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1.
Nat Med ; 25(12): 1916-1927, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792460

RESUMO

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.


Assuntos
Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Mutação/genética , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma/genética , Transcriptoma/imunologia , Sequenciamento Completo do Exoma
2.
Cancer Immunol Immunother ; 68(8): 1273-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243491

RESUMO

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação do Antígeno/genética , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Células Cultivadas , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunidade Celular/genética , Injeções Intramusculares , Interferon gama/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Vacinação
3.
Cells ; 8(5)2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035565

RESUMO

Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs exposed ex vivo to viral hemorrhagic septicemia virus (VHSV) were evaluated by means of transcriptomic and proteomic approaches. Genes and proteins related to antigen presentation molecules, proteasome degradation, and autophagy were up-regulated. VHSV induced accumulation of ubiquitinated proteins in ex vivo VHSV-exposed RBCs and showed at the same time a decrease of proteasome activity. Furthermore, induction of autophagy was detected by evaluating LC3 protein levels. Sequestosome-1/p62 underwent degradation early after VHSV exposure, and it may be a link between ubiquitination and autophagy activation. Inhibition of autophagosome degradation with niclosamide resulted in intracellular detection of N protein of VHSV (NVHSV) and p62 accumulation. In addition, antigen presentation cell markers, such as major histocompatibility complex (MHC) class I & II, CD83, and CD86, increased at the transcriptional and translational level in rainbow trout RBCs exposed to VHSV. In summary, we show that nucleated rainbow trout RBCs can degrade VHSV while displaying an antigen-presenting cell (APC)-like profile.


Assuntos
Apresentação do Antígeno/imunologia , Eritroblastos/imunologia , Eritroblastos/virologia , Septicemia Hemorrágica Viral/imunologia , Septicemia Hemorrágica Viral/virologia , Novirhabdovirus/imunologia , Oncorhynchus mykiss/imunologia , Oncorhynchus mykiss/virologia , Animais , Apresentação do Antígeno/genética , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/análise , Antígenos CD/imunologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/imunologia , Autofagossomos/virologia , Autofagia/efeitos dos fármacos , Autofagia/imunologia , Antígeno B7-2/análise , Antígeno B7-2/imunologia , Biomarcadores/análise , Septicemia Hemorrágica Viral/genética , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoglobulinas/análise , Imunoglobulinas/imunologia , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/imunologia , Niclosamida/farmacologia , Proteínas do Nucleocapsídeo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteômica , Proteína Sequestossoma-1/metabolismo
4.
PLoS Comput Biol ; 15(5): e1007015, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095555

RESUMO

MHC genes, which code for proteins responsible for presenting pathogen-derived antigens to the host immune system, show remarkable copy-number variation both between and within species. However, the evolutionary forces driving this variation are poorly understood. Here, we use computer simulations to investigate whether evolution of the number of MHC variants in the genome can be shaped by the number of pathogen species the host population encounters (pathogen richness). Our model assumed that while increasing a range of pathogens recognised, expressing additional MHC variants also incurs costs such as an increased risk of autoimmunity. We found that pathogen richness selected for high MHC copy number only when the costs were low. Furthermore, the shape of the association was modified by the rate of pathogen evolution, with faster pathogen mutation rates selecting for increased host MHC copy number, but only when pathogen richness was low to moderate. Thus, taking into account factors other than pathogen richness may help explain wide variation between vertebrate species in the number of MHC genes. Within population, variation in the number of unique MHC variants carried by individuals (INV) was observed under most parameter combinations, except at low pathogen richness. This variance gave rise to positive correlations between INV and host immunocompetence (proportion of pathogens recognised). However, within-population variation in host immunocompetence declined with pathogen richness. Thus, counterintuitively, pathogens can contribute more to genetic variance for host fitness in species exposed to fewer pathogen species, with consequences to predictions from "Hamilton-Zuk" theory of sexual selection.


Assuntos
Evolução Molecular , Dosagem de Genes , Complexo Principal de Histocompatibilidade , Imunidade Adaptativa/genética , Alelos , Animais , Apresentação do Antígeno/genética , Biologia Computacional , Simulação por Computador , Variação Genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Modelos Genéticos , Modelos Imunológicos , Mutação , Seleção Genética
5.
Nat Commun ; 10(1): 1772, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992440

RESUMO

Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.


