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1.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209932

RESUMO

Enzymatic transamidation of gliadins by microbial transglutaminase (mTG) inhibits interferon-γ (IFN-γ) secretion by intestinal T cell lines in patients with celiac disease (CD). To gain insight into the cellular mechanisms underlying the down-regulatory effects of transamidation, we tested a single recombinant α-gliadin (r-gliadin) harbouring two immunodominant peptides, p13 (aa. 120-139) and p23 (aa. 220-239), in HLA-DQ8 transgenic mice, a model of gluten sensitivity. Mice were intranasally immunised with r-gliadin or r-gliadin transamidated by mTG (K-r-gliadin) along with cholera toxin, and the response of mesenteric lymph node cells was analysed by cytokine multiplex assay. An in vitro challenge with r-gliadin was characterised by secretion of specific cytokines featuring both innate immunity and the Th1/Th2/Th17 pattern of the adaptive response. Notably, transamidation specifically down-regulated the Th1 response. Structural studies performed on K-r-gliadin confirmed that specific glutamine residues in p13 and p23, previously found to be deamidated by tissue transglutaminase, were also transamidated by mTG. In silico analysis, simulating p13 and p23 peptide binding to HLA-DQ8 showed that these glutamines, in the form of glutamate, could interact by means of salt bridges with peculiar amino acids of the alpha chain of HLA-DQ8, suggesting that their transamidation may influence the HLA-restricted recognition of these peptides. Thus, the structural findings provided a rationale to explain the down-regulation of the r-gliadin-specific Th1 response following transamidation.


Assuntos
Doença Celíaca/tratamento farmacológico , Toxina da Cólera/administração & dosagem , Citocinas/metabolismo , Gliadina/administração & dosagem , Antígenos HLA-DQ/genética , Transglutaminases/metabolismo , Administração Intranasal , Animais , Doença Celíaca/genética , Doença Celíaca/imunologia , Toxina da Cólera/imunologia , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Regulação da Expressão Gênica , Gliadina/química , Gliadina/genética , Gliadina/imunologia , Antígenos HLA-DQ/metabolismo , Imunização , Epitopos Imunodominantes/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
2.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071190

RESUMO

Asthma and type 1 diabetes mellitus (T1DM) are two of the most frequent chronic diseases in children, representing a model of the atopic and autoimmune diseases respectively. These two groups of disorders are mediated by different immunological pathways, T helper (Th)1 for diabetes and Th2 for asthma. For many years, these two groups were thought to be mutually exclusive according to the Th1/Th2 paradigm. In children, the incidence of both diseases is steadily increasing worldwide. In this narrative review, we report the evidence of the potential link between asthma and T1DM in childhood. We discuss which molecular mechanisms could be involved in the link between asthma and T1DM, such as genetic predisposition, cytokine patterns, and environmental influences. Cytokine profile of children with asthma and T1DM shows an activation of both Th1 and Th2 pathways, suggesting a complex genetic-epigenetic interaction. In conclusion, in children, the potential link between asthma and T1DM needs further investigation to improve the diagnostic and therapeutic approach to these patients. The aim of this review is to invite the pediatricians to consider the potential copresence of these two disorders in clinical practice.


Assuntos
Asma/complicações , Asma/imunologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Animais , Asma/genética , Criança , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Microbioma Gastrointestinal , Humanos , Hipersensibilidade Imediata/imunologia , Incidência , Doenças Parasitárias , Fatores de Risco , Linfócitos T Reguladores , Células Th1/imunologia , Células Th2/imunologia
3.
FEBS Lett ; 595(12): 1622-1638, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960414

