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1.
Biomolecules ; 11(8)2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34439836

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinoma Ductal Pancreático/imunologia , Neutrófilos/imunologia , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Comunicação Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Prognóstico , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
J Biol Chem ; 296: 100745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33957119

RESUMO

Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.


Assuntos
Imunidade Adaptativa , Anticorpos Antivirais/química , Antígenos Virais/química , Imunidade Inata , Receptores de Antígenos de Linfócitos T/química , Receptores de Citocinas/química , SARS-CoV-2/imunologia , Alergia e Imunologia/história , Animais , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Apresentação do Antígeno , Antígenos Virais/genética , Antígenos Virais/imunologia , COVID-19/imunologia , COVID-19/virologia , Cristalografia/história , Cristalografia/métodos , História do Século XX , História do Século XXI , Humanos , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , SARS-CoV-2/patogenicidade , Recombinação V(D)J
3.
Cancer Immunol Immunother ; 70(8): 2353-2365, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33527196

RESUMO

Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO+ Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO+ Tregs using single-cell images captured by the DEPArray™ system. The frequency of CD30+OX40+CD45RO+ Tregs was significantly higher in CRC patients than in healthy subjects (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30+OX40+ Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30+OX40+ Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30+OX40+ Tregs as a diagnostic or prognostic biomarker in CRC.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Antígeno Ki-1/imunologia , Receptores OX40/imunologia , Linfócitos T Reguladores/imunologia , Biomarcadores Tumorais/imunologia , Células Cultivadas , Humanos , Antígenos Comuns de Leucócito/imunologia , Estudos Prospectivos , Receptores de Citocinas/imunologia , Estudos Retrospectivos
4.
PLoS One ; 15(12): e0242329, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33259477

RESUMO

Members of the IL-6/IL-12 cytokine family are critical regulators of innate and adaptive immunity and have emerged as key players controlling inflammatory and autoimmune disorders. This cytokine family comprises of IL-12, IL-23, IL-27, and IL-35, each consisting of distinct α- and ß-cytokine subunits that form heterodimers. A new member of this family, IL-39, was identified in the murine species and was shown to consist of the IL-23p19 and Epstein-Barr Virus-induced 3 (EBI3) subunits. Subsequently, it was shown that IL-39 was implicated in the immunopathogenesis of murine experimental lupus erythematosus. The existence of IL-39 in the human system has yet to be confirmed. Based on the clinical success of IL-23p19 neutralizing approaches in moderate-to-severe psoriasis, anti-IL-23p19 antibodies in the clinic may not only neutralize IL-23, but additionally IL-39, implying that IL-39 might also contribute to the pathogenesis of psoriasis. It is therefore pivotal to demonstrate IL-39 expression and to characterize its function in the human system. In this study, we provided evidence for the existence of secreted heterodimeric p19 and EBI3 complexes in supernatants originating from p19 and EBI3 transfected HEK293FT cells. We attempted to detect IL-39 expression from stimulated human primary B cells, human keratinocytes and in vitro polarized human macrophages. Whereas, the expression of p19 and EBI3 mRNA was elevated, we failed to detect p19 and EBI3 heterodimers. Functional assays were conducted with conditioned media containing human IL-39 or with a human recombinant IL-39 Fc protein. Immune cells targeted by IL-39 in mouse, such as neutrophils and PBMCs, did not respond to human IL-39 stimulation and IL-39 failed to activate STAT3 in a reporter cell line. These results suggest that, while the secretion of p19/EBI3 complexes can be forced in human cells, it is secreted below the lower quantity of detection or it has no functional role.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Subunidade p19 da Interleucina-23/genética , Interleucinas/genética , Antígenos de Histocompatibilidade Menor/genética , Receptores de Citocinas/genética , Animais , Humanos , Subunidade p19 da Interleucina-23/imunologia , Interleucinas/imunologia , Camundongos , Antígenos de Histocompatibilidade Menor/imunologia , Neutrófilos/imunologia , Receptores de Citocinas/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia
5.
Curr Drug Targets ; 21(16): 1733-1751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32914713

RESUMO

The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.


Assuntos
Receptores de Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo
6.
Mol Cell Proteomics ; 19(11): 1749-1759, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32788344

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.


