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2.
Biomed Res Int ; 2021: 8112783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447853

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.


Assuntos
Vírus da Influenza A/patogenicidade , MicroRNAs/genética , Infecções por Orthomyxoviridae/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Vírus da Influenza A/isolamento & purificação , Interleucina-17/genética , Interleucina-17/imunologia , MicroRNAs/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , RNA Longo não Codificante/imunologia , RNA Mensageiro/imunologia , Ratos , Ratos Sprague-Dawley
3.
Biomolecules ; 11(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34439812

RESUMO

Intra-amniotic infections (IAI) are one of the reasons for preterm birth. High mobility group box 1 (HMGB1) is a nuclear protein with various physiological functions, including tissue healing. Its excessive extracellular release potentiates inflammatory reaction and can revert its action from beneficial to detrimental. We infected the amniotic fluid of a pig on the 80th day of gestation with 1 × 104 colony forming units (CFUs) of E. coli O55 for 10 h, and evaluated the appearance of HMGB1, receptor for glycation endproducts (RAGE), and Toll-like receptor (TLR) 4 in the amniotic membrane and fluid. Sham-infected amniotic fluid served as a control. The expression and release of HMGB1 were evaluated by Real-Time PCR, immunofluorescence, immunohistochemistry, and ELISA. The infection downregulated HMGB1 mRNA expression in the amniotic membrane, changed the distribution of HMGB1 protein in the amniotic membrane, and increased its level in amniotic fluid. All RAGE mRNA, protein expression in the amniotic membrane, and soluble RAGE level in the amniotic fluid were downregulated. TLR4 mRNA and protein expression and soluble TLR4 were all upregulated. HMGB1 is a potential target for therapy to suppress the exaggerated inflammatory response. This controlled expression and release can, in some cases, prevent the preterm birth of vulnerable infants. Studies on suitable animal models can contribute to the development of appropriate therapy.


Assuntos
Infecções por Escherichia coli/veterinária , Escherichia coli/patogenicidade , Proteína HMGB1/genética , Complicações Infecciosas na Gravidez/veterinária , RNA Mensageiro/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor 4 Toll-Like/genética , Âmnio/imunologia , Âmnio/microbiologia , Âmnio/patologia , Líquido Amniótico/imunologia , Líquido Amniótico/microbiologia , Animais , Modelos Animais de Doenças , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Regulação da Expressão Gênica , Proteína HMGB1/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Gravidez , Complicações Infecciosas na Gravidez/genética , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/microbiologia , Nascimento Prematuro/prevenção & controle , RNA Mensageiro/imunologia , Receptor para Produtos Finais de Glicação Avançada/imunologia , Transdução de Sinais , Suínos , Receptor 4 Toll-Like/imunologia
4.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445774

RESUMO

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 µM), the VDAC-1 inhibitor, DIDS (100 µM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 µM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.


Assuntos
Trifosfato de Adenosina/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Imunidade/efeitos dos fármacos , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Polietilenoimina/farmacologia , Alérgenos/imunologia , Animais , Cálcio/imunologia , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Imunidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/imunologia , RNA Mensageiro/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia
5.
Nat Immunol ; 22(10): 1256-1267, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34462601

RESUMO

Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1s. These cells were present across different organs and had the potential to mature toward CD127intTCF-1int and CD127-TCF-1- ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.


Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Fatores de Transcrição/imunologia , Animais , Feminino , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/imunologia , Linfócitos T/imunologia
6.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
7.
Mol Immunol ; 137: 67-74, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34225136

RESUMO

The purpose of this study was to study the effect of inhibiting NLRC5 expression and function on CD4 + T cells, and islet and skin transplantation in mice. A murine skin graft model and islet cell transplantation model were established, and the expression of NLRC5 was compared in rejection and immune tolerance groups. Mice spleen-derived CD4 + T cells were cultured, purified, and enriched in vitro, and transfected with the shRNA lentiviral vector NLRC5-RNAi-GFP. Changes in cytokine secretion were detected to understand changes in immunological function. Murine islet and skin transplantation models were injected with CD4 + T cells transfected with the lentivirus, and the survival time of the grafts and the levels of IFN-γ and IL-10 were compared between groups. The expression of NLRC5 mRNA in islet and skin grafts was significantly increased. In vitro experiments showed that the expression of IL-4 and IL-10 was up-regulated in CD4 + T cells, and T cells differentiation turned to Th2 after inhibition of NLRC5. In vivo experiments showed that inhibition of NLRC5 prolonged islet and skin graft survival. Pathological examination showed that the rejection of transplanted skin and islets in the NLRC5-RNAi group was mild, and there was a correlation between high expression of NLRC5 and rejection of mouse islet and skin grafts. In summary, inhibition of NLRC5 can prolong islet and skin graft survival induce transplant immune tolerance through induction of the secretion of Th2 cytokines by CD4 + T cells.


