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BACKGROUND: Overexpression of autologous proteins can lead to the formation of autoantibodies and autoimmune diseases. MHC class I polypeptide-related sequence A (MICA) is highly expressed in the enterocytes of patients with celiac disease, which arises in response to gluten. The aim of this study was to investigate anti-MICA antibody formation in patients with celiac disease and its association with other autoimmune processes. METHODS: We tested serum samples from 383 patients with celiac disease, obtained before they took up a gluten-free diet, 428 patients with diverse autoimmune diseases, and 200 controls for anti-MICA antibodies. All samples were also tested for anti-endomysium and anti-transglutaminase antibodies. RESULTS: Antibodies against MICA were detected in samples from 41.7% of patients with celiac disease but in only 3.5% of those from controls (P <0.0001) and 8.2% from patients with autoimmune disease (P <0.0001). These antibodies disappeared after the instauration of a gluten-free diet. Anti-MICA antibodies were significantly prevalent in younger patients (P <0.01). Fifty-eight patients with celiac disease (15.1%) presented a concomitant autoimmune disease. Anti-MICA-positive patients had a higher risk of autoimmune disease than MICA antibody-negative patients (P <0.0001; odds ratio = 6.11). The risk was even higher when we also controlled for age (odds ratio = 11.69). Finally, we found that the associated risk of developing additional autoimmune diseases was 16 and 10 times as high in pediatric patients and adults with anti-MICA, respectively, as in those without. CONCLUSIONS: The development of anti-MICA antibodies could be related to a gluten-containing diet, and seems to be involved in the development of autoimmune diseases in patients with celiac disease, especially younger ones.
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Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Antígenos de Histocompatibilidade Classe I/sangue , Adolescente , Adulto , Doenças Autoimunes/dietoterapia , Doença Celíaca/dietoterapia , Criança , Pré-Escolar , Comorbidade , Dieta Livre de Glúten/métodos , Feminino , Glutens/administração & dosagem , Glutens/efeitos adversos , Humanos , Masculino , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND & AIMS: The advent of new chronic hepatitis C virus (HCV) therapies requires characterization of patients in order to predict adequate treatment. A good candidate marker is Programmed Cell Death-1 (PD-1) which is involved in progression of HCV infection. The aim of this study was to analyse the effect of several single nucleotide polymorphisms of PD-1 gene and several previously associated factors (IL28B and KIR receptors) on treatment responses. METHODS: 407 HCV chronic infected patients treated with PEG-IFN-α and ribavirin were recruited and classified according to their response to treatment. They were genotyped for PD-1 and IL28B polymorphisms, killer immunoglobulin-like receptors (KIR) and HLA genes. A multivariate logistic regression analysis and a Chi-squared Automatic Interaction Detector (CHAID) prediction model of response included these and other clinical parameters. RESULTS: Our results showed that PD-1.3/A allele was significantly associated with sustained virological response (SVR) in a multivariate logistic regression analysis (p<0.01, OR=2.57). Additionally, IL28B C/C genotype was the most significant predictor of an SVR to treatment in all HCV genotypes (74.5%). In IL28B C/C patients, the presence of PD-1.3/A allele increased the probability of an SVR to 93.3%. Moreover, when this analysis was made only with patients infected by HCV-1, the predictive value of IL28B C/C genotype with PD-1.3/A allele was 90%. CONCLUSIONS: PD-1.3/A allele is associated with SVR to treatment and notably increases the predictive value of IL28B C/C genotype. Both markers in conjunction could be a useful tool, more relevant than HCV genotype in some cases, in clinical practice.
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Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Adulto , Feminino , Genótipo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferons , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Resultado do TratamentoRESUMO
Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).
Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.
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COVID-19/genética , Inflamação/genética , Helicase IFIH1 Induzida por Interferon/genética , SARS-CoV-2/patogenicidade , Idoso , COVID-19/complicações , Estado Terminal , RNA Helicases DEAD-box/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The killer cell immunoglobulin-like receptors (KIRs) form a group of regulatory molecules that specifically recognize HLA class I molecules. The aim of this study was to analyze the possible contribution of the KIR3DL1 and KIR3DS1 alleles, in addition to HLA-B27, in the susceptibility to ankylosing spondylitis (AS) in a population of individuals from Spain. METHODS: We genotyped the KIR3DS1 and KIR3DL1 alleles in 2 cohorts of patients with AS and healthy control subjects. In total, 270 patients with AS and 435 healthy, HLA-B27-positive matched control subjects from Spain were enrolled. The KIR3DS1 and KIR3DL1 alleles were genotyped by sequence-specific oligonucleotide probe-polymerase chain reaction, and their association with AS was analyzed. All individuals were typed for HLA-B. RESULTS: The KIR3DS1*013 allele was solely responsible for the increased frequency of the activator receptor KIR3DS1 in patients with AS compared with healthy HLA-B27-positive control subjects (35.7% versus 22.6% [P = 10(-6)], odds ratio 1.90, 95% confidence interval 1.50-2.40). The increased frequency of the KIR3DS1*013 allele in patients with AS was independent of the presence or absence of the HLA-Bw4I80 epitope. Moreover, the null allele KIR3DL1*004 was a unique inhibitory KIR3DL1 allele that showed a negative association with AS in the presence of HLA-Bw4I80. CONCLUSION: The increased frequency of the KIR3DS1*013 allele in patients with AS is clearly independent of the presence of the HLA-Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients with AS in the presence of HLA-Bw4I80. As a consequence, the influence of KIR genotypes on AS susceptibility would be mediated by a general imbalance between protective/inhibitory and risk/activating allotypes.
