RESUMO
Granulomas are frequently encountered by pathologists in all types of lung specimens and arise from diverse etiologies. They should always be reported as necrotizing or non-necrotizing, with microorganism stains performed to evaluate for infection. With attention to distribution, quality (poorly vs well-formed), associated features, and correlation with clinical, radiologic, and laboratory data, the differential diagnosis for granulomatous lung disease can usually be narrowed to a clinically helpful "short list." This review describes a practical approach to pulmonary granulomas and reviews the clinicopathological aspects of common entities, including infectious (mycobacteria, fungi) and noninfectious (hypersensitivity pneumonitis, sarcoid, and vasculitis) causes.
Assuntos
Pneumopatias , Humanos , Diagnóstico Diferencial , Pneumopatias/patologia , Pneumopatias/diagnóstico , Granuloma do Sistema Respiratório/patologia , Granuloma do Sistema Respiratório/diagnóstico , Granuloma/patologia , Granuloma/diagnóstico , Pulmão/patologia , Alveolite Alérgica Extrínseca/diagnóstico , Alveolite Alérgica Extrínseca/patologia , Sarcoidose Pulmonar/patologia , Sarcoidose Pulmonar/diagnóstico , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/patologiaAssuntos
Granuloma do Sistema Respiratório , Pneumopatias , Pneumonia , Humanos , Granuloma/diagnóstico por imagem , Granuloma/patologia , Radiografia , Pneumopatias/diagnóstico por imagem , Pneumopatias/patologia , Hialina , Granuloma do Sistema Respiratório/diagnóstico por imagem , Granuloma do Sistema Respiratório/patologiaRESUMO
INTRODUCTION: Large vessels are often encountered during endobronchial ultrasound (EBUS). Safety of traversing the vessels weighed against a more invasive procedure can be a dilemma. MATERIAL AND METHODS: We describe a case series of 8 patients who underwent transvascular needle aspiration during EBUS, to access a lesion in the absence of an alternate safe window. A 21 gauge EBUS needle was used to traverse either the main or a major branch of the pulmonary artery. RESULTS: Malignancy was suspected at ROSE in five cases. Granuloma and necrosis noted in 2 cases were confirmed as tubercu-losis on culture. Diagnostic yield of EBUS-TVNA was 87.5% (7/8). No complications were noted in the immediate post-operative period as well as during 6 months of follow up. CONCLUSION: EBUS-TVNA in carefully selected patients is a feasible alternative to more invasive procedures with excellent yield. Appropriate intraoperative, perioperative and postoperative monitoring and care must be available in the case of fatal bleeds.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Biópsia Guiada por Imagem/métodos , Neoplasias Pulmonares/patologia , Pulmão/patologia , Linfonodos/patologia , Adulto , Feminino , Granuloma do Sistema Respiratório/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.
Assuntos
Granuloma do Sistema Respiratório/metabolismo , Pulmão/metabolismo , Modelos Biológicos , Mycobacterium tuberculosis/metabolismo , RNA-Seq , Tuberculose Pulmonar/metabolismo , Adulto , Idoso , Feminino , Granuloma do Sistema Respiratório/genética , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/patologia , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologiaRESUMO
Tuberculosis (TB) is still a major worldwide health threat and primarily a lung disease. The innate immune response against Mycobacterium tuberculosis (Mtb) is orchestrated by dendritic cells, macrophages, neutrophils, natural killer cells and apparently mast cells (MCs). MCs are located at mucosal sites including the lungs and contribute in host-defence against pathogens, but little is known about their role during Mtb infection. This study investigates the location and characteristics of MCs in TB lesions to assess their contribution to TB pathology. To this purpose, number, location and phenotype of MCs was studied in 11 necropsies of pulmonary TB and 3 necropsies of non-TB infected lungs that were used as controls. MCs were localised at pneumonic areas, in the granuloma periphery and particularly abundant in fibrotic tissue. Furthermore, MCs displayed intracellular Mtb and IL-17A and TGF-ß immunostaining. These findings were validated by analysing, post-mortem lung tissue microarrays from 44 individuals with pulmonary TB and 25 control subjects. In affected lungs, increased numbers of MCs expressing intracellularly both tryptase and chymase were found at fibrotic sites. Altogether, our data suggest that MCs are recruited at the inflammatory site and that actively produce immune mediators such as proteases and TGF-ß that may be contributing to late fibrosis in TB lesions.
