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1.
Front Immunol ; 12: 681516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489933

RESUMO

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1ß were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-ß were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients.


Assuntos
COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transcriptoma/imunologia , Adulto , Idoso , Biomarcadores/sangue , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade
2.
Immunol Res ; 69(5): 457-460, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34357535

RESUMO

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Doença pelo Vírus Ebola/imunologia , Infecções por Henipavirus/imunologia , Síndrome de Imunodeficiência Adquirida/imunologia , COVID-19/tratamento farmacológico , Quimiocinas/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Doença pelo Vírus Ebola/tratamento farmacológico , Infecções por Henipavirus/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Linfócitos/imunologia , SARS-CoV-2/fisiologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/imunologia
3.
Pan Afr Med J ; 39: 40, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34422163

RESUMO

In its severe form, corona virus disease-19 (COVID-19) is characterized by various immunological abnormalities, dominated by massive pro-inflammatory cytokine and chemokine release, such as IL-6, TNF-α, IL-1b, IFN-y and monocyte chemoattractant protein-1 (MCP-1), associated with T CD3, T CD4 and T CD8 lymphopenia. These two abnormalities are significantly associated with COVID-19 acute severe respiratory syndrome. Conversely, these markers decrease during the favorable course of the disease. Coupled with other biological parameters such as leukopenia, increased level of CRP (C Reactive Protein), ferritin and D-dimers, high levels of IL-6 with CD4 and CD8 T cell lymphopenia may be considered as criteria of disease severity, justifying a rapid admission to the intensive care unit, and are also useful for patient monitoring.


Assuntos
COVID-19/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Biomarcadores/metabolismo , COVID-19/fisiopatologia , Humanos , Índice de Gravidade de Doença
4.
Immunity ; 54(7): 1405-1416.e7, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34216564

RESUMO

Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-Å resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches" stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Fatores Imunológicos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Proteínas Virais/imunologia , Animais , Sítios de Ligação/imunologia , Linhagem Celular , Quimiocinas/imunologia , Microscopia Crioeletrônica/métodos , Infecções por Vírus Epstein-Barr/virologia , Células HEK293 , Humanos , Ligação Proteica/imunologia , Células Sf9 , Transdução de Sinais/imunologia
5.
PLoS One ; 16(7): e0254367, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242356

RESUMO

COVID-19 serological test must have high sensitivity as well as specificity to rule out cross-reactivity with common coronaviruses (HCoVs). We have developed a quantitative multiplex test, measuring antibodies against spike (S) proteins of SARS-CoV-2, SARS-CoV, MERS-CoV, and common human coronavirus strains (229E, NL63, OC43, HKU1), and nucleocapsid (N) protein of SARS-CoV viruses. Receptor binding domain of S protein of SARS-CoV-2 (S-RBD), and N protein, demonstrated sensitivity (94% and 92.5%, respectively) in COVID-19 patients (n = 53), with 98% specificity in non-COVID-19 respiratory-disease (n = 98), and healthy-controls (n = 129). Anti S-RBD and N antibodies appeared five to ten days post-onset of symptoms, peaking at approximately four weeks. The appearance of IgG and IgM coincided while IgG subtypes, IgG1 and IgG3 appeared soon after the total IgG; IgG2 and IgG4 remained undetectable. Several inflammatory cytokines/chemokines were found to be elevated in many COVID-19 patients (e.g., Eotaxin, Gro-α, CXCL-10 (IP-10), RANTES (CCL5), IL-2Rα, MCP-1, and SCGF-b); CXCL-10 was elevated in all. In contrast to antibody titers, levels of CXCL-10 decreased with the improvement in patient health suggesting it as a candidate for disease resolution. Importantly, anti-N antibodies appear before S-RBD and differentiate between vaccinated and infected people-current vaccines (and several in the pipeline) are S protein-based.