Assuntos
Proteínas Sanguíneas/imunologia , Infecções por Coronavirus/imunologia , Tosse/imunologia , Síndrome da Liberação de Citocina/imunologia , Febre/imunologia , Cefaleia/imunologia , Influenza Humana/imunologia , Mialgia/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Proteínas Sanguíneas/genética , COVID-19 , Criança , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Tosse/genética , Tosse/fisiopatologia , Tosse/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Feminino , Febre/genética , Febre/fisiopatologia , Febre/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Cefaleia/genética , Cefaleia/fisiopatologia , Cefaleia/virologia , Humanos , Influenza Humana/genética , Influenza Humana/fisiopatologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mialgia/genética , Mialgia/fisiopatologia , Mialgia/virologia , Orthomyxoviridae/patogenicidade , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Análise Serial de Proteínas , Proteoma/genética , Proteoma/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , SARS-CoV-2 , Transdução de Sinais/imunologia
7.
J Clin Invest ; 130(11): 6124-6140, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32809973

RESUMO

Epstein-Barr virus-induced gene 3 (EBI3) is a subunit common to IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function in cytokines. EBI3-deficient naive CD4+ T cells had reduced IFN-γ production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23Rα, but not another IL-23R subunit, IL-12Rß1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23Rα expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression is inducible in T cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions.


Assuntos
Calnexina/imunologia , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Citocinas/imunologia , Receptores de Interleucina/imunologia , Linfócitos T/imunologia , Substituição de Aminoácidos , Animais , Calnexina/genética , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Mutação de Sentido Incorreto , Receptores de Citocinas/genética , Receptores de Interleucina/genética
8.
Med Sci Monit ; 26: e922854, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32529991

RESUMO

BACKGROUND Oral squamous cell carcinoma (OSCC) is the sixth most prevalent cancer worldwide, with low 5-year survival rate. To identify novel prognostic markers for OSCC and determine the immune and stromal landscape of OSCC, a risk signature for OSCC patients was constructed in this study. MATERIAL AND METHODS Immune and stromal scores for OSCC samples from the Genomic Data Commons Data Portal were computed to delineate the tumor microenvironment landscape of oral cancer based on the Estimation of STromal and Immune cells in MAlignant Tumours using Expression data algorithm. An immune score-based risk signature was constructed by combining random forest and support vector machine methods. Correlation analysis of risk signature gene expression and immune cell infiltration was conducted, and the distinguishing power of individual signature genes was evaluated by analyzing receiver operating characteristics (ROC) curves. Differentially enriched pathways between high and low risk groups were investigated via gene set variation analysis. ROC curves were plotted for signature genes to examine their ability to distinguish the recurrence and survival status of OSCC patients from GSE84846. RESULTS An immune score-related risk signature composed of ARMH1, F2RL2, AC004687.1, COL6A5, AC008750.1, RAB19, CRLF2, GRIP2, and FAM162B performed well in the prognostic stratification of OSCC patients and could effectively distinguish their survival status. Lists of pathways, including cytokine-cytokine receptor interaction and cell adhesion molecules displayed remarkable differential enrichment between high and low risk OSCC patients. CONCLUSIONS An immune score-based risk signature constructed presently may be useful to decide appropriate treatment options for individual OSCC patients.


Assuntos
Neoplasias Bucais/genética , Neoplasias Bucais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Citocinas/genética , Citocinas/imunologia , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Linfócitos do Interstício Tumoral , Masculino , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas , RNA Mensageiro , RNA-Seq , Curva ROC , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Medição de Risco , Máquina de Vetores de Suporte , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
9.
Brain Behav Immun ; 89: 559-568, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32497778

RESUMO

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Pulmão/imunologia , Pulmão/inervação , Pneumonia Viral/imunologia , Receptores de Citocinas/imunologia , Células Receptoras Sensoriais/imunologia , Antirreumáticos/uso terapêutico , Betacoronavirus , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Bases de Dados Factuais , Gânglios Espinais , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Nociceptores/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , RNA-Seq , Receptores de Citocinas/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia , SARS-CoV-2 , Células Receptoras Sensoriais/metabolismo , Transcriptoma , Regulação para Cima
10.
Cytokine Growth Factor Rev ; 55: 94-108, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32386776

