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Although perianal Crohn's disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present a history of perianal lesions are still unclear. This paper aims to define immunological characteristics related to PCD. In this cross-sectional observational study, we enrolled 20 healthy controls and 39 CD patients. Blood samples were obtained for the detection of plasma cytokines and lipopolysaccharides (LPS). Peripheral blood mononuclear cells (PBMCs) were phenotyped by flow cytometry. Leukocytes were stimulated with LPS or anti-CD3/anti-CD28 antibodies. Our results show that CD patients had augmented plasma interleukin (IL)-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with a history of PCD produced higher IL-6, IL-8, and interferon-γ, along with decreased tumor necrosis factor alpha (TNF). CD patients had augmented FoxP3 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulatory markers, though the PCD subjects presented a significant reduction in CTLA-4 expression. CTLA-4 as well as IL-6 and TNF responses were able to distinguish the PCD patients from those who did not present perianal complications. In conclusion, IL-6, TNF, and CTLA-4 exhibit a distinct expression pattern in CD patients with a history of PCD, regardless of disease activity. These findings clarify some mechanisms involved in the development of the perianal manifestations and may have a great impact on the disease management.
Assuntos
Antígeno CTLA-4 , Doença de Crohn , Humanos , Antígeno CTLA-4/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/sangue , Masculino , Feminino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Interleucina-6/sangue , Lipopolissacarídeos/imunologia , Citocinas/sangue , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Transcrição Forkhead/metabolismoRESUMO
Lipid and cholinergic mediators are inflammatory regulators, but their role in the immunopathology of COVID-19 is still unclear. Here, we used human blood and tracheal aspirate (TA) to investigate whether acetylcholine (Ach), fatty acids (FAs), and their derived lipid mediators (LMs) are associated with COVID-19 severity. First, we analyzed the perturbation profile induced by SARS-CoV-2 infection in the transcriptional profile of genes related to the ACh and FA/LM pathways. Blood and TA were used for metabolomic and lipidomic analyses and for quantification of leukocytes, cytokines, and ACh. Differential expression and coexpression gene network data revealed a unique transcriptional profile associated with ACh and FA/LM production, release, and cellular signaling. Transcriptomic data were corroborated by laboratory findings: SARS-CoV-2 infection increased plasma and TA levels of arachidonic acid, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, 11-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid, and ACh. TA samples also exhibited high levels of PGE2, thromboxane B2, 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid, and 6-trans-leukotriene B4 Bioinformatics and experimental approaches demonstrated robust correlation between transcriptional profile in Ach and FA/LM pathways and parameters of severe COVID-19. As expected, the increased neutrophil-to-lymphocyte ratio, neutrophil counts, and cytokine levels (IL-6, IL-10, IL-1ß, and IL-8) correlated with worse clinical scores. Glucocorticoids protected severe and critical patients and correlated with reduced Ach levels in plasma and TA samples. We demonstrated that pulmonary and systemic hyperinflammation in severe COVID-19 are associated with high levels of Ach and FA/LM. Glucocorticoids favored the survival of patients with severe/critical disease, and this effect was associated with a reduction in ACh levels.
Assuntos
Acetilcolina , COVID-19 , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Ácidos Graxos , Glucocorticoides , Humanos , SARS-CoV-2RESUMO
COVID-19 has a broad spectrum of clinical manifestations associated with the host immune response heterogeneity. Despite the advances in COVID-19 research, it is still crucial to seek a panel of molecular markers that enable accurate stratification of COVID-19 patients. Here, we performed a study that combined analysis of blood transcriptome, demographic data, clinical aspects and laboratory findings from 66 participants classified into different degrees of COVID-19 severity and healthy subjects. We identified a perturbation in blood-leukocyte transcriptional profile associated with COVID-19 aggravation, which was mainly related to processes that disfavoured lymphocyte activation and favoured neutrophil activation. This transcriptional profile stratified patients according to COVID-19 severity. Hence, it enabled identification of a turning point in transcriptional dynamics that distinguished disease outcomes and non-hospitalized from hospitalized moderate patients. Central genes of this unique neutrophil signature were S100A9, ANXA3, CEACAM6, VNN1, OLFM4, IL1R2, TCN1 and CD177. Our study indicates the molecular changes that are linked with the differing clinical aspects presented by humans when suffering from COVID-19, which involve neutrophil activation.