Assuntos
Contagem de Leucócitos , Mastócitos/imunologia , Mastócitos/metabolismo , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Antígenos de Bactérias/imunologia , Fibrose , Granuloma do Sistema Respiratório/patologia , Humanos , Imuno-Histoquímica , Triptases/metabolismoRESUMO
Immune dysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by loss-of-function mutations in the gene forkhead box protein 3 (FOXP3). IPEX patients frequently show chronic diarrhea (enteropathy) associated with villous atrophies in the small intestine. Our case is different from this classical information in the literature, since he presented with neonatal onset inflammatory bowel disease within the first months of life accompanied by deep ulcers throughout colonic mucosa. Moreover, he developed chronic lung disease during follow-up and histopathological examinations showed granulomas in both gastrointestinal tract and lung parenchyma. Genetic analysis revealed the diagnosis of IPEX syndrome with a germline mutation in FOXP3. Thus, our study provides an unusual presentation of IPEX syndrome with colitis and granulomas presence in histopathological examinations.
Assuntos
Colite/patologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Granuloma do Sistema Respiratório/patologia , Doenças do Sistema Imunitário/congênito , Colite/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diarreia/genética , Duodeno/patologia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Granuloma/genética , Granuloma/patologia , Granuloma do Sistema Respiratório/genética , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Recém-Nascido , Masculino , MutaçãoRESUMO
Drug adulterants containing contaminants have been known to cause lung disease by inhalation or intravenous intake. Talcosis due to intravenous talc injection has been widely described in the literature, whereas the hypothesis of granulomatosis due to asbestos related to adulterated cocaine injection has not yet been explored. Herein, a case of pulmonary granulomatosis due to asbestos fibres related to cocaine injection in a young woman is described. Inorganic material in the lung was first individuated by light microscopy and last was identified using the SEM-EDX method. This case is unique since the occupational and passive inhalation of asbestos was excluded with absolute certainty.
Assuntos
Amianto/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/complicações , Cocaína/efeitos adversos , Contaminação de Medicamentos , Granuloma de Corpo Estranho/etiologia , Granuloma do Sistema Respiratório/etiologia , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Amianto/administração & dosagem , Autopsia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Usuários de Drogas , Evolução Fatal , Feminino , Granuloma de Corpo Estranho/patologia , Granuloma do Sistema Respiratório/patologia , HumanosRESUMO
The mechanism by which only some individuals infected with Mycobacterium tuberculosis develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to macrophage dysfunction, while their congenic counterpart (B6) mice do not. In this study we report that (a) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by superinduction of stress and type I interferon pathways after prolonged TNF stimulation; (b) the late-stage TNF response was driven via a JNK/IFN-ß/protein kinase R (PKR) circuit; and (c) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and Ddit4. The administration of ISRIB, a small-molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis-infected sst1S mice and concomitantly reduced the bacterial burden. Hence, induction of the ISR and the locked-in state of escalating stress driven by the type I IFN pathway in sst1S macrophages play a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.
Assuntos
Granuloma do Sistema Respiratório/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Estresse Fisiológico/imunologia , Tuberculose Pulmonar/imunologia , Animais , Modelos Animais de Doenças , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/patologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos SCID , Necrose , Tuberculose Pulmonar/patologiaRESUMO
The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed in vitro human granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis-specific disease regulating pathways at play during early stages of granuloma formation. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.
Assuntos
Granuloma do Sistema Respiratório , Pulmão , Sarcoidose Pulmonar , Animais , Células Cultivadas , Modelos Animais de Doenças , Granuloma do Sistema Respiratório/genética , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/metabolismo , Granuloma do Sistema Respiratório/patologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Modelos Teóricos , Sarcoidose Pulmonar/genética , Sarcoidose Pulmonar/imunologia , Sarcoidose Pulmonar/metabolismo , Sarcoidose Pulmonar/patologiaRESUMO
Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.
Assuntos
Imunodeficiência de Variável Comum/patologia , Granuloma do Sistema Respiratório/patologia , Deficiência de IgA/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Linfócitos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Proliferação de Células , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/terapia , Feminino , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/mortalidade , Granuloma do Sistema Respiratório/terapia , Humanos , Deficiência de IgA/imunologia , Deficiência de IgA/mortalidade , Deficiência de IgA/terapia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/terapia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte , Valor Preditivo dos Testes , Prognóstico , Adulto JovemRESUMO
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, usually chronic and has a progressive clinical course. Despite the availability of effective chemotherapy, TB is a leading killer of young adults worldwide and the global multi-drug resistant TB is reaching epidemic proportions. Interrupt transmission through early detection and treatment of the patients is a main element of the drug-resistant TB control strategy. However, many drugable targets in pathogens are already inhibited by current antibiotics and there is not a biomarker that indicate normal or pathogenic biological processes, or pharmacological responses to therapeutic intervention. Studies directed at evaluate key elements of host response to infection may identify biomarkers with measurable characteristics that indicate pathogenic biological processes. Cell-derived microparticles (MPs) are membrane-coated vesicles that represent subcellular elements and have been identified increasingly in a broad range of diseases and emerging as potential novel biomarker to pathological processes. In addition, MPs carry contents from their cells of origin as bioactive molecules as cytokines, enzymes, surface receptors, antigens and genetic information and may provide a means of communication between cells. Molecules-loaded MPs may interplay with the immune system and therefore can acts on inflammation, cell activation and migration. Therefore, MPs may be an important factor to immune process during Mtb infection, especially in pulmonary granulomas and influence the outcome of infection. Their characterization may facilitate an appropriate diagnosis, optimize pharmacological strategies and might be further explored as potential targets for future clinical interventions.
