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Caputo F, Penitenti F, Bergonzoni B, Lungaro L, Costanzini A, Caio G, DE Giorgio R, Ambrosio MR, Zoli G, Testino G. Alcohol use disorders and liver fibrosis: an update. Minerva Med 2024; 115:354-363. [PMID: 38727709 DOI: 10.23736/s0026-4806.24.09203-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.
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Affiliation(s)
- Fabio Caputo
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy -
- Department of Internal Medicine, SS. Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy -
| | - Francesco Penitenti
- Section of Endocrinology, Internal Medicine and Geriatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Barbara Bergonzoni
- Department of Internal Medicine, SS. Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy
| | - Lisa Lungaro
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Anna Costanzini
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Giacomo Caio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Roberto DE Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Maria R Ambrosio
- Section of Endocrinology, Internal Medicine and Geriatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giorgio Zoli
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Internal Medicine, SS. Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy
| | - Gianni Testino
- Unit of Addiction and Hepatology, ASL3, San Martino Polyclinic Hospital, Genoa, Italy
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Paterson CW, Fay KT, Chen CW, Klingensmith NJ, Gutierrez MB, Liang Z, Coopersmith CM, Ford ML. CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice. Immunohorizons 2024; 8:74-88. [PMID: 38226924 PMCID: PMC10835704 DOI: 10.4049/immunohorizons.2300060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 12/21/2023] [Indexed: 01/17/2024] Open
Abstract
Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.
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Affiliation(s)
- Cameron W. Paterson
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
- Lieutenant, Medical Corps, Naval Reserve Officer Training Corp, United States Navy, Atlanta, GA
| | - Katherine T. Fay
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Ching-Wen Chen
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Nathan J. Klingensmith
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Melissa B. Gutierrez
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Zhe Liang
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Craig M. Coopersmith
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Mandy L. Ford
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta GA
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Paterson CW, Gutierrez MB, Coopersmith CM, Ford ML. Impact of chronic alcohol exposure on conventional and regulatory murine T cell subsets. Front Immunol 2023; 14:1142614. [PMID: 37006296 PMCID: PMC10063870 DOI: 10.3389/fimmu.2023.1142614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
Introduction Chronic alcohol use poses significant negative consequences to public health and, among its many biologic effects, is associated with significant T cell dysregulation within the adaptive immune system that has yet to be fully characterized. Novel, automated strategies for high dimensional flow cytometric analysis of the immune system are rapidly improving researchers' ability to detect and characterize rare cell types. Methods Using a murine model of chronic alcohol ingestion in conjunction with viSNE and CITRUS analysis tools, we performed a machine-driven, exploratory analysis comparing rare splenic subpopulations within the conventional CD4+, regulatory CD4+ and CD8+ T cell compartments between alcohol- and water-fed animals. Results While there were no differences in the absolute numbers of bulk CD3+ T cells, bulk CD4+ T cells, bulk CD8+ T cells, Foxp3- CD4+ conventional T cells (Tconv) or Foxp3+ CD4+ regulatory T cells (Treg), we identified populations of naïve Helios+ CD4+Tconv and naïve CD103+ CD8+ splenic T cells that were decreased in chronically alcohol exposed mice versus water-fed controls. In addition, we identified increased CD69+ Treg and decreased CD103+ effector regulatory T cell (eTreg) subsets in conjunction with increased frequency of a population that may represent a transitional phenotype between central regulatory T cell (cTreg) and eTreg. Discussion These data provide further resolution into the character of decreased naïve T cell populations known to be present in alcohol exposed mice, as well as describe alterations in effector regulatory T cell phenotypes associated with the pathogenesis of chronic alcohol-induced immune dysfunction.
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Affiliation(s)
- Cameron W. Paterson
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
- Medical Corps, United States Navy, Navy Reserve Officer Training Corps (NROTC), Atlanta, GA, United States
- Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States
| | - Melissa B. Gutierrez
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
- Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States
| | - Craig M. Coopersmith
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Mandy L. Ford
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, United States
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Zhang P, Li H, Peng B, Zhang Y, Liu K, Cheng K, Ming Y. Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis. Front Endocrinol (Lausanne) 2023; 14:1132085. [PMID: 36817578 PMCID: PMC9932584 DOI: 10.3389/fendo.2023.1132085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Alcoholic and hepatitis B virus (HBV)-related liver cirrhosis has placed a tremendous burden on the healthcare system with limited treatment options. This study explored the differences in the immune status of alcoholic and HBV-related liver cirrhosis. METHODS A total of 15 human liver samples from the Third Xiangya Hospital of Central South University, including five healthy controls (HC group), five alcoholic cirrhosis patients (ALC group), and five HBV-related cirrhosis patients (HBV group) were used. Of these, eight samples, including 3 HC group, 2 ALC group and 3 HBV group, were randomly collected to do single-cell RNA sequencing (scRNA-seq). The degree of steatosis was assessed by H&E staining and the presence of intrahepatic immune cells was evaluated by immunochemistry (IHC). RESULTS The immune status of alcoholic and HBV-related liver cirrhosis differed significantly. ScRNA-seq analysis identified a higher ratio of intrahepatic monocyte/macrophages and an obvious decreased ratio of T cells and B cells in the ALC group than in the HBV group. IHC staining of intrahepatic monocyte/macrophages, T and B cell exhibited similar results with scRNA-seq analysis. CD5L+ Kupffer cells, a cell type involved in lipid metabolism, were the major monocyte/macrophage subset in ALC liver tissue. H&E staining indicated that the level of steatosis was more severe in the ALC than in the HBV group. Ligand/receptor analysis showed that the T cell exhaustion observed in the ALC liver may be related to the expression of Galectin-9 on Kupffer cells. Fewer B cells were also found in the ALC group and most had higher lipid metabolism, reduced ribosomal activity, and a dysregulated mitochondrial oxidative phosphorylation system. Moreover, scRNA-seq showed a significantly lower ratio of plasma B cells, indicating that the humoral immune response in the ALC liver was similarly dysfunctional. Ligand/receptor analysis also discovered that Galectin-9 expressed on Kupffer cells may inhibit humoral immunity. CONCLUSION Patients with ALC have different immune characteristics than those with HBV-induced cirrhosis, including an increased ratio of intrahepatic monocyte/macrophages and a dysfunctional adaptive immune response in the liver. Galectin-9 could serve as a potential therapeutic target for ALC treatment.