Assuntos
COVID-19 , Humanos , COVID-19/genética , Neutrófilos , Transcriptoma , BiomarcadoresRESUMO
BACKGROUND: Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients. METHODS: A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome. RESULTS: There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings. CONCLUSIONS: These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.
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The non-classical histocompatibility antigen G (HLA-G) is an immune checkpoint molecule that has been implicated in viral disorders. We evaluated the plasma soluble HLA-G (sHLA-G) in 239 individuals, arranged in COVID-19 patients (n = 189) followed up at home or in a hospital, and in healthy controls (n = 50). Increased levels of sHLA-G were observed in COVID-19 patients irrespective of the facility care, gender, age, and the presence of comorbidities. Compared with controls, the sHLA-G levels increased as far as disease severity progressed; however, the levels decreased in critically ill patients, suggesting an immune exhaustion phenomenon. Notably, sHLA-G exhibited a positive correlation with other mediators currently observed in the acute phase of the disease, including IL-6, IL-8 and IL-10. Although sHLA-G levels may be associated with an acute biomarker of COVID-19, the increased levels alone were not associated with disease severity or mortality due to COVID-19. Whether the SARS-CoV-2 per se or the innate/adaptive immune response against the virus is responsible for the increased levels of sHLA-G are questions that need to be further addressed.
Assuntos
COVID-19 , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I , Humanos , Proteínas de Checkpoint Imunológico , Plasma , SARS-CoV-2RESUMO
Peripheral inflammation, particularly mediated by monocytes, can cause neuroinflammation in Parkinson's disease (PD). We investigated the mechanism of TLR2-induced cytokine impairment in peripheral monocytes from PD patients and the association between the presence of CD14+ TLR10+ monocytes and PD severity. Peripheral blood mononuclear cells from PD patients and healthy individuals were evaluated for TLR expression on monocyte subsets (CD14 and CD16 expression) using flow cytometry. Moreover, cytokines were evaluated using flow cytometry after stimulation with Pam3 Cys (TLR2/TLR1 agonist) in the absence or presence of neutralizing antibodies to TLR10. The severity of PD was assessed using the unified PD rating scale (UPDRS) and motor activity, anxiety (BAI), depression (BDI), and fatigue (PD Fatigue Scale-16) scales. The frequency of CD14+ TLR10+ monocytes and expression intensity of TLR2 and TLR10 were higher in patients with PD than healthy individuals. The frequency of intermediate monocytes (CD14++ CD16+ ) was not significantly increased in patients with PD, but was the main monocyte subset expressing TLR10. The TLR2/TLR1-impaired cytokine production (IL-6, TNFα, IL-8, and IL-10) in PD patients was reversed by neutralizing TLR10. The high frequency of total CD14+ TLR10+ monocytes was associated with a reduction in the severity of PD according to the evaluation of motor and nonmotor symptoms. Peripheral monocytes from patients with PD showed phenotypic and functional alterations. The expression of TLR10 on monocytes can protect against PD by controlling TLR2-induced cytokine production. Furthermore, data suggested that a low frequency of CD14+ TLR10+ monocytes indicates the severity of PD. The results identified new opportunities for the development of novel PD neuroprotective therapies.