RESUMO

Ixodes scapularis ticks feed on humans and other vertebrate hosts and transmit several pathogens of public health concern. Tick saliva is a complex mixture of bioactive proteins, lipids and immunomodulators, such as I. scapularis sphingomyelinase (IsSMase)-like protein, an ortholog of dermonecrotoxin SMase D found in the venom of Loxosceles spp. of spiders. IsSMase modulates the host immune response towards Th2, which suppresses Th1-mediated cytokines to facilitate pathogen transmission. Arboviruses utilize exosomes for their transmission from tick to the vertebrate host, and exosomes derived from tick saliva/salivary glands suppress C-X-C motif chemokine ligand 12 and interleukin-8 immune response(s) in human skin to delay wound healing and repair processes. IsSMase affects also viral replication and exosome biogenesis, thereby inhibiting tick-to-vertebrate host transmission of pathogenic exosomes. In this review, we elaborate on exosomes and their biogenesis as potential candidates for developing novel control measure(s) to combat tick-borne diseases. Such targets could help with the development of an efficient anti-tick vaccine for preventing the transmission of tick-borne pathogens.


Assuntos
Infecções por Arbovirus , Arbovírus/imunologia , Proteínas de Artrópodes/imunologia , Fatores Imunológicos/imunologia , Ixodes , Esfingomielina Fosfodiesterase/imunologia , Animais , Infecções por Arbovirus/imunologia , Infecções por Arbovirus/prevenção & controle , Infecções por Arbovirus/transmissão , Humanos , Ixodes/imunologia , Ixodes/virologia , Glândulas Salivares/imunologia , Glândulas Salivares/virologia , Células Th1/imunologia , Células Th2/imunologia
4.
FASEB J ; 35(6): e21616, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33978990

RESUMO

IgE-dependent/independent activation of mast cell (MC) has been assumed to play a host defensive role against venom injection in skin. However, its detailed mechanisms remain unknown. We aimed to investigate the contribution of MC-derived prostaglandin D2 (PGD2 )-mediated signaling in host defense against bee venom (BV). To achieve this, we utilized gene-deficient mice of a PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). We first confirmed that subcutaneous injection of BV produced PGD2 equally in wild-type (WT) and CRTH2-deficient (Crth2-/- ) mice skins. The BV injection dropped body temperature and impaired kidney equally in both lines of mice. In WT mice, pre-injection of BV (3 weeks) significantly inhibited the hypothermia and kidney impairment caused by second BV injection. In contrast, this pre-injection was not effective for the second BV injection in Crth2-/- mice. We also found that BV injections increased serum BV-specific IgE levels in WT mice, and its serum transfused mice improved the BV-induced hypothermia in naïve WT mice. In contrast, serum BV-specific IgE level was significantly lower in Crth2-/- mice. FACS analysis showed the BV injection stimulate migration of dendritic cells (DCs) into regional lymph nodes in WT mice. In Crth2-/- mice, its number was significantly smaller than that of WT mice. In conclusion, PGD2 /CRTH2 signaling plays defensive role against second BV injection. This signaling promotes BV-specific IgE production at least partially by promoting DCs migration into regional lymph node.


Assuntos
Imunidade Adaptativa/genética , Venenos de Abelha/toxicidade , Mastócitos/imunologia , Prostaglandina D2/metabolismo , Receptores Imunológicos/fisiologia , Receptores de Prostaglandina/fisiologia , Células Th2/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Feminino , Imunoglobulina E/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
5.
Eur J Pharmacol ; 904: 174193, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34015316

RESUMO

Coronavirus (SARS-CoV-2) is spreading rapidly in the world and is still taking a heavy toll. Studies show that cytokine storms and imbalances in T-helper (Th)1/Th2 play a significant role in most acute cases of the disease. A number of medications have been suggested to treat or control the disease but have been discontinued due to their side effects. Melatonin, as an intrinsic molecule, possesses pharmacological anti-inflammatory and antioxidant properties that decreases in concentration with age; as a result, older people are more prone to various diseases. In this study, patients who were hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) were given a melatonin adjuvant (9 mg daily, orally) for fourteen days. In order to measure markers of Th1 and Th2 inflammatory cytokines (such as interleukin (IL)-2, IL-4, and interferon (IFN)-γ) as well as the expression of Th1 and Th2 regulatory genes (signal transducer and activator of transcription (STAT)4, STAT6, GATA binding protein 3 (GATA3), and T-box expressed in T cell (T-bet)), blood samples were taken from patients at the beginning and end of the treatment. Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19. Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2. In this study, it was shown for the first time that melatonin can be used as a medicinal adjuvant with anti-inflammatory mechanism to reduce and control inflammatory cytokines by regulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19.


