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1.
Cytokine ; 140: 155438, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493861

RESUMO

BACKGROUND: Patients infected by SARS-CoV-2 can develop interstitial pneumonia, requiring hospitalisation or mechanical ventilation. Increased levels of inflammatory biomarkers are associated with development of acute respiratory distress syndrome (ARDS). The aim of the present study was to determine which cytokines are associated with respiratory insufficiency in patients hospitalised for COVID-19. PATIENTS AND METHODS: Data on 67 consecutive patients were collected between March 8 and March 30, 2020. PaO2/FiO2 ratio (P/F) was calculated at hospital admission. The following cytokines were analysed: interleukin (IL)-6, IL-1α, IL-18, tumour necrosis factor (TNF)-ß, macrophage colony-stimulating factor (M-CSF), macrophage migration inhibitory factor (MIF), soluble IL-2 receptor alpha (sIL-2Rα; CD25), IL-12ß, IL-3, interferon (IFN) α2a, monokine induced by gamma interferon (MIG), monocyte-chemotactic protein 3 (MCP3) and hepatocyte growth factor (HGF). RESULTS: P/F lower than 300 was recorded in 22 out of 67 patients (32.8%). P/F strongly correlated with IL-6 (r = -0.62, P < 0.0001), M-CSF (r = -0.63, P < 0.0001), sIL-2Rα (r = -0.54, P < 0.0001), and HGF (r = -0.53, P < 0.0001). ROC curve analyses for IL-6 (AUC 0.83, 95% CI 0.73-0.93, P < 0.0001), M-CSF (AUC 0.87, 95% CI 0.79-0.96, P < 0.0001), HGF (AUC 0.81, 95% CI 0.70-0.93, P < 0.0001), and sIL-2Rα (AUC 0.80, 95% CI, 0.69-0.90, P < 0.0001) showed that these four soluble factors were highly significant. All four soluble factors correlated with LDH, white blood cell count, neutrophil count, lymphocyte count, and CRP. CONCLUSION: IL-6, M-CSF, sIL-2Rα, and HGF are possibly involved in the main biological processes of severe COVID-19, mirroring the level of systemic hyperinflammatory state, the level of lung inflammation, and the severity of organ damage.


Assuntos
/sangue , Citocinas/sangue , Imunidade Inata/imunologia , Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Insuficiência de Múltiplos Órgãos/sangue , Pneumonia/sangue , Idoso , /virologia , Feminino , Fator de Crescimento de Hepatócito/sangue , Interações Hospedeiro-Patógeno , Humanos , Inflamação/complicações , Interleucina-6/sangue , Fator Estimulador de Colônias de Macrófagos/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/complicações , Pneumonia/complicações , Pneumonia/virologia , Estudos Retrospectivos , /fisiologia
2.
PLoS One ; 15(11): e0240784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33166287

RESUMO

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.


Assuntos
Infecções por Coronavirus/patologia , Fadiga/etiologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Fadiga/epidemiologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Prevalência , Índice de Gravidade de Doença
3.
Blood Adv ; 4(20): 5035-5039, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33075136

RESUMO

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) has caused unprecedented human death and has seriously threatened the global economy. Early data suggest a surge in proinflammatory cytokines in patients with severe COVID-19, which has been associated with poor outcomes. We recently postulated that the inflammatory response in patients with severe COVID-19 disease is not inhibited by natural killer (NK) cells, resulting in a "cytokine storm." Here, we assessed the NK-cell functional activity and the associated cytokines and soluble mediators in hospitalized COVID-19 patients. Significantly impaired NK-cell counts and cytolytic activity were observed in COVID-19 patients when compared with healthy controls. Also, cytokines like interleukin 12 (IL12), IL15, and IL21 that are important for NK-cell activity were not detected systematically. Serum concentrations of soluble CD25 (sCD25)/soluble IL2 receptor α (sIL2-Rα) were significantly elevated and were inversely correlated with the percentage of NK cells. Impaired NK-cell cytolytic activity together with other laboratory trends including elevated sCD25 were consistent with a hyperinflammatory state in keeping with macrophage-activation syndrome. Our findings suggest that impaired counts and cytolytic activity of NK cells are important characteristics of severe COVID-19 and can potentially facilitate strategies for immunomodulatory therapies.


