RESUMEN
Chronic granulomatous disease (CGD) is a rare X-linked recessive primary immunodeficiency disease (PID). Herein, a human induced pluripotent stem cell (iPSC) line was generated from the peripheral blood mononuclear cells (PBMCs) of a CGD patient with a mutation (c.785_786delTT) in the CYBB gene. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers. They offer a promising technique for studying the pathogenesis and conducting drug screening for CGD patients.
Asunto(s)
Enfermedad Granulomatosa Crónica , Células Madre Pluripotentes Inducidas , Humanos , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Células Madre Pluripotentes Inducidas/metabolismo , Leucocitos Mononucleares/metabolismo , Diferenciación Celular , Mutación/genéticaRESUMEN
Discoid lupus erythematosus (DLE), a subtype of chronic cutaneous lupus may be observed in a linear pattern. A 21-year-old woman with history of chronic granulomatous disease state presented to our clinic for a chronic six-year skin eruption on her left eyebrow, left cheek, and left forehead. A punch biopsy of involved left forehead skin was performed and revealed perivascular and periadnexal lymphohistiocytic infiltrate without features of morphea or panniculitis, confirming the histopathologic changes of cutaneous lupus erythematous. The patient was diagnosed with linear DLE, mimicking en coup de sabre, within Blaschko lines. The pathogenesis for DLE in association with chronic granulomatous disease is ambiguous; however, X-linked lyonization is crucial for both conditions and may explain cooccurrence of disease states.
Asunto(s)
Enfermedad Granulomatosa Crónica , Lupus Eritematoso Discoide , Paniculitis , Esclerodermia Localizada , Humanos , Femenino , Adulto Joven , Adulto , Esclerodermia Localizada/patología , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/patología , Piel/patología , Lupus Eritematoso Discoide/diagnóstico , Lupus Eritematoso Discoide/patología , Paniculitis/patologíaRESUMEN
Mycobacteriosis, mostly resulting from Mycobacterium tuberculosis (MTb), nontuberculous mycobacteria (NTM), and Mycobacterium leprae (M. leprae), is the long-standing granulomatous disease that ravages several organs including skin, lung, and peripheral nerves, and it has a spectrum of clinical-pathologic features based on the interaction of bacilli and host immune response. Histiocytes in infectious granulomas mainly consist of infected and uninfected macrophages (Mφs), multinucleated giant cells (MGCs), epithelioid cells (ECs), and foam cells (FCs), which are commonly discovered in lesions in patients with mycobacteriosis. Granuloma Mφ polarization or reprogramming is the crucial appearance of the host immune response to pathogen aggression, which gets a command of endocellular microbe persistence. Herein, we recapitulate the current gaps and challenges during Mφ polarization and the different subpopulations of mycobacteriosis.
Asunto(s)
Enfermedad Granulomatosa Crónica/inmunología , Enfermedad Granulomatosa Crónica/microbiología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Infecciones por Mycobacterium/inmunología , Animales , Enfermedad Granulomatosa Crónica/patología , Humanos , Macrófagos/patología , Infecciones por Mycobacterium/patologíaRESUMEN
Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis with variable risk of evolution to acute leukemias. Both disorders are rare and have distinct pathophysiologic mechanisms, with no known association. A 7-month-old boy presenting with recurrent infections and anemia at age 2 months underwent immunological, hematological and genetic investigation that culminated in the diagnosis of both CGD and MDS. Next generation sequencing was performed and identified a silent variant predicted as of Uncertain Significance, located in the splicing site at the end of exon 5 in CYBB. CYBB variants account for at least two thirds of CGD cases, but no previous descriptions of this variant were found in ClinVar or The Human Gene Mutation Database (HGMD) databases. We were able to demonstrate an exon 5 skipping on the proband's cDNA, which strongly suggests the disruption of the NADPH oxidase complex, abrogating the formation of reactive oxygen species from neutrophils. Moreover, erythroid cell lineage could be also affected by NADPH oxidase complex damages. Further investigation is needed to evaluate the potential effect of CYBB gene alterations in hematopoiesis, as well as in MDS and CGD association.