Assuntos
COVID-19 , Citocinas/sangue , Melatonina , Transdução de Sinais , Células Th1 , Células Th2 , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/imunologia , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Melatonina/administração & dosagem , Melatonina/imunologia , Pessoa de Meia-Idade , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Resultado do Tratamento
6.
J Med Chem ; 64(11): 7809-7838, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043358

RESUMO

We report on the design, synthesis, and biological evaluation of a series of nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) desmuramylpeptide agonists with improved in vitro and in vivo adjuvant properties. We identified two promising compounds: 68, a potent nanomolar in vitro NOD2 agonist, and the more lipophilic 75, which shows superior adjuvant activity in vivo. Both compounds had immunostimulatory effects on peripheral blood mononuclear cells at the protein and transcriptional levels, and augmented dendritic-cell-mediated activation of T cells, while 75 additionally enhanced the cytotoxic activity of peripheral blood mononuclear cells against malignant cells. The C18 lipophilic tail of 75 is identified as a pivotal structural element that confers in vivo adjuvant activity in conjunction with a liposomal delivery system. Accordingly, liposome-encapsulated 75 showed promising adjuvant activity in mice, surpassing that of muramyl dipeptide, while achieving a more balanced Th1/Th2 immune response, thus highlighting its potential as a vaccine adjuvant.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/química , Adjuvantes Imunológicos/química , Proteína Adaptadora de Sinalização NOD2/agonistas , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Linhagem Celular , Desenho de Fármacos , Humanos , Imunoglobulina G/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipossomos/química , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteína Adaptadora de Sinalização NOD2/metabolismo , Ovalbumina/imunologia , Relação Estrutura-Atividade , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo
8.
Front Immunol ; 12: 593595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995342

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.


Assuntos
COVID-19 , Citocinas , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Metaloproteinase 1 da Matriz , Metaloproteinase 3 da Matriz , Receptores Imunológicos , Adulto , Idoso , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/sangue , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Masculino , Metaloproteinase 1 da Matriz/sangue , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 3 da Matriz/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Imunológicos/sangue , Receptores Imunológicos/imunologia , Células Th1/imunologia , Células Th2/imunologia
9.
Front Immunol ; 12: 620943, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815374

RESUMO

Inhibition of allergic airway diseases (AAD) by immunomodulation of the adaptive immune system through restoration of the enteric dysbiosis is an emerging therapeutic strategy. Patients with allergic rhinitis (n = 6) and healthy controls (n = 6) were enrolled, and gut microbiome composition analysis was performed by 16S rDNA sequencing. We also established an ovalbumin (OVA)-induced allergic airway inflammation murine model. Dysbiosis of the gut flora was observed in both AAD patients and the mice, with the decrease of the biodiversity and the quantity of the Bacteroidetes phylum. Oral application of Bacteroides (B.) thetaiotaomicron ameliorated the symptoms of OVA-induced airway hyperresponsiveness (AHR) and attenuated the airway inflammation in mice. In addition, nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF) from AAD mice orally administered with B. thetaiotaomicron showed reduced numbers of immune cells, and diminished secretion of T helper (Th)-2 cytokines (IL-4, IL-5, and IL-13) compared with the corresponding control mice, whereas the levels of Th1 cytokineIFN-γ was not changed in both the groups. When B. thetaiotaomicron was co-administered with metronidazole in AAD mice, the immunomodulatory effect was weakened and the allergic inflammatory response was aggravated. The ratios of CD4+Foxp3+ cells, CD4+ICOS+ T cells, CD4+ICOS+ Foxp3+ regulatory T cells, and IL-10-expressing CD4+Foxp3+ cells were increased in lymphocytes of spleen, mesenteric, and cervical lymph nodes of AAD mice administrated with B. thetaiotaomicron. Therefore, our data indicate that oral administration of B. thetaiotaomicron effectively inhibited the development of AAD in murine model; inhibition was mediated by the activation of Tregs and inhibition of Th2 response without promoting a Th1 response.


