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1.
Adv Exp Med Biol ; 1172: 63-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628651

RESUMO

The co-stimulation and co-inhibition signal pathways, immune checkpoints, are among the central mechanisms to regulate the T-cell immunity. Optimal signals involve intricate interactions of numerous ligands and receptors. Manipulation of these signals offers great clinical opportunities and has revolutionized the cancer treatment therapies. The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo in recognition of their discovery of cancer immunotherapy by inhibition of immune checkpoint molecules. Despite the landmark discovery in cancer immunotherapy, the efforts to harness immunity against cancer are also restricted by the limited knowledge on the co-stimulation and co-inhibition signaling networks. Understanding the structures of these molecules, in particular, tackling the interaction paradigms from the structural perspective, help to provide more accurate insights into the signaling mechanisms, which may further facilitate the development of novel biologics and improve the efficacy of the existing biologics against these targets. Here we review our current understanding on the structures of these co-stimulatory and co-inhibitory molecules. Specifically, we focus on the structural basis of several checkpoint molecules among the CD28-B7 family and discuss the therapeutic drugs against these targets for the treatment of human cancers, autoimmune disorders, and transplantation.


Assuntos
Antígenos CD28 , Linfócitos T , Doenças Autoimunes , Antígenos CD28/química , Antígenos CD28/imunologia , Humanos , Imunoterapia , Neoplasias/terapia , Transplante de Órgãos , Transdução de Sinais/imunologia , Linfócitos T/imunologia
2.
Adv Exp Med Biol ; 1172: 79-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628652

RESUMO

The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.


Assuntos
Interleucina-10 , Doenças Autoimunes/imunologia , Humanos , Imunoterapia , Interleucina-10/química , Interleucina-10/imunologia , Transdução de Sinais/imunologia , Relação Estrutura-Atividade
3.
Adv Exp Med Biol ; 1172: 207-226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628658

RESUMO

The NF-κB (Nuclear Factor kappa B) transcription factor plays crucial roles in the regulation of numerous biological processes including development of the immune system, inflammation, and innate and adaptive immune responses. Control over the immune cell functions of NF-κB results from signaling through one of two different routes: the canonical and noncanonical NF-κB signaling pathways. Present at the end of both pathways are the proteins NF-κB, IκB, and the IκB kinase (IKK). These proteins work together to deliver the myriad outcomes that influence context-dependent transcriptional control in immune cells. In the present chapter, we review the structural information available on NF-κB, IκB, and IKK, the critical terminal components of the NF-κB signaling, in relation to their physiological function.


Assuntos
Quinase I-kappa B , Proteínas I-kappa B , Sistema Imunitário , NF-kappa B , Transdução de Sinais , Animais , Humanos , Quinase I-kappa B/imunologia , Proteínas I-kappa B/imunologia , Sistema Imunitário/enzimologia , NF-kappa B/imunologia , Fosforilação , Transdução de Sinais/imunologia
4.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(4): 446-449, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31612687

RESUMO

Macrophage migration inhibitory factor (MIF), a type of pleiotropic immunoregulatory cytokine with a specific structure, participates in the regulation of host cell growth and migration and immune responses. Following parasitic infections, hosts may produce MIF and then participate in the parasite-host interactions. In addition, parasites may secrete parasite-derived MIF, and they jointly participate in parasite-host interactions. This paper reviews the regulation of MIF gene expression following parasitic infections, the role of MIF in parasite-host immune system interactions, and important signaling pathways of MIF-mediated immune responses.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Fatores Inibidores da Migração de Macrófagos , Parasitos , Animais , Regulação da Expressão Gênica/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Parasitos/imunologia , Transdução de Sinais/imunologia
5.
Scand J Immunol ; 90(5): e12820, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31486098