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Affiliation(s)
- Pengpeng Zhang
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Hao Li
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Bo Peng
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Yu Zhang
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Kai Liu
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Ke Cheng
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Yingzi Ming
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
- *Correspondence: Yingzi Ming,
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Liu Y, Dong Y, Wu X, Wang X, Niu J. Identification of Immune Microenvironment Changes and the Expression of Immune-Related Genes in Liver Cirrhosis. Front Immunol 2022; 13:918445. [PMID: 35903097 PMCID: PMC9315064 DOI: 10.3389/fimmu.2022.918445] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Liver inflammation and the immune response have been recognized as critical contributors to cirrhosis pathogenesis. Immunity-related genes (IRGs) play an essential role in immune cell infiltration and immune reactions; however, the changes in the immune microenvironment and the expression of IRGs involved in cirrhosis remain unclear. CD45+ liver cell single-cell RNA (scRNA) sequencing data (GSE136103) from patients with cirrhosis were analyzed. The clusters were identified as known cell types through marker genes according to previous studies. GO and KEGG analyses among differentially expressed genes (DEGs) were performed. DEGs were screened to identify IRGs based on the ImmPort database. The protein-protein interaction (PPI) network of IRGs was generated using the STRING database. IRGs activity was calculated using the AUCell package. RNA microarray expression data (GSE45050) of cirrhosis were analyzed to confirm common IRGs and IRGs activity. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. A total of ten clusters were obtained. CD8+ T cells and NK cells were significantly decreased in patients with cirrhosis, while CD4+ T memory cells were increased. Enrichment analyses showed that the DEGs focused on the regulation of immune cell activation and differentiation, NK-cell mediated cytotoxicity, and antigen processing and presentation. Four common TFs, IRF8, NR4A2, IKZF3, and REL were expressed in both the NK cluster and the DEGs of liver tissues. In conclusion, we proposed that the reduction of the CD8+ T cell cluster and NK cells, as well as the infiltration of CD4+ memory T cells, contributed to immune microenvironment changes in cirrhosis. IRF8, NR4A2, IKZF3, and REL may be involved in the transcriptional regulation of NK cells in liver fibrosis. The identified DEGs, IRGs, and pathways may serve critical roles in the development and progression of liver fibrosis.
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Affiliation(s)
- Yuwei Liu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Yutong Dong
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xiaojing Wu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Junqi Niu, ; Xiaomei Wang,
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Transplantation, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Junqi Niu, ; Xiaomei Wang,
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Lee DU, Fan GH, Hastie DJ, Addonizio EA, Prakasam VN, Ahern RR, Seog KJ, Karagozian R. The Impact of Malnutrition on the Hospital and Infectious Outcomes of Patients Admitted With Alcoholic Hepatitis: 2011 to 2017 Analysis of US Hospitals. J Clin Gastroenterol 2022; 56:349-359. [PMID: 33769393 DOI: 10.1097/mcg.0000000000001528] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/06/2021] [Indexed: 01/13/2023]
Abstract
GOALS We specifically evaluate the effect of malnutrition on the infection risks of patients admitted with alcoholic hepatitis using a national registry of hospitalized patients in the United States. BACKGROUND Malnutrition is a common manifestation of alcoholic hepatitis that affects patient outcomes. STUDY 2011 to 2017 National Inpatient Sample was used to isolated patients with alcoholic hepatitis, stratified using malnutrition (protein-calorie malnutrition, sarcopenia, and weight loss/cachexia) and matched using age, gender, and race with 1:1 nearest neighbor matching method. Endpoints included mortality and infectious endpoints. RESULTS After matching, there were 10,520 with malnutrition and 10,520 malnutrition-absent controls. Mortality was higher in the malnutrition cohort [5.02 vs. 2.29%, P<0.001, odds ratio (OR): 2.25, 95% confidence interval (CI): 1.93-2.63], as were sepsis (14.2 vs. 5.46, P<0.001, OR: 2.87, 95% CI: 2.60-3.18), pneumonia (10.9 vs. 4.63%, P<0.001, OR: 2.51, 95% CI: 2.25-2.81), urinary tract infection (14.8 vs. 9.01%, P<0.001, OR: 1.76, 95% CI: 1.61-1.91), cellulitis (3.17 vs. 2.18%, P<0.001, OR: 1.47, 95% CI: 1.24-1.74), cholangitis (0.52 vs. 0.20%, P<0.001, OR: 2.63, 95% CI: 1.59-4.35), and Clostridium difficile infection (1.67 vs. 0.91%, P<0.001, OR: 1.85, 95% CI: 1.44-2.37). In multivariate models, malnutrition was associated with mortality [P<0.001, adjusted odds ratio (aOR): 1.61, 95% CI: 1.37-1.90] and infectious endpoints: sepsis (P<0.001, aOR: 2.42, 95% CI: 2.18-2.69), pneumonia (P<0.001, aOR: 2.19, 95% CI: 1.96-2.46), urinary tract infection (P<0.001, aOR: 1.68, 95% CI: 1.53-1.84), cellulitis (P<0.001, aOR: 1.46, 95% CI: 1.22-1.74), cholangitis (P=0.002, aOR: 2.27, 95% CI: 1.36-3.80), and C. difficile infection (P<0.001, aOR: 1.89, 95% CI: 1.46-2.44). CONCLUSION This study shows the presence of malnutrition is an independent risk factor of mortality and local/systemic infections in patients admitted with alcoholic hepatitis.
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Affiliation(s)
- David U Lee
- Liver Center, Division of Gastroenterology, Tufts Medical Center, Washington Street, Boston, MA
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Xu HQ, Wang CG, Zhou Q, Gao YH. Effects of alcohol consumption on viral hepatitis B and C. World J Clin Cases 2021; 9:10052-10063. [PMID: 34904075 PMCID: PMC8638036 DOI: 10.12998/wjcc.v9.i33.10052] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/15/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is the main target organ for hepatitis viruses and the vital organ for alcohol metabolism. These two factors of viral hepatitis and alcohol abuse in combination can exert dual harmful actions, leading to enhanced damage to the liver. Epidemiological studies have revealed a higher prevalence of hepatitis C virus (HCV) infection among alcoholics than the general population. The interaction of alcohol with viral hepatitis [e.g., hepatitis B virus (HBV), HCV] and the underlying mechanisms are not fully understood. The effects of alcohol on viral hepatitis include promoted viral replication, weakened immune response, and increased oxidative stress. Clinically, alcohol abuse is correlated with an increased risk of developing end-stage liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and C, suggesting that the combination of alcohol and HBV/HCV lead to more severe liver damage. The influence of mild to moderate alcohol drinking on the HBV-induced liver fibrosis, cirrhosis, and hepatocellular carcinoma among patients infected with HBV remains unclear. Unlike HBV infected patients, no safe level of alcohol intake has been established for patients with HCV. Even light to moderate alcohol use can exert a synergistic effect with viral hepatitis, leading to the rapid progression of liver disease. Furthermore, interferon-based therapy is less effective in alcohol drinkers than in control patients, even after abstinence from alcohol for a period of time. Therefore, abstaining from alcohol is highly recommended to protect the liver, especially in individuals with HBV/HCV infection, to improve the clinical efficacy of antiviral treatment and prevent the rapid progression of chronic viral hepatitis.