Assuntos
Infecções por Coronavirus/imunologia , Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Betacoronavirus/imunologia , Infecções por Coronavirus/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucinas/sangue , Interleucinas/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Índice de Gravidade de Doença , Adulto Jovem
4.
Immunol Res ; 68(6): 398-404, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32989677

RESUMO

This single-center, retrospective study aimed to explore the immune characteristics of COVID-19 and biomarkers to predict the severity of this disease. Patients infected with SARS-CoV-2 (n = 215) treated at the First Affiliated Hospital of Nanchang University from January 24 to March 12, 2020, were included in the study and classified into severe and non-severe groups. Peripheral immunocyte count and cytokine statuses were compared. The correlation between immune status, cytokine levels, and disease severity was analyzed. Leukocyte numbers were normal in both groups; however, they were relatively high (7.19 × 109/L) in patients of the severe group. Leukocyte distributions differed between the two groups; the severe group had a higher percentage of neutrophils and lower percentage of lymphocytes compared with the non-severe group, and absolute lymphocyte numbers were below normal in both groups, and particularly deficient in patients in the severe group. Lymphocyte counts have negative correlation with duration of hospital period whereas neutrophil count has no significant correlation with it. Of tested cytokines, IL-6 levels were significantly higher in the severe group (P = 0.0418). Low level of lymphocyte predicts severity of COVID-19. IL-6 levels were significantly higher in the severe group, especially in some extremely severe patients. But we did not detect the significant correlation between severity of COVID-19 with IL-6 level which may be due to limited case numbers. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Interleucina-6/sangue , Contagem de Linfócitos/estatística & dados numéricos , Pneumonia Viral/diagnóstico , Adulto , Idoso , Betacoronavirus/imunologia , Biomarcadores/análise , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Interleucina-8/sangue , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
5.
Clin Exp Rheumatol ; 38 Suppl 126(4): 142-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32940214

RESUMO

OBJECTIVES: Serum soluble CD25 (sCD25) is associated with T cell activation and regarded as a marker of disease activity in autoimmune disorders. The purpose of our study was to investigate the clinical relevance of sCD25 in patients with primary Sjögren's syndrome (pSS). METHODS: Sixty-five pSS patients and 60 healthy controls (HCs) with comparable age and gender were recruited. Serum samples were collected and sCD25 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory changes were examined after 12 weeks of treatment, and data were recorded in detail. The European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) was used to evaluate disease activity. RESULTS: Serum sCD25 levels were significantly increased in pSS patients, compared to HCs (p<0.001). The increased sCD25 were positively associated with ESSDAI scores (p=0.006), especially the haematological domain (p=0.002), and erythrocyte sedimentation rate, and levels of C-reactive protein, immunoglobulin G and γ-globulin (p<0.001, <0.001, 0.045 and 0.011, respectively). High sCD25 was strongly associated with anaemia (p=0.014) and was inversely correlated with haemoglobin levels (p=0.002). In further analysis, we found that patients with autoimmune haemolytic anaemia (AIHA) had the highest levels of sCD25, followed by patients with chronic disease of anaemia (ACD) and iron-deficiency anaemia (IDA). With the improvement after treatment, serum sCD25 levels were significantly decreased, accompanied by resolved anaemia compared to baseline (p=0.001). CONCLUSIONS: sCD25 was associated with disease severity, especially anaemia in patients with pSS and may serve as an indicator of disease activity.