RESUMO

Allergens are the main trigger that enhances airway type 2 inflammation, and the epithelium is the first line of defense that reacts to its exposure. Therefore, epithelial-derived mediators, such as interleukin (IL)-25, IL-33, thymic stromal lymphopoietin (TSLP) and ezrin, may play a role as alarmins in IL-4/IL-13 signaling in allergic asthma (AA). We investigated the serum levels of IL-25, IL-33, TSLP, ezrin, IL-4 and IL-13, after bronchial challenge with Dermatophagoides pteronyssinus in patients with AA. We examined 18 subjects: nine steroid-free stable patients with AA sensitized to D. pteronyssinus and nine non-atopic healthy subjects (HS). Bronchial allergen challenge was performed using inhaled D. pteronyssinus allergen. IL-4, IL-13, IL-25, IL-33, TSLP and ezrin levels in serum were measured by ELISA at two time points - before and 24 hours after bronchial allergen challenge. The serum levels of IL-25, TSLP and ezrin did not differ between AA and HS groups at baseline. However, after allergen exposure, significant increases in serum levels of IL-25, TSLP and ezrin were observed only in patients with AA. The serum level of IL-33 at baseline was significantly higher in the AA group compared with HS, but the allergen challenge did not provoke an increase of this cytokine in any group. IL-4 and IL-13 levels were significantly higher at baseline in the AA group compared with HS and, after allergen exposure, were significantly increased in the AA group, with no effect on HS. Thus, the epithelial-derived mediators IL-25, TSLP and ezrin, via IL4/IL13 signaling, enhance type 2 inflammation after bronchial challenge with D. pteronyssinus in AA.


Assuntos
Antígenos de Dermatophagoides/imunologia , Asma/sangue , Asma/imunologia , Testes de Provocação Brônquica/métodos , Interleucina-13/sangue , Interleucina-4/sangue , Animais , Citocinas/sangue , Proteínas do Citoesqueleto/sangue , Dermatophagoides pteronyssinus/imunologia , Humanos , Interleucina-17/sangue , Interleucina-33/sangue , Transdução de Sinais/imunologia
6.
Arch Virol ; 164(11): 2659-2669, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385116

RESUMO

Interferon gamma (IFN-γ) is best known for its ability to regulate host immune responses; however, its direct antiviral activity is less well studied. Transmissible gastroenteritis virus (TGEV) is an economically important swine enteric coronavirus and causes acute diarrhea in piglets. At present, little is known about the function of IFN-γ in the control of TGEV infection. In this study, we demonstrated that IFN-γ inhibited TGEV infection directly in ST cells and intestine epithelial IPEC-J2 cells and that the anti-TGEV activity of IFN-γ was independent of IFN-α/ß. Moreover, IFN-γ suppressed TGEV infection in ST cells more efficiently than did IFN-α, and the combination of IFN-γ and IFN-α displayed a synergistic effect against TGEV. Mechanistically, using overexpression and functional knockdown experiments, we demonstrated that porcine interferon regulatory factor 1 (poIRF1) elicited by IFN-γ primarily mediated IFN-γ signaling cascades and the inhibition of TGEV infection by IFN-γ. Importantly, we found that TGEV elevated the expression of poIRF1 and IFN-γ in infected small intestines and peripheral blood mononuclear cells. Thus, IFN-γ plays a crucial role in curtailing enteric coronavirus infection and may serve as an effective prophylactic and/or therapeutic agent against TGEV infection.


Assuntos
Gastroenterite Suína Transmissível/imunologia , Fator Regulador 1 de Interferon/metabolismo , Interferon gama/imunologia , Vírus da Gastroenterite Transmissível/imunologia , Animais , Linhagem Celular , Cercopithecus aethiops , Fator Regulador 1 de Interferon/genética , Interferon-alfa/imunologia , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/imunologia , Suínos , Células Vero
7.
Nat Commun ; 10(1): 3070, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296852