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Affiliation(s)
- Hong-Qin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Chun-Guang Wang
- Department of Surgery, The Second Hospital of Jilin University, Jilin University, Changchun 130041, Jilin Province, China
| | - Qiang Zhou
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Yan-Hang Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
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Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem 2021; 12:87-103. [PMID: 34630912 PMCID: PMC8473419 DOI: 10.4331/wjbc.v12.i5.87] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression are still to be fully elucidated. Oxidative stress, mitochondrial dysfunction, gut dysbiosis and altered immune system response plays an important role in disease pathogenesis, triggering the activation of inflammatory pathways and apoptosis. Despite many recent clinical studies treatment options for ALD are limited, especially at the alcoholic hepatitis stage. We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.
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Affiliation(s)
- Lucy Petagine
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Vinood B Patel
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
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Wang X, Chen X, Lu L, Yu X. Alcoholism and Osteoimmunology. Curr Med Chem 2021; 28:1815-1828. [PMID: 32334496 DOI: 10.2174/1567201816666190514101303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/09/2020] [Accepted: 03/26/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic consumption of alcohol has an adverse effect on the skeletal system, which may lead to osteoporosis, delayed fracture healing and osteonecrosis of the femoral head. Currently, the treatment is limited, therefore, there is an urgent need to determine the underline mechanism and develop a new treatment. It is well-known that normal bone remodeling relies on the balance between osteoclast-mediated bone resorption and - mediated bone formation. Various factors can destroy the balance, including the dysfunction of the immune system. In this review, we summarized the relevant research in the alcoholic osteopenia with a focus on the abnormal osteoimmunology signals. We provided a new theoretical basis for the prevention and treatment of the alcoholic bone. METHODS We searched PubMed for publications from 1 January 1980 to 1 February 2020 to identify relevant and recent literature, summarizing evaluation and the prospect of alcoholic osteopenia. Detailed search terms were 'alcohol', 'alcoholic osteoporosis', 'alcoholic osteopenia' 'immune', 'osteoimmunology', 'bone remodeling', 'osteoporosis treatment' and 'osteoporosis therapy'. RESULTS A total of 135 papers are included in the review. About 60 papers described the mechanisms of alcohol involved in bone remodeling. Some papers were focused on the pathogenesis of alcohol on bone through osteoimmune mechanisms. CONCLUSION There is a complex network of signals between alcohol and bone remodeling and intercellular communication of osteoimmune may be a potential mechanism for alcoholic bone. Studying the osteoimmune mechanism is critical for drug development specific to the alcoholic bone disorder.
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Affiliation(s)
- Xiuwen Wang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lingyun Lu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
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Iaccarino Idelson P, Rendina D, Strazzullo P. Nutrition and the Covid-19 pandemic: Three factors with high impact on community health. Nutr Metab Cardiovasc Dis 2021; 31:756-761. [PMID: 33549427 PMCID: PMC7723026 DOI: 10.1016/j.numecd.2020.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/23/2020] [Accepted: 12/01/2020] [Indexed: 11/05/2022]
Abstract
AIMS In the course of the COVID-19 pandemic, multiple suggestions have been delivered through websites and social media referring to natural substances and various kinds of supplements with thaumaturgical properties in preventing and/or fighting the coronavirus infection. Indeed, there is no clinical trial evidence that a dietary or pharmacological supplementation of any particular substance will increase the effectiveness of the immune defences. There are however three nutritional issues that deserve special attention under the present circumstances, namely vitamin D deficiency, excess salt intake and inappropriate alcohol consumption. Here is a short review of the current knowledge about the possible role of these factors in the immunity defence system and their potential impact on the modulation of the immune response to SARS-COV2 infection. DATA SYNTHESIS For all of these factors there is convincing evidence of an impact on the immune defence structure and function. In the absence of RCT demonstration that increased ingestion of any given substance may confer protection against the new enemy, special attention to correction of these three nutritional criticisms is certainly warranted at the time of COVID pandemic. CONCLUSIONS We propose that the inappropriate intake of salt and alcohol and the risk of inadequate vitamin D status should be object of screening, in particular in subjects at high mortality risk from SARS-COV 2 infection, such as institutionalised elderly subjects and all those affected by predisposing conditions.
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Affiliation(s)
- Paola Iaccarino Idelson
- Department of Clinical Medicine and Surgery, University of Naples Federico II Medical School, Italy.
| | - Domenico Rendina
- Department of Clinical Medicine and Surgery, University of Naples Federico II Medical School, Italy
| | - Pasquale Strazzullo
- Department of Clinical Medicine and Surgery, University of Naples Federico II Medical School, Italy
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Kasztelan-Szczerbinska B, Adamczyk K, Surdacka A, Rolinski J, Michalak A, Bojarska-Junak A, Szczerbinski M, Cichoz-Lach H. Gender-related disparities in the frequencies of PD-1 and PD-L1 positive peripheral blood T and B lymphocytes in patients with alcohol-related liver disease: a single center pilot study. PeerJ 2021; 9:e10518. [PMID: 33552711 PMCID: PMC7825365 DOI: 10.7717/peerj.10518] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Exposure to excessive alcohol consumption dysregulates immune signaling. The programed cell death 1 (PD-1) receptor and its ligand PD-L1 play a critical role in the protection against immune-mediated tissue damage. The aim of our study was evaluation of the PD-1/PDL-1 expression on peripheral T and B lymphocytes, its correlation with markers of inflammation and the severity of liver dysfunction in the course of alcohol-related liver disease (ALD). MATERIAL AND METHODS Fifty-six inpatients with ALD (38 males, 18 females, aged 49.23 ± 10.66) were prospectively enrolled and assigned to subgroups based on their: (1) gender, (2) severity of liver dysfunction (Child-Pugh, MELD scores, mDF), (3) presence of ALD complications, and followed for 30 days. Twenty-five age- and gender-matched healthy volunteers served as the control group. Flow cytometric analysis of the PD-1/PD-L1 expression on peripheral lymphocyte subsets were performed. RESULTS General frequencies of PD-1/PD-L1 positive T and B subsets did not differ between the ALD and control group. When patients were analyzed based on their gender, significantly higher frequencies of PD1/PD-L1 positive B cells in ALD females compared to controls were observed. ALD females presented with significantly higher frequencies of PD-1+ and PD-L1+ B cells, as well as PD-L1+ all T cell subsets in comparison with ALD males. The same gender pattern of the PD-1/PDL1 expression was found in the subgroups with mDF > 32 and MELD > 20. No correlations of PD-1+ and PD-L1+ lymphocyte percentages with mDF, CTP and MELD scores, nor with complications of ALD were observed. Significant correlations of PD-L1 positive B cell frequencies with conventional markers of inflammation were found. CONCLUSIONS Gender-related differences in the frequencies of PD-1/PD-L1 positive T and B cells were observed in patients with ALD. Upregulation of PD-1+/PD-L1+ lymphocytes paralleled both the severity of alcoholic hepatitis and liver dysfunction in ALD females.