Assuntos
Anticorpos Antivirais , COVID-19 , Quimiocinas , Proteínas do Nucleocapsídeo de Coronavírus , Imunoglobulina G , Imunoglobulina M , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Adulto , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , Quimiocinas/sangue , Quimiocinas/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/sangue , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/sangue , Fosfoproteínas/imunologia , Coelhos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/sangue , Glicoproteína da Espícula de Coronavírus/imunologia
6.
Viruses ; 13(6)2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205489

RESUMO

The recently discovered exchange protein directly activated by cAMP (EPAC), compared with protein kinase A (PKA), is a fairly new family of cAMP effectors. Soon after the discovery, EPAC has shown its significance in many diseases including its emerging role in infectious diseases. In a recent study, we demonstrated that EPAC, but not PKA, is a promising therapeutic target to regulate respiratory syncytial virus (RSV) replication and its associated inflammation. In mammals, there are two isoforms of EPAC-EPAC1 and EPAC2. Unlike other viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) and Ebola virus, which use EPAC1 to regulate viral replication, RSV uses EPAC2 to control its replication and associated cytokine/chemokine responses. To determine whether EPAC2 protein has a broad impact on other respiratory viral infections, we used an EPAC2-specific inhibitor, MAY0132, to examine the functions of EPAC2 in human metapneumovirus (HMPV) and adenovirus (AdV) infections. HMPV is a negative-sense single-stranded RNA virus belonging to the family Pneumoviridae, which also includes RSV, while AdV is a double-stranded DNA virus. Treatment with an EPAC1-specific inhibitor was also included to investigate the impact of EPAC1 on these two viruses. We found that the replication of HMPV, AdV, and RSV and the viral-induced immune mediators are significantly impaired by MAY0132, while an EPAC1-specific inhibitor, CE3F4, does not impact or slightly impacts, demonstrating that EPAC2 could serve as a novel common therapeutic target to control these viruses, all of which do not have effective treatment and prevention strategies.


Assuntos
Adenoviridae/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Metapneumovirus/fisiologia , Vírus Sincicial Respiratório Humano/fisiologia , Replicação Viral , Células A549 , Linhagem Celular , Quimiocinas/imunologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Células HEK293 , Humanos , Quinolinas/farmacologia
7.
Trop Med Int Health ; 26(9): 1098-1109, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107115

RESUMO

OBJECTIVES: We measured the production of cytokines, chemokines and antibodies involved in allergic responses and sCD23 levels during Schistosoma mansoni infection. METHODS: Individuals (n = 164) were selected using the ISAAC questionnaire and parasitological exams. The subjects were divided as follows: those infected individuals with allergy-related symptoms (A-I), those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related symptoms (NA-NI). We used supernatants from cell culture (mitogenic stimulation) to measure cytokine and chemokine levels using cytometric bead arrays. Serum levels of anti-Ascaris lumbricoides (Asc) and anti-Blomia tropicalis IgE were measured using ImmunoCAP, and sCD23 was measured using ELISA. RESULTS: Schistosoma mansoni infection was associated with a lower risk of allergy-related symptoms. In A-I, there were higher levels of TNF-α, IL-10, IL-6, IFN-γ and CXCL8 than in NA-NI group, with TNF-α and IL-6 also at higher levels compared to A-NI group. Levels of IL-6, CXCL8, total and anti-Asc IgE, as well as the numbers of eosinophils, were higher in NA-I than in NA-NI, and the antibodies were also lower in A-NI than in NA-I group. In AI and NA-I, there was less production of CCL2 than in NA-NI. There were no differences in the levels of IL-2, IL-4, IL-17, CCL5, sCD23 and anti-Blomia IgE. CONCLUSIONS: Patients with allergy-related symptoms and infected (simultaneously) had higher levels of IL-10; due to the infection, there was increased production of IL-6 and CXCL8 and less CCL2. These data may characterize deviation to Th1 or attenuation of the Th2 response in allergy sufferers in areas endemic for schistosomiasis.


Assuntos
Anticorpos/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Hipersensibilidade Respiratória/parasitologia , Esquistossomose mansoni/imunologia , Adolescente , Adulto , Animais , Anticorpos/sangue , Anticorpos Anti-Helmínticos/sangue , Anticorpos Anti-Helmínticos/imunologia , Brasil/epidemiologia , Quimiocina CCL2/imunologia , Quimiocinas/sangue , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Imunoglobulina E , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070943

