RESUMO
In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.
Assuntos
Elastina , Neutrófilos , Proteína-Arginina Desiminase do Tipo 2 , Proteína-Arginina Desiminase do Tipo 4 , Proteólise , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Neutrófilos/imunologia , Elastina/metabolismo , Feminino , Masculino , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Pessoa de Meia-Idade , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Enfisema Pulmonar/imunologia , Idoso , Proteína-Arginina Desiminase do Tipo 2/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Citrulinação , Desiminases de Arginina em Proteínas/metabolismo , Elastase de Leucócito/metabolismo , Pulmão/imunologia , Pulmão/patologiaRESUMO
A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.
Assuntos
Polipose Adenomatosa do Colo , Predisposição Genética para Doença , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Polipose Adenomatosa do Colo/genética , Ubiquitina-Proteína Ligases/genética , Proteína Axina/genética , Neoplasias Colorretais/genética , Proteína Supressora de Tumor p53/genética , Idoso , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a DNA/genética , Desoxirribonuclease (Dímero de Pirimidina)RESUMO
SARS-CoV-2 can infect wildlife, and SARS-CoV-2 variants of concern might expand into novel animal reservoirs, potentially by reverse zoonosis. White-tailed deer and mule deer of North America are the only deer species in which SARS-CoV-2 has been documented, raising the question of whether other reservoir species exist. We report cases of SARS-CoV-2 seropositivity in a fallow deer population located in Dublin, Ireland. Sampled deer were seronegative in 2020 when the Alpha variant was circulating in humans, 1 deer was seropositive for the Delta variant in 2021, and 12/21 (57%) sampled deer were seropositive for the Omicron variant in 2022, suggesting host tropism expansion as new variants emerged in humans. Omicron BA.1 was capable of infecting fallow deer lung type-2 pneumocytes and type-1-like pneumocytes or endothelial cells ex vivo. Ongoing surveillance to identify novel SARS-CoV-2 reservoirs is needed to prevent public health risks during human-animal interactions in periurban settings.
Assuntos
COVID-19 , Cervos , SARS-CoV-2 , Animais , SARS-CoV-2/imunologia , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/veterinária , Humanos , Cervos/virologia , Irlanda/epidemiologia , Estudos Soroepidemiológicos , População Urbana , Reservatórios de Doenças/virologia , Reservatórios de Doenças/veterinária , Animais Selvagens/virologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Feminino , MasculinoRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with neurological sequelae including haemorrhage, thrombosis and ischaemic necrosis and encephalitis. However, the mechanism by which this occurs is unclear. Neurological disease associated with COVID-19 has been proposed to occur following direct infection of the central nervous system and/or indirectly by local or systemic immune activation. We evaluated the expression of angiotensin-converting enzyme-2 and transmembrane protease, serine 2 (TMPRSS2) in brain tissue from five healthy human donors and observed low-level expression of these proteins in cells morphologically consistent with astrocytes, neurons and choroidal ependymal cells within the frontal cortex and medulla oblongata. Primary human astrocytes, neurons, choroid plexus epithelial cells and pericytes supported productive SARS-CoV-2 infection with ancestral, Alpha, Delta and Omicron variants. Infected cells supported the full viral life cycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 can infect human brain cells, and the mechanism of viral entry warrants further investigation.
Assuntos
Enzima de Conversão de Angiotensina 2 , Astrócitos , COVID-19 , Plexo Corióideo , Células Epiteliais , Neurônios , Pericitos , SARS-CoV-2 , Serina Endopeptidases , Humanos , Pericitos/virologia , SARS-CoV-2/fisiologia , Astrócitos/virologia , Plexo Corióideo/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Neurônios/virologia , COVID-19/virologia , COVID-19/patologia , Células Epiteliais/virologia , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Células Cultivadas , Encéfalo/virologia , Encéfalo/patologia , Sistema Nervoso Central/virologiaRESUMO
BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations. RESULTS: The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions.In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. CONCLUSIONS: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.