Asunto(s)
Enfermedad Granulomatosa Crónica/genética , Hematopoyesis/genética , Síndromes Mielodisplásicos/genética , NADPH Oxidasa 2/genética , Exones/genética , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/patología , Humanos , Lactante , Masculino , Mutación/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/patología , NADPH Oxidasas/genética , Neutrófilos/metabolismo , Neutrófilos/patología , Pediatría , Fagocitos/metabolismo , Empalme del ARN/genética , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Enfermedad Granulomatosa Crónica , Lipoblastoma , Neoplasias del Mediastino , NADPH Oxidasa 2/genética , Neumonía , Niño , Enfermedad Granulomatosa Crónica/diagnóstico por imagen , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/patología , Humanos , Lipoblastoma/diagnóstico por imagen , Lipoblastoma/genética , Lipoblastoma/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/patología , Neumonía/diagnóstico por imagen , Neumonía/genética , Neumonía/patologíaRESUMEN
Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba-/- mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb-/- and Ncf1-/- models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba-/- mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.
Asunto(s)
Linfocitos B/metabolismo , Grupo Citocromo b/genética , Enfermedad Granulomatosa Crónica/patología , Células Mieloides/patología , NADPH Oxidasas/genética , Animales , Sistemas CRISPR-Cas , Linaje de la Célula , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/inmunología , Humanos , Hiperplasia , Masculino , Ratones , Células Mieloides/inmunologíaRESUMEN
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.
Asunto(s)
Inflamasomas/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteínas Recombinantes/farmacología , Superóxido Dismutasa/metabolismo , Animales , Células Cultivadas , Fibrosis Quística/etiología , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Modelos Animales de Enfermedad , Enfermedad Granulomatosa Crónica/etiología , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Patients with chronic granulomatous disease (CGD) who have mutated phagocyte NADPH oxidase are susceptible to infections due to reduced reactive oxygen species production and exhibit autoimmune and inflammatory diseases in the absence of evident infection. Neutrophils and macrophages have been extensively studied since phagocyte NADPH oxidase is mainly found only in them, while the impact of its deficiency on lymphocyte cellularity is less well characterized. We showed herein a zymosan-induced systemic inflammation model that CGD mice deficient in the phagocyte NADPH oxidase gp91phox subunit (NOX2) exhibited more severe thymic atrophy associated with peripheral blood and splenic lymphopenia and reduced lymphopoiesis in the bone marrow in comparison with the wild-type mice. Conversely, the zymosan-exposed CGD mice suffered from more remarkable neutrophilic lung inflammation, circulating and splenic neutrophilia, and enhanced granulopoiesis compared with those in zymosan-exposed wild-type mice. Overall, this study provided evidence that NOX2 deficiency exhibits severe thymic atrophy and lymphopenia concomitant with enhanced neutrophilic inflammation in a zymosan-induced systemic inflammation model.
