RESUMO
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.
Assuntos
Doença Granulomatosa Crônica/genética , Hematopoese/genética , Síndromes Mielodisplásicas/genética , NADPH Oxidase 2/genética , Éxons/genética , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/patologia , Humanos , Lactente , Masculino , Mutação/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , NADPH Oxidases/genética , Neutrófilos/metabolismo , Neutrófilos/patologia , Pediatria , Fagócitos/metabolismo , Splicing de RNA/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.
Assuntos
Doença Granulomatosa Crônica , Hipertensão Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico , Tromboembolia/etiologia , Angiografia/métodos , Anticoagulantes/uso terapêutico , Doença Crônica , Feminino , Doença Granulomatosa Crônica/patologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Pulmão/irrigação sanguínea , Masculino , Imagem de Perfusão , Embolia Pulmonar/complicações , Embolia Pulmonar/terapia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
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.
Assuntos
Humanos , Masculino , Feminino , Embolia Pulmonar/diagnóstico , Tromboembolia/etiologia , Doença Granulomatosa Crônica/patologia , Hipertensão Pulmonar/diagnóstico , Embolia Pulmonar/complicações , Embolia Pulmonar/terapia , Angiografia/métodos , Tomografia Computadorizada por Raios X/métodos , Doença Crônica , Estudos Retrospectivos , Resultado do Tratamento , Imagem de Perfusão , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Pulmão/irrigação sanguínea , Anticoagulantes/uso terapêuticoRESUMO
Interferon-γ (IFN-γ) plays an important role in innate and adaptive immunity against intracellular infections and is used clinically for the prevention and control of infections in chronic granulomatous disease (CGD) and inborn defects in the IFN-γ/interleukin (IL)-12 axis. Using transcriptome profiling (RNA-seq), we sought to identify differentially expressed genes, transcripts and exons in Epstein-Barr virus-transformed B lymphocytes (B-EBV) cells from CGD patients, IFN-γ receptor deficiency patients, and normal controls, treated in vitro with IFN-γ for 48 hours. Our results show that IFN-γ increased the expression of a diverse array of genes related to different cellular programs. In cells from normal controls and CGD patients, IFN-γ-induced expression of genes relevant to oxidative killing, nitric oxide synthase pathway, proteasome-mediated degradation, antigen presentation, chemoattraction, and cell adhesion. IFN-γ also upregulated genes involved in diverse stages of messenger RNA (mRNA) processing including pre-mRNA splicing, as well as others implicated in the folding, transport, and assembly of proteins. In particular, differential exon expression of WARS (encoding tryptophanyl-transfer RNA synthetase, which has an essential function in protein synthesis) induced by IFN-γ in normal and CGD cells suggests that this gene may have an important contribution to the benefits of IFN-γ treatment for CGD. Upregulation of mRNA and protein processing related genes in CGD and IFNRD cells could mediate some of the effects of IFN-γ treatment. These data support the concept that IFN-γ treatment may contribute to increased immune responses against pathogens through regulation of genes important for mRNA and protein processing.
Assuntos
Linfócitos B/metabolismo , Expressão Gênica/efeitos dos fármacos , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/genética , Interferon gama/farmacologia , Receptores de Interferon/deficiência , Linfócitos B/virologia , Linhagem Celular , Éxons/genética , Doença Granulomatosa Crônica/patologia , Herpesvirus Humano 4 , Humanos , Splicing de RNA/genética , RNA Mensageiro/genética , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Triptofano-tRNA Ligase/genética , Receptor de Interferon gamaRESUMO
The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.
Assuntos
Acetofenonas/farmacologia , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiorredoxinas/metabolismo , Animais , Doença Granulomatosa Crônica/induzido quimicamente , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Knockout , NADPH Oxidase 2/genética , NF-kappa B/genética , Oxirredução/efeitos dos fármacos , Sepse/induzido quimicamente , Sepse/genética , Sepse/metabolismo , Sepse/patologia , Tiorredoxinas/genéticaRESUMO
CD4+ T follicular helper cells (TFH) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). TFH lymphocytes were characterized by expression of CXCR5 and PD-1. TFH were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and TFH reg were similar in both CVID groups and in N. TFH responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of TFH cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that TFH are functional in CVID and highlight the association of increased circulating TFH with AI and GD manifestations.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Regulação da Expressão Gênica/imunologia , Doença Granulomatosa Crônica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Autoimunidade , Ligante de CD40/genética , Ligante de CD40/imunologia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/patologia , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/patologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/farmacologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucinas/genética , Interleucinas/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologiaRESUMO
Sarcoidosis is a multisystem granulomatous disease of unknown cause. The osteoarticular involvement in sarcoidosis is rare and is often associated with cutaneous and long-standing chronic multisystem disease. More common in black women, osseous sarcoidosis is difficult to diagnose, with an incidence of 3 to 13%. The most characteristic radiological clinical picture evidences rounded, well-defined cysts, with no periosteal reaction and without peripheral sclerosis. The small bones of hands and feet are the most frequently involved sites. This report aims to demonstrate a rare case of osteoarticular sarcoidosis with characteristic clinical presentation, and highlight the importance of detecting osteoarticular involvement in this pathology.