RESUMO

Cytokines control the immune system by regulating the proliferation, differentiation and function of immune cells. They activate their target cells through binding to specific receptors, which either are transmembrane proteins or attached to the cell-surface via a GPI-anchor. Different tissues and individual cell types have unique expression profiles of cytokine receptors, and consequently this expression pattern dictates to which cytokines a given cell can respond. Furthermore, soluble variants of several cytokine receptors exist, which are generated by different molecular mechanisms, namely differential mRNA splicing, proteolytic cleavage of the membrane-tethered precursors, and release on extracellular vesicles. These soluble receptors shape the function of cytokines in different ways: they can serve as antagonistic decoy receptors which compete with their membrane-bound counterparts for the ligand, or they can form functional receptor/cytokine complexes which act as agonists and can even activate cells that would usually not respond to the ligand alone. In this review, we focus on the IL-2 and IL-6 families of cytokines and the so-called Th2 cytokines. We summarize for each cytokine which soluble receptors exist, were they originate from, how they are generated, and what their biological functions are. Furthermore, we give an outlook on how these soluble receptors can be exploited for therapeutic purposes.


Assuntos
Citocinas , Receptores de Citocinas , Membrana Celular/imunologia , Citocinas/imunologia , Receptores de Citocinas/imunologia
11.
Am J Clin Dermatol ; 21(4): 457-465, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32323259

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by complex pathophysiology involving both skin barrier dysfunction and aberrant type 2 inflammation/immune responses. AD can be a debilitating condition that drastically impairs quality of life, especially in patients with moderate-to-severe disease. Currently, topical therapies such as corticosteroids and non-steroidal immunomodulatory therapy provide limited efficacy for patients with moderate-to-severe AD; limitations include inadequate response, cutaneous toxicity from overuse, and poor tolerance due to stinging and burning. Historically, the development of targeted therapies has been challenging due to the complex and multifaceted etiology of AD. Recent progress in understanding the immunopathology of AD reinforces the development of newly targeted therapeutics. The successful launch of dupilumab, a monoclonal antibody targeting the interleukin (IL)-4α receptor subunit, for AD in 2017 spurred the development of a number of biologics targeting novel cytokine and receptor targets that are now in phase II and III of development. This review aims to explore the rationale behind these novel biological therapies and to summarize current clinical studies of these agents.


Assuntos
Produtos Biológicos/uso terapêutico , Citocinas/antagonistas & inibidores , Dermatite Atópica/tratamento farmacológico , Receptores de Citocinas/antagonistas & inibidores , Animais , Produtos Biológicos/farmacologia , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Terapia de Alvo Molecular/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Resultado do Tratamento
12.
Yale J Biol Med ; 93(1): 19-27, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226331

RESUMO

As biologic therapies become first line treatments for many inflammatory disorders, it becomes increasingly important for the practicing physician to be familiar with how these drugs function at the molecular level. This information is useful in making therapeutic decisions and helping patients understand their treatment options. It is critical to patient safety and clinical response that the molecular differences between these drugs inform prescribing practices. To this end, we present and analyze the available structural biology information about the biologics used in the treatment of psoriasis including inhibitors of tumor necrosis factor alpha (TNFα), interleukin-17 (IL-17), and interleukin-23 (IL-23). We describe and analyze the molecular surface character of known binding epitopes for medications in these classes, showing that significant differences exist in epitope location, hydrophobicity, and charge. Some of these differences can be correlated with clinical data, but our analysis ultimately points to the need for more structural information to allow for a better understanding of the structure-function relationship of biologic therapies.


Assuntos
Anticorpos Monoclonais/farmacologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Terapia de Alvo Molecular/métodos , Psoríase , Fator de Necrose Tumoral alfa/imunologia , Produtos Biológicos/farmacologia , Humanos , Determinação de Necessidades de Cuidados de Saúde , Psoríase/tratamento farmacológico , Psoríase/imunologia , Receptores de Citocinas/imunologia , Pesquisa Médica Translacional/métodos , Pesquisa Médica Translacional/tendências
13.
Fish Physiol Biochem ; 46(4): 1255-1277, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32162151