RESUMO

The medicinal plant noni (Morinda citrifolia) is widely dispersed throughout Southeast Asia, the Caribbean, and Australia. We previously reported that fermented Noni could alleviate atopic dermatitis (AD) by recovering Th1/Th2 immune balance and enhancing skin barrier function induced by 2,4-dinitrochlorobenzene. Noni has a high deacetylasperulosidic acid (DAA) content, whose concentration further increased in fermented noni as an iridoid constituent. This study aimed to determine the anti-AD effects and mechanisms of DAA on HaCaT, HMC-1, and EOL-1 cells. DAA inhibited the gene expression and secretion of AD-related cytokines and chemokines including interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-25, IL-33, thymic stromal lymphopoietin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, thymus and activation-regulated chemokine, macrophage-derived chemokine, and regulated upon activation, normal T cell expressed and secreted, in all cells, and inhibited histamine release in HMC-1 cells. DAA controlled mitogen-activated protein kinase phosphorylation levels and the translocation of nuclear factor-kappa light chain enhancer of activated B cells into the nucleus by inhibiting IκBα decomposition in all the cells. Furthermore, DAA increased the expression of proteins involved in skin barrier functions such as filaggrin and involucrin in HaCaT cells. These results confirmed that DAA could relieve AD by controlling immune balance and recovering skin barrier function.


Assuntos
Dermatite Atópica/tratamento farmacológico , Glicosídeos/farmacologia , Linhagem Celular , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/patologia , Eczema/tratamento farmacológico , Eczema/patologia , Glicosídeos/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Morinda/metabolismo , Extratos Vegetais/farmacologia , Pele/metabolismo , Equilíbrio Th1-Th2/efeitos dos fármacos
9.
Biomed Res Int ; 2021: 6628814, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041299

RESUMO

Objective: Alveolar echinococcosis (AE) is a zoonosis caused by the larval stage of the metacestode Echinococcosis multilocularis with a tumor-like behavior in the targeted organ, especially in the liver. Surgery with albendazole is first-line modality for AE. Drug discontinuation is usually based upon the parasitic viability shown by the positron emission tomography (PET) scan. However, as a demanding and expensive method, it is not widely practiced in majority of the endemic regions. Further understanding on the cytokine and chemokine response profiles in AE patients may provide an interesting insight for potential markers in viability assessment. Methods: Mice were inoculated with Echinococcus multilocularis intrahepatically to develop the hepatic AE murine model. Oral albendazole administration was then applied for three months after the first inoculation, and peripheral and regional immune cells including type 1 T helper cells (Th), Th2, Th17, regulatory T (Treg) cells, related cytokines, and chemokines were examined. Results: The hepatic AE lesion was confirmed by ultrasound examination resulting in a successful rate of 70%. Among the 17 cytokines and chemokines detected, plasma levels of IL-23 were significantly higher in E. multilocularis-infected mice when compared to the control group; furthermore, more obvious increasing levels were found after albendazole treatment (p < 0.05). All chemokine levels other than eotaxin and MCP-3 were slightly higher in E. multilocularis-infected mice compared to the control group (p > 0.05). Eotaxin levels were significantly decreased in mice with E. multilocularis infection followed by albendazole treatment (p < 0.05). Both IL-17A and IL-23 expressions in hepatic AE lesions were significantly higher and related with disease activity. Conclusion: Albendazole administration influenced the balance of immune response and promotes the secretion of proinflammatory factors which is beneficial to parasite clearance. IL-23 seems to be associated with the successful albendazole treatment in mice with E. multilocularis infection; such a change could be translated into clinical application in the near future.


Assuntos
Albendazol/uso terapêutico , Quimiocinas/imunologia , Citocinas/imunologia , Equinococose/tratamento farmacológico , Echinococcus multilocularis/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Equinococose/parasitologia , Equinococose/patologia , Equinococose Hepática/tratamento farmacológico , Equinococose Hepática/parasitologia , Equinococose Hepática/patologia , Feminino , Humanos , Imunidade , Interleucina-23 , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
10.
Front Immunol ; 12: 648946, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936069