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Affiliation(s)
| | - Katarzyna Adamczyk
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Poland, Lublin, Poland
| | - Agata Surdacka
- Department of Clinical Immunology, Medical University of Lublin, Poland, Lublin, Poland
| | - Jacek Rolinski
- Department of Clinical Immunology, Medical University of Lublin, Poland, Lublin, Poland
| | - Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Poland, Lublin, Poland
| | | | - Mariusz Szczerbinski
- Department of Gastroenterology with Endoscopy Unit, Public, Academic Hospital No 4, Lublin, Poland
| | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Poland, Lublin, Poland
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12
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Caslin B, Mohler K, Thiagarajan S, Melamed E. Alcohol as friend or foe in autoimmune diseases: a role for gut microbiome? Gut Microbes 2021; 13:1916278. [PMID: 34224314 PMCID: PMC8259720 DOI: 10.1080/19490976.2021.1916278] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 03/16/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023] Open
Abstract
Alcohol is well known for promoting systemic inflammation and aggravating multiple chronic health conditions. Thus, alcohol may also be expected to serve as a risk factor in autoimmune diseases. However, emerging data from human and animal studies suggest that alcohol may in fact be protective in autoimmune diseases. These studies point toward alcohol's complex dose-dependent relationship in autoimmune diseases as well as potential modulation by duration and type of alcohol consumption, cultural background and sex. In this review, we will explore alcohol's pro- and anti-inflammatory properties in human and animal autoimmune diseases, including autoimmune diabetes, thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis and multiple sclerosis. We will also discuss potential mechanisms of alcohol's anti-inflammatory effects mediated by the gut microbiome.
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Affiliation(s)
- Blaine Caslin
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Kailey Mohler
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Shreya Thiagarajan
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
| | - Esther Melamed
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, United States
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13
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Frank K, Abeynaike S, Nikzad R, Patel RR, Roberts AJ, Roberto M, Paust S. Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice. PLoS One 2020; 15:e0239246. [PMID: 33347446 PMCID: PMC7751976 DOI: 10.1371/journal.pone.0239246] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a well-established mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and analyzed the expression of cytokines IFN-γ, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice through multiparametric flow cytometry. We found increases in IFN-γ and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils were primary contributors to increased IFN-γ and IL-17 levels while other cell types played a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-γ and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.
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Affiliation(s)
- Kayla Frank
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Shawn Abeynaike
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Rana Nikzad
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Reesha R. Patel
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Amanda J. Roberts
- Animal Models Core, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Marisa Roberto
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States of America
| | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States of America
- * E-mail:
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14
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Sex differences in the association between tumor growth and T cell response in a melanoma mouse model. Cancer Immunol Immunother 2020; 69:2157-2162. [PMID: 32638080 DOI: 10.1007/s00262-020-02643-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022]
Abstract
Epidemiological evidence suggests that females have an advantage over males in cases of melanoma incidence, progression, and survival. However, the biological mechanisms underlying these sex differences remain unclear. With the knowledge that females generally have a more robust immune system than males, we investigated sex differences in melanoma progression in a B16-F10/BL6 syngeneic mouse model. We observed significantly less tumor volume and growth rate over 14 days in female mice compared to male mice. Furthermore, higher populations of CD4+ and CD8+ T cells, which indicate adaptive immune responses, were found in the circulating blood and tumors of females and corresponded with less tumor growth, and vice versa in males. Our results highlight a mouse model that represents melanoma progression in the human population and displays a higher immune response to melanoma in females compared to males. These findings suggest that the immune system may be one of the mechanisms responsible for sex differences in melanoma.
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15
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Zuluaga P, Sanvisens A, Teniente-Serra A, El Ars O, Fuster D, Quirant-Sánchez B, Martínez-Cáceres E, Muga R. Loss of naive T lymphocytes is associated with advanced liver fibrosis in alcohol use disorder. Drug Alcohol Depend 2020; 213:108046. [PMID: 32485655 DOI: 10.1016/j.drugalcdep.2020.108046] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/16/2020] [Accepted: 04/22/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Alcohol use disorder (AUD) is associated with changes in cellular immunity. The objective of the present study was to analyze the contribution of AUD to the differentiation of T cells and associations with advanced liver fibrosis (ALF). METHODS This cross-sectional study included patients admitted for treatment of AUD between 2013 and 2016. T cell immune-phenotyping defined four profiles of cellular differentiation according to the expression of CCR7 and CD45RA: naive T cells, central memory (TCM) cells, effector memory (TEM) cells, and terminal effector (TEMRA) cells. CD4+ memory cells were subdivided into Th1, Th2, and Th17 according to the expression of CXCR3 and CCR6. The stages of cellular differentiation were compared to healthy controls. ALF was defined as FIB-4 > 3.25. RESULTS Seventy-nine patients (81% men) with a median age of 50 years (IQR: 45-56 years) and median ethanol consumption of 150 g/day (IQR: 100-200 g/day) were included in the study. Compared to healthy controls, patients with AUD had fewer CD4+ naive cells (p < 0.001), more TCM and TEM cells (p = 0.003 and p = 0.050, respectively), and larger Th2 populations (p = 0.03). Among CD8+ cells, the percentage of TCM, TEM, and TEMRA were higher in patients with AUD than in the healthy controls (p < 0.05). Patients with ALF had fewer CD4+ and CD8+ naive cells (p < 0.05) and more CD4+ memory cells than patients without ALF. CONCLUSIONS Altered lymphocyte differentiation in AUD patients suggests immunosenescence. An increase in memory cells and decrease in naive cells is associated with ALF.
