RESUMO
Celiac disease (CD) is an immune-mediated gastrointestinal (GI) disorder driven by innate and adaptive immune responses to gluten. Presentation of CD has changed over time, with non-GI symptoms, such as anemia and osteoporosis, presenting more commonly. With improved screening and diagnostic methods, the reported prevalence of CD has increased globally, and there is considerable global variation in diagnostic and treatment practices. The objective of this study was to describe the current state of CD diagnosis and treatment patterns. A targeted review of literature from MEDLINE, Embase, the Cochrane Library, and screening of relevant conference abstracts was performed. The generally recommended diagnostic approach is GI endoscopy with small bowel biopsy; however, in selected patients, biopsy may be avoided and diagnosis based on positive serology and clinical symptoms. Diagnosis often is delayed; the average diagnostic delay after symptom onset is highly variable and can last up to 12 years. Barriers to accurate and timely diagnosis include atypical presentation, lack of physician awareness about current diagnostic criteria, misdiagnosis, and limited access to specialists. Currently, strict adherence to a gluten-free diet (GFD) is the only recommended treatment, which is not successful in all patients. Only one-third of patients are monitored regularly following diagnosis. Unmet needs for CD include improvements in the accuracy and timeliness of diagnosis, and the development of treatments for both refractory CD and GFD nonresponsive CD. Further research should investigate the impact of education about gluten-free eating and the availability of gluten-free foods support adherence and improve outcomes in patients with CD.
Assuntos
Doença Celíaca/dietoterapia , Doença Celíaca/diagnóstico , Dieta Livre de Glúten , Biópsia , Diagnóstico Tardio , Endoscopia Gastrointestinal , HumanosRESUMO
Graft-versus-host disease (GVHD) is the leading cause of nonrelapse mortality among patients who receive allogeneic hematopoietic cell transplantation (allo-HCT). In its acute form (aGVHD), GVHD involves the skin, liver, and gastrointestinal (GI) tract, with GI involvement most strongly associated with poor prognosis. This retrospective cohort study used US healthcare claims data for 2008 to 2015 to identify patients who developed GI aGVHD after allo-HCT performed as curative treatment for hematologic malignancy and compared them with patients who did not develop aGVHD in terms of outcomes related to survival, infections, healthcare resource utilization (HRU), and costs. Whereas the patients without aGVHD saw a 66% improvement in 1-year survival between 2009 and 2015, this effect was not observed in patients with GI aGVHD. Compared with patients without evidence of aGVHD, patients with GI aGVHD were 3.9-fold more likely to develop an infection in the year after allo-HCT. Similarly, patients who developed GI aGVHD were 4.3-fold more likely to have an inpatient admission after allo-HCT discharge, and such an admission cost on average 47% more than an admission for patients without aGVHD. Our findings confirm that GI involvement in aGVHD is associated with higher mortality, risk of infection, HRU, and cost compared with absence of aGVHD.
Assuntos
Sistemas de Gerenciamento de Base de Dados/normas , Neoplasias Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Doença Aguda , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: The prevalence of celiac disease (CD) has rapidly increased over recent decades, but costs related to CD remain poorly quantified. OBJECTIVE: This systematic review assessed the economic burden of CD in North America and Europe. METHODS: MEDLINE, EMBASE, EconLit, and the Cochrane Library databases were systematically searched to identify English-language literature from 2007 to 2018 that assessed costs, cost effectiveness, and health resource utilization for CD. RESULTS: Forty-nine studies met the inclusion criteria, of which 28 (57.1%) addressed costs of testing and diagnosis; 33 (67.3%) were from Europe. The cost per positive CD diagnosis of testing patients already undergoing esophagogastroduodenoscopy for other indications ranged from 1300 Canadian dollars ($Can) in Canada (2016 value) to 44,712 in the Netherlands (2013 value). Adding the CD test was cost effective when it combined diagnostic modalities (e.g., serology and biopsy). Direct annual excess costs to a US payer per diagnosed CD patient totaled $US6000 (2013 value) more than for a person without CD, chiefly due to outpatient care. Hospitalizations, emergency visits, and medication use were more common with CD. After initiating a gluten-free diet (GFD), patients visited primary care providers less often, used more medications, and missed fewer days from school and work. CONCLUSIONS: Most of the few available economic studies of CD assess testing and diagnosis costs, especially in Europe. Methods of testing generally are considered cost effective when they combine diagnostic modalities in symptomatic patients. Most costs to a payer of managing CD derive from outpatient care. Following GFD initiation, patients lose fewer days from work and school than pretreatment.