Asunto(s)
Linfopenia/metabolismo , Linfopoyesis/fisiología , NADPH Oxidasa 2/deficiencia , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Timo/metabolismo , Zimosan/toxicidad , Animales , Atrofia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Enfermedad Granulomatosa Crónica/inducido químicamente , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Linfopenia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Síndrome de Respuesta Inflamatoria Sistémica/patología , Timo/efectos de los fármacos , Timo/patologíaRESUMEN
Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocyte function due to defective NADPH oxidase (phox). Compared with the common types of CYBB/gp91phox, NCF1/p47phox, and CYBA/p22phox deficiency, NCF4/p40phox deficiency is a mild and atypical form of CGD without invasive bacterial or fungal infections. It can be diagnosed using serum-opsonized E.coli as a stimulus in dihydrorhodamine (DHR) assay. Patients with CYBC1/Eros deficiency, a new and rare form of CGD, present as loss of respiratory burst and gp91phox expression in phagocytes. Neutrophils from patients with CGD are deficient in neutrophil extracellular traps (NETosis), autophagy, and apoptosis. The hyper-activation of NF-ĸB and inflammasome in CGD phagocytes also lead to long-lasting production of pro-inflammatory cytokines and inflammatory manifestations, such as granuloma formation and inflammatory bowel disease-like colitis. Patients with CGD and X-linked female carriers also have a higher incidence of autoimmune diseases. The implementation of antimicrobial, anti-fungal, and interferon-γ prophylaxis has greatly improved overall survival. Residual NADPH oxidase activity is significantly associated with disease severity and the chance of survival of the patient. New therapeutic approaches using immunomodulators for CGD-related inflammatory manifestations are under investigation, including pioglitazone, tamoxifen, and rapamycin. Hematopoietic stem cell transplantation (HSCT) is the curative treatment. Outcomes of HSCT have improved substantially over the last decade with overall survival more than 84-90%, but there are debates about designing optimal conditioning protocols using myeloablative or reduced-intensity regimens. The gene therapy for X-linked CGD using hematopoietic stem and progenitor cells transduced ex vivo by lentiviral vector encoding the human gp91phox gene demonstrated persistence of adequate oxidase-positive neutrophils in a small number of patients. Gene therapy using genome-editing technology such as CRISPR/Cas9 nucleases is a promising approach for patients with CGD in the future.
Asunto(s)
Enfermedad Granulomatosa Crónica , Animales , Terapia Genética , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/patología , Enfermedad Granulomatosa Crónica/terapia , Humanos , NADPH Oxidasas/genética , Neutrófilos/patologíaRESUMEN
World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of inborn errors of immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007 and 2019 was done. IEI was identified in n = 52/90 (57.7%) patients presenting with BCG complications. Of these, n = 13(14.4%) patients were diagnosed with severe combined immune deficiency, n = 15(16.7%) with chronic granulomatous disease, n = 19(21.1%) with Inborn errors of IFN-γ immunity, n = 4(4.4%) with Combined immunodeficiency and n = 1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.
Asunto(s)
Vacuna BCG/efectos adversos , Enfermedad Granulomatosa Crónica/patología , Inmunodeficiencia Combinada Grave/patología , Tuberculosis Pulmonar/prevención & control , Vacunación/efectos adversos , Vacuna BCG/inmunología , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/inmunología , Humanos , India , Lactante , Masculino , Mycobacterium tuberculosis/inmunología , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/inmunología , Resultado del TratamientoRESUMEN
Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.
Asunto(s)
Enfermedad Granulomatosa Crónica/terapia , Células Madre Hematopoyéticas/metabolismo , Interleucina-1beta/genética , Receptores CXCR4/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Animales , Sistemas CRISPR-Cas/genética , Células Cultivadas , Modelos Animales de Enfermedad , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Terapia Genética/métodos , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/patología , Humanos , Inflamación/genética , Inflamación/patología , Inflamación/terapia , Ratones , ARN/genética , ARN/uso terapéutico , Transducción de Señal/genéticaRESUMEN