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Affiliation(s)
- Paola Zuluaga
- Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Arantza Sanvisens
- Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Aina Teniente-Serra
- Department of Immunology, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Oumaima El Ars
- Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Daniel Fuster
- Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Bibiana Quirant-Sánchez
- Department of Immunology, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Eva Martínez-Cáceres
- Department of Immunology, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
| | - Roberto Muga
- Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Autònoma de Barcelona, Spain.
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16
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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17
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Vogle A, Qian T, Zhu S, Burnett E, Fey H, Zhu Z, Keshavarzian A, Shaikh M, Hoshida Y, Kim M, Aloman C. Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption. Sci Rep 2020; 10:2451. [PMID: 32051453 PMCID: PMC7016184 DOI: 10.1038/s41598-020-59188-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/20/2020] [Indexed: 12/13/2022] Open
Abstract
Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45+ cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury.
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Affiliation(s)
- Alyx Vogle
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Tongqi Qian
- University of Texas Southwestern Medical Center, Division of Digestive Diseases, Department of Internal Medicine, Texas, USA
| | - Shijia Zhu
- University of Texas Southwestern Medical Center, Division of Digestive Diseases, Department of Internal Medicine, Texas, USA
| | - Elizabeth Burnett
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Holger Fey
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Zhibin Zhu
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Maliha Shaikh
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Yujin Hoshida
- University of Texas Southwestern Medical Center, Division of Digestive Diseases, Department of Internal Medicine, Texas, USA
| | - Miran Kim
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA
| | - Costica Aloman
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, USA.
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18
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Li Y, Zhang F, Modrak S, Little A, Zhang H. Chronic Alcohol Consumption Enhances Skeletal Muscle Wasting in Mice Bearing Cachectic Cancers: The Role of TNFα/Myostatin Axis. Alcohol Clin Exp Res 2019; 44:66-77. [PMID: 31657476 DOI: 10.1111/acer.14221] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/03/2019] [Accepted: 10/23/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic alcohol consumption enhances cancer-associated cachexia, which is one of the major causes of decreased survival. The precise molecular mechanism of how alcohol consumption enhances cancer-associated cachexia, especially skeletal muscle loss, remains to be elucidated. METHODS We used a mouse model of chronic alcohol consumption, in which 20% (w/v) alcohol was provided as sole drinking fluid, and Lewis lung carcinoma to study the underlying mechanisms. RESULTS We found that alcohol consumption up-regulated the expression of MAFbx, MuRF-1, and LC3 in skeletal muscle, suggesting that alcohol enhanced ubiquitin-mediated proteolysis and LC3-mediated autophagy. Alcohol consumption enhanced phosphorylation of Smad2/3, p38, and ERK and decreased the phosphorylation of FOXO1. These are the signaling molecules governing protein degradation pathways. Moreover, alcohol consumption slightly up-regulated the expression of insulin receptor substrate-1, did not affect phosphatidylinositol-3 kinase, but decreased the phosphorylation of Akt and mammalian target of rapamycin (mTOR), and down-regulated the expression of Raptor and p70 ribosomal kinase S6 kinase, suggesting that alcohol impaired protein synthesis signaling pathway in skeletal muscle of tumor-bearing mice. Alcohol consumption enhanced the expression of myostatin in skeletal muscle, plasma, and tumor, but did not affect the expression of myostatin in non-tumor-bearing mice. In TNFα knockout mice, the effects of alcohol-enhanced expression of myostatin and protein degradation-related signaling molecules, and decreased protein synthesis signaling in skeletal muscle were abolished. Consequently, alcohol consumption neither affected cancer-associated cachexia nor decreased the survival of TNFα KO mice bearing cachectic cancer. CONCLUSIONS Chronic alcohol consumption enhances cancer-associated skeletal muscle loss through suppressing Akt/mTOR-mediated protein synthesis pathway and enhancing protein degradation pathways. This process is initiated by TNFα and mediated by myostatin.
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Affiliation(s)
- Yuanfei Li
- From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.,Department of Oncology, (YL), The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Faya Zhang
- From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Samantha Modrak
- From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Alex Little
- From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Hui Zhang
- From the Department of Pharmaceutical Sciences (YL, FZ, SM, AL, HZ) College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
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19
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Li S, Tan HY, Wang N, Feng Y, Wang X, Feng Y. Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease. Front Immunol 2019; 10:1328. [PMID: 31244862 PMCID: PMC6581703 DOI: 10.3389/fimmu.2019.01328] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.
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Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Yigang Feng
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Laboratory of Wudang Local Chinese Medicine Research, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
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20
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Little A, Li Y, Zhang F, Zhang H. Chronic alcohol consumption exacerbates murine cytomegalovirus infection via impairing nonspecific and specific NK activation in mice. FASEB Bioadv 2018; 1:18-31. [PMID: 32123809 PMCID: PMC6996384 DOI: 10.1096/fba.1019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 09/05/2018] [Indexed: 01/12/2023] Open
Abstract
Chronic alcohol consumption increases the susceptibility to infectious diseases by compromising the immune system. Cytomegalovirus infection is common in humans and usually is asymptomatic in immunocompetent people. However, it can induce life‐threatening medical complications in immunocompromised individuals such as alcoholics. How chronic alcohol consumption exacerbates cytomegalovirus infection is not known. Herein, we used a mouse cytomegalovirus model to study the underlying cellular and molecular mechanism. We found that alcohol consumption increased viral titers in spleen after 4 days of infection, enhanced body weight loss and inhibited splenomegaly during the acute phase of infection. Blood level of IFN‐β, splenic IFN‐γ and granzyme B‐producing NK cells were lower in alcohol‐consuming mice than in water‐drinking mice at 12 hours after viral infection. Moreover, alcohol consumption decreased IL‐15‐producing DC after 36 hours infection, inhibited NK cell, specifically Ly49H+ NK cell maturation and proliferation 3‐6 days after viral infection. Surprisingly, alcohol consumption enhanced NK cell and CD8+ T‐cell continuous activation and increased granzyme B‐producing cells. However, alcohol consumption decreased the expression of perforin in spleen and liver. Taken together, chronic alcohol consumption exacerbates cytomegalovirus infection via impairing nonspecific and specific NK cell activation, specifically IFN‐γ and perforin production.