Assuntos
Doença Celíaca/economia , Doença Celíaca/terapia , Efeitos Psicossociais da Doença , Assistência Ambulatorial/economia , Análise Custo-Benefício , Dieta Livre de Glúten/economia , Europa (Continente) , Humanos , América do Norte , Cooperação e Adesão ao TratamentoRESUMO
BACKGROUND: Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, which is the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). However, to the authors' knowledge, little is known regarding whether MetS is associated with the risk of EA. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, the authors evaluated whether MetS was associated with EA. A total of 3167 cases of EA were compared with individually matched population controls (5:1); a subset of 575 EA cases were able to be individually matched with 575 Barrett esophagus controls. MetS was defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the period 1 to 3 years before the diagnosis of EA or control selection. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Potential effect modification by GERD symptoms and sex was examined in stratified models. RESULTS: EA was found to be significantly associated with MetS (odds ratio, 1.16; 95% confidence interval, 1.06-1.26) compared with population controls. In males, the association was restricted to those individuals without prior GERD; however, in females, MetS was found to be associated with EA regardless of GERD status. Effect modification by sex was observed (P for interaction = .01). MetS was not found to be associated with EA risk when compared with Barrett esophagus controls. CONCLUSIONS: In this older population, MetS was found to be associated with an increased risk of EA in males without GERD and females regardless of GERD status. Given the lack of an association when compared with Barrett esophagus controls, MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. Cancer 2017;123:657-665. © 2016 American Cancer Society.
Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Síndrome Metabólica/epidemiologia , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Idoso , Esôfago de Barrett/etiologia , Esôfago de Barrett/patologia , Bases de Dados Factuais , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Medicare , Síndrome Metabólica/complicações , Síndrome Metabólica/patologia , Fatores de Risco , Programa de SEER , Estados UnidosRESUMO
BACKGROUND: The absolute risk of oesophageal adenocarcinoma (EA) among individuals with Barrett's oesophagus (BE) is low and a majority of EA cases are diagnosed among individuals with no prior BE diagnosis. To ensure that insights from EA case-control studies are transferable to clinical management of BE populations, we conducted a case-case study to compare the clinical presentation, medical history and survival of EA cases with and without a prior BE diagnosis in the Surveillance, Epidemiology and End Results Medicare database. METHODS: Eligible EA cases were diagnosed at age ⩾68 years during 1994-2009. There were 5271 EA cases in this study, 87% of which did not have a prior diagnosis of BE (EA-no prior BE). RESULTS: Multivariable case-case comparisons evidenced adverse associations of GERD, ever cigarette smoking, hypertension, dyslipidemia, weight loss, peptic ulcer and irritable bowel disease each in EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose and diabetes did not differ between groups. EA-prior BE cases were diagnosed with less advanced disease, were more likely to undergo surgery and less likely to receive chemotherapy and radiotherapy, and had better overall mean survival (2.5 vs 1.4 years). This survival advantage persisted in the multivariable Cox model (HR=0.69, 95%CI: 0.60, 0.78), despite adjustment for many factors including stage, grade and clinical interventions. CONCLUSIONS: This study provides evidence that EA cases occurring among individuals previously diagnosed with BE are different from the large majority of EA cases that occur without a prior BE diagnosis. Regardless of whether these differences emanate from aetiology, biology and/or selection biases, they underscore the importance of a prudent approach in using knowledge from EAC case-control studies in the management of BE populations.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/diagnóstico , Neoplasias Esofágicas/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos ProporcionaisRESUMO
Gastroesophageal reflux disease (GERD) causes local chronic inflammation that increases risks of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA), yet symptomatic GERD is absent in approximately half of all such patients. Obesity exacerbates GERD and is also a component of metabolic syndrome (MetS). We evaluated the hypothesis that MetS is a GERD-independent mechanism by which obesity is associated with increased risks of BE and EA using data from the UK Clinical Practice Research Datalink. BE cases (n=10,215) and EA cases (n=592) were each individually matched to five population controls based on age, sex, and general practice. MetS was defined as occurrence of at least three of the following: obesity, type 2 diabetes, hypertension, and high cholesterol. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. MetS was marginally associated with BE (OR=1.12, 95%CI 1.00-1.25). Similar effects were found for the individual component factors of obesity, hypertension, and high cholesterol. History of GERD modified the association (P-effect modification <1E-5), with the MetS-BE association confined to patients without a history of GERD (OR=1.33, 95%CI 1.12-1.58). No association between MetS and risk of EA was detected in the main or stratified analyses. In this large population-based case-control study, individuals with MetS had a marginally increased risk of BE in the absence of GERD. The systemic inflammatory state (MetS) may represent a reflux-independent inflammatory pathway that increases the risk of BE. MetS did not increase risk of EA in this study population.