Assuntos
Aloenxertos/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Sobrevivência de Enxerto/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Mensageiro/imunologia , Transplante de Pele/métodos , Células Th2/imunologia , Tolerância ao Transplante/imunologia , Transplante Homólogo/métodos
8.
Adv Drug Deliv Rev ; 176: 113900, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34324884

RESUMO

The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.


Assuntos
Amplificação de Genes/imunologia , Imunidade Inata/imunologia , Imunoterapia/métodos , RNA Mensageiro/imunologia , Vacinas Sintéticas/imunologia , Animais , COVID-19/genética , COVID-19/imunologia , COVID-19/prevenção & controle , Amplificação de Genes/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/tendências , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética
9.
Cell ; 184(15): 3936-3948.e10, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34192529

RESUMO

In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.


Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Substituição de Aminoácidos , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Ligação Competitiva , Humanos , Imunoglobulina G/metabolismo , Mutação/genética , Domínios Proteicos , Hipermutação Somática de Imunoglobulina/genética
10.
PLoS One ; 16(6): e0249499, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34133415

RESUMO

SARS-CoV-2 spike antigen-specific IgG and IgA elicited by infection mediate viral neutralization and are likely an important component of natural immunity, however, limited information exists on vaccine induced responses. We measured COVID-19 mRNA vaccine induced IgG and IgA in serum serially, up to 145 days post vaccination in 4 subjects. Spike antigen-specific IgG levels rose exponentially and plateaued 21 days after the initial vaccine dose. After the second vaccine dose IgG levels increased further, reaching a maximum approximately 7-10 days later, and remained elevated (average of 58% peak levels) during the additional >100 day follow up period. COVID-19 mRNA vaccination elicited spike antigen-specific IgA with similar kinetics of induction and time to peak levels, but more rapid decline in serum levels following both the 1st and 2nd vaccine doses (<18% peak levels within 100 days of the 2nd shot). The data demonstrate COVID-19 mRNA vaccines effectively induce spike antigen specific IgG and IgA and highlight marked differences in their persistence in serum.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/virologia , Vacinas contra COVID-19/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/imunologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Adulto Jovem
12.
Gene ; 793: 145750, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34077777

RESUMO

OBJECTIVE: Graves' disease (GD) is a common autoimmune disease manifesting with diffuse symmetric thyroid gland enlargement, pretibial myxedema, and Graves' ophthalmopathy (GO). Recently, the vitamin D receptor (VDR) gene has been linked to various autoimmune diseases. This study aimed to investigate the association of VDR gene polymorphisms with susceptibility to GD and GO in the Southwest Chinese Han population. METHODS: A two-stage association study was performed in 1,209 controls and 650 GD patients by PCR-RFLP assay. Real-time PCR and ELISA were carried out to quantify gene expression and cytokine production. RESULTS: The first-stage study showed that the frequency of VDR/Apa I AA genotype was significantly increased in GD (Pc = 1.67 × 10-2, OR = 1.98). The second-stage and combined studies confirmed the association of VDR/Apa I with GD (AA genotype: Pc = 3.45 × 10-4, OR = 1.87; A allele: Pc = 2.62 × 10-2, OR = 1.20). The stratification analysis showed that GO patients had a higher frequency of the VDR/Apa I AA genotype (Pc = 8.69 × 10-5, OR = 2.84). Functional experiments showed a decreased VDR expression and TGF-ß1 production as well as an increased IL-17 production in VDR/Apa I AA genotype carriers. CONCLUSION: The VDR/Apa I polymorphism is significantly associated with GD and GO, and it may be involved in the development of GD and GO by influencing VDR mRNA expression levels and the secretion levels of cytokines.