Human exposure to carbon nanotubes (CNT) has been associated with the development of pulmonary sarcoid-like granulomatous disease. Our previous studies demonstrated that multi-walled carbon nanotubes (MWCNT) induced chronic pulmonary granulomatous inflammation in mice. Granuloma formation was accompanied by decreased peroxisome proliferator-activated receptor gamma (PPARγ) and disrupted intracellular lipid homeostasis in alveolar macrophages. Others have shown that PPARγ activation increases mitochondrial fatty acid oxidation (FAO) to reduce free fatty acid accumulation. Hence, we hypothesized that the disrupted lipid metabolism suppresses mitochondrial FAO. To test our hypothesis, C57BL/6 J mice were instilled by an oropharyngeal route with 100 µg MWCNT freshly suspended in 35 % Infasurf. Control sham mice received vehicle alone. Sixty days following instillation, mitochondrial FAO was measured in permeabilized bronchoalveolar lavage (BAL) cells. MWCNT instillation reduced the mitochondrial oxygen consumption rate of BAL cells in the presence of palmitoyl-carnitine as mitochondrial fuel. MWCNT also reduced mRNA expression of mitochondrial genes regulating FAO, carnitine palmitoyl transferase-1 (CPT1), carnitine palmitoyl transferase-2 (CPT2), hydroxyacyl-CoA dehydrogenase subunit beta (HADHB), and PPARγ coactivator 1 alpha (PPARGC1A). Importantly, both oxidative stress and apoptosis in alveolar macrophages and lung tissues of MWCNT-instilled mice were increased. Because macrophage PPARγ expression has been reported to be controlled by miR-27b which is known to induce oxidative stress and apoptosis, we measured the expression of miR-27b. Results indicated elevated levels in alveolar macrophages from MWCNT-instilled mice compared to controls. Given that inhibition of FAO and apoptosis are linked to M1 and M2 macrophage activation, respectively, the expression of both M1 and M2 key indicator genes were measured. Interestingly, results showed that both M1 and M2 phenotypes of alveolar macrophages were activated in MWCNT-instilled mice. In conclusion, alveolar macrophages of MWCNT-instilled mice had increased miR-27b expression, which may reduce the expression of PPARγ resulting in attenuation of FAO. This reduction in FAO may lead to activation of M1 macrophages. The upregulation of miR-27b may also induce apoptosis, which in turn can cause M2 activation of alveolar macrophages. These observations indicate a possible role of miR-27b in impaired mitochondrial function in the chronic activation of alveolar macrophages by MWCNT and the development of chronic pulmonary granulomatous inflammation.
Asunto(s)
Enfermedad Granulomatosa Crónica/inducido químicamente , Enfermedades Pulmonares/inducido químicamente , Macrófagos Alveolares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Animales , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Mitocondrias/metabolismo , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
The diverse clinicopathological spectrum of pulmonary aspergillosis is a consequence of varying levels of invasiveness of this ubiquitous fungus, which largely depends on the host immune response and pre-existing lung disease. The clinical presentation of pulmonary aspergillosis spans a wide spectrum from hypersensitivity to life threatening angio-invasive and disseminated disease. We report the case of a young immunocompetent male with no underlying lung disease, who presented with an incidentally detected 'infective mass' lesion in the lung associated with minimal respiratory symptoms. The diagnostic challenges posed by the unusual clinical, radiological and histological picture as well as the therapeutic dilemmas faced are discussed in this report.
Asunto(s)
Aspergillus/aislamiento & purificación , Enfermedad Granulomatosa Crónica/etiología , Enfermedades Pulmonares Fúngicas/patología , Aspergilosis Pulmonar/diagnóstico , Administración Oral , Adulto , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/etiología , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/patología , Hemoptisis/diagnóstico , Hemoptisis/etiología , Humanos , Biopsia Guiada por Imagen/métodos , Hallazgos Incidentales , Enfermedades Pulmonares Fúngicas/diagnóstico por imagen , Masculino , Neumonectomía/métodos , Cuidados Posoperatorios , Aspergilosis Pulmonar/microbiología , Aspergilosis Pulmonar/patología , Aspergilosis Pulmonar/cirugía , Radiografía Torácica/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Voriconazol/administración & dosificación , Voriconazol/uso terapéuticoRESUMEN
Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
Asunto(s)
Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad Granulomatosa Crónica/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
B cells mediate humoral immune response and contribute to the regulation of cellular immune response. Members of the Nuclear Factor kappaB (NF-κB) family of transcription factors play a major role in regulating B-cell functions. NF-κB subunit c-Rel is predominantly expressed in lymphocytes, and in B cells, it is required for survival, proliferation, and antibody production. Dysregulation of c-Rel expression and activation alters B-cell homeostasis and is associated with B-cell lymphomas and autoimmune pathologies. Based on its essential roles, c-Rel may serve as a potential prognostic and therapeutic target. This review summarizes the current understanding of the multifaceted role of c-Rel in B cells and B-cell diseases.