Assuntos
Bacteroides thetaiotaomicron/fisiologia , Microbioma Gastrointestinal/imunologia , Hipersensibilidade/imunologia , Hipersensibilidade Respiratória/imunologia , Sistema Respiratório/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Humanos , Imunomodulação , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Inflamação , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Ovalbumina/imunologia
10.
Toxicol Appl Pharmacol ; 420: 115532, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33845054

RESUMO

Limited information is available regarding the effects of arsenic exposure on immune function. We have recently reported that chronic exposure to As was associated asthma, as determined by spirometry and respiratory symptoms. Because T helper 2 (Th2)-driven immune responses are implicated in the pathogenesis of allergic diseases, including asthma, we studied the associations of serum Th1 and Th2 mediators with the As exposure markers and the features of asthma among individuals exposed to As. A total of 553 blood samples were selected from the same study subjects recruited in our previous asthma study. Serum levels of Th1 and Th2 cytokines were analyzed by immunoassay. Subjects' arsenic exposure levels (drinking water, hair and nail arsenic concentrations) were determined by inductively coupled plasma mass spectroscopy. Arsenic exposure levels of the subjects showed significant positive associations with serum Th2-mediators- interleukin (IL)-4, IL-5, IL-13, and eotaxin without any significant changes in Th1 mediators- interferon-γ and tumor necrosis factor-α. The ratios of Th2 to Th1 mediators were significantly increased with increasing exposure to As. Notably, most of the Th2 mediators were positively associated with serum levels of total immunoglobulin E and eotaxin. The serum levels of Th2 mediators were significantly higher in the subjects with asthma than those without asthma. The results of our study suggest that the exacerbated Th2-driven immune responses are involved in the increased susceptibility to allergic asthma among individuals chronically exposed to As.


Assuntos
Arsênio/efeitos adversos , Asma/induzido quimicamente , Citocinas/sangue , Células Th1/efeitos dos fármacos , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Poluentes Químicos da Água/efeitos adversos , Adolescente , Adulto , Asma/diagnóstico , Asma/imunologia , Asma/metabolismo , Bangladesh , Carga Corporal (Radioterapia) , Estudos Transversais , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Adulto Jovem
11.
Front Immunol ; 12: 603228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815363

RESUMO

Background: New World Hantaviruses (NWHs) are the etiological agent underlying hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with high mortality rates in humans. In Panama, infections with Choclo Orthohantavirus (CHOV) cause a much milder illness characterized by higher seroprevalence and lower mortality rates. To date, the cytokine profiles and antibody responses associated with this milder form of HCPS have not been defined. Therefore, in this study, we examined immune serological profiles associated with CHOV infections. Methods: For this retrospective study, sera from fifteen individuals with acute CHOV-induced HCPS, were analyzed alongside sera from fifteen convalescent phase individuals and thirty-three asymptomatic, CHOV-seropositive individuals. Cytokine profiles were analyzed by multiplex immunoassay. Antibody subclasses, binding, and neutralization against CHOV-glycoprotein (CHOV-GP) were evaluated by ELISA, and flow cytometry. Results: High titers of IFNγ, IL-4, IL-8, and IL-10 serum cytokines were found in the acute individuals. Elevated IL-4 serum levels were found in convalescent and asymptomatic seropositive individuals. High titers of IgG1 subclass were observed across the three cohorts analyzed. Neutralizing antibody response against CHOV-GP was detectable in few acute individuals but was strong in both convalescent and asymptomatic seropositive individuals. Conclusion: A Th1/Th2 cytokine signature is characteristic during acute mild HCPS caused by CHOV infection. High expression of Th2 and IL-8 cytokines are correlated with clinical parameters in acute mild HCPS. In addition, a strong IL-4 signature is associated with different cohorts, including asymptomatic individuals. Furthermore, asymptomatic individuals presented high titers of neutralizing antibodies.


