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1.
NPJ Biofilms Microbiomes ; 7(1): 57, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230496

RESUMO

Bacterial vaginosis (BV) is a gynecologic disorder characterized by a shift in cervicovaginal microbiota from Lactobacillus spp. dominance to a polymicrobial biofilm composed of diverse anaerobes. We utilized a well-characterized human three-dimensional cervical epithelial cell model in conjunction with untargeted metabolomics and immunoproteomics analyses to determine the immunometabolic contribution of three members of the Veillonellaceae family: Veillonella atypica, Veillonella montpellierensis and Megasphaera micronuciformis at this site. We found that Veillonella spp. infections induced significant elevation of polyamines. M. micronuciformis infections significantly increased soluble inflammatory mediators, induced moderate levels of cell cytotoxicity, and accumulation of cell membrane lipids relative to Veillonella spp. Notably, both V. atypica and V. montpellierensis infections resulted in consumption of lactate, a key metabolite linked to gynecologic and reproductive health. Collectively our approach and data provide unique insights into the specific contributions of Veillonellaceae members to the pathogenesis of BV and women's health.


Assuntos
Metabolismo Energético , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiologia , Vagina/metabolismo , Vagina/microbiologia , Veillonellaceae/fisiologia , Aminoácidos/metabolismo , Técnicas de Cultura de Células , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metabolismo dos Lipídeos , Metaboloma , Metabolômica/métodos , Vaginose Bacteriana/metabolismo , Vaginose Bacteriana/microbiologia
2.
Nat Commun ; 12(1): 4070, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210959

RESUMO

Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. Mucins are primarily defined by their variable tandem repeat (TR) domains that are densely decorated with different O-glycan structures in distinct patterns, and these arguably convey much of the informational content of mucins. Here, we develop a cell-based platform for the display and production of human TR O-glycodomains (~200 amino acids) with tunable structures and patterns of O-glycans using membrane-bound and secreted reporters expressed in glycoengineered HEK293 cells. Availability of defined mucin TR O-glycodomains advances experimental studies into the versatile role of mucins at the interface with pathogenic microorganisms and the microbiome, and sparks new strategies for molecular dissection of specific roles of adhesins, glycoside hydrolases, glycopeptidases, viruses and other interactions with mucin TRs as highlighted by examples.


Assuntos
Mucinas/metabolismo , Membrana Mucosa/metabolismo , Polissacarídeos/genética , Polissacarídeos/metabolismo , Engenharia Genética , Glicosilação , Células HEK293 , Humanos , Microbiota , Mucina-1/genética , Mucina-1/metabolismo
3.
Front Immunol ; 12: 625649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093520

RESUMO

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.


Assuntos
Colo do Útero/virologia , Proteínas do Sistema Complemento/imunologia , Perfilação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/patogenicidade , Membrana Mucosa/virologia , Proteoma , Proteômica , Transcriptoma , Colo do Útero/imunologia , Colo do Útero/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Feminino , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Fatores de Tempo , Técnicas de Cultura de Tecidos , Internalização do Vírus , Replicação Viral
4.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074061

RESUMO

BACKGROUND: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eritritol/farmacologia , Intolerância à Glucose/dietoterapia , Imunidade Inata/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Eritritol/administração & dosagem , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Intolerância à Glucose/metabolismo , Imunidade Inata/genética , Inflamação/dietoterapia , Inflamação/genética , Inflamação/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Obesidade/genética , Obesidade/metabolismo
5.
Eur J Med Res ; 26(1): 52, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108042