Assuntos
Citocinas/sangue , Monócitos/metabolismo , Doença de Parkinson/sangue , Receptor 10 Toll-Like/sangue , Receptor 2 Toll-Like/sangue , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Estudos ProspectivosRESUMO
BACKGROUND: Although the pancreatic ductal adenocarcinoma (PDAC) presents high mortality and metastatic potential, there is a lack of effective therapies and a low survival rate for this disease. This PDAC scenario urges new strategies for diagnosis, drug targets, and treatment. METHODS: We performed a gene expression microarray meta-analysis of the tumor against normal tissues in order to identify differentially expressed genes (DEG) shared among all datasets, named core-genes (CG). We confirmed the CG protein expression in pancreatic tissue through The Human Protein Atlas. It was selected five genes with the highest area under the curve (AUC) among these proteins with expression confirmed in the tumor group to train an artificial neural network (ANN) to classify samples. RESULTS: This microarray included 461 tumor and 187 normal samples. We identified a CG composed of 40 genes, 39 upregulated, and one downregulated. The upregulated CG included proteins and extracellular matrix receptors linked to actin cytoskeleton reorganization. With the Human Protein Atlas, we verified that fourteen genes of the CG are translated, with high or medium expression in most of the pancreatic tumor samples. To train our ANN, we selected the best genes (AHNAK2, KRT19, LAMB3, LAMC2, and S100P) to classify the samples based on AUC using mRNA expression. The network classified tumor samples with an f1-score of 0.83 for the normal samples and 0.88 for the PDAC samples, with an average of 0.86. The PDAC-ANN could classify the test samples with a sensitivity of 87.6 and specificity of 83.1. CONCLUSION: The gene expression meta-analysis and confirmation of the protein expression allow us to select five genes highly expressed PDAC samples. We could build a python script to classify the samples based on RNA expression. This software can be useful in the PDAC diagnosis.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Pancreáticas/genética , Área Sob a Curva , Estudos de Casos e Controles , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Redes Neurais de Computação , Análise de Sequência com Séries de Oligonucleotídeos , Software , Regulação para CimaRESUMO
To analyze the participation of the enzyme 5-lipoxygenase (5-LO) in skin repair, WT wounds were compared to those in 5-LO deficient mice (5-LO-/-), which presented faster closure and reduced inflammatory infiltrate in the skin, together with increased CD4 regulatory T cells markers in the draining lymph nodes. The 5-LO-/- wounds also had diminished TNF-α, CCL11, CCL7, CCL2, CXCL9, CCR1 and CXCR2 mRNA expression in the lesions, besides differential extracellular matrix remodeling. Furthermore, when cysteinyl leukotriene (cysLT) and leukotriene (LTB4) receptors were antagonized in WT mice, there was a remarkable reduction in TNF-α expression and faster skin healing, similarly to the findings in 5-LO-/- animals. Finally, our results suggested that 5-LO products, in special cysLT and LTB4, underline skin inflammation that follows skin injury and their neutralization may be an important strategy to improve cutaneous healing.
Assuntos
Araquidonato 5-Lipoxigenase/imunologia , Cisteína/imunologia , Citocinas/imunologia , Mediadores da Inflamação/imunologia , Leucotrieno B4/imunologia , Leucotrienos/imunologia , Cicatrização/imunologia , Animais , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Cisteína/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Expressão Gênica/imunologia , Mediadores da Inflamação/metabolismo , Leucotrieno B4/metabolismo , Leucotrienos/metabolismo , Camundongos da Linhagem 129 , Camundongos Knockout , Pele/imunologia , Pele/metabolismo , Pele/patologia , Cicatrização/genéticaRESUMO
Infection with Strongyloides sp. induces a host immune response, predominantly the Th2 type, that is able to eliminate the parasite. However, little is known about the role of the nitric oxide (NO) mediator, induced by the enzyme nitric oxide synthase (NOS), in strongyloidiasis. Therefore, in this study, we investigated the immune response of mice genetically deficient in the enzyme inducible nitric oxide synthase (iNOS-/- ), infected with Strongyloides venezuelensis. C57BL/6 wild-type (WT) and iNOS-/- mice were individually inoculated by subcutaneous injection of 3000 S. venezuelensis L3 larvae. In the absence of iNOS, mice were more susceptible to the infection than WT animals, in which the parasite was completely eliminated. The overall production of cytokines and specific IgG, IgG1 or IgE antibodies against the parasite was significantly lowered in infected iNOS-/- mice. The expression of iNOS was observed in the intestine of WT hosts but mainly in the wall of the parasite, despite the presence of iNOS in mice. Altogether, we concluded that iNOS expression may play an important role in the control of S. venezuelensis infection.