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Affiliation(s)
- Alex Little
- Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical Sciences, Washington State University Spokane Washington
| | - Yuanfei Li
- Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical Sciences, Washington State University Spokane Washington.,Department of Oncology The First Hospital of Shanxi Medical University Taiyuan China
| | - Faya Zhang
- Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical Sciences, Washington State University Spokane Washington
| | - Hui Zhang
- Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical Sciences, Washington State University Spokane Washington
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21
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22
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Dakup PP, Porter KI, Little AA, Gajula RP, Zhang H, Skornyakov E, Kemp MG, Van Dongen HPA, Gaddameedhi S. The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models. Oncotarget 2018; 9:14524-14538. [PMID: 29581861 PMCID: PMC5865687 DOI: 10.18632/oncotarget.24539] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/10/2018] [Indexed: 12/19/2022] Open
Abstract
Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2-/- mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2-/- clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2-/- mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.
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Affiliation(s)
- Panshak P Dakup
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Kenneth I Porter
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Alexander A Little
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Rajendra P Gajula
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
| | - Elena Skornyakov
- Sleep and Performance Research Center, Washington State University, Spokane, WA, USA.,Department of Physical Therapy, Eastern Washington University, Spokane, WA, USA
| | - Michael G Kemp
- Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, OH, USA
| | - Hans P A Van Dongen
- Sleep and Performance Research Center, Washington State University, Spokane, WA, USA.,Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Shobhan Gaddameedhi
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA.,Sleep and Performance Research Center, Washington State University, Spokane, WA, USA
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Ethanol-Induced Alterations of T Cells and Cytokines after Surgery in a Murine Infection Model. Int J Inflam 2018; 2017:1067598. [PMID: 29348965 PMCID: PMC5733944 DOI: 10.1155/2017/1067598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/02/2017] [Accepted: 10/17/2017] [Indexed: 01/04/2023] Open
Abstract
Background Interactions between alcohol, infection, and surgery and their effect on differentiation and functionality of T helper cells are not yet completely understood. We hypothesized that alcohol and surgery disturb differentiation of T helper cells and contribute to an impaired immune response. Methods Mice were treated with alcohol for two weeks. Saline treatment served as control. Clinical performance and weight were assessed. On day 14, a median laparotomy was performed and animals were challenged with Klebsiella pneumoniae intranasally. Bacterial load was determined in lungs and blood. T helper cell subpopulations and the released cytokines were assessed in lungs, spleens, and plasma. Key transcription factors of T cell differentiation were evaluated. Results Alcohol significantly impaired clinical appearance and body weight of animals with postsurgical infection (p < 0.05). Bacterial load was significantly higher after alcohol treatment (p < 0.05). T helper cell subsets and released cytokine levels were significantly altered in lung, but not in spleen. Expression of transcription factors of T helper cell lineage commitment did not translate into different counts of T helper cells. Conclusions Alcohol and surgery lead to significant cellular and functional modulations of T helper cells during postsurgical infection. These effects may contribute to an impaired immune response after surgery.
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Kim A, McCullough RL, Poulsen KL, Sanz-Garcia C, Sheehan M, Stavitsky AB, Nagy LE. Hepatic Immune System: Adaptations to Alcohol. Handb Exp Pharmacol 2018; 248:347-367. [PMID: 29374837 DOI: 10.1007/164_2017_88] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver. Over time, this non-resolving inflammatory response contributes to the progression of alcoholic liver disease (ALD). Here we review the contributions of the cellular components of the immune system to the progression of ALD, as well as the pathophysiological roles for soluble and circulating mediators of immunity, including cytokines, chemokines, complement, and extracellular vesicles, in ALD. Finally, we compare the role of the innate immune response in health and disease in the liver to our growing understanding of the role of neuroimmunity in the development and maintenance of a healthy central nervous system, as well as the progression of neuroinflammation.
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Affiliation(s)
- Adam Kim
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Rebecca L McCullough
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Kyle L Poulsen
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Carlos Sanz-Garcia
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Megan Sheehan
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Abram B Stavitsky
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
| | - Laura E Nagy
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
- Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
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Monnig MA. Immune activation and neuroinflammation in alcohol use and HIV infection: evidence for shared mechanisms. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2017; 43:7-23. [PMID: 27532935 PMCID: PMC5250549 DOI: 10.1080/00952990.2016.1211667] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/07/2016] [Accepted: 07/07/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Emerging research points to innate immune mechanisms in the neuropathological and behavioral consequences of heavy alcohol use. Alcohol use is common among people living with HIV infection (PLWH), a chronic condition that carries its own set of long-term effects on brain and behavior. Notably, neurobiological and cognitive profiles associated with heavy alcohol use and HIV infection share several prominent features. This observation raises questions about interacting biological mechanisms as well as compounded impairment when HIV infection and heavy drinking co-occur. OBJECTIVE AND METHOD This narrative overview discusses peer-reviewed research on specific immune mechanisms of alcohol that exhibit apparent potential to compound the neurobiological and psychiatric sequelae of HIV infection. These include microbial translocation, systemic immune activation, blood-brain barrier compromise, microglial activation, and neuroinflammation. RESULTS Clinical and preclinical evidence supports overlapping mechanistic actions of HIV and alcohol use on peripheral and neural immune systems. In preclinical studies, innate immune signaling mediates many of the detrimental neurocognitive and behavioral effects of alcohol use. Neuropsychopharmacological research suggests potential for a feed-forward cycle in which heavy drinking induces innate immune signaling, which in turn stimulates subsequent alcohol use behavior. CONCLUSION Alcohol-induced immune activation and neuroinflammation are a serious health concern for PLWH. Future research to investigate specific immune effects of alcohol in the context of HIV infection has potential to identify novel targets for therapeutic intervention.
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Affiliation(s)
- Mollie A. Monnig
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI
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Zhang F, Little A, Zhang H. Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15. J Leukoc Biol 2016; 101:1015-1027. [PMID: 27837016 DOI: 10.1189/jlb.1a0716-298rr] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/18/2016] [Accepted: 10/20/2016] [Indexed: 01/13/2023] Open
Abstract
NK cells are innate immune cells and have important roles in antiviral and antitumor immunity. Based on the transcriptional regulation, organ distribution, and cell function, NK cells have recently been further divided into cytotoxic conventional NK cells (cNK) and noncytotoxic helper-like group 1 innate lymphoid cells (ILC1s). It is well known that chronic alcohol consumption decreases peripheral NK cell number and cytolytic activity; however, the underlying mechanism remains to be elucidated. How chronic alcohol consumption affects ILC1s is, to our knowledge, completely unexplored. Herein, we used a well-established mouse model of chronic alcohol consumption to study the effects of alcohol on transcription factor expression, maturation, and cytokine production of cNK cells and ILC1s in various organs. We found that alcohol consumption significantly decreased Eomes-expressing cNK cells in all the examined organs, except BM, but did not significantly affect ILC1s. Alcohol consumption compromised cNK cell development and maturation. Exogenous IL-15/IL-15Rα treatment caused full recovery of Eomes-expressing cNK cell number and maturation. Taken together, our data indicated that chronic alcohol consumption decreases cNK cell number and cytolytic activity by arresting cNK cell development at the CD27+CD11b+ stage. This developmental arrest of NK cells results from a lack of IL-15 availability in the microenvironment. IL-15/IL-15Rα treatment can recover alcohol consumption-induced developmental defect in NK cells.