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Predisposição Genética para Doença , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Espondilite Anquilosante/genética , Alelos , Estudos de Coortes , Frequência do Gene , Variação Genética , Genótipo , Antígenos HLA-B/genética , Humanos , Razão de Chances , Reação em Cadeia da Polimerase/métodos , Valores de ReferênciaRESUMO
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV)-infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-embedded tissue microarrays were constructed to assess ERAP1 expression (HCV = 38; alcoholic = 20) by immunohistochemistry. A statistical algorithm was applied to derive a fibrogenesis prediction model. The ERAP1 variants rs30187/T (K528, pc < 0.001) and rs27044/G (Q730, pc < 0.001) were related with severe fibrosis. These results were validated in the two independent cohorts. Furthermore, patients with the rs30187/T allele had stronger ERAP1 protein expression than those with the rs30187/C (p < 0.05). The statistical model showed that patients with rs30187 C/T and T/T genotypes took 15.58 years (median) to develop advanced fibrosis, but this value was 32.08 years in patients carrying C/C genotype (p < 0.005). ERAP1 variants may influence the clinical course of fibrogenesis in HCV-infected patients. These polymorphisms could be exploited as constitutive new markers of fibrosis evolution. The results highlight the possibility of using modulators of ERAP1 to generate a protective immune response against chronic HCV infection. KEY MESSAGES: What is known Several ERAP1 polymorphisms are associated with autoimmune diseases and cancer. ERAP1 trims peptides to HLA class I presentation. What is new here ERAP1 polymorphisms are associated with fibrogenesis. The ERAP1 polymorphisms genotype could help us in clinical management of patients. Potential translational impact The use of modulators of ERAP1 could generate a protective response depending on SNPs.
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Aminopeptidases/genética , Hepacivirus , Hepatite C/complicações , Hepatite C/virologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo Genético , Alelos , Aminopeptidases/metabolismo , Biomarcadores , Suscetibilidade a Doenças , Retículo Endoplasmático , Predisposição Genética para Doença , Genótipo , Humanos , Cirrose Hepática/patologia , Antígenos de Histocompatibilidade Menor/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise Serial de TecidosRESUMO
Background: Dialysis is the first procedure to partially replace renal function in end-stage renal diseases, despite several adverse side effects, such as infections. The primary aim of this study was to evaluate the levels of immune CMV-specific CD8+ T cells in a representative cohort of pre-transplant patients receiving hemodialysis (HD) or peritoneal dialysis (PD). The secondary aim was to monitor the CMV-specific CD8+ T cells in kidney transplant recipients undergoing different types of dialysis during the first year following their transplant. Methods: Sixty-nine patients were enrolled and examined with respect to the type of dialysis they received. HLA class I dextramers for CMV were used to determine the quantity of CMV-specific CD8+ T cells. The CMV DNA viral load was also determined. Forty-two of the patients enrolled in the study underwent solid organ transplantation and were analyzed during their first year post-transplantation. Results: Patients receiving HD had fewer CMV-specific CD8+ T cells than those in PD (p < 0.05). We also observed that patients in PD had more CMV-specific CD8+ T cells during the follow-up period than those in HD (p < 0.05), independently of the CMV DNA. Finally, PD patients had a higher frequency of CD8+ Effector-Memory RA T cells (TEMRA) and a lower frequency of central memory T cells (TCM) than did HD patients. Conclusions: These results indicate the better status of CMV-specific T cell immunity in PD patients. The use of CMV T cell dextramers would be advantageous for monitoring the CD8+ T-specific response, enabling the use of prophylactic treatment to be optimized.
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Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/terapia , Citomegalovirus/imunologia , Falência Renal Crônica/terapia , Transplante de Rim , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , DNA Viral/sangue , Feminino , Humanos , Falência Renal Crônica/imunologia , Falência Renal Crônica/virologia , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic. The aim of this study was to perform a KIR genotype analysis and examine, in concert with HLA-B27 genotypes, their influence on ankylosing spondylitis (AS) susceptibility in two Asian populations (one from China, 42 patients and 30 controls, and another from Thailand, 30 patients and 16 controls). In the Chinese population, we observed an increase of KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies in AS patients (p(c) < 0.005, p(c) < 0.001, and p(c) < 0.01, respectively). A similar increase was reported in the Thai population: KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies were higher in AS (p(c) < 0.05, p < 0.05, and p(c) < 0.05, respectively). Upon analyzing the KIR3DL1/3DS1 genotypes, we determined significant differences in both populations. The frequency of 3DL1/3DL1 was decreased in AS (p(c) < 0.005 and p(c) < 0.05 in the Chinese and Thai populations, respectively), whereas 3DL1/3DS1 demonstrated an increased frequency in AS (p(c) < 0.005 in the Chinese population and p(c) < 0.05 in the Thai population).