Assuntos
Anticorpos Antivirais , Citocinas , Infecções por Hantavirus , Hantavirus , Imunoglobulina G , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Hantavirus/imunologia , Hantavirus/metabolismo , Infecções por Hantavirus/sangue , Infecções por Hantavirus/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
12.
Front Immunol ; 12: 599512, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841393

RESUMO

Since immune infiltration is closely associated with the progression and prognosis of atherosclerosis, we aimed to describe the abundance of 24 immune cell types within atherosclerotic tissues. In the current study, we used the Immune Cell Abundance Identifier (ImmuCellAI), a web-based tool, to estimate the abundance of 24 immune cells based on the microarray profiles of atherosclerotic carotid artery samples to analyze the proportions and the dysregulation of immune cell types within carotid atherosclerosis. We found that atherosclerotic immune cells had a diverse landscape dominated by T cells and myeloid cells and that macrophages and dendritic cells (DCs) showed different abundance in normal and atherosclerotic tissues. Moreover, the expression of macrophages was closely related to the level of the expression of DCs and of exhausted T cells, while the expression of T-helper type 1 (Th1) cells was strongly correlated with the expression of T-helper type 2 (Th2) cells and effector memory cells. Our data confirm a distinct profile of atherosclerosis-infiltrating immune cell subpopulations, which may inspire an immunological direction for research on atherosclerosis.


Assuntos
Artérias Carótidas , Doenças das Artérias Carótidas , Células Dendríticas , Regulação da Expressão Gênica/imunologia , Macrófagos , Células Th1 , Células Th2 , Idoso , Artérias Carótidas/imunologia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/patologia , Bases de Dados de Ácidos Nucleicos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Humanos , Memória Imunológica , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
13.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800208

RESUMO

(1) Background: six mammalian ceramide synthases (CerS1-6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22-C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.


Assuntos
Asma/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Esfingosina N-Aciltransferase/deficiência , Células Th17/imunologia , Células Th2/imunologia , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Camundongos , Camundongos Knockout , Ovalbumina/toxicidade , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Esfingosina N-Aciltransferase/imunologia , Células Th17/patologia , Células Th2/patologia
14.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806085

RESUMO

Cicadae Periostracum (CP), derived from the slough of Cryptotympana pustulata, has been used as traditional medicine in Korea and China because of its diaphoretic, antipyretic, anti-inflammatory, antioxidant, and antianaphylactic activities. The major bioactive compounds include oleic acid (OA), palmitic acid, and linoleic acid. However, the precise therapeutic mechanisms underlying its action in asthma remain unclear. The objective of this study was to determine the antiasthmatic effects of CP in an ovalbumin (OVA)-induced asthmatic mouse model. CP and OA inhibited the inflammatory cell infiltration, airway hyperresponsiveness (AHR), and production of interleukin (IL)7 and Th2 cytokines (IL-5) in the bronchoalveolar lavage fluid and OVA-specific imunoglobin E (IgE) in the serum. The gene expression of IL-5, IL-13, CCR3, MUC5AC, and COX-2 was attenuated in lung tissues. CP and OA might inhibit the nuclear translocation of GATA-binding protein 3 (GATA-3) and retinoic acid receptor-related orphan receptor γt (RORγt) via the upregulation of forkhead box p3 (Foxp3), thereby preventing the activation of GATA-3 and RORγt. In the in vitro experiment, a similar result was observed for Th2 and GATA-3. These results suggest that CP has the potential for the treatment of asthma via the inhibition of the GATA-3/Th2 and IL-17/RORγt signaling pathways.