Assuntos
Adenocarcinoma/etiologia , Esôfago de Barrett/etiologia , Neoplasias Esofágicas/etiologia , Refluxo Gastroesofágico/complicações , Síndrome Metabólica/complicações , Obesidade/complicações , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Fatores de RiscoRESUMO
Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people; however, the etiology of these cancers is poorly understood. We therefore investigated associations of body mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux and use of nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50-59, 60-69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR = 8.06, 95% CI: 4.52, 14.37; peffect modification = 0.01) and BMI (ORBMI ≥ 30 vs . <25 = 4.19, 95% CI: 2.23, 7.87; peffect modification = 0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.
Assuntos
Adenocarcinoma/epidemiologia , Adenocarcinoma/etiologia , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Esôfago de Barrett/complicações , Feminino , Refluxo Gastroesofágico/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , FumarRESUMO
BACKGROUND: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. METHODS: In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the χ(2) test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. RESULTS: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. CONCLUSION: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. IMPACT: These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance.
Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , MicroRNAs/genética , Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Progressão da Doença , Neoplasias Esofágicas/patologia , HumanosRESUMO
GOALS: To evaluate the association between metabolic syndrome (MetS) and risk of Barrett esophagus (BE) using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database compared with 2 control groups--Medicare population controls and endoscopy controls. BACKGROUND: BE principally arises as an adaptation to the proinflammatory state induced by gastroesophageal reflux disease (GERD). The relationship between obesity and BE is presumed to be mediated by GERD. However, evidence suggests central adiposity also increases risk of BE independent of GERD. Central adiposity is one risk factor defining MetS, which confers a systemic proinflammatory state--a potential GERD-independent mechanism by which obesity could increase the risk of BE. STUDY: MetS was defined as diagnosis of at least 3 of the following conditions: obesity, elevated triglycerides, high blood pressure, and elevated fasting glucose. Multivariable logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. RESULTS: In 2198 incident BE cases, prior MetS was significantly associated with BE (odds ratio, 1.20; 95% confidence interval: 1.07, 1.36) compared with population controls. However, GERD status modified the association; among those without prior GERD, MetS increased risk of BE by 34%; however, no association was observed among those with a prior GERD diagnosis (P-value for effect modification <0.001). MetS was not associated with risk of BE compared with endoscopy controls. CONCLUSIONS: MetS increased the risk of BE compared with population controls, an association driven by and confined to the non-GERD stratum. MetS may mediate an association between central adiposity and BE for those without GERD.
Assuntos
Esôfago de Barrett/etiologia , Refluxo Gastroesofágico/complicações , Síndrome Metabólica/complicações , Adiposidade , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Endoscopia Gastrointestinal/estatística & dados numéricos , Jejum/sangue , Feminino , Humanos , Hipertensão , Modelos Logísticos , Masculino , Medicare/estatística & dados numéricos , Obesidade/sangue , Obesidade/complicações , Obesidade Abdominal , Razão de Chances , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Triglicerídeos/sangue , Estados UnidosRESUMO
BACKGROUND: The advantages of endoscopic ultrasound (EUS) and computed tomography (CT)-positron emission tomography (PET) with respect to survival for esophageal cancer patients are unclear. This study aimed to assess the effects of EUS, CT-PET, and their combination on overall survival with respect to cases not receiving these procedures. METHODS: Patients who were ≥66 years old when diagnosed with esophageal cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare linked database. Cases were split into 4 analytic groups: EUS only (n = 318), CT-PET only (n = 853), EUS+CT-PET (n = 189), and no EUS or CT-PET (n = 2439). Survival times were estimated with the Kaplan-Meier method and were compared with the log-rank test for each group versus the no EUS or CT-PET group. Multivariate Cox proportional hazards models were used to compare 1-, 3-, and 5-year survival rates. RESULTS: Kaplan-Meier analyses showed that EUS, CT-PET, and EUS+CT-PET patients had improved survival for all stages (with the exception of stage 0 disease) in comparison with patients undergoing no EUS or CT-PET. Receipt of EUS increased the likelihood of receiving endoscopic therapies, esophagectomy, and chemoradiation. Multivariate Cox proportional hazards models showed that receipt of EUS was a significant predictor of improved 1- (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.59; P < .0001), 3- (HR, 0.57; 95% CI, 0.48-0.66; P < .0001), and 5-year survival (HR, 0.59; 95% CI, 0.50-0.68). Similar results were noted when the results were stratified on the basis of histology and for the CT-PET and EUS+CT-PET groups. CONCLUSIONS: Receipt of either EUS or CT-PET alone in esophageal cancer patients was associated with improved 1-, 3-, and 5-year survival. Future studies should identify barriers to the dissemination of these staging modalities.