Assuntos
Antituberculosos/uso terapêutico , Micropartículas Derivadas de Células/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar , Biomarcadores/análise , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/patologia , Humanos , Inflamação/patologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/patologiaRESUMO
Sarcoid-like granulomatosis is a known but rare adverse reaction to immune checkpoint inhibitors and chemotherapy in the treatment of advanced solid tumors. We present a case of a 29-year-old female with a pathologically confirmed poorly differentiated invasive ductal carcinoma of the breast with presumed metastases to the lungs, hilar lymph nodes, liver, and spleen. Despite appropriate chemotherapy, the patient developed pulmonary lesions that were interpreted on imaging studies as progression of malignancy. Autopsy revealed disseminated sarcoid-like granulomatosis with multiple noncaseating granulomata with associated fibrosis in the lungs, liver, and spleen. No residual invasive carcinoma or metastatic disease was identified. This case illustrates the difficulty in differentiating this nonneoplastic process from progressive disease in the clinical setting.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Granuloma do Sistema Respiratório/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Feminino , Granuloma do Sistema Respiratório/induzido quimicamente , Humanos , Pulmão/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologiaRESUMO
Various reports of disease-related lung pathologies in common variable immunodeficiency disorder (CVID) patients have been published, with differing histological and high-resolution computed tomography (HRCT) findings. Data were extracted from the validated Oxford Primary Immune Deficiencies Database (PID) database (1986-2016) on adult, sporadic CVID patients with suspected interstitial lung disease (ILD). Histology of lung biopsies was studied in relation to length of follow-up, clinical outcomes, HRCT findings and chest symptoms, to look for evidence for different pathological processes. Twenty-nine CVID patients with lung histology and/or radiological evidence of ILD were followed. After exclusions, lung biopsies from 16 patients were reanalysed for ILD. There were no well-formed granulomata, even though 10 patients had systemic, biopsy-proven granulomata in other organs. Lymphocytic infiltration without recognizable histological pattern was the most common finding, usually with another feature. On immunochemistry (n = 5), lymphocytic infiltration was due to T cells (CD4 or CD8). Only one patient showed B cell follicles with germinal centres. Interstitial inflammation was common; only four of 11 such biopsies also showed interstitial fibrosis. Outcomes were variable and not related to histology, suggesting possible different pathologies. The frequent nodules on HRCT were not correlated with histology, as there were no well-formed granulomata. Five patients were asymptomatic, so it is essential for all patients to undergo HRCT, and to biopsy if abnormal HRCT findings are seen. Internationally standardized pathology and immunochemical data are needed for longitudinal studies to determine the precise pathologies and prognoses in this severe complication of CVIDs, so that appropriate therapies may be found.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunodeficiência de Variável Comum/imunologia , Bases de Dados Factuais , Doenças Pulmonares Intersticiais/imunologia , Pulmão/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Biópsia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Imunodeficiência de Variável Comum/patologia , Feminino , Seguimentos , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/patologia , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologiaRESUMO
Mycobacterium tuberculosis (MTB) is a pathogen that infects and kills millions yearly. The mycobacterium's cell wall glycolipid trehalose 6,6'-dimycolate (TDM) has been used historically to model MTB induced inflammation and granuloma formation. Alterations to the model can significantly influence the induced pathology. One such method incorporates intraperitoneal pre-exposure, after which the intravenous injection of TDM generates pathological damage effectively mimicking the hypercoagulation, thrombus formation, and tissue remodeling apparent in lungs of infected individuals. The purpose of these experiments is to examine the histological inflammation involved in the TDM mouse model that induces development of the hemorrhagic response. TDM induced lungs of C57BL/6 mice to undergo granulomatous inflammation. Further histological examination of the peak response demonstrated tissue remodeling consistent with hypercoagulation. The observed vascular occlusion indicates that obstruction likely occurs due to subendothelial localized activity leading to restriction of blood vessel lumens. Trichrome staining revealed that associated damage in the hypercoagulation model is consistent with intra endothelial cell accumulation of innate cells, bordered by collagen deposition in the underlying parenchyma. Overall, the hypercoagulation model represents a comparative pathological instrument for understanding mechanisms underlying development of hemorrhage and vascular occlusion seen during MTB infection.