Assuntos
Predisposição Genética para Doença , Oftalmopatia de Graves/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Desoxirribonucleases de Sítio Específico do Tipo II/química , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Oftalmopatia de Graves/etnologia , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/patologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores de Calcitriol/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
13.
Hematology ; 26(1): 417-431, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34130612

RESUMO

BACKGROUND: Myelodysplastic syndrome (MDS) is a haematopoietic malignancy that is characterized by a heterogeneous clinical course and dysplastic maturation of blood lineages. Immune dysregulation has gained attention as one of the fundamental mechanisms responsible for the development of MDS. This study aimed to screen immune-related biomarkers and pathways in MDS. METHODS: Differentially expressed mRNAs (DE-mRNAs) and differentially expressed microRNAs (DE-miRNAs) in different subtypes of MDS were sourced from the Gene Expression Omnibus (GEO) database. DE-mRNAs were intersected with immune-related gene sets to collect immune-related mRNAs, which were put into the Search Tool for the Retrieval of Interacting Genes (STRING) to construct protein-protein interaction (PPI) networks. Target mRNAs of DE-miRNAs were predicted using the miRDB database and intersected with screened immune-related mRNAs to construct miRNA-mRNA interaction networks. Topological analysis of constructed networks was applied to screen key molecules, which were assessed in independent datasets and previous literature. Enrichment analysis was applied to screen dysregulated pathways in MDS. RESULTS: Screened key mRNAs were mainly from the Toll-like receptor (TLR) family, including TLR2, TLR4, TLR7, and from the chemokine family, including C-X-C motif chemokine ligand 10 (CXCL10) and CC chemokine ligand 4 (CCL4). Cytokine-cytokine receptor interactions were among the major pathways in the enrichment analysis results. Hsa-miR-30b, hsa-miR-30e and hsa-miR-221 were validated as key miRNAs and modulate cytokine-cytokine receptor interactions by targeting immune-related mRNAs. CONCLUSION: Dysregulated cytokines reflect the immunization status in MDS. Immune-related miRNA-mRNA interactions not only provide a perspective to our understanding of immunologic derangement in the pathogenesis of MDS but also provide new therapeutic opportunities.


Assuntos
MicroRNAs/genética , Síndromes Mielodisplásicas/genética , RNA Mensageiro/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunidade , MicroRNAs/imunologia , Síndromes Mielodisplásicas/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/imunologia , Transcriptoma
15.
Front Immunol ; 12: 632304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953709

RESUMO

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1-22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1-22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.


Assuntos
Vacinas Bacterianas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/imunologia , Lipídeos/imunologia , Listeria/imunologia , Mycobacterium/imunologia , RNA Mensageiro/imunologia , Streptococcus/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteção Cruzada , Reações Cruzadas , Células Dendríticas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Interferon gama/imunologia , Lipídeos/química , Listeria/enzimologia , Listeria/genética , Camundongos , RNA Mensageiro/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
16.
J Immunol ; 206(11): 2552-2565, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34031147

RESUMO

CD40 ligand (CD40L) mRNA stability is dependent on an activation-induced pathway that is mediated by the binding complexes containing the multifunctional RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1) to a 3' untranslated region of the transcript. To understand the relationship between regulated CD40L and the requirement for variegated expression during a T-dependent response, we engineered a mouse lacking the CD40L stability element (CD40LΔ5) and asked how this mutation altered multiple aspects of the humoral immunity. We found that CD40LΔ5 mice expressed CD40L at 60% wildtype levels, and lowered expression corresponded to significantly decreased levels of T-dependent Abs, loss of germinal center (GC) B cells and a disorganized GC structure. Gene expression analysis of B cells from CD40LΔ5 mice revealed that genes associated with cell cycle and DNA replication were significantly downregulated and genes linked to apoptosis upregulated. Importantly, somatic hypermutation was relatively unaffected although the number of cells expressing high-affinity Abs was greatly reduced. Additionally, a significant loss of plasmablasts and early memory B cell precursors as a percentage of total GL7+ B cells was observed, indicating that differentiation cues leading to the development of post-GC subsets was highly dependent on a threshold level of CD40L. Thus, regulated mRNA stability plays an integral role in the optimization of humoral immunity by allowing for a dynamic level of CD40L expression on CD4 T cells that results in the proliferation and differentiation of pre-GC and GC B cells into functional subsets.