Assuntos
Endossonografia , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/mortalidade , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Medicare , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Programa de SEER , Sensibilidade e Especificidade , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Outcome data comparing endoscopic eradication therapy (EET) and esophagectomy are limited in patients with early esophageal cancer (EC). OBJECTIVE: To compare overall survival and EC-related mortality in patients with early EC treated with EET and esophagectomy. DESIGN AND SETTING: Population-based study. PATIENTS: Patients with early EC (stages T0 and T1) were identified from the Surveillance, Epidemiology, and End Results database (1998-2009). Demographics, tumor specific data, and survival were compared. Cox proportional hazards regression models were used to evaluate the association between treatment and EC-specific mortality. INTERVENTION: EET and esophagectomy. MAIN OUTCOME MEASUREMENTS: Mid- (2 years) and long- (5 years) term overall survival and EC-specific mortality, outcomes based on histology and stage, treatment patterns, and predictors of cancer-specific mortality. RESULTS: A total of 430 (21%) and 1586 (79%) patients underwent EET and esophagectomy, respectively. There was no difference in the 2-year (EET: 10.5% vs esophagectomy: 12.7%, P = .27).and 5-year (EET: 36.7% vs esophagectomy: 42.8%, P = .16) EC-related mortality rates between the 2 groups. EET patients had higher mortality rates attributed to non-EC causes (5 years: 46.6% vs 20.6%, P < .001). Similar results were noted when comparisons were limited to patients with stage T0 and T1a disease and esophageal adenocarcinoma. There was no difference in EC-specific mortality in the EET compared with the surgery group (hazard ratio 1.4; 95% confidence interval, 0.9-2.03). Variables associated with mortality were older age, year of diagnosis, radiation therapy, higher stage, and esophageal squamous cell carcinoma. LIMITATIONS: Comorbidities and recurrence rates were not available. CONCLUSIONS: This population-based study demonstrates comparable mid- and long-term EC-related mortality in patients with early EC undergoing EET and surgical resection.
Assuntos
Carcinoma de Células Escamosas/cirurgia , Endoscopia Gastrointestinal/métodos , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Estadiamento de Neoplasias , Programa de SEER , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Assessment of cancer incidence trends within the U.S. have mostly relied upon Surveillance, Epidemiology, and End Results (SEER) data, with implicit inference that such is representative of the general population. However, many cancer policy decisions are based at a more granular level. To help inform such, analyses of regional cancer incidence data are needed. Leveraging the unique resource of National Program of Cancer Registries (NPCR)-SEER, we assessed whether regional rates and trends of esophageal cancer significantly deviated from national estimates. METHODS: From NPCR-SEER, we extracted cancer case counts and populations for whites aged 45-84 years by calendar year, histology, sex, and census region for the period 1999-2008. We calculated age-standardized incidence rates (ASRs), annual percent changes (APCs), and male-to-female incidence rate ratios (IRRs). RESULTS: This analysis included 65,823 esophageal adenocarcinomas and 27,094 esophageal squamous cell carcinomas diagnosed during 778 million person-years. We observed significant geographic variability in incidence rates and trends, especially for esophageal adenocarcinomas in males: ASRs were highest in the Northeast (17.7 per 100,000) and Midwest (18.1). Both were significantly higher than the national estimate (16.0). In addition, the Northeast APC was 62% higher than the national estimate (3.19% vs. 1.97%). Lastly, IRRs remained fairly constant across calendar time, despite changes in incidence rates. CONCLUSION: Significant regional variations in esophageal cancer incidence trends exist in the U.S. Stable IRRs may indicate the predominant factors affecting incidence rates are similar in men and women.