RESUMO

CARD9 and CARD11 drive immune cell activation by nucleating Bcl10 polymerization, but are held in an autoinhibited state prior to stimulation. Here, we elucidate the structural basis for this autoinhibition by determining the structure of a region of CARD9 that includes an extensive interface between its caspase recruitment domain (CARD) and coiled-coil domain. We demonstrate, for both CARD9 and CARD11, that disruption of this interface leads to hyperactivation in cells and to the formation of Bcl10-templating filaments in vitro, illuminating the mechanism of action of numerous oncogenic mutations of CARD11. These structural insights enable us to characterize two similar, yet distinct, mechanisms by which autoinhibition is relieved in the course of canonical CARD9 or CARD11 activation. We also dissect the molecular determinants of helical template assembly by solving the structure of the CARD9 filament. Taken together, these findings delineate the structural mechanisms of inhibition and activation within this protein family.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/ultraestrutura , Guanilato Ciclase/ultraestrutura , Domínios Proteicos , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Microscopia Crioeletrônica , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Guanilato Ciclase/metabolismo , Células HEK293 , Humanos , Mutação , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica em alfa-Hélice , Multimerização Proteica/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Transdução de Sinais/imunologia
8.
Scand J Immunol ; 90(5): e12804, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31267559

RESUMO

Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (ß2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition. However, other tumour cells highly express ß2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.


Assuntos
Antígenos CD/imunologia , Tolerância Imunológica/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Neoplasias/terapia , Evasão Tumoral/imunologia , Microglobulina beta-2/imunologia , Imunidade Adaptativa/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
9.
Scand J Immunol ; 90(5): e12807, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31282004

RESUMO

Exosomes are a potent means for intercellular communication. However, exosomes have received intensive research focus in immunobiology only relatively recently. Because they transport proteins, lipids and genetic material between cells, they are especially suited to amplify their parental cell's message and overcome the physical constraints of cell-to-cell contact, that is exosome release gives cells the ability to alter distant, non-contiguous cells. As progress is made in this field, it has become increasingly obvious that exosomes are involved in most biological processes. In the immune system, exosomes are fundamental tools used by every immune cell type to fulfil its function and promote inflammation or tolerance. In this review, we first summarize key aspects of immune cell-specific exosomes and their functions. Then, we describe how exosomes have been shown to be indispensable orchestrators of the immune response in two immunological scenarios, namely transplant rejection or tolerance, and tumour evasion or initiation of anti-tumour immune responses.


Assuntos
Exossomos/metabolismo , Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Neoplasias/imunologia , Evasão Tumoral/imunologia , Linfócitos B/imunologia , Transporte Biológico/fisiologia , Comunicação Celular/fisiologia , Células Dendríticas/imunologia , Humanos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia
10.
Yakugaku Zasshi ; 139(7): 993-998, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31257258

RESUMO

Prion diseases, including human Creutzfeldt-Jakob disease, are infectious, intractable central neurodegenerative diseases, which are also zoonoses that commonly infect not only higher organisms but also a wide variety of animals. Pathogenic prions induce abnormal prion protein (PrP), which is produced by structural conversion of normal PrP, a beta-sheet-rich structure with high aggregation propensity. Thus, it is believed that the host is immunotolerant against prions because there is no difference in the primary structure of normal and abnormal PrP, and prions do not induce a marked immune response. Recently, using mutated Toll-like receptor (TLR) 4-transgenic mice, a bioassay after prion inoculation has intriguingly found that the TLR4-signaling pathway may have a protective role against prion infection. Meanwhile, we reported that a transcription factor, interferon regulatory factor-3 (IRF-3), located downstream of TLR4 signaling, showed resistance to prions. IRF-3-inducing type I interferon (I-IFN) is a critical factor for the host defense against pathogen invasion. These findings indicate that the TLR-signaling pathway of the innate immune system might regulate prion invasion. However, the details have not been fully determined. In this symposium, we will introduce new findings including the relationship between I-IFN and prions.


Assuntos
Imunidade Inata/imunologia , Doenças Priônicas/imunologia , Proteínas Priônicas/imunologia , Animais , Síndrome de Creutzfeldt-Jakob , Humanos , Fator Regulador 3 de Interferon , Interferon Tipo I , Camundongos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Zoonoses
11.
J Microbiol Biotechnol ; 29(7): 1053-1060, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31280523