RESUMO

BACKGROUND: We are laryngologists. We observe natural phonatory and swallowing functions in clinical examinations with a trans-nasal laryngeal fiberscope (TNLF). Before each observation, we use epinephrine to enlarge and smooth the common nasal meatus (bottom of nostril) and then insert a wet swab inside the nose, as in taking a swab culture in the nasopharynx. During the current COVID-19 pandemic situation, this careful technique prevents any complications, including nasal bleeding, painfulness, and induced sneezing. Here, we introduce our routine to observe esophageal movement in swallowing in a natural (sitting) position without anesthesia. CASE PRESENTATION: The case was a 70-year-old female who complained that something was stuck in her esophagus; there was a strange sensation below the larynx and pharynx. After enlarging and smoothing the common nasal meatus, we inserted the TNLF (slim type ⌀2.9 mm fiberscope, VNL8-J10, PENTAX Medical, Tokyo, Japan.) in the normal way. We then observed the phonatory and swallowing movements of the vocal folds. As usual, to not interfere with natural movements, we used no anesthesia. We found no pathological condition in the pyriform sinus. We asked the patient to swallow the fiberscope. During the swallow, we pushed the TNLF and inserted the tip a bit deeper, which made the fiberscope easily enter the esophagus, like in the insertion of a nasogastric tube. We then asked the patient to swallow a sip of water or saliva to clear and enlarge the lumen of the esophagus. This made it possible to observe the esophagus easily without any air supply. With tone enhancement scan, the esophagus was found to be completely normal except for glycogenic acanthosis. CONCLUSIONS: The advantage of this examination is that it is easily able to perform without anesthesia and with the patient in sitting position. It is quick and minimally invasive, enabling observation the physiologically natural swallowing. It is also possible to observe without anesthesia down to the level of the esophagogastric junction using with a thin type flexible bronchoscope. In the future, gastric fiberscopes might be thinner, even with narrow band imaging (NBI) function. Before that time, physicians should remember to just insert along the bottom of the nose.


Assuntos
COVID-19/prevenção & controle , Esôfago/metabolismo , Glicogênio/metabolismo , Intubação Intratraqueal/métodos , Idoso , Anestesia , COVID-19/epidemiologia , COVID-19/virologia , Epitélio/metabolismo , Feminino , Humanos , Intubação Intratraqueal/instrumentação , Membrana Mucosa/metabolismo , Cavidade Nasal , Pandemias , Reprodutibilidade dos Testes , SARS-CoV-2/fisiologia , Espirro
6.
Viruses ; 13(5)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062811

RESUMO

It is well known that approximately 50% of cattle infected with foot-and-mouth disease (FMD) virus (FMDV) may become asymptomatic carrier (persistently infected) animals. Although transmission of FMDV from carrier cattle to naïve cattle has not been demonstrated experimentally, circumstantial evidence from field studies has linked FMDV-carrier cattle to cause subsequent outbreaks. Therefore, the asymptomatic carrier state complicates the control and eradication of FMD. Current serological diagnosis using tests for antibodies to the viral non-structural proteins (NSP-ELISA) are not sensitive enough to detect all carrier animals, if persistently infected after vaccination and do not distinguish between carriers and non-carriers. The specificity of the NSP ELISA may also be reduced after vaccination, in particular after multiple vaccination. FMDV-specific mucosal antibodies (IgA) are not produced in vaccinated cattle but are elevated transiently during the acute phase of infection and can be detected at a high level in cattle persistently infected with FMDV, irrespective of their vaccination status. Therefore, detection of IgA by ELISA may be considered a diagnostic alternative to RT-PCR for assessing FMDV persistent infection in ruminants in both vaccinated and unvaccinated infected populations. This study reports on the development and validation of a new mucosal IgA ELISA for the detection of carrier animals using nasal, saliva, and oro-pharyngeal fluid (OPF) samples. The diagnostic performance of the IgA ELISA using nasal samples from experimentally vaccinated and infected cattle demonstrated a high level of specificity (99%) and an improved level of sensitivity (76.5%). Furthermore, the detection of carrier animals reached 96.9% when parallel testing of samples was carried out using both the IgA-ELISA and NSP-ELISA.


Assuntos
Doenças dos Bovinos/imunologia , Doenças dos Bovinos/virologia , Vírus da Febre Aftosa/imunologia , Febre Aftosa/imunologia , Febre Aftosa/virologia , Imunoglobulina A Secretora/imunologia , Membrana Mucosa/imunologia , Animais , Bovinos , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/epidemiologia , Surtos de Doenças , Ensaio de Imunoadsorção Enzimática , Febre Aftosa/diagnóstico , Febre Aftosa/epidemiologia , Membrana Mucosa/metabolismo , Curva ROC , Vacinas/imunologia
7.
Elife ; 102021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34047696

RESUMO

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.


Assuntos
Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Imunidade nas Mucosas , Interferon Tipo I/metabolismo , Interleucina-18/metabolismo , Membrana Mucosa/virologia , Ativação de Neutrófilo , Neutrófilos/virologia , Vagina/virologia , Animais , Anticorpos/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Herpes Genital/metabolismo , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/imunologia , Interações Hospedeiro-Patógeno , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/inervação , Membrana Mucosa/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Células Vero
8.
Front Immunol ; 12: 616309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968018