Assuntos
Adenocarcinoma/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Censos , Neoplasias Esofágicas/epidemiologia , Programa de SEER , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Meio-Oeste dos Estados Unidos/epidemiologia , New England/epidemiologia , Noroeste dos Estados Unidos/epidemiologia , Fatores Sexuais , Sudeste dos Estados Unidos/epidemiologia , População BrancaRESUMO
Rhinoviruses are prevalent human pathogens that are associated with life-threatening acute asthma exacerbations. The innate immune response to rhinovirus infection, which may play an important role in virus-induced asthma induction, has not been comprehensively investigated. We examined the innate immune response in cells infected with human rhinovirus 1a (HRV1a). Beta interferon (IFN-beta) mRNA was induced in HRV1a-infected cells at levels significantly lower than in cells infected with Sendai virus. To understand the basis for this observation, we determined whether components of the pathway leading to IFN-beta induction were altered during infection. Dimerization of the transcription factor IRF-3, which is required for synthesis of IFN-beta mRNA, is not observed in cells infected with HRV1a. Beginning at 7 h postinfection, IPS-1, a protein that is essential for cytosolic sensing of viral RNA, is degraded in HRV1a-infected cells. Induction of apoptosis by puromycin led to the cleavage of IPS-1, but treatment of HRV1a-infected cells with the pan-caspase inhibitor, zVAD, did not block cleavage of IPS-1. IPS-1 is cleaved in vitro by caspase-3 and by the picornaviral proteinases 2A(pro) and 3C(pro). Expression of HRV1a and polioviral 2A(pro) and 3C(pro) led to degradation of IPS-1 in cells. These results suggest that IPS-1 is cleaved during HRV1a infection by three different proteases. Cleavage of IPS-1 may be a mechanism for evasion of the type I IFN response, leading to a more robust infection.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções por Picornaviridae/metabolismo , Rhinovirus/metabolismo , Apoptose , Linhagem Celular Tumoral , Dimerização , Células HeLa , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/biossíntese , Transcrição Gênica , Ativação TranscricionalRESUMO
Infections with RNA viruses are sensed by the innate immune system through membrane-bound Toll-like receptors or the cytoplasmic RNA helicases RIG-I and MDA-5. It is believed that MDA-5 is crucial for sensing infections by picornaviruses, but there have been no studies on the role of this protein during infection with poliovirus, the prototypic picornavirus. Beginning at 4 h postinfection, MDA-5 protein is degraded in poliovirus-infected cells. Levels of MDA-5 declined beginning at 6 h after infection with rhinovirus type 1a or encephalomyocarditis virus, but the protein was stable in cells infected with rhinovirus type 16 or echovirus type 1. Cleavage of MDA-5 is not carried out by either poliovirus proteinase 2Apro or 3Cpro. Instead, degradation of MDA-5 in poliovirus-infected cells occurs in a proteasome- and caspase-dependent manner. Degradation of MDA-5 during poliovirus infection correlates with cleavage of poly(ADP) ribose polymerase (PARP), a hallmark of apoptosis. Induction of apoptosis by puromycin leads to cleavage of both PARP and MDA-5. The MDA-5 cleavage product observed in cells treated with puromycin is approximately 90 kDa, similar in size to the putative cleavage product observed in poliovirus-infected cells. Poliovirus-induced cleavage of MDA-5 may be a mechanism to antagonize production of type I interferon in response to viral infection.
Assuntos
RNA Helicases DEAD-box/metabolismo , Poliovirus/imunologia , Proteases Virais 3C , Caspases/metabolismo , Linhagem Celular , Cisteína Endopeptidases/metabolismo , Vírus da Encefalomiocardite/imunologia , Enterovirus Humano B/imunologia , Células HeLa , Humanos , Helicase IFIH1 Induzida por Interferon , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Rhinovirus/imunologia , Proteínas Virais/metabolismoRESUMO
Inhibitory oligonucleotides (IN-ODN) differing from stimulatory CpG ODN (ST-ODN) by as few as two bases can block ST-ODN-induced proliferation, apoptosis protection and IL-6 secretion in B lymphocytes and the production of IL-12p40 by non-B cells. The main objective of this study was to determine the ODN sequence requirements for inhibition in mice. Starting with a strongly inhibitory 15-mer prototype phosphorothioate sequence, we tested the 60 sequences that differed from the prototype by one base, revealing the three areas that are critical for activity. Between these areas were the spacer sequences where base composition mattered little, but the number of bases was important. Truncation of three bases at the 3' end of the 15-mer and one at the 5' end was tolerated with minimal loss of activity. This approach yielded an 'optimal' sequence of 5' CC x notC notC xxGGGx or CC x notC notC xGGGxx 3', where x is any base. The sequence requirements for optimal inhibition of B cell responses to Type B (K) ODN and mixed splenocyte IL-12p40 responses to Type A (D) ODN were strikingly similar. Inhibition of ST-ODN by IN-ODN was competitive. A hypothetical model of the ODN-binding site is proposed. Synthetic IN-ODN with the sequence characteristics defined here should provide antidotes for excessive innate reactions to DNA.