Assuntos
Ligante de CD40/imunologia , Imunidade Humoral/imunologia , Estabilidade de RNA/imunologia , RNA Mensageiro/imunologia , Animais , Ligante de CD40/genética , Camundongos , Camundongos Endogâmicos C57BL , Processamento Pós-Transcricional do RNA/genética , Processamento Pós-Transcricional do RNA/imunologia , Estabilidade de RNA/genética , RNA Mensageiro/genética
17.
J Dig Dis ; 22(7): 433-441, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33978316

RESUMO

OBJECTIVE: To evaluate the expression of C-C motif chemokine ligand 5 (CCL5) in hepatocellular carcinoma (HCC) and to explore its role in regulating the immune microenvironment and the related mechanism in tumor immunity. METHODS: The mRNA expression level of CCL5 in HCC and adjacent non-cancerous tissues was measured by quantitative polymerase chain reaction and the protein expression was examined by immunohistochemistry. Serum CCL5 expression was measured by an enzyme-linked immunosorbent assay (ELISA). C57BL/6 wild-type (WT) and Ccl5-knockout (Ccl5-/- ) mice were utilized to conduct the diethylnitrosamine-induced HCC model. The immune cell population was determined by flow cytometry, and peripheral serum immunoglobulin M (IgM) level was quantified by ELISA. RESULTS: CCL5 expression was low in HCC tissue and peripheral blood compared with adjacent non-cancerous tissues or controls, and its expression was correlated with the overall survival, cancer recurrence and distant metastasis. In the HCC mouse model, liver-to-body weight ratio was of the Ccl5-/- group were higher than that of the WT group. Moreover, compared with the WT mice, the number of B cells in the tumor tissue of the Ccl5-/- mice was lower, while there were no significant differences in the other immune cell populations. Furthermore, serum IgM level of the Ccl5-/- mice was significantly lower than that of the WT mice. CONCLUSION: CCL5 expression is decreased in HCC tissues. CCL5 deficiency reduces B cell recruitment and decreases IgM secretion in HCC, potentially leading to tumor progression.


Assuntos
Linfócitos B/imunologia , Carcinoma Hepatocelular , Quimiocina CCL5/biossíntese , Quimiocina CCL5/deficiência , Neoplasias Hepáticas , Microambiente Tumoral/imunologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Quimiocina CCL5/sangue , Progressão da Doença , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recidiva Local de Neoplasia , RNA Mensageiro/biossíntese , RNA Mensageiro/imunologia
19.
Clin Microbiol Infect ; 27(8): 1173.e1-1173.e4, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33957273

RESUMO

OBJECTIVES: We aimed to evaluate the rates of antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine among kidney transplant recipients, and to identify factors associated with reduced immunogenicity. METHODS: This was a prospective cohort study including consecutive kidney transplant recipients in a single referral transplant centre. Participants were tested for anti-spike (anti-S) antibodies 2-4 weeks after a second vaccine dose. Primary outcome was rate of seropositivity. Univariate and multivariate analyses were conducted to identify factors associated with seropositivity. RESULTS: Of 308 kidney transplant recipients included, only 112 (36.4%) tested positive for anti-S antibodies 2-4 weeks after receiving the second dose of BNT162b2 vaccine. Median antibody titre was 15.5 AU/mL (interquartile range (IQR) 3.5-163.6). Factors associated with antibody response were higher estimated glomerular filtration rate (eGFR) (odds ratio (OR) 1.025 per mL/min/1.73 m2, 95% confidence interval (CI) 1.014-1.037, p < 0.001), lower mycophenolic acid dose (OR 2.347 per 360 mg decrease, 95%CI 1.782-3.089, p < 0.001), younger age (OR 1.032 per year decrease, 95%CI 1.015-1.05, p < 0.001) and lower calcineurin inhibitor (CNI) blood level (OR 1.987, 95%CI 1.146-3.443, p 0.014). No serious adverse events resulting from the vaccine were reported. CONCLUSIONS: Kidney transplant recipients demonstrated an inadequate antibody response to SARS-CoV-2 mRNA vaccination. Immunosuppression level was a significant factor in this response. Strategies to improve immunogenicity should be examined in future studies.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina/imunologia , Transplante de Rim/efeitos adversos , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/genética , Estudos de Coortes , Feminino , Humanos , Imunidade , Imunogenicidade da Vacina/genética , Imunossupressão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , SARS-CoV-2/genética , Transplantados
20.
JAMA Oncol ; 7(8): 1133-1140, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34047765

RESUMO

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear. Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls. Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel). Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL. Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses. Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (ß, -3.5; 95% CI, -5.6 to -1.5). Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Neoplasias/imunologia , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Imunogenicidade da Vacina/imunologia , Imunoglobulina G/imunologia , Israel , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vacinação/métodos
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