Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Nat Immunol ; 21(10): 1232-1243, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929275

RESUMO

The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a 'CD2 corolla'. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.


Assuntos
Antígenos CD2/metabolismo , Antígenos CD58/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Sinapses Imunológicas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adesão Celular , Células Cultivadas , Humanos , Tolerância Imunológica , Ativação Linfocitária , Ligação Proteica , Receptor Cross-Talk , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Análise de Célula Única
3.
J Obstet Gynaecol Can ; 43(11): 1288-1291, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34048955

RESUMO

BACKGROUND: Lymphatic malformations are benign cystic lesions that, while rare, tend to affect the pediatric age group. There are no reported cases diagnosed prenatally. CASE: A 28-year-old G1 woman at 34 weeks gestation was scanned for placental localization at a community ultrasound clinic. A fetal cystic, sublingual structure was identified. The patient was referred to our tertiary care centre, where a small (1.3 cm) avascular, cystic structure under the tongue of the fetus was confirmed. Antenatal course and delivery were unremarkable. The lesion resolved spontaneously with time. CONCLUSION: This report highlights a unique case in which a sublingual lymphatic malformation was detected prenatally during a third-trimester ultrasound.


Assuntos
Placenta , Ultrassonografia Pré-Natal , Adulto , Criança , Feminino , Feto , Idade Gestacional , Humanos , Gravidez
4.
Am J Respir Cell Mol Biol ; 63(5): 681-689, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32697598

RESUMO

Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria toxin in CD11c-DTR mice was used to deplete macrophages. CCR2-/- mice were used to assess the contribution of recruited macrophages. Eosinophils and neutrophils were depleted with specific antibodies. Platelet-neutrophil aggregation was prevented with an antibody against P-selectin. The potential roles of phagocytosis of neutrophils by macrophages and of transcellular metabolism between epithelial cells and neutrophils were explored in coculture systems. We found that depletion of neutrophils was the only intervention that inhibited the synthesis of cysLTs at 24 hours after chlorine exposure. Although macrophages did synthesize cysLTs in response to phagocytosis of neutrophils, depletion of macrophages did not reduce the increment in cysLTs triggered by chlorine exposure. However, coculture of airway epithelial cells with neutrophils resulted in a significant increase in the synthesis of cysLTs, dependent on the expression of 5-lipoxygenase by neutrophils. We conclude that cysLT synthesis following chlorine exposure may be dependent on transcellular metabolism by neutrophil-epithelial interactions.


Assuntos
Cloro/toxicidade , Cisteína/metabolismo , Leucotrienos/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Líquido da Lavagem Broncoalveolar , Técnicas de Cocultura , Cisteína/biossíntese , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Interleucina-5/antagonistas & inibidores , Interleucina-5/metabolismo , Leucotrienos/biossíntese , Lipossomos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Pneumonia/metabolismo , Pneumonia/patologia
5.
FASEB J ; 26(4): 1704-16, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22247333

RESUMO

Asthma is a chronic inflammatory disease that is associated with airway remodeling, including hyperplasia of airway epithelial cells and airway smooth muscle cells, and goblet cell differentiation. We wished to address the potential role of histamine, a key biogenic amine involved in allergic reactions, in airway remodeling through the epidermal growth factor receptor (EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands, amphiregulin and heparin-binding epidermal growth factor-like growth factor (HB-EGF), from airway epithelial cells. Amphiregulin and HB-EGF were expressed in airway epithelium of patients with asthma. Histamine up-regulated their mRNA expression (amphiregulin 3.2-fold, P<0.001; HB-EGF 2.3-fold, P<0.05) and triggered their release (amphiregulin EC(50) 0.50 µM, 31.2 ± 2.7 pg/ml with 10 µM histamine, P<0.01; HB-EGF EC(50) 0.54 µM, 78.5 ± 1.8 pg/ml with 10 µM histamine, P<0.001) compared to vehicle control (amphiregulin 19.3 ± 0.9 pg/ml; HB-EGF 60.2 ± 1.0 pg/ml), in airway epithelial cells. Histamine increased EGFR phosphorylation (2.1-fold by Western blot analysis) and induced goblet cell differentiation (CLCA1 up-regulation by real-time qPCR) in normal human bronchial epithelial (NHBE) cells. Moreover, amphiregulin and HB-EGF caused proliferation and migration of both NHBE cells and human airway smooth muscle cells. These results suggest that histamine may induce airway remodeling via the epithelial-derived EGFR ligands amphiregulin and HB-EGF.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Brônquios/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Histamina/farmacologia , Adulto , Anfirregulina , Asma/metabolismo , Asma/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular , Proliferação de Células , Família de Proteínas EGF , Células Epiteliais/citologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligantes , Pessoa de Meia-Idade , Receptores Histamínicos H1/metabolismo , Adulto Jovem
6.
Nat Commun ; 12(1): 4365, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272369