Asunto(s)
Linfocitos B/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Apoptosis , Autoinmunidad , Linfocitos B/inmunología , Centro Germinal/metabolismo , Enfermedad Granulomatosa Crónica/inmunología , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Pronóstico , Proteínas Proto-Oncogénicas c-rel/químicaRESUMEN
Neutrophils release neutrophil extracellular traps (NETs) in response to numerous pathogenic microbes as the last suicidal resource (NETosis) in the fight against infection. Apart from the host defense function, NETs play an essential role in the pathogenesis of various autoimmune and inflammatory diseases. Therefore, understanding the molecular mechanisms of NETosis is important for regulating aberrant NET release. The initiation of NETosis after the recognition of pathogens by specific receptors is mediated by an increase in intracellular Ca2+ concentration, therefore, the use of Ca2+ ionophore A23187 can be considered a semi-physiological model of NETosis. Induction of NETosis by various stimuli depends on reactive oxygen species (ROS) produced by NADPH oxidase, however, NETosis induced by Ca2+ ionophores was suggested to be mediated by ROS produced in mitochondria (mtROS). Using the mitochondria-targeted antioxidant SkQ1 and specific inhibitors of NADPH oxidase, we showed that both sources of ROS, mitochondria and NADPH oxidase, are involved in NETosis induced by A23187 in human neutrophils. In support of the critical role of mtROS, SkQ1-sensitive NETosis was demonstrated to be induced by A23187 in neutrophils from patients with chronic granulomatous disease (CGD). We assume that Ca2+-triggered mtROS production contributes to NETosis either directly (CGD neutrophils) or by stimulating NADPH oxidase. The opening of the mitochondrial permeability transition pore (mPTP) in neutrophils treated by A23187 was revealed using the electron transmission microscopy as a swelling of the mitochondrial matrix. Using specific inhibitors, we demonstrated that the mPTP is involved in mtROS production, NETosis, and the oxidative burst induced by A23187.
Asunto(s)
Trampas Extracelulares/metabolismo , Enfermedad Granulomatosa Crónica/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , NADPH Oxidasa 2/metabolismo , Neutrófilos/metabolismo , Estallido Respiratorio/fisiología , Adolescente , Calcimicina/farmacología , Calcio/metabolismo , Cationes Bivalentes/metabolismo , Células Cultivadas , Niño , Transporte de Electrón , Depuradores de Radicales Libres/farmacología , Enfermedad Granulomatosa Crónica/sangre , Voluntarios Sanos , Humanos , Mutación con Pérdida de Función , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Proteínas de Transporte de Membrana Mitocondrial/ultraestructura , Poro de Transición de la Permeabilidad Mitocondrial , NADPH Oxidasa 2/antagonistas & inhibidores , NADPH Oxidasa 2/genética , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/ultraestructura , Oxidación-Reducción/efectos de los fármacos , Plastoquinona/análogos & derivados , Plastoquinona/farmacología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Estallido Respiratorio/efectos de los fármacosRESUMEN
OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension (PH) that arises from obstruction of the pulmonary vessels by recanalized thromboembolic material. CTEPH has a wide range of radiologic presentations. Commonly, it presents as main pulmonary artery enlargement, peripheral vascular obstructions, bronchial artery dilations, and mosaic attenuation patterns. Nevertheless, other uncommon presentations have been described, such as lung cavities. These lesions may be solely related to chronic lung parenchyma ischemia but may also be a consequence of concomitant chronic infectious conditions. The objective of this study was to evaluate the different etiologies that cause lung cavities in CTEPH patients. METHODS: A retrospective data analysis of the medical records of CTEPH patients in a single reference PH center that contained or mentioned lung cavities was conducted between 2013 and 2016. RESULTS: Seven CTEPH patients with lung cavities were identified. The cavities had different sizes, locations, and wall thicknesses. In two patients, the cavities were attributed to pulmonary infarction; in 5 patients, an infectious etiology was identified. CONCLUSION: Despite the possibility of being solely associated with chronic lung parenchyma ischemia, most cases of lung cavities in CTEPH patients were associated with chronic granulomatous diseases, reinforcing the need for active investigation of infectious agents in this setting.