Assuntos
Doenças Autoimunes , Subunidade alfa de Receptor de Interleucina-2 , Síndrome de Sjogren , Biomarcadores , Sedimentação Sanguínea , Proteína C-Reativa , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Síndrome de Sjogren/diagnóstico
7.
Clin Exp Immunol ; 201(1): 76-84, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32365221

RESUMO

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Linfócitos T/virologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , China/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Progressão da Doença , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pró-Calcitonina/sangue , Pró-Calcitonina/imunologia , Prognóstico , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
8.
Psychopharmacology (Berl) ; 237(6): 1861-1871, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32221694

RESUMO

AIM: To investigate whether circulating T cells including regulatory T cells (Treg) and derived cytokines contribute to the immune imbalance observed in schizophrenia. METHODS: Forty patients with schizophrenia and 40 age, sex, body mass index, education, and smoking status-matched healthy controls (HC) are included in the study. We stained cells with anti-CD14, anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD20, and anti-CD16/56. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with the human FoxP3 kit containing anti-CD4/anti-CD25 and intracellular anti-Foxp3. PBMCs were cultured for 72 h and stimulated with anti-CD3/anti-CD28. Cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, and IL-17A) were measured from the culture supernatant and plasma using the Th1/Th2/Th17 cytokine bead array kit. RESULTS: In comparison with HC, Treg percentages in schizophrenia were higher (1.17 ± 0.63 vs 0.81 ± 0.53, P = 0.005) in unstimulated but lower in the stimulated condition (0.73 ± 0.69 vs 0.97 ± 0.55, P = 0.011). Activated T cell percentages were higher in schizophrenia than HC in unstimulated (2.22 ± 0.78 vs 1.64 ± 0.89, P = 0.001) and stimulated (2.25 ± 1.01 vs 1.72 ± 1.00, P = 0.010) conditions. The culture supernatant levels of IL-6 (7505.17 ± 5170.07 vs 1787.81 ± 1363.32, P < 0.001), IL-17A (191.73 ± 212.49 vs 46.43 ± 23.99, P < 0.001), TNF-α (1557 ± 1059.69 vs 426.57 ± 174.62, P = 0.023), and IFN-γ (3204.13 ± 1397.06 vs 447.79 ± 270.13, P < 0.001); and plasma levels of IL-6 (3.83 ± 3.41vs 1.89 ± 1.14, P = 0.003) and IL-17A (1.20 ± 0.84 vs 0.83 ± 0.53, P = 0.033) were higher in patients with schizophrenia than HC. CONCLUSION: Our explorative study shows reduced level of Foxp3 expressing Treg in a stimulated condition with induced levels of proinflammatory cytokines in patients with schizophrenia.


Assuntos
Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Esquizofrenia/sangue , Esquizofrenia/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Estudos Transversais , Feminino , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-17/sangue , Interleucina-17/imunologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
10.
J Acquir Immune Defic Syndr ; 82(2): 181-187, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513074

RESUMO

BACKGROUND: Women living with HIV (WLHIV) have increased risk of spontaneous preterm delivery (SPTD). We sought to identify plasma predictors of SPTD and their correlations with factors that increase the risk of SPTD, such as vitamin D deficiency and use of protease inhibitors. DESIGN: Plasma was obtained from 103 WLHIV with SPTD (≤35 weeks gestation) and 205 controls with term deliveries (TDs; ≥37 weeds) matched to cases 2:1 by race and gestational age at blood draw. TNFα, IFNγ, IL6, IL8, IL1ß, IL18, IL17, granulocyte colony stimulating factor (GCSF), MCP1, IP10, sIL2Rα, sCD14, vascular endothelial factor a, monocyte colony stimulation factor, GROα, MMP9, IL10, TGFß, sCTLA4, and eicosanoids were compared between cases adjusting for known SPTD risk factors. RESULTS: Participants had similar demographic characteristics, but cases had higher plasma HIV RNA, lower CD4 cells, and more advanced HIV disease compared with controls. High sIL2Rα was associated with increased risk of SPTD. High sCD14, GCSF, PGF2α, and 5-HEPE were marginally associated with increased risk of SPTD. Women who initiated protease inhibitors-containing antiretroviral treatment before or during the first trimester had higher levels of GCSF and 5-HEPE compared with women without such exposure before plasma collection. Vitamin D insufficiency was associated with higher inflammatory sCD14 and PGF2α, and lower anti-inflammatory 5-HEPE. CONCLUSIONS: The best plasma predictor of SPTD in WLHIV was sIL2Rα, a marker of T-cell activation. Markers of monocyte activation and eicosanoids were marginally increased in WLHIV and SPTD, suggesting that they may also play a role in the pathogenesis of this disorder.