Assuntos
Asma , Misturas Complexas , Fator de Transcrição GATA3/imunologia , Hemípteros/química , Interleucina-17/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Ácido Oleico , Transdução de Sinais , Células Th2/imunologia , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Misturas Complexas/química , Misturas Complexas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleico/química , Ácido Oleico/farmacologia , Ovalbumina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th2/patologia
15.
J Inorg Biochem ; 219: 111454, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33878530

RESUMO

In recent years, some viruses have caused a grave crisis to global public health, especially the human coronavirus. A truly effective vaccine is therefore urgently needed. Vaccines should generally have two features: delivering antigens and modulating immunity. Adjuvants have an unshakable position in the battle against the virus. In addition to the perennial use of aluminium adjuvant, nanoparticles have become the developing adjuvant candidates due to their unique properties. Here we introduce several typical nanoparticles and their antivirus vaccine adjuvant applications. Finally, for the combating of the coronavirus, we propose several design points, hoping to provide ideas for the development of personalized vaccines and adjuvants and accelerate the clinical application of adjuvants.


Assuntos
Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Nanopartículas/química , Vacinas Virais/imunologia , Alumínio/química , Anticorpos Neutralizantes/efeitos dos fármacos , Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , Fosfatos de Cálcio/química , Quitosana/química , Ouro/química , Humanos , Nanopartículas/administração & dosagem , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Vacinas Virais/química
16.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760131

RESUMO

The present study aimed to examine the effects of 2.5 µm particulate matter (PM2.5) on airway inflammation and to investigate the possible underlying mechanism. Specifically, the focus was on the imbalance of T helper (Th)1/Th2 cells and the dysregulated expression of transcription factors, including trans­acting T cell­specific transcription factor 3 (GATA3), runt­related transcription factor 3 (Runx3) and T­box transcription factor TBX21 (T­bet). In this study, ambient PM2.5 was collected and analyzed, male BALB/c mice were sensitized and treated with PBS, ovalbumin (OVA), PM2.5 or OVA + PM2.5. The effects of PM2.5 alone or PM2.5 + OVA on immunopathological changes, the expression of transcription factors GATA3, Runx3 and T­bet, and the imbalance of Th1/Th2 were investigated. It was found that PM2.5 + OVA co­exposure significantly enhanced inflammatory cell infiltration, increased higher tracheal secretions in lung tissue and upregulated respiratory resistance response to acetylcholine compared with PM2.5 or OVA single exposure and control groups. In addition, higher protein and mRNA expression levels of Th2 inflammatory mediators interleukin (IL)­4, IL­5 and IL­13 in bronchoalveolar lavage fluid were observed in PM2.5 + OVA treated mice, whereas the expression levels of GATA3 and STAT6 were exhibited in mice exposed to OVA + PM2.5 compared with the OVA and PM2.5 groups. By contrast, PM2.5 exposure decreased the protein and mRNA expression levels of Th1 cytokine interferon­Î³ and transcription factors Runx3 and T­bet, especially among asthmatic mice, different from OVA group, PM2.5 exposure only failed to influence the expression of T­bet. To conclude, PM2.5 exposure evoked the allergic airway inflammation response, especially in the asthmatic mouse model and led to Th1/Th2 imbalance. These effects worked mainly by upregulating GATA3 and downregulating Runx3. These data suggested that Runx3 may play an important role in PM2.5­aggravated asthma in BALB/c mice.


Assuntos
Obstrução das Vias Respiratórias/genética , Asma/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Fator de Transcrição GATA3/genética , Fator de Transcrição STAT6/genética , Poluentes Atmosféricos/toxicidade , Obstrução das Vias Respiratórias/induzido quimicamente , Obstrução das Vias Respiratórias/imunologia , Obstrução das Vias Respiratórias/patologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Camundongos , Material Particulado/toxicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia
17.
Scand J Immunol ; 94(2): e13035, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33655533