RESUMO

Thermal drying is a common process used in the food industry for the modification of agricultural products. However, while various studies have investigated the alteration in physiochemical properties and chemical composition after drying, research focusing on the relationship between different dehydration conditions and bioactivity is scarce. In the current study, we prepared dried ginger under nine different conditions by varying the processing time and temperature and compared their immunomodulatory effects. Interestingly, depending on the drying condition, there were significant differences in the immunestimulating activity of the dried ginger samples. Gingers processed at 50°C 1h displayed the strongest activation of macrophages measured by TNF-α and IL-6 levels, whereas, freezedried or 70°C- and 90°C-dried ginger showed little effect. Similar results were recapitulated in primary bone marrow-derived macrophages, further confirming that different dehydration conditions can cause significant differences in the immune-stimulating activity of ginger. Induction of ERK, p38, and JNK signaling was found to be the major underlying molecular mechanism responsible for the immunomodulatory effect of ginger. These results highlight the potential to improve the bioactivity of functional foods by selectively controlling processing conditions.


Assuntos
Dessecação , Gengibre/imunologia , Animais , Sobrevivência Celular , Citocinas/metabolismo , Feminino , Gengibre/química , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Temperatura Ambiente , Fatores de Tempo , Água/análise
12.
APMIS ; 127(9): 642-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274210

RESUMO

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14+ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14+ monocytes and CD4+ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14+ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14+ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14+ monocytes activity to HCV clearance in Huh7.5 cells and to CD4+ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14+ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14+ monocytes from chronic hepatitis C patients. GSI-stimulated CD14+ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14+ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14+ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14+ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14+ monocytes in chronic HCV infection.


Assuntos
Hepatite C Crônica/imunologia , Monócitos/imunologia , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Adulto , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Regulação para Baixo/imunologia , Feminino , Hepacivirus/imunologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th17/imunologia , Adulto Jovem
13.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Mol Immunol ; 112: 312-321, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31229844

RESUMO

Precise glycosylation plays a crucial and distinctive role in thymic T cell development. The core fucosylation is dramatically up-regulated at the transition from CD4-CD8- (DN) to CD4+CD8+ (DP) in the thymic development. Ablation of core fucosylation in T cells did reduce the size of the thymus due to a significant loss of CD4+ SP, CD8+ SP and DP thymocytes in core fucosyltransferase (Fut8) knockout (Fut8-/-) mice. T cell receptors (TCRs) are heavily core fucosylated glycoproteins. Loss of core fucosylation of TCR contributed to the reduced phosphorylation of ZAP70 (pZAP70) in Fut8-/- DP cells was observed. Compare to the Fut8+/+OT-II DP thymocytes, pZAP70 was significantly reduced in Fut8-/- OT-II DP thymocytes with OVA323-339 stimulation. Also, the pZAP70 of Fut8+/+OT-I DP thymocytes with OVA257-264 stimulation was remarkably attenuated by treatment of the fucosidase. Upon anti-CD3/CD28 Abs stimulation, the increased apoptosis was found in Fut8-/- thymocytes compared with Fut8+/+ thymocytes. Moreover, the TCRhiCD69hi (post-positive selection thymocytes) was markedly depleted in the Fut8-/- thymus without any stimulation. The expression of CD5 was significantly down-regulated on the DP cells in the Fut8-/- thymus. Our results therefore demonstrate that ablation of core fucosylation results in the abnormal T cell development due to the attenuated signaling via TCR.


Assuntos
Fucose/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Apoptose/imunologia , Antígenos CD5/imunologia , Diferenciação Celular/imunologia , Fucosiltransferases/imunologia , Glicosilação , Lectinas Tipo C/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/imunologia , Timócitos/imunologia , Proteína-Tirosina Quinase ZAP-70/imunologia
15.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
16.
Vet Microbiol ; 233: 140-146, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31176400

RESUMO

Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), and is characterized by respiratory diseases in piglet and reproductive disorders in sow. Identification of sustainable and effective measures to mitigate PRRSV transmission is a pressing problem. The nucleocapsid (N) protein of PRRSV plays a crucial role in inhibiting host innate immunity during PRRSV infection. In the current study, a new host-restricted factor, tripartite motif protein 25 (TRIM25), was identified as an inhibitor of PRRSV replication. Co-immunoprecipitation assay indicated that the PRRSV N protein interferes with TRIM25-RIG-I interactions by competitively interacting with TRIM25. Furthermore, N protein inhibits the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress interferon ß production. Furthermore, with increasing TRIM25 expression, the inhibitory effect of N protein on the ubiquitination of RIG-I diminished. These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. This not only provides a theoretical basis for the development of drugs to control PRRSV replication, but also better explains the mechanism through which the PRRSV N protein inhibits innate immune responses of the host.