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Affiliation(s)
- Faya Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA
| | - Alex Little
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA
| | - Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA
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Gaither KA, Little AA, McBride AA, Garcia SR, Brar KK, Zhu Z, Platt A, Zhang F, Meadows GG, Zhang H. The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach. Cancer Immunol Immunother 2016; 65:1123-34. [PMID: 27481107 PMCID: PMC11029158 DOI: 10.1007/s00262-016-1876-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 07/21/2016] [Indexed: 01/13/2023]
Abstract
ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.
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Affiliation(s)
- Kari A Gaither
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Alexander A Little
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Alisha A McBride
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Savanna R Garcia
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Kiranjot K Brar
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Zhaohui Zhu
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Amity Platt
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Faya Zhang
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Gary G Meadows
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
| | - Hui Zhang
- Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
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Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65:242-51. [PMID: 26375241 PMCID: PMC4911891 DOI: 10.1016/j.pnpbp.2015.09.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 08/24/2015] [Accepted: 09/02/2015] [Indexed: 02/08/2023]
Abstract
Several studies have described a dose-dependent effect of alcohol on human health with light to moderate drinkers having a lower risk of all-cause mortality than abstainers, while heavy drinkers are at the highest risk. In the case of the immune system, moderate alcohol consumption is associated with reduced inflammation and improved responses to vaccination, while chronic heavy drinking is associated with a decreased frequency of lymphocytes and increased risk of both bacterial and viral infections. However, the mechanisms by which alcohol exerts a dose-dependent effect on the immune system remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. This review will summarize our current understanding of the impact of moderate versus excessive alcohol consumption on the innate and adaptive branches of the immune system derived from both in vitro as well as in vivo studies carried out in humans and animal model studies.
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Zakhari S. Chronic alcohol drinking: Liver and pancreatic cancer? Clin Res Hepatol Gastroenterol 2015; 39 Suppl 1:S86-91. [PMID: 26193868 DOI: 10.1016/j.clinre.2015.05.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 05/13/2015] [Accepted: 05/16/2015] [Indexed: 02/07/2023]
Abstract
Cancer is a multifactorial disease that results from complex interactions of numerous risk factors - genetic and environmental - over time, eventually leading to the diseased phenotypes. Thus, while epidemiological studies can point to risk factors, they cannot determine cause and effect relationships, and are unable to give biological and clinical insights into carcinogenesis. The link between any risk factor and carcinogenesis needs to be validated in experimental models. This is particularly true in epidemiological studies on alcohol consumption and its consequences. While there is no doubt that heavy alcohol consumption has devastating health effects, the inconsistencies in alcohol-related epidemiological studies and cancer suffer from possible sources of the variability in outcomes, ranging from inaccuracy of self-report of consumption to the problem of correlating cancer that started decades earlier to current or recent alcohol consumption. To further study the interactions between alcohol and cancer, the use of "Molecular Pathological Epidemiology" (MPE) advocated by Ogino et al. for dissecting the interplay between etiological factors, cellular and molecular characteristics, and disease progression in cancer is appropriate. MPE does not consider cancer as a single entity, rather it integrates analyses of epidemiological studies with the macroenvironment and molecular and microenvironment. This approach allows investigating the relationships between potential etiological agents and cancer based on molecular signatures. More research is needed to fully elucidate the link between heavy alcohol consumption and pancreatic cancer, and to further investigate the roles of acetaldehyde and FAEEs in pancreatic carcinogenesis.
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Affiliation(s)
- Samir Zakhari
- 1250 Eye Street, NW, suite 400, Washington, DC 20005, USA.
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Zaldivar Fujigaki JL, Arroyo Valerio AG, López Alvarenga JC, Gutiérrez Reyes EG, Kershenobich D, Hernández Ruiz J. Alterations in Activation, Cytotoxic Capacity and Trafficking Profile of Peripheral CD8 T Cells in Young Adult Binge Drinkers. PLoS One 2015; 10:e0132521. [PMID: 26151816 PMCID: PMC4494878 DOI: 10.1371/journal.pone.0132521] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/15/2015] [Indexed: 12/14/2022] Open
Abstract
Background Excess of alcohol consumption is a public health problem and has documented effects on the immune system of humans and animals. Animal and in vitro studies suggest that alcohol abuse changes CD8 T cell (CD8) characteristics, however it remains unknown if the CD8 profile of binge drinkers is different in terms of activation, trafficking and cytotoxic capacity. Aim To analyze the peripheral CD8 cytotoxic capacity, activation and trafficking phenotypic profile of Mexican young adults with regard to alcohol consumption pattern. Methods 55 Mexican young adults were stratified as Light (20), Intermediate (18) or Binge drinkers (17) according to their reported alcohol consumption pattern. Blood samples were obtained and hematic biometry and liver enzyme analysis were performed. Peripheral CD8 profile was established by expression of Granzyme B (GB), CD137, CD127, CD69, TLR4, PD1, CCR2, CCR4, CCR5 and CXCR4 by FACS. Data was analyzed by ANOVA, posthoc DMS and Tamhane, and principal component analysis (PCA) with varimax rotation, p<0.05. Results The Binge drinking group showed increased γGT together with increased expression of CD69 and reduced expression of TLR4, PD1, CCR2 and CXCR4 in peripheral CD8 cells. Other parameters were also specific to Binge drinkers. PCA established 3 factors associated with alcohol consumption: “Early Activation” represented by CD69 and TLR4 expression in the CD8 population; “Effector Activation” by CD69 expression in CD8 CD127+CD137+ and CD8 CD25+ CD137+; and Trafficking by CXCR4 expression on total CD8 and CD8 GB+CXCR4+, and CCR2 expression on total CD8. Binge drinking pattern showed low expression of Early Activation and Trafficking factors while Light drinking pattern exhibited high expression of Effector Activation factor. Conclusions Alcohol consumption affects the immune phenotype of CD8 cells since binge drinking pattern was found to be associated with high CD69 and low TLR4, CXCR4 and CCR2 expression, which suggest recent activation, decreased sensitivity to LPS and lower migration capacity in response to chemokines SDF-1 and MCP-1. These results indicate that a binge-drinking pattern of alcohol consumption may induce an altered immune profile that could be related with liver damage and the increased susceptibility to infection reported to this behavior.