Assuntos
Anticorpos Antiprotozoários/imunologia , Mucosa Intestinal/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico/metabolismo , Strongyloides/metabolismo , Estrongiloidíase/imunologia , Animais , Anticorpos Antiprotozoários/biossíntese , Arvicolinae/parasitologia , Citocinas/biossíntese , Citocinas/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Mucosa Intestinal/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Strongyloides/citologia , Strongyloides/isolamento & purificação , Estrongiloidíase/parasitologia , Células Th2/imunologiaRESUMO
The clinical benefits of short-term therapy with glucocorticoids (GC) in patients with inflammatory bowel disease (IBD) are widely known. However, the effects of this treatment towards the re-establishment of the regulatory network in IBD are not fully explored. We have evaluated the immunological effects of the abbreviated GC therapy in experimental colitis induced by 3% dextran sulphate sodium in C57BL/6 mice. Treatment with GC improved disease outcome, constrained circulating leucocytes and ameliorated intestinal inflammation. The control of the local inflammatory responses involved a reduction in the expression of interferon-γ and interleukin-1ß, associated with augmented mRNA levels of peroxisome proliferator-activated receptors (α and γ) in intestine. Furthermore, there was a reduction of CD4+ T cells producing interferon-γ, together with an increased frequency of the putative regulatory population of T cells producing interleukin-10, in spleen. These systemic alterations were accompanied by a decrease in the proliferative potential of splenocytes of mice treated in vivo with GC. Notably, treatment with GC also led to an increase in the frequency of the regulatory markers GITR, CTLA-4, PD-1, CD73 and FoxP3, more prominently in spleen. Taken together, our results pointed to a role of GC in the control of leucocyte responsiveness and re-establishment of a regulatory system, which probably contributed to disease control and the restoration of immune balance. Finally, this is the first time that GC treatment was associated with the modulation of a broad number of regulatory markers in an experimental model of colitis.
Assuntos
Colite/tratamento farmacológico , Glucocorticoides/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD4/metabolismo , Células Cultivadas , Protocolos Clínicos , Colite/induzido quimicamente , Sulfato de Dextrana , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Humanos , Imunomodulação , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Receptores Ativados por Proliferador de Peroxissomo/metabolismoAssuntos
COVID-19 , Complemento C3 , Ativação do Complemento , Inativadores do Complemento , Humanos , SARS-CoV-2RESUMO
OBJECTIVES: Toll-like receptors (TLRs) are expressed in several immune cells including blood monocytes and resident macrophages, such as microglia in the central nervous system. TLRs recognize pathogen- or damage-associated molecular patterns, leading to the release of inflammatory and toxic molecules, which can contribute to neuroinflammation associated with Parkinson's disease (PD). The aim of this study was to compare the potential of peripheral blood cells from PD patients or healthy subjects to produce cytokines after exposure to TLR agonists, and to investigate TLR2 and TLR4 expression on monocyte subsets. METHODS: Twenty-one patients and 21 healthy controls were recruited. Patients were evaluated according to the Unified Parkinson's Disease Rating Scale, and Hoehn and Yahr stage. Cytokines were measured in supernatants of whole blood cultures after incubation with TLR2, TLR4, or TLR7/8 agonists, by cytometric bead array. Expression of CD14, CD16, TLR2, and TLR4 was analyzed by cytometry. RESULTS: Patient blood cells produced lower levels of cytokines in response to TLR2 and also after TLR7/8/R848 activation than controls. Percentages of CD14+CD16+ or CD14+CD16- monocytes and TLR2 and TLR4 expression were similar between patients and controls. CONCLUSIONS: Blood leukocyte TLR2 and TLR7/8 responses are impaired in PD. This was neither associated with imbalance in monocyte subsets nor with TLR2/TLR4 expression on these cells. The association between a decreased TLR response in periphery and damage of brain in PD must be further investigated.