Assuntos
Fatores Corda/metabolismo , Endotélio Vascular/patologia , Granuloma do Sistema Respiratório/patologia , Pulmão/irrigação sanguínea , Mycobacterium tuberculosis/metabolismo , Pneumonia/patologia , Tuberculose Pulmonar/patologia , Animais , Coagulação Sanguínea , Modelos Animais de Doenças , Endotélio Vascular/microbiologia , Feminino , Granuloma do Sistema Respiratório/sangue , Granuloma do Sistema Respiratório/induzido quimicamente , Granuloma do Sistema Respiratório/microbiologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Pneumonia/sangue , Pneumonia/induzido quimicamente , Pneumonia/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/induzido quimicamente , Tuberculose Pulmonar/microbiologia , Remodelação VascularRESUMO
CASE SERIES: Avian mycobacteriosis is a significant disease of a wide range of bird species worldwide. The most common causative agent, Mycobacterium avium, is reported to also infect a range of mammals, including humans. Of 11 brolgas (Antigone rubicunda) submitted to the University of Melbourne for postmortem examination over a 10-year period, 7 were diagnosed with mycobacteriosis. All were from a wildlife park and kept in permanent enclosures as part of a breeding program. Most of the brolgas with mycobacteriosis were in poor body condition and had widely disseminated granulomas throughout the body, especially within the liver, spleen and gastrointestinal tract. Respiratory tract involvement was common, with all disseminated cases having pulmonary or air sac granulomas. Rare to moderate numbers of acid-fast organisms were detected in granulomas by histological examination. Where examined by appropriate bacteriological examinations, M. avium complex was isolated from affected tissues. CONCLUSION: This case series is the first known report of mycobacteriosis in brolgas and highlights the pathological changes seen. The complications in maintaining an avian mycobacteriosis-free breeding program and in eradication of the disease from an enclosed wildlife environment are discussed.
Assuntos
Granuloma do Sistema Respiratório/veterinária , Tuberculose Aviária/fisiopatologia , Animais , Animais Selvagens , Animais de Zoológico , Autopsia/veterinária , Aves , Granuloma/patologia , Granuloma/veterinária , Granuloma do Sistema Respiratório/patologia , Fígado/patologia , Mycobacterium avium/isolamento & purificação , Baço/patologia , Tuberculose Aviária/epidemiologia , Vitória/epidemiologiaAssuntos
Doenças do Cão/diagnóstico , Fibrose/veterinária , Granuloma do Sistema Respiratório/veterinária , Linfadenite/veterinária , Eosinofilia Pulmonar/veterinária , Animais , Doenças do Cão/patologia , Cães , Fibrose/patologia , Granuloma do Sistema Respiratório/diagnóstico , Granuloma do Sistema Respiratório/patologia , Pulmão/patologia , Linfadenite/patologia , Masculino , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/patologiaRESUMO
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Assuntos
Granuloma do Sistema Respiratório/patologia , Linfócitos/imunologia , Mycobacterium tuberculosis/fisiologia , Células Supressoras Mieloides/imunologia , Tuberculose Pulmonar/imunologia , Antígeno B7-H1/metabolismo , Carga Bacteriana , Proliferação de Células , Células Cultivadas , Replicação do DNA , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Granuloma do Sistema Respiratório/microbiologia , Humanos , Tolerância Imunológica , Interleucina-10/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Regulação para CimaAssuntos
Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/patologia , Sarcoidose/patologia , Diagnóstico Diferencial , Feminino , Granuloma do Sistema Respiratório/etiologia , Granuloma do Sistema Respiratório/patologia , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/epidemiologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Fenótipo , Prevalência , Estudos Retrospectivos , Sarcoidose/complicações , Sarcoidose/diagnóstico por imagem , Sarcoidose/epidemiologia , Fumar/efeitos adversos , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Human Mycobacterium tuberculosis infection was thought to result in either active symptomatic tuberculosis (TB) or latent asymptomatic infection. It is now clear that this binary classification is insufficient to describe the myriad of infection outcomes. In active TB, symptomatic disease can be mild to severe, with a range of lung and thoracic lymph node involvement or extrapulmonary manifestations. Most humans control the infection and develop latent TB infection, with differential risks of reactivation to active TB. However, some frequently exposed persons appear to be resistant to infection, whereas others may initially become infected yet subsequently eliminate all bacilli. The immunologic factors influencing these varied outcomes are still not clear, but likely involve a range of different responses. In this article, we review the data supporting the spectrum of M. tuberculosis infection in humans as well as data in nonhuman primates that allow dissection of the immune responses leading to the varied outcomes of infection.
Assuntos
Resistência à Doença/imunologia , Granuloma do Sistema Respiratório/microbiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Antígenos de Bactérias/imunologia , Granuloma do Sistema Respiratório/patologia , Humanos , Linfócitos T/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologiaRESUMO
Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.