RESUMO

Background: Vascular endothelial cells (EC) are critical for regulation of local immune responses, through coordination of leukocyte recruitment from the blood and egress into the tissue. Growing evidence supports an additional role for endothelium in activation and costimulation of adaptive immune cells. However, this function remains somewhat controversial, and the full repertoire and durability of an enhanced endothelial costimulatory phenotype has not been wholly defined. Methods: Human endothelium was stimulated with continuous TNFα or IFNγ for 1-48hr; or primed with TNFα or IFNγ for only 3hr, before withdrawal of stimulus for up to 45hr. Gene expression of cytokines, costimulatory molecules and antigen presentation molecules was measured by Nanostring, and publicly available datasets of EC stimulation with TNFα or IFNγ were leveraged to further corroborate the results. Cell surface protein expression was detected by flow cytometry, and secretion of cytokines was assessed by Luminex and ELISA. Key findings were confirmed in primary human endothelial cells from 4-6 different vascular beds. Results: TNFα triggered mostly positive immune checkpoint molecule expression on endothelium, including CD40, 4-1BB, and ICOSLG but in the context of only HLA class I and immunoproteasome subunits. IFNγ promoted a more tolerogenic phenotype of high PD-L1 and PD-L2 expression with both HLA class I and class II molecules and antigen processing genes. Both cytokines elicited secretion of IL-15 and BAFF/BLyS, with TNFα stimulated EC additionally producing IL-6, TL1A and IL-1ß. Moreover, endothelium primed for a short period (3hr) with TNFα mostly failed to alter the costimulatory phenotype 24-48hr later, with only somewhat augmented expression of HLA class I. In contrast, brief exposure to IFNγ was sufficient to cause late expression of antigen presentation, cytokines and costimulatory molecules. In particular HLA class I, PD-1 ligand and cytokine expression was markedly high on endothelium two days after IFNγ was last present. Conclusions: Endothelia from multiple vascular beds possess a wide range of other immune checkpoint molecules and cytokines that can shape the adaptive immune response. Our results further demonstrate that IFNγ elicits prolonged signaling that persists days after initiation and is sufficient to trigger substantial gene expression changes and immune phenotype in vascular endothelium.


Assuntos
Células Endoteliais/imunologia , Endotélio Vascular/imunologia , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Quimiocinas/metabolismo , Análise por Conglomerados , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Interferon gama/farmacologia , Fenótipo , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia
11.
Front Immunol ; 12: 668507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981314

RESUMO

SARS-COV-2 virus is responsible for the ongoing devastating pandemic. Since the early phase of the pandemic, the "cytokine-storm" appeared a peculiar aspect of SARS-COV-2 infection which, at least in the severe cases, is responsible for respiratory treat damage and subsequent multi-organ failure. The efforts made in the last few months elucidated that the cytokine-storm results from a complex network involving cytokines/chemokines/infiltrating-immune-cells which orchestrate the aberrant immune response in COVID-19. Clinical and experimental studies aimed at depicting a potential "immune signature" of SARS-COV-2, identified three main "actors," namely the cytokine IL-6, the chemokine CXCL10 and the infiltrating immune cell type macrophages. Although other cytokines, chemokines and infiltrating immune cells are deeply involved and their role should not be neglected, based on currently available data, IL-6, CXCL10, and infiltrating macrophages could be considered prototype factors representing each component of the immune system. It rapidly became clear that a strong and continuous interplay among the three components of the immune response is mandatory in order to produce a severe clinical course of the disease. Indeed, while IL-6, CXCL10 and macrophages alone would not be able to fully drive the onset and maintenance of the cytokine-storm, the establishment of a IL-6/CXCL10/macrophages axis is crucial in driving the sequence of events characterizing this condition. The present review is specifically aimed at overviewing current evidences provided by both in vitro and in vivo studies addressing the issue of the interplay among IL-6, CXCL10 and macrophages in the onset and progression of cytokine storm. SARS-COV-2 infection and the "cytokine storm."


Assuntos
COVID-19/imunologia , Quimiocina CXCL10/imunologia , Síndrome da Liberação de Citocina/imunologia , Interleucina-6/imunologia , Macrófagos/imunologia , COVID-19/complicações , COVID-19/virologia , Quimiocinas/imunologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Humanos , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia
12.
Gene ; 792: 145735, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34048875

RESUMO

Human immunodeficiency virus (HIV) infection causes acquired immunodeficiency syndrome (AIDS), one of the most devastating diseases affecting humankind. Here, we have proposed a framework to examine the differences among microarray gene expression data of uninfected and three different HIV-1 infection stages using module preservation statistics. We leverage the advantage of gene co-expression networks (GCN) constructed for each infection stages to detect the topological and structural changes of a group of differentially expressed genes. We examine the relationship among a set of co-expression modules by constructing a module eigengene network considering the overall similarity/dissimilarity among the genes within the modules. We have utilized different module preservation statistics with two composite statistics: "Zsummary" and "MedianRank" to examine the changes in co-expression patterns between modules. We have found several interesting results on the preservation characteristics of gene modules across different stages. Some genes are identified to be preserved in a pair of stages while altering their characteristics across other stages. We further validated the obtained results using permutation test and classification techniques. The biological significances of the obtained modules have also been examined using gene ontology and pathway-based analysis. Additionally, we have identified a set of key immune regulatory hub genes in the associated protein-protein interaction networks (PPINs) of the differentially expressed (DE) genes, which interacts with HIV-1 proteins and are likely to act as potential biomarkers in HIV-1 progression.