RESUMO
Sjögren's disease (SjD) is a chronic, progressive autoimmune condition of exocrine and extraglandular tissues. It can present with isolated disease characterized by lymphocytic infiltration of salivary or lacrimal glands, but in approximately one-third of the patients, lymphocytic infiltration extends beyond exocrine glands to involve extraglandular organs such as the lungs. Pulmonary complications have been reported to occur between 9 and 27% of patients with SjD across studies. Respiratory manifestations occur on a spectrum of severity and include airways disease, interstitial lung disease, cystic lung disease, and lymphoma. Lung involvement can greatly affect patients' quality of life, has a major impact on the overall prognosis, and frequently leads to alteration in the treatment plans, highlighting the importance of maintaining a high index of clinical suspicion and taking appropriate steps to facilitate early recognition and intervention.
Assuntos
Pneumopatias , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/fisiopatologia , Pneumopatias/etiologia , Qualidade de Vida , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , PrognósticoRESUMO
This case describes a woman in her 20s with a 6-month history of progressive exertional dyspnoea and cough. Examination revealed hypoxia on room air, sinus tachycardia, finger clubbing and bibasal inspiratory crackles. Inflammatory markers were mildly elevated and empirical antimicrobial therapy was commenced. A multidisciplinary discussion consensus diagnosis of acute interstitial pneumonitis was made based on the findings of high-resolution CT of the chest, macrophage predominant bronchoalveolar lavage cell differential and surgical lung biopsy. There was clinical and radiological deterioration despite glucocorticoids and antifibrotic therapy. A body mass index of 37.5 kg/m2 precluded her from lung transplant assessment and consideration. Following consultation with the weight management service, she was commenced on glucagon-like peptide 1 (GLP-1) analogue therapy. She had a remarkable response within 6 months, was listed for lung transplantation, and within 18 months of her initial presentation, a double lung transplantation was performed.
Assuntos
Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Pulmão , Feminino , Humanos , Pulmão/patologia , Dispneia/diagnóstico , Tosse/patologia , Redução de PesoRESUMO
ARID1B-related disorders constitute a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability (ID) with or without nonspecific dysmorphic features. Here, we describe an 11-year-old boy with an ARID1B mutation whose phenotype changed from severe developmental delay and ID to a complex neurodevelopmental disorder with multidimensional impairments, including normal intelligence despite heterogeneous IQ scores, severe motor coordination disorder, oral language disorder and attention-deficit/hyperactivity disorder. Phenotypic changes occurred after early intensive remediation and paralleled the normalization of myelination impairments, as evidenced by early brain imaging. WHAT THIS PAPER ADDS?: This report describes a 10-year multidisciplinary follow-up of a child with an ARID1B mutation who received early intensive remediation and whose phenotype changed during development. Clinical improvement paralleled the normalization of myelination impairments. This case supports a dimensional approach for complex neurodevelopmental disorders.
Assuntos
Proteínas de Ligação a DNA , Deficiência Intelectual , Micrognatismo , Fenótipo , Fatores de Transcrição , Humanos , Masculino , Criança , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Micrognatismo/genética , Micrognatismo/diagnóstico por imagem , Seguimentos , Face/anormalidades , Face/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/anormalidades , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/diagnóstico por imagem , Pescoço/anormalidades , Pescoço/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/genética , Imageamento por Ressonância Magnética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Transtornos das Habilidades Motoras/genética , Mutação , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/diagnóstico por imagem , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/genéticaRESUMO
Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.
RESUMO
Genetic analysis pre-lung transplantation diagnosed a case of hereditary pulmonary alveolar proteinosis (PAP) complicated by fibrosis in adulthood. The need for genetic testing in GM-CSF autoantibody negative and unclassifiable PAP is highlighted. https://bit.ly/3QcsYwM.