Assuntos
Células Sanguíneas/metabolismo , Citocinas/metabolismo , Doença de Parkinson/sangue , Receptor 2 Toll-Like/metabolismo , Receptor 7 Toll-Like/metabolismo , Idoso , Células Sanguíneas/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , Lipoproteínas/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Estatística como AssuntoRESUMO
The adrenal glands are able to modulate immune responses through neuroimmunoendocrine interactions and cortisol secretion that could suppress exacerbated inflammation such as in inflammatory bowel disease (IBD). Therefore, here we evaluated the role of these glands in experimental colitis induced by 3% dextran sulfate sodium (DSS) in C57BL/6 mice subjected to adrenalectomy, with or without glucocorticoid (GC) replacement. Mice succumbed to colitis without adrenals with a higher clinical score and augmented systemic levels of IL-6 and lower LPS. Furthermore, adrenalectomy negatively modulated systemic regulatory markers. The absence of adrenals resulted in augmented tolerogenic lamina propria dendritic cells but no compensatory local production of corticosterone and decreased mucosal inflammation associated with increased IFN-γ and FasL in the intestine. To clarify the importance of GC in this scenario, GC replacement in adrenalectomized mice restored different markers to the same degree of that observed in DSS group. Finally, this is the first time that adrenal-derived hormones, especially GC, were associated with the differential local modulation of the gut infiltrate, also pointing to a relationship between adrenalectomy and the modulation of systemic regulatory markers. These findings may elucidate some neuroimmunoendocrine mechanisms that dictate colitis outcome.
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Glândulas Suprarrenais/metabolismo , Colite/imunologia , Adrenalectomia , Animais , Colite/induzido quimicamente , Dexametasona/farmacologia , Sulfato de Dextrana/toxicidade , Ensaio de Imunoadsorção Enzimática , Proteína Ligante Fas/metabolismo , Citometria de Fluxo , Glucocorticoides/farmacologia , Interferon gama/metabolismo , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17(+) and TRAP(+) cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression.
Assuntos
Periodontite Crônica/metabolismo , Interleucina-17/genética , Metaloproteinase 2 da Matriz/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Fator de Crescimento Transformador beta/genéticaRESUMO
Despite major improvements in its treatment and diagnosis, sepsis is still a leading cause of death and admittance to the intensive care unit (ICU). Failure to identify patients at high risk of developing septic shock contributes to an increase in the sepsis burden and rapid molecular tests are currently the most promising avenue to aid in patient risk determination and therapeutic anticipation. The primary goal of this study was to evaluate the genetic susceptibility that affects sepsis outcome in 72 sepsis patients admitted to the ICU. Seven polymorphisms were genotyped in key inflammatory response genes in sepsis, including tumour necrosis factor-α, interlelukin (IL)-1ß, IL-10, IL-8, Toll-like receptor 4, CXCR1 and CXCR2. The primary finding showed that patients who were homozygous for the major A allele in IL-10 rs1800896 had almost five times higher chance to develop septic shock compared to heterozygotes. Similarly, selected clinical features and CXCR2 rs1126579 single nucleotide polymorphisms modulated septic shock susceptibility without affecting survival. These data support the hypothesis that molecular testing has clinical usefulness to improve sepsis prognostic models. Therefore, enrichment of the ICU portfolio by including these biomarkers will aid in the early identification of sepsis patients who may develop septic shock.