Assuntos
Antígenos CD/genética , Quimiocinas/genética , Infecções por HIV/genética , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/genética , Proteínas do Vírus da Imunodeficiência Humana/genética , Doença Aguda , Antígenos CD/classificação , Antígenos CD/imunologia , Quimiocinas/classificação , Quimiocinas/imunologia , Doença Crônica , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno/imunologia , Proteínas do Vírus da Imunodeficiência Humana/classificação , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Análise em Microsséries , Anotação de Sequência Molecular , Ligação Proteica , Transdução de Sinais
13.
Cancer Metastasis Rev ; 40(2): 447-476, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33959849

RESUMO

Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.


Assuntos
Quimiocinas/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Animais , Humanos , Metástase Neoplásica , Neoplasias/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
14.
Immunity ; 54(5): 859-874, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33838745

RESUMO

Chemokines are chemotactic cytokines that regulate the migration of immune cells. Chemokines function as cues for the coordinated recruitment of immune cells into and out of tissue and also guide the spatial organization and cellular interactions of immune cells within tissues. Chemokines are critical in directing immune cell migration necessary to mount and then deliver an effective anti-tumor immune response; however, chemokines also participate in the generation and recruitment of immune cells that contribute to a pro-tumorigenic microenvironment. Here, we review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.


Assuntos
Quimiocinas/imunologia , Imunidade/imunologia , Neoplasias/imunologia , Animais , Carcinogênese/imunologia , Movimento Celular/imunologia , Humanos , Microambiente Tumoral/imunologia
15.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925575

RESUMO

Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell-cell interactions in the TME to regulate many cancer hallmarks. This review summarizes the current understanding of the complex cytokine/chemokine networks in the HNSCC TME, their role in activating diverse signaling pathways and promoting tumor progression, metastasis, and therapeutic resistance development.


Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Microambiente Tumoral/imunologia , Apoptose , Carcinoma de Células Escamosas/metabolismo , Quimiocinas/imunologia , Citocinas/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico , Transdução de Sinais , Microambiente Tumoral/fisiologia
16.
Theranostics ; 11(10): 4957-4974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754038

RESUMO

Rationale: TCR-T cell therapy plays a critical role in the treatment of malignant cancers. However, it is unclear how TCR-T cells are affected by PD-L1 molecule in the tumor environment. We performed an in-depth evaluation on how differential expressions of tumor PD-L1 can affect the functionality of T cells. Methods: We used MART-1-specific TCR-T cells (TCR-TMART-1), stimulated with MART-127-35 peptide-loaded MEL-526 tumor cells, expressing different proportions of PD-L1, to perform cellular assays and high-throughput single-cell RNA sequencing. Results: Different clusters of activated or cytotoxic TCR-TMART-1 responded divergently when stimulated with tumor cells expressing different percentages of PD-L1 expression. Compared to control T cells, TCR-TMART-1 were more sensitive to exhaustion, and secreted not only pro-inflammatory cytokines but also anti-inflammatory cytokines with increasing proportions of PD-L1+ tumor cells. The gene profiles of chemokines were modified by increased expression of tumor PD-L1, which concurrently downregulated pro-inflammatory and anti-inflammatory transcription factors. Furthermore, increased expression of tumor PD-L1 showed distinct effects on different inhibitory checkpoint molecules (ICMs). In addition, there was a limited correlation between the enrichment of cell death signaling in tumor cells and T cells and increased tumor PD-L1 expression. Conclusion: Overall, though the effector functionality of TCR-T cells was suppressed by increased expression percentages of tumor PD-L1 in vitro, scRNA-seq profiles revealed that both the anti-inflammatory and pro-inflammatory responses were triggered by a higher expression of tumor PD-L1. This suggests that the sole blockade of tumor PD-L1 might inhibit not only the anti-inflammatory response but also the pro-inflammatory response in the complicated tumor microenvironment. Thus, the outcome of PD-L1 intervention may depend on the final balance among the highly dynamic and heterogeneous immune regulatory circuits.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , Testes Imunológicos de Citotoxicidade , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Imunoterapia Adotiva , Inflamação/genética , Inflamação/imunologia , Antígeno MART-1/imunologia , Melanoma/imunologia , RNA-Seq , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Neoplasias Cutâneas/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética
17.
Front Immunol ; 12: 559925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776989

RESUMO

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the ß-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC (n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1ß, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients.