RESUMO

Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM) cells, central memory T (TCM) cells, and tissue-resident memory T (TRM) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. TRM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, TRM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8+ TRM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4+ TRM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4+ TRM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4+ TRM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4+ TRM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Imunidade nas Mucosas , Memória Imunológica , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Plasticidade Celular/imunologia , Suscetibilidade a Doenças , Epigênese Genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Especificidade de Órgãos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
PLoS One ; 16(4): e0249729, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822814

RESUMO

NG2 immunoreactive cells (NG2 cells) are found in the brain and peripheral tissues including the skin, intestinal tracts, and bladder. In a previous study, we observed the presence of NG2 cells in the stomach using bioluminescence imaging techniques in NG2-firefly luciferase (fLuc) transgenic (Tg) rats. Here, we aimed to identify and characterize NG2 cells in the adult rat stomach. Immunohistochemical studies showed that NG2 cells were mainly present in the lamina propria and most of the cells were gastric telocytes, co-expressing CD34, and platelet-derived growth factor receptor alpha (PDGFRα), with a small oval-shaped cell body and extremely long and thin cellular prolongations. In the rat stomach, NG2-expressing telocytes comprised two subpopulations: NG2+/CD34+/PDGFRα+ and NG2+/CD34+/PDGFRα-. Furthermore, we showed that the expression of NG2 gene in the aged rat stomach decreased relative to that of the young rat stomach and the decline of NG2 expression in aged rats was mainly observed in NG2+/CD34+/PDGFRα+ telocytes. These findings suggested age-related alterations in NG2+/CD34+/PDGFRα+ telocytes of rat stomach.


Assuntos
Antígenos/metabolismo , Mucosa Gástrica/metabolismo , Proteoglicanas/metabolismo , Estômago/fisiologia , Telócitos/metabolismo , Fatores Etários , Animais , Antígenos CD34/metabolismo , Membrana Mucosa/citologia , Membrana Mucosa/metabolismo , Ratos , Ratos Transgênicos , Ratos Wistar , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Estômago/citologia , Telócitos/citologia
10.
AAPS PharmSciTech ; 22(4): 145, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33913042

RESUMO

Incorporation of permeation enhancers is one of the most widely employed approaches for delivering drugs across biological membranes. Permeation enhancers aid in delivering drugs across various physiological barriers such as brain capillary endothelium, stratum corneum, corneal epithelium, and mucosal membranes that pose resistance to the entry of a majority of drugs. Borneol is a natural, plant-derived, lipophilic, volatile, bicyclic monoterpenoid belonging to the class of camphene. It has been used under the names "Bing Pian" or "Long Nao" in Traditional Chinese Medicine for more than 1000 years. Borneol has been incorporated predominantly as an adjuvant in the traditional Chinese formulations of centrally acting drugs to improve drug delivery to the brain. This background knowledge and anecdotal evidence have led to extensive research in establishing borneol as a permeation enhancer across the blood-brain barrier. Alteration in cell membrane lipid structures and modulation of multiple ATP binding cassette transporters as well as tight junction proteins are the major contributing factors to blood-brain barrier opening functions of borneol. Owing to these mechanisms of altering membrane properties, borneol has also shown promising potential to improve drug delivery across other physiological barriers as well. The current review focuses on the role of borneol as a permeation enhancer across the blood-brain barrier, mucosal barriers including nasal and gastrointestinal linings, transdermal, transcorneal, and blood optic nerve barrier.


Assuntos
Canfanos/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Barreira Hematoencefálica , Canfanos/farmacocinética , Humanos , Membrana Mucosa/metabolismo , Permeabilidade
11.
Nat Commun ; 12(1): 2147, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846309

RESUMO

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).


Assuntos
Canal Anal/citologia , Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Genitália/citologia , HIV-1/fisiologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Monócitos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Forma Celular , Colagenases/metabolismo , Derme/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Membrana Mucosa/metabolismo , Fagócitos/metabolismo , Fenótipo , Receptores CCR5/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Transcrição Genética
12.
Front Immunol ; 12: 606043, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717086

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug effect. There are multiple hypotheses to explain the development of MRONJ. Reduced bone remodeling and infection or inflammation are considered central to the pathogenesis of MRONJ. In recent years, increasing evidence has shown that bisphosphonates (BPs)-mediated immunity dysfunction is associated with the pathophysiology of MRONJ. In a healthy state, mucosal immunity provides the first line of protection against pathogens and oral mucosal immune cells defense against potentially invading pathogens by mediating the generation of protective immunoinflammatory responses. In addition, the immune system takes part in the process of bone remodeling and tissue repair. However, the treatment of BPs disturbs the mucosal and osteo immune homeostasis and thus impairs the body's ability to resist infection and repair from injury, thereby adding to the development of MRONJ. Here, we present the current knowledge about immunity dysfunction to shed light on the role of local immune disorder in the development of MRONJ.