Assuntos
Infecções por HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , Complicações Infecciosas na Gravidez/sangue , Nascimento Prematuro/etiologia , Vitamina D/análogos & derivados , Biomarcadores/sangue , Eicosanoides/sangue , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , RNA Viral/análise , Vitamina D/sangue
11.
Minerva Anestesiol ; 85(12): 1289-1298, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31486618

RESUMO

BACKGROUND: Critically ill patients may develop a potentially fatal hyperinflammatory condition known as secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill patients, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25. METHODS: In a prospective observational study, 32 patients with ferritin ≥500 µg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible. RESULTS: Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, P=0.008); both associated with other risk factors of poor outcome in critically ill, such as thrombocytopenia (rs=-0.534, P=0.002 and rs=-0.421, P=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, P<0.001) and life support treatments (rs=0.479, P=0.006). Interestingly, ferritin levels were inversely associated with natural killer (NK)-cell cytotoxicity (rs=-0.462, P=0.047) and degranulation (rs=-0.504, P=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells. CONCLUSIONS: Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.


Assuntos
Citotoxicidade Imunológica , Ferritinas/sangue , Inflamação/sangue , Inflamação/imunologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfócitos/fisiologia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
12.
J Neuroimmunol ; 336: 577042, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479869

RESUMO

Intravenous immunoglobulin (IVIg) serves as the first line therapy in Guillain-Barré syndrome (GBS), however, its action mechanism remains unknown. We hereby stimulated peripheral blood mononuclear cells (PBMCs) from patients with GBS and healthy controls using IVIg and an IgG-derived natural Treg epitopes, namely Tregitopes. Our results showed that IVIg significantly promoted both the expansion of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and secretion of IL-10 and TGF-ß1 while Tregitopes promoted secretion of IL-10 and TGF-ß1 only. Further study is necessary to elucidate the molecular mechanism of IVIg and Tregitopes on Tregs and the secretion of IL-10 and TGF-ß1 in GBS.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Citocinas/sangue , Fatores de Transcrição Forkhead/sangue , Síndrome de Guillain-Barré/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/efeitos dos fármacos
13.
Cancer Immunol Res ; 7(9): 1511-1522, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31383650

RESUMO

Ligand-receptor complexes play a central role in mediating a range of processes in immunology and cancer biology. The ability to directly quantify the fraction of receptors occupied by a ligand in a given biospecimen, as opposed to assessing the concentration of ligand and receptor separately, could provide an additional and valuable clinical and research tool for assessing whether receptors are occupied by a ligand. To address this need, a biomarker platform was developed to quantify the fraction of receptors occupied by a ligand using pairs of RNA aptamers, where one aptamer binds preferentially to the unoccupied receptor and the other to the ligand-receptor complex. Bound aptamer was quantified using RT-qPCR colorimetric probes specific for each aptamer. The binding ratio of aptamer correlated with the fraction of receptors occupied by a ligand. This assay, termed as LIRECAP (LIgand-REceptor Complex-binding APtamer) assay, was used to determine the fraction of soluble CD25 occupied by IL2 in the serum from subjects with B-cell lymphoma. No correlation was found between the type of lymphoma and total soluble CD25 or IL2 independently. In contrast, the fraction of soluble CD25 occupied by IL2 was significantly higher in follicular lymphoma patient serum compared with diffuse large B-cell lymphoma patient serum. We conclude that this technology has the potential to serve as a high-throughput biomarker platform to quantify the fraction of receptors occupied by a ligand.