Assuntos
Adenocarcinoma de Pulmão/genética , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Idoso , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Conjuntos de Dados como Assunto , Receptores ErbB/genética , Feminino , Genômica , Humanos , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Linfócitos T Citotóxicos/imunologia , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/imunologia
6.
Nat Med ; 25(3): 389-402, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30842677

RESUMO

Despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Understanding genomic correlates of response and resistance to checkpoint blockade may enhance benefits for patients with cancer by elucidating biomarkers for patient stratification and resistance mechanisms for therapeutic targeting. Here we review emerging genomic markers of checkpoint blockade response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways. Compelling evidence also points to a role for T cell functionality, checkpoint regulators, chromatin modifiers, and copy-number alterations in mediating selective response to immune checkpoint blockade. Ultimately, efforts to contextualize genomic correlates of response into the larger understanding of tumor immune biology will build a foundation for the development of novel biomarkers and therapies to overcome resistance to checkpoint blockade.


Assuntos
Apresentação do Antígeno/genética , Antígenos de Neoplasias/genética , Antineoplásicos Imunológicos/uso terapêutico , Reparo do DNA/genética , Genoma/genética , Neoplasias/tratamento farmacológico , Linfócitos T/imunologia , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinogênese/genética , Montagem e Desmontagem da Cromatina/genética , Variações do Número de Cópias de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Mutação , Neoplasias/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais
7.
J Immunol ; 202(8): 2451-2459, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30850480

RESUMO

Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4+ T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII-/-]) were created and metabolically characterized. FITC+ glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII-/- were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet-fed C57BL/6 mice. Unexpectedly, mMHCII-/- mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4+ T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8+ T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclusion, loss of either ATM or adipocyte APC function, but not both, improves systemic glucose metabolism because of maintenance of AT regulatory T cells.


Assuntos
Adipócitos/imunologia , Tecido Adiposo/imunologia , Apresentação do Antígeno , Glucose/imunologia , Macrófagos/imunologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Glucose/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Macrófagos/citologia , Camundongos , Camundongos Knockout
8.
PLoS Biol ; 17(1): e3000131, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703088

RESUMO

Central players of the adaptive immune system are the groups of proteins encoded in the major histocompatibility complex (MHC), which shape the immune response against pathogens and tolerance to self-peptides. The corresponding genomic region is of particular interest, as it harbors more disease associations than any other region in the human genome, including associations with infectious diseases, autoimmune disorders, cancers, and neuropsychiatric diseases. Certain MHC molecules can bind to a much wider range of epitopes than others, but the functional implication of such an elevated epitope-binding repertoire has remained largely unclear. It has been suggested that by recognizing more peptide segments, such promiscuous MHC molecules promote immune response against a broader range of pathogens. If so, the geographical distribution of MHC promiscuity level should be shaped by pathogen diversity. Three lines of evidence support the hypothesis. First, we found that in pathogen-rich geographical regions, humans are more likely to carry highly promiscuous MHC class II DRB1 alleles. Second, the switch between specialist and generalist antigen presentation has occurred repeatedly and in a rapid manner during human evolution. Third, molecular positions that define promiscuity level of MHC class II molecules are especially diverse and are under positive selection in human populations. Taken together, our work indicates that pathogen load maintains generalist adaptive immune recognition, with implications for medical genetics and epidemiology.


Assuntos
Imunidade Adaptativa/genética , Antígenos de Histocompatibilidade Classe II/genética , Complexo Principal de Histocompatibilidade/genética , Sequência de Aminoácidos/genética , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Evolução Biológica , Patógenos Transmitidos pelo Sangue , Epitopos/genética , Epitopos/fisiologia , Evolução Molecular , Variação Genética/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Complexo Principal de Histocompatibilidade/fisiologia , Peptídeos/genética , Seleção Genética/genética
9.
Nat Commun ; 10(1): 863, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787294