Assuntos
Anemia Falciforme/imunologia , Citocinas/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Doenças Vasculares/imunologia , Adolescente , Adulto , Anemia Falciforme/metabolismo , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Modelos Imunológicos , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Mapas de Interação de Proteínas/imunologia , Doenças Vasculares/metabolismo , Adulto Jovem
18.
J Allergy Clin Immunol ; 147(5): 1892-1906, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33571538

RESUMO

BACKGROUND: Early life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-ß-dependent postnatal development, but the role of AM maturation factors such as TGF-ß in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear. OBJECTIVE: Our aim was to test the hypothesis that AM-derived TGF-ß1 regulates pathogenic immunity to inhaled allergen in early life. METHODS: Conditional knockout (Tgfb1ΔCD11c) mice, with TGF-ß1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies. RESULTS: AM-intrinsic TGF-ß1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-ß1 signaling was also observed in pediatric human AMs. TGF-ß1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8. CONCLUSION: Our results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-ß1 as a key regulator of this.


Assuntos
Alérgenos/imunologia , Macrófagos Alveolares/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Quimiocinas/imunologia , Hipersensibilidade/imunologia , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/imunologia , Fator de Crescimento Transformador beta1/genética
19.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33597299

RESUMO

Severe traumatic injuries are a widespread and challenging clinical problem, and yet the factors that drive successful healing and restoration of function are still not well understood. One recently identified risk factor for poor healing outcomes is a dysregulated immune response following injury. In a preclinical model of orthopedic trauma, we demonstrate that distinct systemic immune profiles are correlated with impaired bone regeneration. Most notably, elevated blood levels of myeloid-derived suppressor cells (MDSCs) and the immunosuppressive cytokine interleukin-10 (IL-10) are negatively correlated with functional bone regeneration as early as 1 wk posttreatment. Nonlinear multivariate regression also implicated these two factors as the most influential in predictive computational models. These results support a significant relationship between early systemic immune responses to trauma and subsequent local bone regeneration and indicate that elevated circulating levels of MDSCs and IL-10 may be predictive of poor functional healing outcomes and represent novel targets for immunotherapeutic intervention.


Assuntos
Biomarcadores/sangue , Regeneração Óssea/fisiologia , Fraturas não Consolidadas/imunologia , Células Supressoras Mieloides/imunologia , Animais , Quimiocinas/sangue , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Fêmur/lesões , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/fisiopatologia , Fraturas não Consolidadas/terapia , Imunidade/fisiologia , Interleucina-10/sangue , Interleucina-10/imunologia , Análise Multivariada , Ratos Sprague-Dawley , Microtomografia por Raio-X
20.
Cell Immunol ; 361: 104280, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33445053

RESUMO

Myeloid derived suppressor cells (MDSC) are a heterogenous population of immature myeloid cells that accumulate in tumor bearing host and migrate to lymphoid organs and tumor tissues. This process is controlled by a set of defined pro-inflammatory cytokines and chemokines, which are upregulated in malignancies. MDSC have strong immunosuppressive potential and constitute a major component of the tumor microenvironment (TME). Tumor cells take advantage of the suppressive mechanisms of MDSC to establish an immunosuppressive TME which inhibits antitumor immune responses thereby promoting cancer progression. An immunosuppressive TME acts as a significant barrier to immunotherapeutic interventions. Pre-clinical and clinical studies have demonstrated that enrichment and activation of MDSC is correlated with tumor progression, recurrence and metastasis. In this review we discuss the potential impact of MDSC on tumor progression and its role as a biomarker of prognostic significance in cancer with a special focus on hepatocellular cancer (HCC).


Assuntos
Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/imunologia , Animais , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Progressão da Doença , Humanos , Imunossupressão , Neoplasias Hepáticas/imunologia , Células Mieloides/imunologia , Células Supressoras Mieloides/fisiologia , Recidiva Local de Neoplasia/imunologia , Microambiente Tumoral/imunologia
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