Asunto(s)
Enfermedad Granulomatosa Crónica , Hipertensión Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico , Tromboembolia/etiología , Angiografía/métodos , Anticoagulantes/uso terapéutico , Enfermedad Crónica , Femenino , Enfermedad Granulomatosa Crónica/patología , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Pulmón/irrigación sanguínea , Masculino , Imagen de Perfusión , Embolia Pulmonar/complicaciones , Embolia Pulmonar/terapia , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Chronic granulomatous disease (CGD) is an immune deficiency characterized by defective neutrophil function and increased risk of life-threatening infections. Allogeneic hematopoietic cell transplantation is curative for CGD, and conditioning regimen impacts transplant-related outcomes. We report a single-center prospective study (NCT01821781) of four patients with CGD transplanted using a reduced-intensity conditioning regimen (RIC) containing alemtuzumab, fludarabine, melphalan, and thiotepa. Patients had early immune reconstitution with low incidence of infections. Disease-free survival was 75% at a median of five years after transplant. This RIC regimen presents an alternative approach for transplant of patients with CGD who may not tolerate busulfan-based conditioning.
Asunto(s)
Alemtuzumab/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Melfalán/administración & dosificación , Tiotepa/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Niño , Preescolar , Estudios de Seguimiento , Enfermedad Granulomatosa Crónica/patología , Humanos , Lactante , Agonistas Mieloablativos/administración & dosificación , Pronóstico , Estudios Prospectivos , Vidarabina/administración & dosificaciónRESUMEN
Despite great interest, the mechanism of neutrophil extracellular traps (NETs) release is not fully understood and some aspects of this process, e.g. the role of reactive nitrogen species (RNS), still remain unclear. Therefore, our aim was to investigate the mechanisms underlying RNS-induced formation of NETs and contribution of RNS to NETs release triggered by various physiological and synthetic stimuli. The involvement of RNS in NETs formation was studied in primary human neutrophils and differentiated human promyelocytic leukemia cells (HL-60 cells). RNS (peroxynitrite and nitric oxide) efficiently induced NETs release and potentiated NETs-inducing properties of platelet activating factor and lipopolysaccharide. RNS-induced NETs formation was independent of autophagy and histone citrullination, but dependent on the activity of phosphoinositide 3-kinases (PI3K) and myeloperoxidase, as well as selective degradation of histones H2A and H2B by neutrophil elastase. Additionally, NADPH oxidase activity was required to release NETs upon stimulation with NO, as shown in NADPH-deficient neutrophils isolated from patients with chronic granulomatous disease. The role of RNS was further supported by increased RNS synthesis upon stimulation of NETs release with phorbol 12-myristate 13-acetate and calcium ionophore A23187. Scavenging or inhibition of RNS formation diminished NETs release triggered by these stimuli while scavenging of peroxynitrite inhibited NO-induced NETs formation. Our data suggest that RNS may act as mediators and inducers of NETs release. These processes are PI3K-dependent and ROS-dependent. Since inflammatory reactions are often accompanied by nitrosative stress and NETs formation, our studies shed a new light on possible mechanisms engaged in various immune-mediated conditions.
Asunto(s)
Trampas Extracelulares/efectos de los fármacos , Neutrófilos/metabolismo , Ácido Peroxinitroso/farmacología , Adenina/análogos & derivados , Adenina/farmacología , ADN/metabolismo , Trampas Extracelulares/metabolismo , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Humanos , Elastasa de Leucocito/metabolismo , Neutrófilos/citología , Neutrófilos/inmunología , Óxido Nítrico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Granulomatous fungal infections are common worldwide, and they can result in mediastinal lymphadenopathy. However, infectious pulmonary artery masses are rare and have only been associated with tuberculosis or mucormycosis. Here, we present a case of histoplasmosis resulting in a pulmonary artery mass, which was treated with debulking and reconstruction of pulmonary vasculature.