Assuntos
Aptâmeros de Nucleotídeos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/metabolismo , Linfoma Folicular/metabolismo , Técnica de Seleção de Aptâmeros , Biomarcadores , Biologia Computacional/métodos , Ensaio de Imunoadsorção Enzimática , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Ligantes , Linfoma Folicular/sangue , Ligação Proteica , Transdução de Sinais
14.
Vet Immunol Immunopathol ; 215: 109904, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420068

RESUMO

During immune activation, CD25 is expressed by T cells, and its soluble form (sCD25) is released into the extracellular matrix and the bloodstream. In humans, serum sCD25 concentrations are used as a surrogate marker for autoimmune diseases, malignancies, and transplant rejection. However, a canine-specific assay for the measurement of sCD25 in dog serum has not previously been described. Therefore, the aims of this study were to develop and analytically validate a radioimmunoassay to measure sCD25 in canine serum, to establish a reference interval for canine sCD25, and to test the clinical utility of this assay with serum samples for dogs with various diseases. A competitive radioimmunoassay (RIA) was developed and analytically validated. Analytical validation consisted of lower limit of detection (LLOD), dilutional parallelism, spiking recovery, and intra- and inter-assay variability using pooled surplus canine serum samples. A reference interval was established in healthy dogs and serum samples from dogs with various types of neoplasia, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease and serum samples with an increased C-reactive protein concentration (CRP) were analyzed to test the clinical utility of the assay. LLOD was calculated to be 0.5 ng/mL. The mean (±SD) observed-to-expected ratio (O/E) for serial dilutions was 101.7 ±â€¯14.0%, and the mean (± SD) O/E for spiking recovery was 93.2 ±â€¯4.2%. Coefficients of variation (CVs) for intra-assay variability were ≤12.5% (mean ±â€¯SD: 7.5 ±â€¯4.2%), and inter-assay CVs were ≤15.7% (mean ±â€¯SD: 11 ±â€¯4.4%). A reference interval (RI) for canine sCD25 of 1.2-4.2 ng/mL was established from a population of 112 clinically healthy dogs. Dogs with neoplasia and dogs with suspected small intestinal disease had decreased concentrations of serum sCD25 when compared to healthy dogs (p < 0.0001, respectively). However, the majority of clinical samples used in this study were within the reference interval. Median concentrations of serum sCD25 were 1.9 ng/mL for healthy dogs. Dogs with cancer, IBD, liver disease, suspected pancreatitis, or suspected small intestinal disease, as well as sera with an increased serum CRP concentration, had median serum sCD25 concentrations of 1.6 ng/mL, 2.1 ng/mL, 2.2 ng/mL, 1.7 ng/mL, 1.5 ng/mL, and 1.8 ng/mL, respectively. Thus, the RIA described here is linear, accurate, precise, and reproducible for measuring sCD25 in canine serum. However, this assay shows little clinical utility of sCD25 as a biomarker for dogs with inflammatory, autoimmune, and/or neoplastic conditions.


Assuntos
Doenças do Cão/sangue , Cães/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Radioimunoensaio/veterinária , Animais , Doenças do Cão/imunologia , Ensaio de Imunoadsorção Enzimática/veterinária , Humanos , Radioimunoensaio/métodos , Valores de Referência , Sensibilidade e Especificidade
15.
Hum Mol Genet ; 28(19): 3293-3300, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276585

RESUMO

Immune-mediated diseases (IMDs) arise when tolerance is lost and chronic inflammation is targeted towards healthy tissues. Despite their growing prevalence, therapies to treat IMDs are lacking. Cytokines and their receptors orchestrate inflammatory responses by regulating elaborate signalling networks across multiple cell types making it challenging to pinpoint therapeutically relevant drivers of IMDs. We developed an analytical framework that integrates Mendelian randomization (MR) and multiple-trait colocalization (moloc) analyses to highlight putative cell-specific drivers of IMDs. MR evaluated causal associations between the levels of 10 circulating cytokines and 9 IMDs within human populations. Subsequently, we undertook moloc analyses to assess whether IMD trait, cytokine protein and corresponding gene expression are driven by a shared causal variant. Moreover, we leveraged gene expression data from three separate cell types (monocytes, neutrophils and T cells) to discern whether associations may be attributed to cell type-specific drivers of disease. MR analyses supported a causal role for IL-18 in inflammatory bowel disease (IBD) (P = 1.17 × 10-4) and eczema/dermatitis (P = 2.81 × 10-3), as well as associations between IL-2rα and IL-6R with several other IMDs. Moloc strengthened evidence of a causal association for these results, as well as providing evidence of a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis. In contrast, IL-2rα and IL-6R associations were found to be T cell specific. Our analytical pipeline can help to elucidate putative molecular pathways in the pathogeneses of IMDs, which could be applied to other disease contexts.


Assuntos
Citocinas/genética , Eczema/genética , Doenças Inflamatórias Intestinais/genética , Análise da Randomização Mendeliana/métodos , Citocinas/sangue , Eczema/imunologia , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/imunologia , Interleucina-18/sangue , Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/genética , Locos de Características Quantitativas , Receptores de Interleucina-6/sangue , Receptores de Interleucina-6/genética , Linfócitos T/imunologia
16.
Chembiochem ; 20(17): 2236-2240, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270926

RESUMO

The soluble interleukin-2 receptor α (sIL-2Rα) is a broad indicator of clinical disease activity in various inflammatory diseases. Here we have developed, for the first time, a rapid, washing-free colorimetric aptasensor based on a sIL-2Rα aptamer (Kd =1.33 nm). The aptasensor was fabricated with Au nanoparticles (AuNPs) adsorbing sIL-2Rα aptamers. On addition of sIL-2Rα, the aptamers become desorbed from the AuNPs, and this in turn weakens the absorption corresponding to AuNP-catalyzed oxidation of ortho-phenylenediamine (oPD) with H2 O2 . The aptasensor was characterized by TEM imaging, ζ potential measurements, dynamic light scattering (DLS) analysis, and UV/Vis spectrometry, followed by further optimization. The fabricated sensor exhibited great analytical performance, with a linear range of 1 to 100 nm and a detection limit of 1 nm both in buffer and in spiked human serum within 25 min. Other proteins, such as bovine serum albumin (BSA), IL-17Rα, IL-5Rα, IL-13Rα2 , and CD166, showed negligible effects on the aptasensor. Thanks to the great advantages of the aptamers and AuNPs, this aptasensor provides a rapid, simple, and inexpensive process that might offer insights into various diagnostic applications of sIL-2Rα.


Assuntos
Aptâmeros de Nucleotídeos/química , Colorimetria/métodos , Ouro , Subunidade alfa de Receptor de Interleucina-2/análise , Nanopartículas Metálicas/química , Adsorção , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Limite de Detecção , Solubilidade
17.
Sci Rep ; 9(1): 9468, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263199

RESUMO

Quantitative high resolution computed tomography (HRCT) may objectively assess systemic sclerosis (SSc)-interstitial lung disease (ILD) extent, using three basic densitometric measures: mean lung attenuation (MLA), skewness, and kurtosis. This prospective study aimed to develop a composite index - computerized integrated index (CII) - that accounted for MLA, skewness, and kurtosis by means of Principal Component Analysis over HRCTs of 83 consecutive SSc subjects, thus eliminating redundancies. Correlations among CII, cardiopulmonary function and immune-inflammatory biomarkers (e.g. sIL-2Rα and CCL18 serum levels) were explored. ILD was detected in 47% of patients at visual HRCT assessment. These patients had worse CII values than patients without ILD. The CII correlated with lung function at both baseline and follow-up, and with sIL-2Rα and CCL18 serum levels. The best discriminating CII value for ILD was 0.1966 (AUC = 0.77; sensitivity = 0.81 [95%CI:0.68-0.92]; specificity = 0.66 [95%CI:0.52-0.80]). Thirty-four percent of patients without visual trace of ILD had a CII lower than 0.1966, and 67% of them had a diffusing lung capacity for CO <80% of predicted. We showed that this new composite CT index for SSc-ILD assessment correlates with both lung function and immune-inflammatory parameters and could be sufficiently sensitive for capturing early lung density changes in visually ILD-free patients.


Assuntos
Quimiocinas CC/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Doenças Pulmonares Intersticiais , Pulmão , Escleroderma Sistêmico , Tomografia Computadorizada por Raios X , Idoso , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/diagnóstico por imagem
18.
J Shoulder Elbow Surg ; 28(9): e291-e303, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227466

RESUMO

BACKGROUND: Comparing techniques of general anesthesia and regional anesthesia in arthroscopic shoulder surgery, some studies have shown differences in the intensity of immediate postoperative pain and neuroendocrine response, but the inflammatory response when using balanced general anesthesia (BGA) vs. an ultrasound-guided (USG) single-dose interscalene block (SDIB) has not been compared. MATERIALS AND METHODS: In a single-center, prospective, randomized clinical trial, the inflammatory response of 2 groups of 10 patients scheduled to undergo arthroscopic shoulder surgery was evaluated through measurement of a panel of cytokines that act on cells of the adaptive immune response to promote or inhibit inflammation, chemokines involved in chemotaxis, the erythrocyte sedimentation rate (ESR), the high-sensitivity C-reactive protein (CRP) level, and the white blood cell (WBC) count in 3 blood samples (before anesthesia, immediately postoperatively, and 24 hours postoperatively) with 2 types of anesthesia (BGA vs. USG SDIB). Postoperative pain intensity (immediately, at 12 hours, and at 24 hours) was also assessed. RESULTS: The ESR and CRP level increased significantly at 24 hours after surgery; however, the increase in ESR (P < .0001) and CRP level (P < .0001) was lower in the USG SDIB group. Significant increases in the levels of soluble interleukin 2 receptor α (P = .022) and interleukin 12p40 (P = .016) occurred in the immediate postoperative period in the USG SDIB group. Immediate postoperative pain showed a significant increase (P < .001) in the BGA group. CONCLUSIONS: In arthroscopic shoulder surgery, the use of a USG SDIB compared with the use of BGA is possibly associated with improved pain control in the immediate postoperative period and lower immunosuppression, even at 24 hours after surgery.


Assuntos
Anestesia Geral , Bloqueio do Plexo Braquial/métodos , Citocinas/sangue , Inflamação/sangue , Adulto , Idoso , Artroscopia/efeitos adversos , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Feminino , Humanos , Inflamação/etiologia , Subunidade p40 da Interleucina-12/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Manejo da Dor , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Ombro/cirurgia , Ultrassonografia de Intervenção
19.
J Am Acad Dermatol ; 81(2): 510-519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009665

RESUMO

BACKGROUND: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD. OBJECTIVE: To analyze blood inflammatory proteins of early pediatric AD. METHODS: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD. RESULTS: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11). LIMITATIONS: Different baseline expression levels in healthy pediatric vs adult samples. CONCLUSIONS: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.


Assuntos
Quimiocinas/sangue , Dermatite Atópica/sangue , Elafina/sangue , Inflamação/sangue , Metaloproteinases da Matriz/sangue , Receptores de Interleucina/sangue , Fatores Etários , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Doença Crônica , Dermatite Atópica/metabolismo , Selectina E/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/sangue , Masculino , Peroxidase/sangue , Proteoma/metabolismo , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fator de Crescimento Transformador alfa/sangue
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