Assuntos
Suscetibilidade a Doenças/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Arcada Osseodentária/efeitos dos fármacos , Arcada Osseodentária/patologia , Osteonecrose/etiologia , Animais , Biomarcadores , Conservadores da Densidade Óssea/efeitos adversos , Citocinas/biossíntese , Difosfonatos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Imunidade nas Mucosas , Mediadores da Inflamação/metabolismo , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiologia , Membrana Mucosa/patologia , Osteogênese , Osteonecrose/metabolismo , Osteonecrose/patologia , Transdução de Sinais , Cicatrização
13.
Front Immunol ; 12: 614115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717097

RESUMO

Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to poor T-cell responsiveness upon mucosal antigenic stimulation, mucosal immunity remains difficult to obtain through vaccines and requires appropriate adjuvants. We previously demonstrated that administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses. We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant. First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the lamina propria while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes. Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization. Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA+ plasma cells in the upper vaginal mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.


Assuntos
Adjuvantes Imunológicos , Imunidade nas Mucosas , Interleucina-7/imunologia , Membrana Mucosa/imunologia , Vacinas/imunologia , Vagina/imunologia , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Biomarcadores , Quimiocinas/metabolismo , Feminino , Hepevirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunização , Macaca mulatta , Membrana Mucosa/metabolismo , Vírus da Imunodeficiência Símia/imunologia , Vacinas/administração & dosagem
14.
Ann Clin Lab Sci ; 51(1): 124-130, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33653791

RESUMO

EBV positive mucocutaneous ulcer (EBVMCU) is a newly recognized clinicopathologic entity in the 2017 World Health Organization (WHO) classification. Patients frequently present with an isolated ulcerative lesion in mucosal and cutaneous sites with immunosuppression as the main risk factor. The disease typically follows an indolent clinical course. Herein we describe a series of three patients diagnosed with EBVMCU. Histopathologic examination of these cases shows ulceration in mucosal or cutaneous surface with a substantial number of large atypical transformed cells in the background of dense polymorphous infiltrates. One patient regressed spontaneously with no treatment, one patient needed Rutiximab, and one patient had persistent EBVMCU process with possible transformation to large B cell lymphoma. The aim of the present case series is to highlight the pathologic, diagnostic and clinical features of patients with EBVMCU.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Úlcera/metabolismo , Adulto , Idoso , Humanos , Imunossupressores/farmacologia , Linfoma Difuso de Grandes Células B/complicações , Transtornos Linfoproliferativos/etiologia , Masculino , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Lesões Pré-Cancerosas , Dermatopatias/complicações , Úlcera/virologia
15.
Cancer Med ; 10(8): 2627-2635, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33724703

RESUMO

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population.


Assuntos
Biomarcadores Tumorais/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/patologia , Prognóstico , Taxa de Sobrevida
16.
Neurosci Lett ; 748: 135689, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33582191

RESUMO

Mas-related G coupled receptors (Mrgprs) are a superfamily of receptors expressed in sensory neurons that are known to transmit somatic sensations from the skin to the central nervous system. Interestingly, Mrgprs have recently been implicated in sensory and motor functions of mucosal-associated neuronal circuits. The gastrointestinal and pulmonary tracts are constantly exposed to noxious stimuli. Therefore, it is likely that neuronal Mrgpr signaling pathways in mucosal tissues, akin to their family members expressed in the skin, might relay messages that alert the host when mucosal tissues are affected by damaging signals. Further, Mrgprs have been proposed to mediate the cross-talk between sensory neurons and immune cells that promotes host-protective functions at barrier sites. Although the mechanisms by which Mrgprs are activated in mucosal tissues are not completely understood, these exciting studies implicate Mrgprs as potential therapeutic targets for conditions affecting the intestinal and airway mucosa. This review will highlight the central role of Mrgpr signaling pathways in the regulation of homeostasis at mucosal tissues.