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Predisposição Genética para Doença , Interleucina-10/genética , Polimorfismo Genético , Receptores de Interleucina-8B/genética , Choque Séptico/genética , Idoso , Feminino , Marcadores Genéticos , Genótipo , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Distribuição AleatóriaRESUMO
Breast cancer is a leading cause of neoplasia-associated death in women worldwide. Regulatory T (Treg) and Th17 cells are enriched within some tumors, but the role these cells play in invasive ductal carcinoma (IDC) of the breast is unknown. We show that CD25(+) CD4(+) T cells from PBMCs and tumor express high levels of Foxp3, GITR, CTLA-4, and CD103, indicating that tumor-infiltrating Treg cells are functional and possibly recruited by CCL22. Additionally, we observed upregulation of Th17-related molecules (IL-17A, RORC, and CCR6) and IL-17A produced by tumor-infiltrating CD4(+) and CD8(+) T lymphocytes. The angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor are possibly induced by IL-17 and indicative of poor disease prognosis. Treg and Th17 cells were synchronically increased in IDC patients, with positive correlation between Foxp3, IL-17A, and RORC expression, and associated with tumor aggressiveness. Therefore, Treg and Th17 cells can affect disease progression by Treg-cell-mediated suppression of the effector T-cell response, as indicated by a decrease in the proliferation of T cells isolated from PBMCs of IDC patients and induction of angiogenic factors by IL-17-producing Th17. The understanding of regulation of the Treg/Th17 axis may result in novel perspectives for the control of invasive tumors.
Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal/imunologia , Interleucina-17/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Antígenos CD/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal/patologia , Proliferação de Células , Transformação Celular Neoplásica/imunologia , Quimiocina CCL22/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Humanos , Interleucina-17/genética , Invasividade Neoplásica , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores CCR6/metabolismo , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Cassava (Manihot esculenta Crantz) is one of the most important tropical crops showing tolerance to abiotic stress and adaptations to a wide range of environmental conditions. Here, we aimed to isolate and characterize the full-length cDNA and genomic sequences of a cassava translationally controlled tumor protein gene (MeTCTP), and evaluate its potential role in response to salt stress. The MeTCTP full-length cDNA sequence encodes for a deduced protein with 168 amino acid residues, with theoretical isoelectric point and molecular weight of 4.53 and 19 kDa, respectively, containing two putative signatures of TCTP family and one site for myristoylation. The MeTCTP genomic sequence includes four introns and five exons within a 1,643 bp coding region, and a 264 bp partial promoter sequence containing several putative cis-acting regulatory elements, among them, two putative GT-1 motifs, which may be related to response to sodium chloride (NaCl) and pathogen infection. Semi-quantitative RT-PCR assays showed that MeTCTP transcripts were higher in roots than leaves, and were significantly increased in detached leaves treated with NaCl. Furthermore, the recombinant MeTCTP conferred a protective function against salt stress in bacterial cells. We report for the first time the molecular cloning and characterization of a cassava TCTP with potential role in salt-stress response. Since salinity is one the most important abiotic factors affecting the production of crops worldwide, the MeTCTP gene could be a candidate gene for generation of salt tolerant crops.
Assuntos
Biomarcadores Tumorais/genética , Manihot/genética , Regiões Promotoras Genéticas , Tolerância ao Sal/genética , Sequência de Aminoácidos , Biomarcadores Tumorais/biossíntese , Clonagem Molecular , Regulação da Expressão Gênica de Plantas , Manihot/crescimento & desenvolvimento , Folhas de Planta/genética , Homologia de Sequência de Aminoácidos , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Atopic dermatitis (AD) is a common inflammatory skin condition that significantly affects patients' lives and imposes both economic and non-economic burdens. The precise societal and individual consequences of AD remain incompletely understood. This study aimed to characterize AD in Portuguese patients and assess its personal, familial, and societal implications, including health status and quality of life. The research, conducted from June 2019 to January 2020, involved 204 confirmed AD patients in Portugal, who completed a 70-question questionnaire. Results show that, on average, patients experienced a two-year delay in diagnosis, with two-thirds having allergic comorbidities. Late-onset AD (after age 20) was found to be correlated with worsening symptoms post-diagnosis. Globally, patients reported substantial effects on health, quality of life, and mental well-being. Effects include significant levels of anxiety, frustration and sleep disorders. Severe AD correlated with more suffering and reduced perceived health, indicating a link between disease severity and quality of life. Remarkably, despite questionable effectiveness, 92% of severe AD patients were prescribed antihistamines, while only 19% received biological treatments. In Portugal, delayed AD diagnosis hinders timely treatment, and despite its profound impact and high comorbidity rates, AD patients tend to remain undertreated. Recognizing the personal and societal repercussions is crucial for enhancing care, contributing to improving QoL, social functioning and global well-being.