Assuntos
Proteína DEAD-box 58/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Proteínas com Motivo Tripartido/antagonistas & inibidores , Proteínas com Motivo Tripartido/genética , Ubiquitinação , Motivos de Aminoácidos , Animais , Linhagem Celular , Cercopithecus aethiops , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Proteínas do Nucleocapsídeo/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Ligação Proteica , RNA Interferente Pequeno , Transdução de Sinais/imunologia , Suínos , Transfecção , Replicação Viral
17.
Nat Commun ; 10(1): 2735, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227713

RESUMO

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.


Assuntos
Interleucina-33/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Neoplasias Gástricas/imunologia , Aminopiridinas/administração & dosagem , Animais , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Cromolina Sódica/administração & dosagem , Modelos Animais de Doenças , Epitélio/imunologia , Epitélio/patologia , Feminino , Mucosa Gástrica/citologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Microambiente Tumoral/imunologia
18.
Nat Commun ; 10(1): 2603, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197149

RESUMO

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.


Assuntos
Autoimunidade/genética , Proteína 11 Semelhante a Bcl-2/genética , Elementos Facilitadores Genéticos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Timócitos/fisiologia , Animais , Apoptose/genética , Apoptose/imunologia , Autoimunidade/imunologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Sistemas CRISPR-Cas/genética , Elementos Facilitadores Genéticos/genética , Feminino , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Timo/citologia , Timo/imunologia
19.
Scand J Immunol ; 90(3): e12795, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31148206

RESUMO

Antigen-specific molecules of the immune system, namely antibodies, the membrane immunoglobulins (mIgs) of B cells and T cell receptors (TcRs), can all signal their interaction with antigen. There are different mechanisms by which this signalling could occur. These mechanisms can be divided into two general categories: allosteric and non-allosteric. In allosteric mechanisms, the monovalent binding of the antigen to the receptor triggers a conformational change at the binding site that is propagated to an invariant part of the receptor, a change recognized by a sensing unit. We argue allosteric mechanisms are implausible. Non-allosteric mechanisms depend on steric effects due to the antigen's size and/or multivalency. We consider two non-allosteric mechanisms by which the mIg of B cells has been envisaged to signal its interaction with antigen: the popular cross-linking model and the dissociation activation model. We argue, on the basis of both experimental observations and physiological considerations, that the dissociation activation model, developed by Reth and his colleagues, is uniquely plausible.


Assuntos
Anticorpos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Sistema Imunitário/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia
20.
Cancer Sci ; 110(8): 2357-2367, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169331

RESUMO

Dendritic cells (DCs) are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses against cancer. Tumor cells can escape from immune attack by secreting suppressive cytokines that solely or cooperatively impair the immune function of DCs. However, the underlying mechanisms are not fully defined. Vascular endothelial growth factor (VEGF) has been identified as a major cytokine in the tumor microenvironment. To elucidate the effects of VEGF on the motility and immune function of mature DCs (mDCs), the cells were treated with 50 ng/mL VEGF and investigated by proteomics and molecular biological technologies. The results showed that VEGF can impair the migration capacity and immune function of mDCs through the RhoA-cofilin1 pathway mediated by the VEGF receptor 2, suggesting impaired motility of mDCs by VEGF is one of the aspects of immune escape mechanisms of tumors. It is clinically important to understand the biological behavior of DCs and the immune escape mechanisms of tumor as well as how to improve the efficiency of antitumor therapy based on DCs.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Movimento Celular/imunologia , Células Dendríticas/metabolismo , Transdução de Sinais/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Fatores de Despolimerização de Actina/imunologia , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Proteína rhoA de Ligação ao GTP/imunologia
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