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1.
BMC Cancer ; 21(1): 314, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761922

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.


Assuntos
Quimiorradioterapia/efeitos adversos , Monitoramento de Medicamentos/métodos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/terapia , Autorrelato/estatística & dados numéricos , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Quimiorradioterapia/métodos , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Diarreia/epidemiologia , Diarreia/imunologia , Erupção por Droga/diagnóstico , Erupção por Droga/epidemiologia , Erupção por Droga/imunologia , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Hepatite/diagnóstico , Hepatite/epidemiologia , Hepatite/imunologia , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Hipotireoidismo/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Pneumonia/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Prospectivos
2.
Biomed Res Int ; 2021: 1782765, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33506011

RESUMO

Natural killer T (NKT) cells are a key component of innate immunity. Importantly, a growing body of evidence indicates that NKT cells play an integral role in various acute and chronic liver injuries. NKT cells participate in the progression of an injury through the secretion of cytokines, which promote neutrophil infiltration and enhance Fas ligand (FasL) and granzyme-mediated NKT cytotoxic activity. Therefore, examining the role of NKT cells in hepatic disease is critical for a comprehensive understanding of disease pathogenesis and may provide insight into novel approaches for treatment. For more than a century, mouse models that imitate the physiopathological conditions of human disease have served as a critical tool in biological and medical basic research, including studies of liver disease. Here, we review the role of NKT cells in various mouse models of hepatitis.


Assuntos
Citocinas/imunologia , Hepatite/imunologia , Células T Matadoras Naturais/imunologia , Animais , Modelos Animais de Doenças , Hepatite/patologia , Hepatite B/imunologia , Hepatite B/patologia , Hepatite Animal/imunologia , Hepatite Animal/patologia , Hepatite Crônica/imunologia , Hepatite Crônica/patologia , Camundongos
3.
PLoS Pathog ; 17(1): e1009252, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513208

RESUMO

Neonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR-/-, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR-/- mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR-/- mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease in humans.


Assuntos
Enterovirus Humano B/patogenicidade , Infecções por Enterovirus/virologia , Genoma Viral/genética , Hepatite/virologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Interferon Tipo I/metabolismo , Receptores Fc/metabolismo , Transdução de Sinais , Animais , Enterovirus Humano B/genética , Infecções por Enterovirus/imunologia , Feminino , Expressão Gênica , Hepatite/imunologia , Hepatócitos/imunologia , Hepatócitos/virologia , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade , Fígado/imunologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Fc/genética
4.
Methods Mol Biol ; 2225: 275-292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108669

RESUMO

Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.


Assuntos
Anti-Inflamatórios/farmacologia , Hepatite/prevenção & controle , Fatores Imunológicos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Virais/farmacologia , Isquemia Quente/métodos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Hepatite/genética , Hepatite/imunologia , Hepatite/patologia , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/biossíntese , Fatores Imunológicos/imunologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Fígado/patologia , Camundongos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Coloração e Rotulagem/métodos , Proteínas Virais/biossíntese , Proteínas Virais/imunologia
5.
Front Immunol ; 11: 585502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329563

RESUMO

Deciphering the mechanisms by which Plasmodium parasites develop inside hepatocytes is an important step toward the understanding of malaria pathogenesis. We propose that the nature and the magnitude of the inflammatory response in the liver are key for the establishment of the infection. Here, we used mice deficient in the multidrug resistance-2 gene (Mdr2-/-)-encoded phospholipid flippase leading to the development of liver inflammation. Infection of Mdr2-/- mice with Plasmodium berghei ANKA (PbANKA) sporozoites (SPZ) resulted in the blockade of hepatic exo-erythrocytic forms (EEFs) with no further development into blood stage parasites. Interestingly, cultured primary hepatocytes from mutant and wild-type mice are equally effective in supporting EEF development. The abortive infection resulted in a long-lasting immunity in Mdr2-/- mice against infectious SPZ where neutrophils and IL-6 appear as key effector components along with CD8+ and CD4+ effector and central memory T cells. Inflammation-induced breakdown of liver tolerance promotes anti-parasite immunity and provides new approaches for the design of effective vaccines against malaria disease.


Assuntos
Hepatite/imunologia , Hepatócitos/parasitologia , Malária , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Animais , Feminino , Hepatócitos/imunologia , Inflamação/imunologia , Fígado/imunologia , Fígado/parasitologia , Malária/imunologia , Malária/parasitologia , Camundongos , Plasmodium berghei , Esporozoítos
6.
Med. clín (Ed. impr.) ; 155(12): 541-547, dic. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-198358

RESUMO

In recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumour histology or baseline mutations. However, immune activation associated with check-point inhibitors is not selective and a large variety of immune-related adverse events have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. Though diagnosis and treatment of these toxicities have been established according to the recommendations from clinical trials and in line with the autoimmune disorders that they mimic, increasing real-world data is coming up showing that these adverse events may have differential characteristics and management, especially in terms of the use of corticoids, second-line treatments, salvage therapy for life-threatening cases and reintroduction of immunotherapy. Herein we present a comprehensive review of current recommendations and real-world data on the main immune-related adverse events of immunotherapy


En los últimos años la inmunoterapia se ha convertido en un pilar fundamental para el tratamiento del cáncer, con altas tasas de respuesta, independientemente de la histología tumoral o de las mutaciones basales. Sin embargo, la activación inmune asociada a los inhibidores de control no es selectiva, habiéndose asociado una gran variedad de efectos adversos relacionados con la inmunidad a los agentes anti-PD1, anti-PD-1/L-1 y anti-CTLA-4. Aunque se han establecido el diagnóstico y el tratamiento de estas toxicidades en virtud de las recomendaciones de los ensayos clínicos, en consonancia con los trastornos autoinmunes que imitan, el incremento de los datos del mundo real refleja que dichos efectos adversos pueden tener características y manejos diferenciales, especialmente en términos de uso de corticoides, tratamientos de segunda línea, terapia de rescate para casos potencialmente letales, y reintroducción de la inmunoterapia. Presentamos aquí una revisión amplia de las recomendaciones actuales y los datos del mundo real sobre los principales efectos adversos de la inmunoterapia


Assuntos
Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias/imunologia , Neoplasias/terapia , Ensaios Clínicos como Assunto , Imunoterapia/efeitos adversos , Hepatite/imunologia , Hepatite/terapia , Miosite/imunologia , Miosite/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
7.
Life Sci ; 260: 118307, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841665

RESUMO

AIM: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied. MATERIALS AND METHODS: Two doses of febuxostat (10 and 20 mg/kg, orally) were administered either 1 h before or 30 min after the administration of Con A. Febuxostat at a low dose (10 mg/kg) before and after Con A modulated the elevation of serum ALT, liver uric acid, liver myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) induced by Con A. The same dose of febuxostat before Con A also decreased serum total bilirubin and neutrophil infiltration, as evidenced by flow cytometry and histopathological analysis. KEY FINDINGS: Febuxostat at a high dose (20 mg/kg) significantly improved serum ALT, AST, albumin, total bilirubin, liver uric acid, MPO, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-1ß, and neutrophil infiltration induced by Con A administration. The results of histopathological examination of liver cells paralleled the observed biochemical improvements. Hepatocyte apoptosis as evidenced by immunohistochemical examination of cleaved caspase-3 was markedly decreased in the febuxostat protection and treatment groups, in a dose-dependent manner SIGNIFICANCE: These results indicate that febuxostat, especially at the higher dose, may be an effective inhibitor of immune reactions evoked by Con A administration.


Assuntos
Quimiocina CCL2/análise , Concanavalina A/farmacocinética , Febuxostat/administração & dosagem , Hepatite/prevenção & controle , Interleucina-1beta/análise , Fator de Necrose Tumoral alfa/análise , Animais , Apoptose/efeitos dos fármacos , Caspase 3/análise , Febuxostat/farmacologia , Hepatite/imunologia , Hepatite/fisiopatologia , Fígado/química , Fígado/patologia , Fígado/fisiopatologia , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Peroxidase/análise , Ácido Úrico/análise
8.
Rev Soc Bras Med Trop ; 53: e20200152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578715

RESUMO

During the yellow fever (YF) outbreak in Brazil, many cases of fulminant hepatitis were seen, although mild to moderate hepatitis was mostly observed with complete recovery. This report presents a case of late-onset hepatitis due to YF relapse. The patient sought medical attention after jaundice recurrence 40 days after the first YF hepatitis episode. This case highlights the importance of patient follow-up after the complete resolution of YF symptoms and discharge.


Assuntos
Hepatite/complicações , Febre Amarela/complicações , Adulto , Hepatite/imunologia , Humanos , Masculino , Recidiva
9.
Am J Surg Pathol ; 44(5): 617-625, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187043

RESUMO

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.


Assuntos
Imunodeficiência de Variável Comum/complicações , Hepatite/etiologia , Hipertensão Portal/etiologia , Cirrose Hepática/etiologia , Fígado/patologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Hepatite/imunologia , Hepatite/patologia , Humanos , Hipertensão Portal/imunologia , Hipertensão Portal/patologia , Fígado/imunologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Valor Preditivo dos Testes , Turquia , Estados Unidos , Adulto Jovem
10.
Sci Rep ; 10(1): 1071, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974518

RESUMO

In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4+ T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFNγ suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4+ T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFNγ. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFNγ. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFNγ-expressing Th1 cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Hepatite/imunologia , Fígado/imunologia , Linfócitos/imunologia , Animais , Citocinas/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th2/imunologia
11.
Microb Pathog ; 139: 103863, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31712120

RESUMO

Mycoplasma pneumoniae (M. pneumoniae) is a small bacterium characterized by the absence of cell wall. It is a human pathogen causing upper and lower respiratory infections, both in adults and children. However, it is also considered to be implicated in the pathogenesis of several types of extra-respiratory diseases, including some gastrointestinal disorders. The liver involvement in children during or after M. pneumoniae infections is analyzed and discussed in this review. Through a systematic literature search, it is evidenced that M. pneumoniae is not infrequently associated with alteration of liver function, but rarely causes acute and severe hepatitis in children. M. pneumoniae should be considered as an unusual cause of acute hepatitis in children, whenever the most common hepatotropic viruses have been excluded. The pathogenesis of M. pneumoniae-related hepatitis is likely to be immune-mediated: both the innate and adaptive immune responses may play a fundamental role. However, the exact pathological mechanisms have to be elucidated yet. Further clinical studies are needed in order to understand the actual relevance of this microorganism in liver disease and its pathogenesis.


Assuntos
Hepatite/complicações , Pneumonia por Mycoplasma/complicações , Pneumonia por Mycoplasma/microbiologia , Doença Aguda , Criança , Bases de Dados Factuais , Gastroenteropatias/complicações , Hepatite/imunologia , Hepatite/microbiologia , Humanos , Fígado , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/imunologia
12.
J Oncol Pharm Pract ; 26(2): 459-461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30909794

RESUMO

Immune checkpoint inhibitors have ushered in a new era in cancer management. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor. This inhibits suppression of the T-cell activity, which can in turn cause increased killing of cancer cells. This alteration in the activity of the T cells can cause them to lose their ability to identify host cells and leads to immune-related adverse effects (irAE). Nivolumab-induced hepatotoxicity is rare and accounts for 3-6% of all irAE. We present a case of nivolumab-induced hepatitis. A woman who was treated for recurrent renal cell carcinoma presented with hepatitis. Workup for other causes was negative and the hepatitis was attributed to the administration of nivolumab. She was started on oral steroids followed which she initially improved. However, she later presented with massive upper gastrointestinal bleeding secondary to gastroduodenal ulcers and subsequently developed acute tubular necrosis and passed from the complications. Immune checkpoint inhibitors have proven to be a promising approach in the management of a wide array of neoplasms by immunomodulation. As these agents are becoming standard of therapy in the management of cancers, a heightened vigilance in the diagnosis of irAE is warranted. With heightened vigilance, early recognition can lead to decreased mortality and morbidity.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Hepatite/diagnóstico , Hepatite/etiologia , Imunoterapia/efeitos adversos , Nivolumabe/efeitos adversos , Idoso , Antineoplásicos Imunológicos/imunologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Feminino , Hepatite/imunologia , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/imunologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/imunologia , Nivolumabe/uso terapêutico
15.
Front Immunol ; 11: 563434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33391254

RESUMO

Background and Aims: The mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD). Methods: Mice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development. Results: MyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8+ T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8+ T cells were significantly reduced in MyMRKO. Conclusions: Proinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/genética , Células Mieloides/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores de Mineralocorticoides/deficiência , Imunidade Adaptativa , Animais , Deficiência de Colina , Dieta/efeitos adversos , Dieta/métodos , Modelos Animais de Doenças , Feminino , Hepatite/imunologia , Hepatite/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Mineralocorticoides/genética
16.
Rev. Soc. Bras. Med. Trop ; 53: e20200152, 2020. graf
Artigo em Inglês | LILACS, Coleciona SUS, Sec. Est. Saúde SP | ID: biblio-1136830

RESUMO

Abstract During the yellow fever (YF) outbreak in Brazil, many cases of fulminant hepatitis were seen, although mild to moderate hepatitis was mostly observed with complete recovery. This report presents a case of late-onset hepatitis due to YF relapse. The patient sought medical attention after jaundice recurrence 40 days after the first YF hepatitis episode. This case highlights the importance of patient follow-up after the complete resolution of YF symptoms and discharge.