RESUMO

INTRODUCTION: The growing incidence of non-tuberculous mycobacteria (NTM) and changes in epidemiological factors have indicated that immune dysregulation may be associated with the emergence of NTM. Minireview entails to acknowledge complex interaction and new ways NTM are evolving around diverse immune status. METHODS: In order to perform this review, we selected peer reviewed, NLM database articles under the terms NTM, mycobacterium complex 'AND' -Host- immune response, immunity regulation, Disease, Single Nucleotide Polymorphism (SNP´s), and -pathogen- followed by a snow ball rolling basis search on immune components and NTM related with diseases distribution. RESULTS: The universal exposure and diversity of NTM are well-documented; however, hospitals seldom establish vigilant control of water quality or immunodeficiencies for patients with NTM infections. Depending on the chemical structures and immune mechanisms presented by various NTM varieties, they can trigger different effects in dendritic and natural killer cells, which release interleukin (IL)-17, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and rIL-1B. The T helper (Th)2-acquired immune response is responsible for autoimmune responses in patients with NTM infections, and, quite disturbingly, immunocompetent patients have been reported to suffer from NTM infections. CONCLUSION: New technologies and a comprehensive view has taught us; to acknowledge metabolic/immune determinants and trade-offs along transit through mutualism-parasite continuous.


Assuntos
Imunidade Inata/imunologia , Micobactérias não Tuberculosas/imunologia , Virulência/imunologia , Animais , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucina-1beta/imunologia , Células Matadoras Naturais/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/imunologia
18.
Ann Allergy Asthma Immunol ; 126(5): 516-523, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667639

RESUMO

OBJECTIVE: To provide a concise summary of the current literature regarding gastrointestinal immunopathology of food protein-induced enterocolitis syndrome (FPIES) and other non-immunoglobulin E (IgE)-mediated food allergic diseases. DATA SOURCES: Data were extracted from PubMed, MEDLINE, and ScienceDirect databases. STUDY SELECTIONS: Original articles, review articles, and guidelines published in the past 5 years in peer-reviewed journals were first summarized. The original articles cited were then reviewed and relevant results were extracted. RESULTS: Patients with FPIES and non-IgE-mediated food allergic diseases developed vomiting, diarrhea, and food aversion expelled food allergen from their bodies. Aside from T helper type 2 (TH2) immunity, TH1, TH17, innate immunity, and epithelial mucosal barrier defect were also found to be important in the pathogenesis. Eosinophils, widely identified in the biopsy samples, were key players or were late-recruited cells for tissue repairs in those diseases. Intestinal dysbiosis and their metabolites stimulated enterochromaffin cells or enteroendocrine cells to produce serotonin, interfering with intestinal motility and subsequently affecting brain function. FPIES and non-IgE-mediated food allergic diseases were likely part of the atopic march. Allergic inflammation in intestinal mucosa might result in subsequent inflammation in the airway mucosa, suggesting the theory of "one mucosa, one disease." CONCLUSION: The immune responses of FPIES and non-IgE-mediated food allergic diseases were not limited to the gastrointestinal tract, but also trigger wider inflammatory responses beyond it. Further research will be required to determine the systemic effect and intestinal microbiome of those diseases.


Assuntos
Proteínas na Dieta/imunologia , Enterocolite/patologia , Hipersensibilidade Alimentar/patologia , Trato Gastrointestinal/imunologia , Imunidade Inata/imunologia , Alérgenos/imunologia , Enterocolite/imunologia , Hipersensibilidade Alimentar/imunologia , Humanos , Sistema Respiratório/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
19.
Lancet Infect Dis ; 21(7): 950-961, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705727