Assuntos
Doença Granulomatosa Crônica/patologia , Doenças Musculoesqueléticas/patologia , Sarcoidose/patologia , Dermatopatias/patologia , Idoso de 80 Anos ou mais , Feminino , Doença Granulomatosa Crônica/diagnóstico por imagem , Ossos da Mão/diagnóstico por imagem , Ossos da Mão/patologia , Humanos , Doenças Musculoesqueléticas/diagnóstico por imagem , Radiografia , Sarcoidose/diagnóstico por imagem , Dermatopatias/diagnóstico por imagem , Telangiectasia/patologiaRESUMO
Sarcoidosis is a multisystem granulomatous disease of unknown cause. The osteoarticular involvement in sarcoidosis is rare and is often associated with cutaneous and long-standing chronic multisystem disease. More common in black women, osseous sarcoidosis is difficult to diagnose, with an incidence of 3 to 13%. The most characteristic radiological clinical picture evidences rounded, well-defined cysts, with no periosteal reaction and without peripheral sclerosis. The small bones of hands and feet are the most frequently involved sites. This report aims to demonstrate a rare case of osteoarticular sarcoidosis with characteristic clinical presentation, and highlight the importance of detecting osteoarticular involvement in this pathology.
Assuntos
Idoso de 80 Anos ou mais , Feminino , Humanos , Doença Granulomatosa Crônica/patologia , Doenças Musculoesqueléticas/patologia , Sarcoidose/patologia , Dermatopatias/patologia , Doença Granulomatosa Crônica , Ossos da Mão/patologia , Ossos da Mão , Doenças Musculoesqueléticas , Sarcoidose , Dermatopatias , Telangiectasia/patologiaRESUMO
The sequence of hepatic necrotic-inflammatory events produced by Entamoeba dispar are originally described in this work. For the first time were described in details the experimental lesions produced by E. dispar, as well as the distribution of the trophozoites detected by the immunohistochemistry. Animals experimentally infected with E. dispar presented necrosis, thrombosis and chronic granulomatous inflammation. Immunoreactive products derived from trofozoites were observed close or associated with trophozoites, epithelioid cells, leucocytes and hepatocytes. Few are the articles on the literature about virulence of E. dispar, which is approximately 9 times more frequent than to E. histolytica. Variation in the virulence is, therefore expected and signalizing the need of the continuity of studies with E. dispar strains from different places in the world. Taking into account that E. dispar is a closely related species to E. histolytica, these studies could determine new elements involved with E. histolytica pathogenesis, helping us to understand better the disease.
Assuntos
Entamoeba/fisiologia , Entamebíase/complicações , Hepatopatias Parasitárias/patologia , Fígado/patologia , Animais , Cricetinae , Entamebíase/imunologia , Entamebíase/patologia , Doença Granulomatosa Crônica/patologia , Imuno-Histoquímica , Inflamação/patologia , Necrose/etiologia , Necrose/patologia , Ratos , Trombose/etiologia , Trombose/patologiaRESUMO
This work investigated the functional role of nuclear factor-kappaB (NF-kappaB) in respiratory burst activity and in expression of the human phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes CYBB, CYBA, NCF1, and NCF2. U937 cells with a stably transfected repressor of NF-kappaB (IkappaBalpha-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared with control U937 cells. We further tested Epstein-Barr virus (EBV)-transformed B cells from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an inherited disorder of NF-kappaB function. Superoxide release and CYBB gene expression by EDA-ID cells were significantly decreased compared with healthy cells and similar to cells from patients with X-linked chronic granulomatous disease (X91(0) CGD). NCF1 gene expression in EDA-ID S32I cells was decreased compared with healthy control cells and similar to that in autosomal recessive (A47(0)) CGD cells. Gel shift assays demonstrated loss of recombinant human p50 binding to a NF-kappaB site 5' to the CYBB gene in U937 cells treated with NF-kappaB inhibitors, repressor-transfected U937 cells, and EDA-ID patients' cells. Zymosan phagocytosis was not affected by transfection of U937 cells with the NF-kappaB repressor. These studies show that NF-kappaB is necessary for CYBB and NCF1 gene expression and activation of the phagocyte NADPH oxidase in this model system.