RESUMO

Salinity is a major ecological factor in the marine environment, and extremely important for the survival, development, and growth of fish. In this study, gill transcriptomes were examined by high-throughput sequencing at three different salinities (12 ppt as low salinity, 22 ppt as control salinity, and 32 ppt as high salinity) in an importantly economical fish silvery pomfret. A total of 187 genes were differentially expressed, including 111 up-regulated and 76 down-regulated transcripts in low-salinity treatment group and 107 genes differentially expressed, including 74 up-regulated and 33 down-regulated transcripts in high-salinity treatment group compared with the control group, respectively. Some pathways including NOD-like receptor signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor pathway, cardiac muscle contraction, and vascular smooth muscle contraction were significantly enriched. qPCR analysis further confirmed that mRNA expression levels of immune (HSP90A, IL-1ß, TNFα, TLR2, IP-10, MIG, CCL19, and IL-11) and ion transport-related genes (WNK2, NPY2R, CFTR, and SLC4A2) significantly changed under salinity stress. Low salinity stress caused more intensive expression changes of immune-related genes than high salinity. These results imply that salinity stress may affect immune function in addition to regulating osmotic pressure in silvery pomfret.


Assuntos
Peixes/metabolismo , Brânquias/metabolismo , Estresse Salino/fisiologia , Transcriptoma , Animais , Sequência de Bases , Regulação para Baixo , Peixes/genética , Peixes/imunologia , Regulação da Expressão Gênica , Brânquias/imunologia , Anotação de Sequência Molecular , Proteínas NLR/imunologia , Pressão Osmótica , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptores de Citocinas/imunologia , Estresse Salino/genética , Estresse Salino/imunologia , Transdução de Sinais , Receptores Toll-Like/metabolismo , Regulação para Cima
14.
PLoS Negl Trop Dis ; 14(1): e0008021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961868

RESUMO

Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.


Assuntos
Doenças do Cão/tratamento farmacológico , Doenças do Cão/imunologia , Interleucina-12/administração & dosagem , Interleucina-15/administração & dosagem , Leishmaniose Visceral/imunologia , Animais , Doenças do Cão/genética , Doenças do Cão/parasitologia , Cães , Imunidade Celular , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Leishmania infantum/fisiologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/veterinária , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/parasitologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
15.
J Asthma ; 57(1): 1-10, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30588853

RESUMO

Objective: Local cytokine milieu (especially Th2 inflammatory type) secreted into the asthmatic airways affect the alternative activated macrophages polarization (M2). TSLP and IL-33 are important alarmins of allergic response associated with Th2 inflammation. The aim of the study was to investigate the expression of the receptors for epithelial derived cytokines: TSLP (TSLPR) and IL-33 (ST2) on induced sputum CD206 positive macrophages from asthma and healthy subjects and analyze the relationships between these receptors and clinical features of the disease. Methods: Immunofluorescence staining for CD206 and TSLPR or ST2 on sputum macrophages was performed in 20 adult patients with stable asthma - 75% with atopy (3 intermittent, 12 mild-to-moderate, 5 severe, of which 11 were on biological anty-IgE treatment) and 23 healthy adult controls - 48% with atopy. Results: Our study demonstrated an increased expression of TSLP and IL-33 receptors on bronchial CD206 positive macrophages in asthma group. TSLPR but not ST2 had also greater expression on CD206 negative macrophages in asthma patients. Increased expression of both investigated receptors was related to longer disease duration and impaired lung function. We observed increased count of CD206lowTSLPhigh macrophages as well as positive correlation of these cells with total serum IgE in patients with atopy. Conclusions: The macrophage response during allergic reaction is likely to be connected with TSLP but rather not with IL-33 action. Our study indicates an important role of crosstalk between macrophages, TSLP and IL-33 in asthma pathophysiology.


Assuntos
Asma/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Macrófagos/imunologia , Receptores de Citocinas/metabolismo , Adulto , Asma/patologia , Estudos Transversais , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Interleucina-33/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Masculino , Lectinas de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Superfície Celular/metabolismo , Receptores de Citocinas/imunologia , Escarro/citologia , Escarro/imunologia
17.
Front Immunol ; 10: 1293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316496

RESUMO

Tumor necrosis factor receptor (TNFR)-associated factors or (TRAFs) are important mediators of Interleukin-17 (IL-17) cytokine signaling and contribute to driving tissue responses that are crucial for protective immunity but are often implicated in immunopathology. By amplifying tissue immune activity, IL-17 cytokine pathways contribute to maintaining barrier function as well as activation of innate and adaptive immunity necessary for host defense. IL-17 receptors signaling is orchestrated in part, by the engagement of TRAFs and the subsequent unlocking of downstream cellular machinery that can promote pathogen clearance or contribute to immune dysregulation, chronic inflammation, and disease. Originally identified as signaling adaptors for TNFR superfamily, TRAF proteins can mediate the signaling of a variety of intercellular and extracellular stimuli and have been shown to regulate the downstream activity of many cytokine receptors including receptors for IL-1ß, IL-2, IL-6, IL-17, IL-18, IL-33, type I IFNs, type III IFNs, GM-CSF, M-CSF, and TGF-ß Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I- like receptors, and C-type lectin receptors. This review will focus on discussing studies that reveal our current understanding of how TRAFs mediate and regulate biochemical activities downstream of the IL-17 cytokines signaling.