Assuntos
Gânglios Espinais/metabolismo , Membrana Mucosa/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Humanos , Prurido/metabolismo , Transdução de Sinais/fisiologia
17.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494146

RESUMO

Ensuring salmon health and welfare is crucial to maximize production in recirculation aquaculture systems. Healthy and robust mucosal surfaces of the skin and intestine are essential to achieve this goal because they are the first immunological defenses and are constantly exposed to multistressor conditions, such as infectious diseases, suboptimal nutrition, and environmental and handling stress. In this work, Atlantic salmon, split from a single cohort, were subjected to acute hypoxia stress or 15-min crowding stress and observed over a 24-h recovery period. Samples were collected from fish at 0, 1, 3, 6, 12 and 24 h post-stress to analyze plasma-circulating markers of endocrine function (cortisol), oxidative stress (glutathione peroxidase) and immune function (interleukin 10 (IL-10), annexin A1). In addition, mucosal barrier function parameters were measured in the skin mucus (Muc-like protein and lysozyme) and distal intestine (simple folds, goblet cell size and goblet cell area). The results showed that both acute stress models induced increases of circulating cortisol in plasma (1 h post-stress), which then returned to baseline values (initial control) at 24 h post-stress. Moreover, the hypoxia stress was mostly related to increased oxidative stress and IL-10 production, whereas the crowding stress was associated with a higher production of Muc-like protein and lysozyme in the skin mucus. Interestingly, in the distal intestine, smaller goblet cells were detected immediately and one hour after post-hypoxia stress, which could be related to rapid release of the cellular content to protect this organ. Finally, the correlation of different markers in the hypoxic stress model showed that the circulating levels of cortisol and IL-10 were directly proportional, while the availability of Muc-like proteins was inversely proportional to the size of the goblet cells. On the other hand, in the crowding stress model, a proportional relationship was established between plasma cortisol levels and skin mucus lysozyme. Our results suggest key differences in energy partitioning between the two acute stress models and support the need for further investigation into the interplay of multistressor conditions and strategies to modulate immunological aspects of mucosal surfaces.


Assuntos
Biomarcadores/sangue , Imunidade nas Mucosas , Intestinos/imunologia , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Salmo salar/fisiologia , Animais , Glutationa Peroxidase/sangue , Hidrocortisona/sangue , Hipóxia/sangue , Hipóxia/imunologia , Intestinos/citologia , Pele/metabolismo
18.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494358

RESUMO

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects.


Assuntos
Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/fisiologia , Úlcera/etiologia , Úlcera/metabolismo , Animais , Biomarcadores , Biópsia , Infecções por Vírus Epstein-Barr/virologia , Humanos , Imuno-Histoquímica , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Fenótipo , Úlcera Cutânea/etiologia , Úlcera Cutânea/metabolismo , Úlcera Cutânea/patologia , Úlcera/patologia
19.
FASEB J ; 35(2): e21282, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33484474

RESUMO

Cellular viral reservoirs are rapidly established in tissues upon HIV-1/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut-associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV-1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4ß7 antibody or α4ß7/α4ß1 dual antagonist TR-14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post-SIV inoculation. The results showed that blockade of α4ß7/α4ß1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell-associated SIV RNA/DNA to controls. Surprisingly, TR-14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV-1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Animais , Anticorpos Neutralizantes/imunologia , Integrinas/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Fenilalanina/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral
20.
J Med Virol ; 93(3): 1443-1448, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32880993

RESUMO

Our study intended to longitudinally explore the prediction effect of immunoglobulin A (IgA) on pulmonary exudation progression in COVID-19 patients. The serum IgA was tested with chemiluminescence method. Autoregressive moving average model was used to extrapolate the IgA levels before hospital admission. The positive rate of IgA and IgG in our cohort was 97% and 79.0%, respectively. In this study, the IgA levels peaks within 10-15 days after admission, while the IgG levels peaks at admission. We found that the time difference between their peaks was about 10 days. Viral RNA detection results showed that the positive rate in sputum and feces were the highest. Blood gas analysis showed that deterioration of hypoxia with the enlargement of pulmonary exudation area. And alveolar-arterial oxygen difference and oxygenation index were correlated with IgA and IgG. The results of biopsy showed that the epithelium of lung was exfoliated and the mucosa was edematous. In severe COVID-19 patients, the combination of IgA and IgG can predict the progress of pulmonary lesions and is closely related to hypoxemia and both also play an important defense role in invasion and destruction of bronchial and alveolar epithelium by SARS-CoV-2.


Assuntos
COVID-19/patologia , COVID-19/virologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Escarro/virologia , Idoso , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/virologia , Anticorpos Antivirais/sangue , Brônquios/metabolismo , Brônquios/virologia , COVID-19/sangue , COVID-19/metabolismo , Feminino , Humanos , Hipóxia/sangue , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Oxigênio/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , RNA Viral/genética , SARS-CoV-2/genética
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