Chronic granulomatous disease (CGD) is an inborn error of immunity. CGD is characterized by a deficiency in the function of the NADPH oxidase complex. CGD has been an opportunity to study the function of reactive oxygen species (ROS) in the innate immune system. The absence of ROS produced by NADPH oxidase in neutrophils and macrophages leads to an increased susceptibility to bacterial and fungal infections since ROS participate in the elimination of microorganisms. Inflammatory and autoimmune manifestations are also present in CGD; however, the causal connection between the lack of ROS and inflammatory symptoms is not entirely clear. Different in vitro assays have been conducted in humans and clinical trials have been conducted in mice in order to try to understand this relationship. Studies show that ROS react with different molecules of the immune system, either by inhibiting or by stimulating their function, which explains why various inflammation pathways that are not related to each other are affected in CGD; therefore, the described mechanisms of affectation have been diverse, such as a greater production of proinflammatory cytokines, an increase in TH17 lymphocytes, and an alteration in processes like spherocytosis, apoptosis, autophagy, and inflammosome. Understanding the mechanisms that lead to inflammation in the deficiency of the NADPH oxidase complex has led to the proposal of new treatments that act on processes like autophagy, inflammosome, or blocking proinflammatory cytokines. In this review, we describe the different inflammatory manifestations in CGD and the molecular mechanisms through which the lack of ROS leads to hyperinflammation.

La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad. Se caracteriza por deficiencia en la función del complejo de la NADPH oxidasa. La EGC ha sido una oportunidad para estudiar la función de las especies reactivas de oxígeno (ROS) en el sistema inmune innato. La ausencia de ROS producidas por la NADPH oxidasa en los neutrófilos y en los macrófagos lleva a mayor susceptibilidad a infecciones bacterianas y fúngicas, debido a que las ROS participan en la eliminación de los microorganismos. Las manifestaciones inflamatorias y autoinmunes también están presentes en la EGC, sin embargo, no es del todo clara la relación de causalidad entre la falta de ROS y los síntomas inflamatorios. Se han realizado diversos ensayos in vitro en humanos y experimentales en ratones para tratar de entender esta relación. Los estudios muestran que las ROS reaccionan con diferentes moléculas del sistema inmune, inhibiendo o estimulando su función, lo que explica que en la EGC se afecten varias vías de la inflamación que no están relacionadas entre sí; por lo tanto, han sido diversos los mecanismos de afectación descritos, como por ejemplo una mayor producción de citocinas proinflamatorias, un incremento en los linfocitos TH17 y una alteración en procesos como eferocitosis, apoptosis, autofagia e inflamasoma. El entendimiento de los mecanismos que llevan a la inflamación en la deficiencia del complejo de la NADPH oxidasa ha llevado a plantear nuevos tratamientos que actúan en procesos como la autofagia, el inflamosoma o el bloqueo de citocinas proinflamatorias. En esta revisión describimos las diferentes manifestaciones inflamatorias en EGC y los mecanismos moleculares a través de los cuales la falta de ROS conduce a la hiperinflamación.