RESUMO

The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-level analysis of HIV-1 negative vaccinees reveals that type I interferons that activate the IRF7 antiviral program and type II interferon-stimulated genes implicated in antigen-presentation are both associated with a reduced risk of HIV-1 acquisition. In contrast, genes upstream and downstream of NF-κB, mTORC1 and host genes required for viral infection are associated with an increased risk of HIV-1 acquisition among vaccinees and placebo recipients, defining a vaccine independent association with HIV-1 acquisition. Our transcriptomic analysis of RV144 trial samples identifies IRF7 as a mediator of protection and the activation of mTORC1 as a correlate of the risk of HIV-1 acquisition.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon gama/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Humanos , Imunização , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , NF-kappa B/metabolismo , Placebos/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
10.
Proc Natl Acad Sci U S A ; 116(8): 3112-3117, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718433

RESUMO

CD8+ T cells are essential effectors in antiviral immunity, recognizing short virus-derived peptides presented by MHC class I (pMHCI) on the surface of infected cells. However, the fraction of viral pMHCI on infected cells that are immunogenic has not been shown for any virus. To approach this fundamental question, we used peptide sequencing by high-resolution mass spectrometry to identify more than 170 vaccinia virus pMHCI presented on infected mouse cells. Next, we screened each peptide for immunogenicity in multiple virus-infected mice, revealing a wide range of immunogenicities. A surprisingly high fraction (>80%) of pMHCI were immunogenic in at least one infected mouse, and nearly 40% were immunogenic across more than half of the mice screened. The high number of peptides found to be immunogenic and the distribution of responses across mice give us insight into the specificity of antiviral CD8+ T cell responses.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Animais , Formação de Anticorpos/genética , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade Celular/genética , Fenômenos Imunogenéticos/genética , Ativação Linfocitária/imunologia , Camundongos , Peptídeos/genética , Linfócitos T Citotóxicos/imunologia , Vírus Vaccinia/imunologia , Vírus Vaccinia/patogenicidade
11.
Mol Immunol ; 113: 16-21, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29224918

RESUMO

The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or microbes. It is therefore important to identify the molecular mechanisms behind MHC class I expression, processing and antigen presentation. The identification of NLRC5 as regulator of MHC class I transcription was a huge step forward in understanding the transcriptional mechanism involved. Nevertheless, many questions concerning MHC class I transcription are yet unsolved. Here we illuminate current knowledge on MHC class I and NLRC5 transcription, we highlight some remaining questions and discuss the use of quickly developing high-content screening tools to reveal unknowns in MHC class I transcription in the near future.


Assuntos
Redes Reguladoras de Genes/genética , Genes MHC Classe I/genética , Animais , Apresentação do Antígeno/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transcrição Genética/genética
12.
Immunogenetics ; 71(3): 161-170, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30215098

RESUMO

Immune response to disease requires coordinated expression of an army of molecules. The highly polymorphic MHC class I and class II molecules are key to control of specificity of antigen presentation. Processing of the antigen, to peptides or other moieties, requires other sets of molecules. For classical class I, this includes TAP peptide transporters, proteasome components and Tapasin, genes which are encoded within the MHC. Similarly, HLA-DO and -DM, which influence presentation by HLA class II molecules, are encoded in the MHC region. Analysis of MHC mutants, including point mutations and large deletions, has been central to understanding the roles of these genes. Mouse genetics has also played a major role. Many other genes have been identified including those controlling expression of HLA class I and class II at the transcriptional level. Another genetic approach that has provided insight has been the analysis of microorganisms, including viruses and bacteria that escape immune recognition by blocking these antigen processing and presentation pathways. Here, we provide a brief history of the genetic approaches, both traditional and modern, that have been used in the quest to understand antigen processing and presentation.


Assuntos
Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Imunogenética , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Animais , Humanos
13.
Nat Med ; 24(12): 1837-1844, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420755

RESUMO

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.


Assuntos
Linhagem da Célula/genética , Sistema Imunitário , Esclerose Múltipla/genética , Transcriptoma/genética , Processamento Alternativo/genética , Animais , Apresentação do Antígeno/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/fisiopatologia , Regulação da Expressão Gênica/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/genética , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Análise de Célula Única
14.
Invest Ophthalmol Vis Sci ; 59(13): 5599-5614, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481277

RESUMO

Purpose: Sjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands. Methods: Lacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software. Results: Our results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes. Conclusions: These data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.