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Povo Asiático , Predisposição Genética para Doença , Receptores KIR2DL5/genética , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Alelos , China , Humanos , Polimorfismo Genético , TailândiaRESUMO
[This corrects the article DOI: 10.18632/oncotarget.16657.].
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INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.
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Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , 2',5'-Oligoadenilato Sintetase/genética , Adulto , Idoso , Aspartato Aminotransferases/sangue , Endorribonucleases/genética , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Humanos , Interferons , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de Citocina/genética , TYK2 Quinase/genéticaRESUMO
Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.
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Metilação de DNA/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Inibidor Tecidual de Metaloproteinase-3/genética , Proteína ADAM17/metabolismo , Adulto , Idoso , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Linhagem Celular Tumoral , Aberrações Cromossômicas , Decitabina , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , PrognósticoRESUMO
We aimed to analyze the possible association of KIR/HLA-C genotypes with the susceptibility to Crohn's disease (CD) in a Spanish population. A total of 125 patients with CD and 339 healthy controls were selected for this study. KIR and HLA-C typing were developed by sequence-specific oligonucleotide probing. We found that the centromeric A/A genotype and HLA-C1 combination was significantly increased in CD patients (P<10(-3)). The KIR2DL3/2DL3 genotype was significantly increased in CD patients (P<0.0005). Moreover, we also observed a highly significant increase of KIR2DL3-HLA-C1 homozygosis in CD patients (P<0.0005). Our results confirm the relevance of the KIR2DL2/KIR2DL3 genes and their interaction with HLA-C to CD. We show that the contribution of the KIR genes to CD susceptibility extends beyond the association with individual KIRs, with an imbalance between activating and inhibitory KIR genes seeming to influence the susceptibility to CD.
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Doença de Crohn/imunologia , Antígenos HLA-C/genética , Células Matadoras Naturais/imunologia , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Doença de Crohn/genética , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Polimorfismo Genético , EspanhaRESUMO
The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS.
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Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-17/genética , Espondilite Anquilosante/genética , Alelos , Estudos de Casos e Controles , Exoma/genética , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Receptores de Interleucina-17/fisiologia , Análise de Sequência de DNA , Índice de Gravidade de DoençaRESUMO
The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p<0.05) and KIR2DL3*001 was associated with sustained viral response (SVR) (41.6% vs. 61.2%, p<0.005). The KIR2DL3*001-HLA-C1 association was also significant (24.5% vs. 45.7%, p<0.001). From the frequencies of KIR obtained, 35 genotypes were assigned on the basis of previous studies. The centromeric A/A genotype was more frequent in SVR (44.1% vs. 34.5%, p<0.005) and the centromeric B/B genotype was found to be significantly more frequent in NSVR (20.9% vs. 11.2%, p<0.001). The logic regression model showed the importance of KIR genes in predicting the response to combined treatment, since the positive predictive value (PPV) was improved (from 55.9% to 75.3%) when the analysis of KIR was included in addition to the IFNL3 rs12979860 polymorphism. The study of KIR receptors may be a powerful tool for predicting the combined treatment response in patients with chronic HCV infection in association with the determination of IFNL3 polymorphism.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Ribavirina/uso terapêutico , Quimioterapia Combinada , Genótipo , Haplótipos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/genética , Células Matadoras Naturais/imunologia , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Resultado do TratamentoAssuntos
Predisposição Genética para Doença/epidemiologia , Antígeno HLA-B27/genética , Antígeno HLA-B40/genética , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/genética , Alelos , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Humanos , Incidência , Masculino , Razão de Chances , Valores de Referência , Medição de Risco , Espanha/epidemiologia , Espondilite Anquilosante/diagnósticoRESUMO
Human embryonic stem cells (hESCs) are especially resistant to several cellular stresses, but the existence and induction of Endoplasmic Reticulum (ER) stress by culture conditions are unknown. Using qPCR, here, we investigated the behavior of the principal sensors of ER stress and their relation with the feeder layer, the type of conditioned media used in feeder free systems and the upregulation of several differentiation markers. We observed the preservation of pluripotency, and detected differential expression of differentiation markers in HS181 and SHEF1 hESCs growing on Adipose-derived mesenchymal stem cells (ASCs) and feeder-free system with different conditioned media (HEF-CM and ASC-CM). Taken together, these results demonstrate evidence of ER stress events that cells must resolve to survive and maintenance of markers of pluripotency. The early differentiation status defined could progress into a more differentiated state, and may be influenced by culture conditions.