Assuntos
Dermatite Atópica , Humanos , Adulto Jovem , Adulto , Dermatite Atópica/diagnóstico , Qualidade de Vida , Portugal/epidemiologia , Comorbidade , Pele , Índice de Gravidade de DoençaRESUMO
During infection, the host response develops effector mechanisms to combat the parasite. However, this response can become uncontrolled or regulated by mechanisms that modulate the inflammatory reaction. The number of parasites that infects the host, such as trypomastigotes in Chagas disease, may also influence immune activation and disease pathology. We evaluated the inflammation and immune regulation that follows Trypanosoma cruzi infection with low (300), intermediate (3000) or high (30000) parasite loads. Our results showed that the load of parasite inoculum influenced disease outcome: the higher the number of parasites in the inoculum, the lower were the survival rates. There was a strong association between parasitism and inflammatory infiltrate in the heart and the parasite inoculum determined cytokine interplay in this tissue, as shown by increased interferon-γ, tumour necrosis factor-α, interleukin-17 (IL-17) and IL-23 in the 300 and 30000 inoculum groups, higher IL-4 and IL-10 in the intermediate-inoculum mice, and elevated IL-6 production in the heart of mice in the 3000 and 30000 groups. The number of T cells and antigen-presenting cells was augmented in the infected groups, especially for the splenic CD4(+) CD25(+) regulatory T cells expressing CD45RB(low) , GITR, PD-1 and FoxP3 in the group with the highest inoculum. Interestingly, these mice also presented an apparent decrease in CD4(+) CD25(+) FoxP3(+) cells in the cardiac infiltrate, in contrast to the intermediate inoculum group, which showed elevated numbers of these regulatory leucocytes in the heart. Finally, our results demonstrated that parasite load during T. cruzi infection is linked to the response pattern that will result in parasite/inflammation control or tissue damage.
Assuntos
Doença de Chagas/imunologia , Citocinas/imunologia , Linfócitos T Reguladores/imunologia , Trypanosoma cruzi/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Diferenciação/imunologia , Doença de Chagas/patologia , Relação Dose-Resposta Imunológica , Masculino , Camundongos , Miocárdio/imunologia , Miocárdio/patologia , Linfócitos T Reguladores/patologiaRESUMO
In human and murine models strongyloidiasis induce a Th2 type response. In the current study we investigated the role of different loads of Strongyloides venezuelensis in the immune response raised against the parasite and the participation of the major histocompatibility complex (MHC) class II molecule in the disease outcome in face of the different parasite burden. The C57BL/6 wild type (WT) and MHC II(-/-) mice were individually inoculated by subcutaneous injection with 500 or 3000 S. venezuelensis L3. The MHC II(-/-) mice infected with 3000L3 were more susceptible to S. venezuelensis infection when compared with WT groups, in which the parasite was completely eliminated. The production of Th2 cytokines and specific IgG1 or IgE antibodies against parasite were significantly lowered in MHC II(-/-) infected mice with different larvae inoculums. The infection of MHC II(-/-) mice with S. venezuelensis induced slight inflammatory alterations in the small intestine, and these lesions were lower when compared with WT mice, irrespective of the parasite load utilized to infect animals. Finally, we concluded that MHC class II molecules are essential in the immune response against S. venezuelensis mainly when infection occurs with high parasite inoculum.