RESUMO

BACKGROUND: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 µg or 6 µg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 µg with Algel-IMDG, 6 µg with Algel-IMDG, or 6 µg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 µg and 6 µg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. METHODS: We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12-65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 µg with Algel-IMDG or 6 µg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519. FINDINGS: Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 µg with Algel-IMDG group (n=190) or 6 µg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 µg with Algel-IMDG group (197·0 [95% CI 155·6-249·4]) than the 3 µg with Algel-IMDG group (100·9 [74·1-137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2-96·2] of 184 participants in the 3 µg with Algel-IMDG group and 174 (98·3% [95·1-99·6]) of 177 participants in the 6 µg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7-110·2) in the 3 µg with Algel-IMDG group and 160·1 (135·8-188·8) in the 6 µg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4-92·3]) of 184 participants in the 3 µg with Algel-IMDG group and 171 (96·6% [92·8-98·8]) of 177 participants in the 6 µg with Algel-IMDG group. The 3 µg with Algel-IMDG and 6 µg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 µg with Algel-IMDG group (38 [20·0%; 95% CI 14·7-26·5] of 190) and the 6 µg with Algel-IMDG group (40 [21·1%; 15·5-27·5] of 190) was observed on days 0-7 and days 28-35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0-49·9) in the 3µg with Algel-IMDG group, 69·5 (53·7-89·9) in the 6 µg with Algel-IMDG group, 53·3 (40·1-71·0) in the 6 µg with Algel group, and 20·7 (14·5-29·5) in the Algel alone group. INTERPRETATION: In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 µg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. FUNDING: Bharat Biotech International. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , SARS-CoV-2/imunologia , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Criança , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th2/imunologia , Vacinação/efeitos adversos , Adulto Jovem
20.
Front Immunol ; 12: 611474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746954

RESUMO

The lipocalin beta-lactoglobulin (BLG) is a major protein compound in cow's milk, and we detected it in cattle stable dust. BLG may be a novel player in the farm protective effect against atopic sensitization and hayfever. In previous studies, we demonstrated that only the ligand-filled holo-form of BLG prevented sensitization to itself. Here, we investigated whether holo-BLG could, in an innate manner, also protect against allergic sensitization to unrelated birch pollen allergens using a murine model. BALB/c mice were nasally pretreated four times in biweekly intervals with holo-BLG containing quercetin-iron complexes as ligands, with empty apo-BLG, or were sham-treated. Subsequently, mice were intraperitoneally sensitized two times with apo-BLG or with the unrelated birch pollen allergen apo-Bet v 1, adjuvanted with aluminum hydroxide. After subsequent systemic challenge with BLG or Bet v 1, body temperature drop was monitored by anaphylaxis imaging. Specific antibodies in serum and cytokines of BLG- and Bet v 1-stimulated splenocytes were analyzed by ELISA. Additionally, human peripheral blood mononuclear cells of pollen allergic subjects were stimulated with apo- versus holo-BLG before assessment by FACS. Prophylactic treatment with the holo-BLG resulted in protection against allergic sensitization and clinical reactivity also to Bet v 1 in an unspecific manner. Pretreatment with holo-BLG resulted in significantly lower BLG-as well as Bet v 1-specific antibodies and impaired antigen-presentation with significantly lower numbers of CD11c+MHCII+ cells expressing CD86. Pretreatment with holo-BLG also reduced the release of Th2-associated cytokines from Splenocytes in BLG-sensitized mice. Similarly, in vitro stimulation of PBMCs from birch pollen allergic subjects with holo-BLG resulted in a relative decrease of CD3+CD4+ and CD4+CRTh2 cells, but not of CD4+CD25+CD127- Treg cells, compared to apo-BLG stimulation. In conclusion, prophylactic treatment with holo-BLG protected against allergy in an antigen-specific and -unspecific manner by decreasing antigen presentation, specific antibody production and abrogating a Th2-response. Holo-BLG therefore promotes immune resilience against pollen allergens in an innate manner and may thereby contribute to the farm protective effect against atopic sensitization.


Assuntos
Alérgenos/imunologia , Proteção Cruzada/imunologia , Lactoglobulinas/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/prevenção & controle , Administração Intranasal , Animais , Especificidade de Anticorpos , Apresentação do Antígeno/imunologia , Bovinos , Citocinas/metabolismo , Feminino , Imunização Passiva , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactoglobulinas/administração & dosagem , Camundongos , Pólen/efeitos adversos , Células Th2/imunologia , Células Th2/metabolismo
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