Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.
人肝脏 CD69 + CD103-CD8 + T 细胞的功能依赖于健康和病理肝脏的 hif2 α 活性。
- 作者列表："Kim JH","Han JW","Choi YJ","Rha MS","Koh JY","Kim KH","Kim CG","Lee YJ","Kim AR","Park J","Kim HK","Min BS","Seo SI","Kang M","Park HJ","Han DH","Kim SI","Kim MS","Lee JG","Lee DH","Kim W","Park JY","Park SH","Joo DJ","Shin EC
BACKGROUND & AIMS:Human liver CD69+CD8+ T cells are ∼95% CD103- and ∼5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. METHODS:Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with liver cirrhosis (LC) during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A (AHA). Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative RT-PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. RESULTS:Human liver CD69+CD103-CD8+ T cells exhibited a phenotype of tissue residency and terminal differentiation with HIF-2α upregulation. CD103- T cells included both hepatotropic and non-hepatotropic viruses-specific cells whereas CD103+ T cells did only hepatotropic virus-specific cells. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells following T-cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with AHA or LC. CONCLUSIONS:Liver CD69+CD103-CD8+ T cells have the phenotype of tissue residency and terminally differentiation, and their effector functions depends on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology.
背景与目的：人肝CD69+CD8+T细胞分别为95%CD103-和5%CD103+。尽管CD69+CD103+CD8+T细胞表现出组织常驻性和对抗原的强烈反应，但CD69+CD103-CD8+T细胞尚不清楚。 方法：取肝移植术中健康活体供、受者的肝灌流液及配对外周血。取急性甲型肝炎（AHA）患者肝组织。用流式细胞仪进行表型和功能分析。基因表达谱通过微阵列和定量RT-PCR检测。用PT-2385抑制缺氧诱导因子（HIF）-2α的表达。 结果：人肝CD69+CD103-CD8+T细胞在HIF-2α上调下表现为组织定居和终末分化表型。CD103-T细胞包括嗜肝和非嗜肝病毒特异性细胞，而CD103+T细胞只包括嗜肝病毒特异性细胞。尽管在T细胞受体或白细胞介素-15刺激下，CD103-细胞在每个细胞基础上比CD103+细胞弱，但它们仍然是肝脏中主要的CD69+CD8+效应细胞群，存活的细胞死亡较少。HIF-2α抑制剂抑制CD69+CD103-CD8+T细胞的效应功能和存活。此外，AHA和LC患者肝CD69+CD103-CD8+T细胞HIF-2α表达显著增加。 结论：肝CD69+CD103-CD8+T细胞具有组织定居和终末分化的表型，其效应功能依赖于HIF-2α。此外，在肝脏病理过程中观察到肝CD69+CD103-CD8+T细胞被HIF-2α上调激活。
METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.
METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
METHODS:BACKGROUND:Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences. MATERIALS AND METHODS:One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well. RESULTS:The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression. CONCLUSIONS:The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region.