Assuntos
Citocinas/imunologia , Interleucina-17/imunologia , Transdução de Sinais/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia , Imunidade Adaptativa/imunologia , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata/imunologia , Interleucina-17/metabolismo , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo
18.
J Clin Invest ; 129(8): 3201-3213, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31264967

RESUMO

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.


Assuntos
Células Dendríticas/imunologia , Interleucinas/imunologia , Falência Hepática Aguda/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Animais , Células Dendríticas/patologia , Feminino , Humanos , Subunidade p35 da Interleucina-12/genética , Subunidade p35 da Interleucina-12/imunologia , Interleucinas/genética , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Falência Hepática Aguda/prevenção & controle , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Linfócitos T Reguladores/patologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia
19.
Front Immunol ; 10: 988, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139181

RESUMO

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the development of acute and chronic graft-vs.-host disease (GVHD) remain preeminent causes of death and morbidity. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and IL-39. This family of cytokines is biologically distinct in that they are composed of functional heterodimers, which bind to cognate heterodimeric receptor chains expressed on T cells. Of these, IL-12 and IL-23 share a common ß cytokine subunit, p40, as well as a receptor chain: IL-12Rß1. IL-12 and IL-23 have been documented as proinflammatory mediators of GVHD, responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively. The role of IL-27 is less defined, seemingly immune suppressive via IL-10 secretion by Type 1 regulatory (Tr1) cells yet promoting inflammation through impairing CD4+ T regulatory (Treg) development and/or enhancing Th1 differentiation. More recently, IL-35 was described as a potent anti-inflammatory agent produced by regulatory B and T cells. The role of the newest member, IL-39, has been implicated in proinflammatory B cell responses but has not been explored in the context of allo-HCT. This review is directed at discussing the current literature relevant to each IL-12-family cytokine and cognate receptor engagement, as well as the consequential downstream signaling implications, during GVHD pathogenesis. Additionally, we will provide an overview of translational strategies targeting the IL-12 family cytokines, their receptors, and subsequent signal transduction to control GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Interleucina-12/imunologia , Receptores de Citocinas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Aloenxertos , Animais , Doença Enxerto-Hospedeiro/patologia , Humanos , Linfócitos T Auxiliares-Indutores/patologia
20.
Paediatr Respir Rev ; 32: 82-90, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31128878

RESUMO

Bronchiolitis is one of the leading causes of hospitalisation in infancy, with highly variable clinical presentations ranging from mild disease safely managed at home to severe disease requiring invasive respiratory support. Identifying immune biomarkers that can predict and stratify this variable disease severity has important implications for clinical prognostication/disposition. A systematic literature search of the databases Embase, PubMed, ScienceDirect, Web of Science, and Wiley Online Library was performed. English language studies that assessed the association between an immune biomarker and bronchiolitis disease severity among children aged less than 24 months were included. 252 distinct biomarkers were identified across 90 studies. A substantial degree of heterogeneity was observed in the bronchiolitis definitions, measures of disease severity, and study designs. 99 biomarkers showed some significant association with disease severity, but only 18 were significant in multiple studies. However, all of these candidate biomarkers had comparable studies that reported conflicting results. Conclusion: The heterogeneity among included studies and the lack of a consistently significant biomarker highlight the need for consensus on bronchiolitis definitions and severity measures, as well as further studies assessing their clinical utility both in isolation and in combination.


Assuntos
Bronquiolite Viral/imunologia , Citocinas/imunologia , Receptores de Citocinas/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Células Apresentadoras de Antígenos/imunologia , Biomarcadores , Quimiocinas/imunologia , Citocinas/genética , Humanos , Lactente , Recém-Nascido , Leucócitos/imunologia , Linfócitos/imunologia , Polimorfismo Genético , Receptores de Quimiocinas/imunologia , Índice de Gravidade de Doença , Receptores Toll-Like/genética
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