Assuntos
Humanos , Masculino , Adulto , Febre Amarela/complicações , Hepatite/complicações , Recidiva , Hepatite/imunologia
17.
Rev. Soc. Bras. Med. Trop ; 53: e20200141, 2020. tab, graf
Artigo em Inglês | LILACS, Coleciona SUS, Sec. Est. Saúde SP | ID: biblio-1136831

RESUMO

Abstract INTRODUCTION: Canine visceral leishmaniasis (CVL) is an endemic disease in Brazil, and integrated control actions have been adopted by the Brazilian Ministry of Health to control its spread. However, the transmission profile is unknown in areas with recent CVL cases, including Itaúna, located in the Brazilian state of Minas Gerais, where the present study was carried out. METHODS: A total of 2,302 dogs from 12 neighborhoods were serologically tested for canine VL using the current diagnostic protocol adopted by the Brazilian Ministry of Health. Test positivity rate (TPR) and CVL prevalence were determined for each neighborhood. The presence of Leishmania was assessed in 60 seropositive dogs which had been recommended for euthanasia. Twenty-two of them (37%) were asymptomatic, and 38 (63%) were symptomatic for CVL. Parasitological (myeloculture and smear/imprint) and molecular (PCR) methods were employed for Leishmania detection in bone marrow, spleen, mesenteric lymph nodes, and ear skin. The infecting Leishmania species was identified by DNA sequencing. RESULTS: CVL prevalence (per 1,000 dogs) varied from 0.0-166.67, depending on the neighborhood, with a mean of 68.96 (SD 51.38). Leishmania DNA was detected in at least one tissue from all seropositive dogs, with comparable TPR among tissues. Leishmania parasites were identified in most (54/60) seropositive dogs, and the infecting parasite was identified as Leishmania infantum in all of these. CONCLUSIONS: Prevalence of CVL is a contributor to the spread of visceral leishmaniasis in Itaúna.


Assuntos
Humanos , Masculino , Adulto , Febre Amarela/complicações , Hepatite/complicações , Recidiva , Hepatite/imunologia
18.
Exp Mol Med ; 51(12): 1-9, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827070

RESUMO

During viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as "bystander activation." Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Hepatite/imunologia , Hepatite/virologia , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-15/metabolismo , Viroses/imunologia , Viroses/metabolismo
19.
Sci Rep ; 9(1): 14620, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601823

RESUMO

Galectin-3 (Gal-3) controls intercellular and cell-extracellular matrix interactions during immunological responses. In chronic inflammation, Gal-3 is associated with fibrotic events, regulates B cell differentiation and delays lupus progression. Gal-3 deficient mice (Lgals3-/-) have intense germinal center formation and atypical plasma cell generation correlated to high levels IgG, IgE, and IgA. Here, we used pristane (2,6,10,14-tetramethylpentadecane) to induce lupus-like syndrome in Lgals3-/- and Lgals3+/+ BALB/c mice. Mesentery and peritoneal cells were monitored because promptly react to pristane injected in the peritoneal cavity. For the first time, mesenteric tissues have been associated to the pathogenesis of experimental lupus-like syndrome. In Lgals3+/+ pristane-induced mice, mesentery was hallmarked by intense fibrogranulomatous reaction restricted to submesothelial regions and organized niches containing macrophages and B lymphocytes and plasma cells. In contrast, Lgals3-/- pristane-treated mice had diffuse mesenteric fibrosis affecting submesothelium and peripheral tissues, atypical M1/M2 macrophage polarization and significant DLL1+ cells expansion, suggesting possible involvement of Notch/Delta pathways in the disease. Early inflammatory reaction to pristane was characterized by significant disturbances on monocyte recruitment, macrophage differentiation and dendritic cell (DC) responses in the peritoneal cavity of pristane-induced Lgals3-/- mice. A correlative analysis showed that mesenteric damages in the absence of Gal-3 were directly associated with severe portal inflammation and hepatitis. In conclusion, it has suggested that Gal-3 orchestrates histological organization in the mesentery and prevents lupoid hepatitis in experimental lupus-like syndrome by controlling macrophage polarization, Notch signaling pathways and DC differentiation in mesenteric structures.


Assuntos
Galectina 3/metabolismo , Hepatite/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos Peritoneais/imunologia , Mesentério/patologia , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Galectina 3/genética , Hepatite/patologia , Humanos , Injeções Intraperitoneais , Fígado/imunologia , Fígado/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/complicações , Mesentério/citologia , Mesentério/imunologia , Camundongos , Camundongos Knockout , Terpenos/administração & dosagem , Terpenos/imunologia
20.
Gastroenterology ; 157(4): e8-e9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476298
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