Assuntos
Doenças Autoimunes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Aparelho Lacrimal/metabolismo , Fatores Sexuais , Síndrome de Sjogren/metabolismo , Animais , Apresentação do Antígeno/genética , Quimiocinas/genética , Feminino , Inflamação/genética , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NOD , RNA Mensageiro/genética
15.
Nat Med ; 24(11): 1762-1772, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30349087

RESUMO

Identifying immunodominant T cell epitopes remains a significant challenge in the context of infectious disease, autoimmunity, and immuno-oncology. To address the challenge of antigen discovery, we developed a quantitative proteomic approach that enabled unbiased identification of major histocompatibility complex class II (MHCII)-associated peptide epitopes and biochemical features of antigenicity. On the basis of these data, we trained a deep neural network model for genome-scale predictions of immunodominant MHCII-restricted epitopes. We named this model bacteria originated T cell antigen (BOTA) predictor. In validation studies, BOTA accurately predicted novel CD4 T cell epitopes derived from the model pathogen Listeria monocytogenes and the commensal microorganism Muribaculum intestinale. To conclusively define immunodominant T cell epitopes predicted by BOTA, we developed a high-throughput approach to screen DNA-encoded peptide-MHCII libraries for functional recognition by T cell receptors identified from single-cell RNA sequencing. Collectively, these studies provide a framework for defining the immunodominance landscape across a broad range of immune pathologies.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Epitopos Imunodominantes/genética , Proteômica , Sequência de Aminoácidos/genética , Apresentação do Antígeno/genética , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Listeria monocytogenes/patogenicidade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única
16.
Iran J Immunol ; 15(3): 197-206, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30246695

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) complex is a gene family involved in antigen presentation associated with protection or susceptibility to inflammatory, infectious and autoimmune diseases. Atherosclerosis is a chronic inflammatory disease in which HLA molecules play a role in the initiation and development of the disease through presentation of self or foreign antigens to T cells. OBJECTIVE: To investigate the association of HLA-DRB1 alleles with atherosclerosis in a sample of southwestern Iranians. METHODS: We performed an analytical cross-sectional study involving 96 patients with atherosclerosis and 72 controls. HLA-DRB1 genotyping was performed by PCR-SSP method. RESULTS: We observed a significantly lower frequency of DRB1*01 in patients with coronary artery atherosclerosis than in controls (4.68% vs. 13.1, P=0.0052, OR=3.09, CI 95%: 1.35-7.05). However, this allele showed a positive association with high blood pressure (P=0.009) in patients. Furthermore, DRB1*16 allele was associated with hyperlipidemia (P=0.008) in patients. CONCLUSION: Our results demonstrated that DRB1*01 may be a protective allele against atherosclerosis in individuals who live in southwest of Iran. The mechanism of this protection needs further investigation.


Assuntos
Aterosclerose/genética , Genótipo , Cadeias HLA-DRB1/genética , Hipertensão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Aterosclerose/imunologia , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
17.
World J Gastroenterol ; 24(30): 3347-3360, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30122875

RESUMO

The clinical outcome of hepatitis B virus (HBV) infection depends on the success or failure of the immune responses to HBV, and varies widely among individuals, ranging from asymptomatic self-limited infection, inactive carrier state, chronic hepatitis, cirrhosis, hepatocellular carcinoma, to liver failure, depending on the success or failure of immune response to HBV. Genome-wide association studies (GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits. In this review, we discuss GWAS for persistence of HBV infection, antibody response to hepatitis B vaccine, and HBV-related advanced liver diseases. HBV persistence is associated with multiple genes with diverse roles in immune mechanisms. The strongest associations are found within the classical human leukocyte antigen (HLA) genes, highlighting the central role of antigen presentation in the immune response to HBV. Associated variants affect both epitope binding specificities and expression levels of HLA molecules. Several other susceptibility genes regulate the magnitude of adaptive immune responses, determining immunity vs tolerance. HBV persistence and nonresponse to vaccine share the same risk variants, implying overlapping genetic bases. On the other hand, the risk variants for HBV-related advanced liver diseases are largely different, suggesting different host-virus dynamics in acute vs chronic HBV infections. The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.


Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/imunologia , Hepatite B/genética , Alelos , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Estudo de Associação Genômica Ampla , Antígenos HLA/imunologia , Hepatite B/imunologia , Hepatite B/terapia , Hepatite B/virologia , Vacinas contra Hepatite B/imunologia , Humanos , Imunogenicidade da Vacina/genética , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos
18.
J Invest Dermatol ; 138(11): 2365-2376, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29857068

RESUMO

Cutaneous diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we analyzed exome sequencing of 37 cutaneous DLBCLs, including 31 DLBCLs, leg type (DLBCL-LT) and 6 cutaneous DLBCLs-not otherwise specified (DLBCL-NOS). As reported previously, 77% of DLBCL-LT harbor NF-κB-activating MYD88 mutations. In nearly all MYD88-wild-type DLBCL-LT, we found cancer-promoting mutations that either activate the NF-κB pathway through alternative genes (NFKBIE or REL) or activate other canonical cancer pathways (BRAF, MED12, PIK3R1, and STAT3). After NF-κB, the second most commonly mutated pathway putatively enables immune evasion via mutations predicted to downregulate antigen processing (B2M, CIITA, HLA) or T-cell co-stimulation (CD58). DLBCL-LT have little genetic overlap with the genetically heterogeneous DLBCL-NOS. Instead, they resemble primary central nervous system and testicular large B-cell lymphomas (primary central nervous system lymphomas and primary testicular lymphomas). Like primary central nervous system lymphomas/primary testicular lymphomas, 40% of DLBCL-LT (vs. 0% of DLBCLs-not otherwise specified) harbored PDL1/PDL2 translocations, which lead to overexpression of PD-L1 or PD-L2 in 50% of the cases. Collectively, these data broaden our understanding of cutaneous DLBCLs and suggest novel therapeutic approaches (e.g., BRAF or PI3K inhibitors). Additionally, they suggest novel treatment paradigms, wherein DLBCL-LT can be targeted with strategies (e.g., immune checkpoint blockers) currently being developed for genomically similar primary central nervous system lymphomas/primary testicular lymphomas.


Assuntos
Perna (Membro)/patologia , Linfoma Difuso de Grandes Células B/genética , Mutação/genética , Fator 88 de Diferenciação Mieloide/genética , Neoplasias Cutâneas/genética , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Antígeno B7-H1/genética , Feminino , Humanos , Evasão da Resposta Imune/genética , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/genética , Transdução de Sinais , Sequenciamento Completo do Exoma
19.
World J Gastroenterol ; 24(17): 1839-1858, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29740200

RESUMO

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/terapia , Microambiente Tumoral/imunologia , Apresentação do Antígeno/genética , Antígenos de Neoplasias/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Humanos , Tolerância Imunológica/genética , Imunoterapia/tendências , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Ativação Linfocitária/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia
20.
Oncogene ; 37(33): 4562-4580, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29743596

RESUMO

The antigen-presenting ability of dendritic cells (DCs) plays an important and irreplaceable role in recognising and clearing viruses. Antiviral responses must rapidly defend against infection while minimising inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. MicroRNAs (microRNAs), small non-coding RNAs, can regulate mouse or avian DCs to inhibit the infection and replication of avian influenza virus (AIV). Here, we performed a global analysis to understand how avian DCs respond to H9N2 AIV and provide a potential mechanism to explain how avian microRNAs can defend against H9N2 AIV replication. First, we found that both active and inactive H9N2 AIV enhanced the ability of DCs to present antigens and activate T lymphocytes. Next, total microarray analyses suggested that H9N2 AIV stimulation involved protein localisation, nucleotide binding, leucocyte transendothelial migration and MAPK signalling. Moreover, we constructed 551 transcription factor (TF)-miRNA-mRNA loops based on the above analyses. Furthermore, we found that the haemagglutinin (HA) fragment, neither H5N1-HA or H9N2-HA, could not activate DCs, while truncated HA greatly increased the immune function of DCs by activating ERK and STAT3 signalling pathways. Lastly, our results not only suggested that gga-miR1644 targets muscleblind-like protein 2 (MBNL2) to enhance the ability of avian DCs to inhibit virus replication, but also suggested that gga-miR6675 targets the nuclear localisation sequence of polymerase basic protein 1 (PB1) to trigger the silencing of PB1 genes, resulting in the inhibition of H9N2 AIV replication. Altogether, our innovative study will shed new light on the role of avian microRNAs in evoking avian DCs and inhibiting virus replication.


Assuntos
Aves/virologia , Células Dendríticas/virologia , Vírus da Influenza A Subtipo H9N2/genética , Influenza Aviária/virologia , MicroRNAs/genética , Animais , Apresentação do Antígeno/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Replicação Viral/genética
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