RESUMO

Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαß isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Epitopos de Linfócito T/imunologia , Neoplasias Pulmonares/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Transferência Adotiva , Alelos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Peptídeos/genética , Peptídeos/imunologia , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Med ; 27(11): 1970-1981, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34675383

RESUMO

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Interleucina-1/metabolismo , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Células Estromais/imunologia , Adulto , Idoso , Feminino , Fibroblastos/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/fisiologia , Remodelação Vascular/fisiologia
8.
Clin Cancer Res ; 26(16): 4313-4325, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32430479

RESUMO

PURPOSE: The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression. EXPERIMENTAL DESIGN: Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids. RESULTS: Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway. CONCLUSIONS: Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Interleucinas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Animais , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Subunidade beta de Receptor de Interleucina-10/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptores de Interleucina/genética , Transdução de Sinais/genética , Proteínas ras/genética , Interleucina 22
9.
Cell Rep ; 28(12): 3077-3091.e5, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533032

RESUMO

MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8+ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8+ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/patologia , Células CACO-2 , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/patologia , Células THP-1
10.
Nat Rev Immunol ; 15(10): 615-29, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26358393

RESUMO

Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. In this Review, we highlight new insights into the functions of well-known cytokines in CRC, describe recently discovered roles for a growing number of novel players, and emphasize the complexity and therapeutic implications of the cytokine milieu. We also discuss how cancer mutations and epigenetic adaptations influence the oncogenic potential of cytokines, a relatively unexplored area that could yield crucial insights into tumour immunology and facilitate the effective application of cytokine-modulatory therapies for CRC.


Assuntos
Neoplasias Colorretais/imunologia , Citocinas/imunologia , Mediadores da Inflamação/imunologia , Transdução de Sinais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Modelos Imunológicos , Mutação , Transdução de Sinais/genética
11.
Stem Cell Res ; 12(3): 599-609, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24595007

RESUMO

Bone marrow stromal cells (BMSCs) contain a subset of multipotent stem cells. Here, we demonstrate that serotonin, a biogenic amine released by platelets and mast cells, can induce the smooth muscle differentiation of BMSCs. Brown Norway rat BMSCs stimulated with serotonin had increased expression of the smooth muscle markers smooth muscle myosin heavy chain (MHC) and α actin (α-SMA) by qPCR and Western blot, indicating smooth muscle differentiation. This was accompanied by a concomitant down-regulation of the microRNA miR-25-5p, which was found to negatively regulate smooth muscle differentiation. Serotonin upregulated serum response factor (SRF) and myocardin, transcription factors known to induce contractile protein expression in smooth muscle cells, while it down-regulated Elk1 and Kruppel-like factor 4 (KLF4), known to induce proliferation. Serotonin increased SRF binding to promoter regions of the MHC and α-SMA genes, assessed by chromatin immunoprecipitation assay. Induction of smooth muscle differentiation by serotonin was blocked by the knock-down of SRF and myocardin. Transforming growth factor (TGF)-ß1 was constitutively expressed by BMSCs and serotonin triggered its release. Inhibition of miR-25-5p augmented TGF-ß1 expression, however the differentiation of BMSCs was not mediated by TGF-ß1. These findings demonstrate that serotonin promotes a smooth muscle-like phenotype in BMSCs by altering the balance of SRF, myocardin, Elk1 and KLF4 and miR-25-5p is involved in modulating this balance. Therefore, serotonin potentially contributes to the pathogenesis of diseases characterized by tissue remodeling with increased smooth muscle mass.


Assuntos
Diferenciação Celular , Miócitos de Músculo Liso/metabolismo , Serotonina/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Fator 4 Semelhante a Kruppel , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos de Músculo Liso/citologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ratos , Serotonina/genética , Fator de Resposta Sérica/genética , Fator de Resposta Sérica/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
12.
Lancet Respir Med ; 1(2): 137-47, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24429094

RESUMO

Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. Persistent bacterial infection, especially with Pseudomonas aeruginosa, stimulates interleukin-8 release from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease.


Assuntos
Asma , Fibrose Cística , Músculo Liso , Sistema Respiratório , Asma/diagnóstico , Asma/etiologia , Asma/imunologia , Asma/fisiopatologia , Testes de Provocação Brônquica , Sinalização do Cálcio , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Inflamação/imunologia , Interleucinas/metabolismo , Músculo Liso/metabolismo , Músculo Liso/fisiopatologia , Sistema Respiratório/metabolismo , Sistema Respiratório/fisiopatologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA