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1.
Pancreas ; 50(5): 710-718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34016897

RESUMO

OBJECTIVES: Clinical practice lacks biomarkers to predict the severity of acute pancreatitis (AP). We studied if intracellular signaling of circulating leukocytes could predict persistent organ dysfunction (OD) and secondary infections in AP. METHODS: A venous blood sample was taken from 174 patients with AP 72 hours or less from onset of symptoms and 31 healthy controls. Phosphorylation levels (p) of appropriately stimulated signal transducer and activator of transcription 1 (STAT1), STAT6, nuclear factor-κB (NF-κB), Akt, and nonstimulated STAT3 in monocytes, neutrophils, and lymphocytes was measured using phosphospecific flow cytometry. RESULTS: The patients showed higher pSTAT3 and lower pSTAT1, pSTAT6, pNF-κB, and pAkt than healthy controls. pSTAT3 in all leukocyte subtypes studied increased, and pSTAT1 in monocytes and T cells decreased in an AP severity-wise manner. In patients without OD at sampling, high pSTAT3 in monocytes and T lymphocytes were associated with development of persistent OD. In patients with OD, low interleukin-4-stimulated pSTAT6 in monocytes and neutrophils and Escherichia coli-stimulated pNF-κB in neutrophils predicted OD persistence. High pSTAT3 in monocytes, CD8+ T cells, and neutrophils; low pSTAT1 in monocytes and T cells; and low pNF-κB in lymphocytes predicted secondary infections. CONCLUSIONS: Leukocyte STAT3, STAT1, STAT6, and NF-κΒ phosphorylations are potential predictors of AP severity.


Assuntos
Leucócitos/metabolismo , NF-kappa B/sangue , Pancreatite/sangue , Fatores de Transcrição STAT/sangue , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Fosforilação , Valor Preditivo dos Testes , Estudos Prospectivos , Fator de Transcrição STAT1/sangue , Fator de Transcrição STAT3/sangue , Fator de Transcrição STAT6/sangue , Índice de Gravidade de Doença , Adulto Jovem
3.
PLoS One ; 11(12): e0167975, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27942004

RESUMO

OBJECTIVE: To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA). METHODS: 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test. RESULTS: At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042). CONCLUSION: Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Linfócitos/metabolismo , Monócitos/metabolismo , Fator de Transcrição STAT1/sangue , Fator de Transcrição STAT6/sangue , Doença Crônica , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Projetos Piloto , Resultado do Tratamento
4.
Ann Allergy Asthma Immunol ; 113(2): 173-179.e1, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24980391

RESUMO

BACKGROUND: Asthma is a common immune disorder characterized by increased IgE levels. The interleukin (IL)-4 and IL-13 pathway is central for IgE regulation, and previous studies have reported many genetic variants of IL-4/IL-13 signaling in relation to asthma, but few have focused on the gene-to-gene interactions that are likely to contribute to disease complexity. OBJECTIVE: To assess the combined effects of 7 functional single-nucleotide polymorphisms (SNPs) on asthma susceptibility, total serum IgE levels, and gene expression in children. METHODS: Seven SNPs (rs2243250, rs1800925, rs1805010, rs324011, rs2251746, rs2494262, and rs2427837) were genotyped children with asthma (n = 500) and a control group (n = 523), and total serum IgE levels and gene expressions were measured in children with asthma. RESULTS: Children with asthma had a likelier possibility of carrying more risk genotypes. Mean IgE levels increased from the minimum of 71.07 KU/L in children with no tested polymorphisms to a maximum of 901.7 KU/L in children carrying 7 risk genotypes. Gene expression analysis showed that patients with 4 SNPs (rs2243250, rs1800925, rs1805010, and rs3224011) had higher expression levels of IL-4, IL-13, and STAT6. Moreover, serum IgE level generally correlated well with IL-4 (r = 0.236, P = .011) and IL-13 (r = 0.211, P = .021) expressions; IL-4 expression correlated positively with IL-13 (r = 0.962, P = .000) and STAT6 (r = 0.190, P = .022) expressions, and STAT6 expression correlated with IL-4RA expression (r = 0.904, P = .000). CONCLUSION: These data suggest that combinations of multiple SNPs might magnify the impact on disease risk. Only a combined analysis of the variants in the IL-4/IL-13 pathway could show the functional interplay of multiple genes in asthma.


Assuntos
Asma/sangue , Asma/genética , Predisposição Genética para Doença , Imunoglobulina E/sangue , Interleucina-13/genética , Interleucina-4/genética , Adolescente , Criança , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Interleucina-13/sangue , Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/genética , Masculino , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT6/sangue
5.
Folia Primatol (Basel) ; 82(2): 71-80, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21646786

RESUMO

Regional populations of rhesus and long-tailed macaques exhibit fundamental differences in mitochondrial DNA, short tandem repeat and single nucleotide polymorphism variation between mainland and insular Southeast Asian populations. Some studies have revealed genetic admixture between these species due to natural hybridization and human-assisted intercrosses. A quantitative real-time PCR (qPCR) assay was developed to efficiently determine the species of origin of a macaque biological sample, and to quantify the species-specific template DNA. Prior knowledge of species identity and DNA concentrations are crucial for maintaining cost-effective methods and accurate DNA analysis. DNA from 109 regionally representative rhesus and long-tailed macaques was qPCR amplified to determine the species and template quantities. Of the 19 Vietnamese long-tailed macaques, 3 samples were discovered to be hybrids.


Assuntos
Macaca fascicularis/genética , Macaca mulatta/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Fator de Transcrição STAT6/genética , Animais , Sudeste Asiático , China , Hibridização Genética , Índia , Macaca fascicularis/sangue , Macaca mulatta/sangue , Repetições de Microssatélites , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real/economia , Reação em Cadeia da Polimerase em Tempo Real/instrumentação , Fator de Transcrição STAT6/sangue , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie
6.
Clin Exp Rheumatol ; 29(1 Suppl 64): S23-34, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21470488

RESUMO

OBJECTIVES: Churg-Strauss syndrome (CSS) is a rare systemic vasculitis associated with eosinophilia and granuloma formation. The contribution of individual T-helper cell lineages in pathogenesis of CSS is unknown. We hypothesised that in CSS an imbalance of major effector T-cell subpopulations takes place, and is further influenced by the mode of treatment. METHODS: We investigated the immunophenotype, cytokine production and transcriptome profile in peripheral blood lymphocytes (PBL) from 19 patients with stable CSS (10 were treated with glucocorticoids alone (CSS/GC), 9 with steroids and other immunosuppressive drugs (CSS/IS)), and 13 healthy controls. Furthermore, serum IL-5 and CCR4-active chemokines (CCL17, CCL22) were measured in six patients with active disease and upon remission. RESULTS: All CSS patients had decreased percentage of FoxP3+ regulatory T cells. In the CSS/GC group we found an increase in the Th17/Treg ratio and up-regulation of both Th2 and Th17 markers as evidenced by (1) over expression of Th2-related genes (GATA3, STAT6) in PBL, (2) elevated concentrations of serum IL-5 and CCL17, and (3) a concomitant increase in the number of Th17 cells, and secretion of IL-17A by stimulated PBL. The level of CCR4-active chemokines was increased in active-CSS, and correlated with blood eosinophilia. The combined treatment with steroids and other immunosuppressive drugs was associated with a significant decrease in both Th2-related chemokines and the number of Th17 cells. CONCLUSIONS: Our results indicate that both Th2 and Th17 lineages are involved in the pathogenesis of CSS, while CCR4-active chemokines contribute to eosinophilia in the active disease. These phenomena are down regulated by immunosuppressive therapy.


Assuntos
Síndrome de Churg-Strauss/imunologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Células Th1/imunologia , Células Th17/imunologia , Adulto , Análise de Variância , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL17/sangue , Síndrome de Churg-Strauss/sangue , Síndrome de Churg-Strauss/tratamento farmacológico , Síndrome de Churg-Strauss/genética , Quimioterapia Combinada , Feminino , Fatores de Transcrição Forkhead/sangue , Fator de Transcrição GATA3/sangue , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Interleucina-17/sangue , Interleucina-5/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Polônia , Receptores CCR4/sangue , Fator de Transcrição STAT6/sangue , Fator de Transcrição STAT6/genética , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Resultado do Tratamento
7.
Eur J Immunol ; 39(5): 1252-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19338001

RESUMO

Previous reports have suggested that autoimmune sequelae may be an unavoidable consequence of successful immunization against tumor-associated antigens, which are typically non-mutated self-antigens. Using a melanoma model, we demonstrated that CD4(+) T-cell-mediated anti-tumor immunity and autoimmunity could be separated by modulating the STAT4/STAT6 signaling axis. Our results have revealed an unexpected dichotomy in the effector phase following cancer vaccination where anti-tumor immunity is mediated via a STAT6 and IL-4-dependent pathway, whereas autoimmune pathology is mediated via STAT4 through a mechanism that relies partially on IFN-gamma. Our results offer a possibility to elicit specific anti-tumor responses without triggering unwanted tissue autoimmune diseases.


Assuntos
Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Melanoma Experimental/imunologia , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT6/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Imunofenotipagem , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-4/sangue , Interleucina-4/imunologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição Associado à Microftalmia/sangue , Fator de Transcrição Associado à Microftalmia/imunologia , Fator de Transcrição STAT4/sangue , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT6/sangue , Fator de Transcrição STAT6/deficiência , Transdução de Sinais/imunologia
8.
Ann Hematol ; 85(12): 833-40, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16871390

RESUMO

Marked polyclonal immunoglobulin (Ig)G4 hypergammaglobulinemia has exceptionally been reported. Here we report on two Algerian patients who presented a syndrome characterized by anemia, plasmacytic lymphadenopathy, renal manifestations, and a marked polyclonal IgG4 hypergammaglobulinemia leading to a hyperviscosity syndrome in one case. The IgG4-expressing cell percentage was significantly increased in the peripheral blood lymphocytes collected from the two patients upon diagnosis. Moreover, in contrast with normal sera, both patients' sera significantly increased the percentage of IgG4-expressing cells when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of the patients' activated T cells. Anti-interleukin (IL) 4 and/or anti-IL-13 antibodies were unable to antagonize the IgG4 production. IL-4 and IL-13 serum concentrations were found to be normal in the two patients. The increased IgG4 production was found to be mediated by soluble factor(s), most probably secreted by activated T cells, which did not require the signal transducer and activator of transcription 6 signaling pathway.


Assuntos
Anemia/complicações , Hipergamaglobulinemia/complicações , Imunoglobulina G/sangue , Nefropatias/complicações , Doenças Linfáticas/complicações , Adolescente , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Imunoglobulina G/metabolismo , Nefropatias/sangue , Ativação Linfocitária , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia , Fator de Transcrição STAT6/sangue , Fator de Transcrição STAT6/metabolismo
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