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Affiliation(s)
- José Luis Zaldivar Fujigaki
- Laboratory of Liver, Pancreas and Motility, Department of Experimental Medicine, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | - Esperanza Gabriela Gutiérrez Reyes
- Laboratory of Liver, Pancreas and Motility, Department of Experimental Medicine, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - David Kershenobich
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Joselin Hernández Ruiz
- Laboratory of Liver, Pancreas and Motility, Department of Experimental Medicine, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Dirección de Investigación, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
- * E-mail:
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Zhang F, Zhu Z, Meadows GG, Zhang H. Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide. Int Immunopharmacol 2015; 28:359-68. [PMID: 26118634 DOI: 10.1016/j.intimp.2015.06.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/27/2015] [Accepted: 06/15/2015] [Indexed: 12/24/2022]
Abstract
Alcohol consumption increases the incidence of multiple types of cancer. However, how chronic alcohol consumption affects tumor progression and host survival remains largely unexplored. Using a mouse B16BL6 melanoma model, we studied the effects of chronic alcohol consumption on s.c. tumor growth, iNKT cell antitumor immune response, and host survival. The results indicate that although chronic alcohol consumption inhibits melanoma growth, this does not translate into increased host survival. Immunizing mice with a melanoma cell lysate does not significantly increase the median survival of water-drinking, melanoma-bearing mice, but significantly increases the median survival of alcohol-consuming, melanoma-bearing mice. Even though survival is extended in the alcohol-consuming mice after immunization, the median survival is not different from the immunized mice in the water-drinking group. Immunization with tumor cell lysate combined with α-galatosylceramide activation of iNKT cells significantly increases host survival of both groups of melanoma-bearing mice compared to their respective non-immunized counterparts; however, the median survival of the alcohol-consuming group is significantly lower than that of the water-drinking group. Alcohol consumption increases NKT cells in the thymus and blood and skews NKT cell cytokine profile from Th1 dominant to Th2 dominant in the tumor-bearing mice. In summary, these results indicate that chronic alcohol consumption activates the immune system, which leads to the inhibition of s.c. melanoma growth and enhances the immune response to immunization with melanoma lysate. With tumor progression, alcohol consumption accelerates iNKT cell dysfunction and compromises antitumor immunity, which leads to decreased survival of melanoma-bearing mice.
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Affiliation(s)
- Faya Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210-1495, United States
| | - Zhaohui Zhu
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210-1495, United States
| | - Gary G Meadows
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210-1495, United States
| | - Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210-1495, United States.
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Alcohol consumption and antitumor immunity: dynamic changes from activation to accelerated deterioration of the immune system. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:313-31. [PMID: 25427915 DOI: 10.1007/978-3-319-09614-8_18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The molecular mechanisms of how alcohol and its metabolites induce cancer have been studied extensively. However, the mechanisms whereby chronic alcohol consumption affects antitumor immunity and host survival have largely been unexplored. We studied the effects of chronic alcohol consumption on the immune system and antitumor immunity in mice inoculated with B16BL6 melanoma and found that alcohol consumption activates the immune system leading to an increase in the proportion of IFN-γ-producing NK, NKT, and T cells in mice not injected with tumors. One outcome associated with enhanced IFN-γ activation is inhibition of melanoma lung metastasis. However, the anti-metastatic effects do not translate into increased survival of mice bearing subcutaneous tumors. Continued growth of the subcutaneous tumors and alcohol consumption accelerates the deterioration of the immune system, which is reflected in the following: (1) inhibition in the expansion of memory CD8+ T cells, (2) accelerated decay of Th1 cytokine-producing cells, (3) increased myeloid-derived suppressor cells, (4) compromised circulation of B cells and T cells, and (5) increased NKT cells that exhibit an IL-4 dominant cytokine profile, which is inhibitory to antitumor immunity. Taken together, the dynamic effects of alcohol consumption on antitumor immunity are in two opposing phases: the first phase associated with immune stimulation is tumor inhibitory and the second phase resulting from the interaction between the effects of alcohol and the tumor leads to immune inhibition and resultant tumor progression.
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Parlet CP, Waldschmidt TJ, Schlueter AJ. Chronic ethanol feeding induces subset loss and hyporesponsiveness in skin T cells. Alcohol Clin Exp Res 2014; 38:1356-64. [PMID: 24512045 DOI: 10.1111/acer.12358] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 12/27/2013] [Indexed: 01/07/2023]
Abstract
BACKGROUND Chronic alcoholism is associated with increased incidence and severity of cutaneous infection. Skin-resident T cells orchestrate numerous immunological functions that are critically involved in both tissue homeostasis and cutaneous immunity. The impact of chronic ethanol (EtOH) exposure on skin T cells has not previously been examined; given their important role in maintaining the immune barrier function of the skin further study is warranted. METHODS Mice were administered EtOH in the drinking water for 12 to 16 weeks. Flow cytometry was used to evaluate impact of EtOH feeding on skin T cell numbers, rates of proliferation, and apoptosis as well as activation marker expression and cytokine production after ex vivo stimulation. RESULTS Chronic EtOH feeding caused a baseline reduction in dendritic epidermal T cell (DETC) numbers that corresponded with reduced expression of the activation marker JAML following phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Chronic EtOH feeding did not alter total numbers of dermal T cells, but specific subset loss was observed in Foxp3(+) regulatory T cells (Tregs) as well as CD3hi, Vγ3(+) and CD3int, Vγ3(-) dermal γδ T cells. EtOH-induced dysfunction in the latter population, which represents prototypical interleukin-17 (IL-17)-producing dermal γδT17s, was made evident by diminished IL-17 production following anti-CD3 stimulation. Additionally, the capacity of lymph node γδ T cells to produce IL-17 following anti-CD3 and PMA/ionomycin stimulation was impaired by chronic EtOH feeding. CONCLUSIONS Chronic EtOH feeding induced defects in both numbers and function of multiple skin T cell subsets. The decreased density and poor responsiveness of DETCs and γδT17 cells in particular would be expected to compromise immune effector mechanisms necessary to maintain a protective barrier and restrict pathogen invasion. These findings demonstrate the sensitivity of skin T cells to EtOH and provide new mechanisms to help explain the propensity of alcoholics to suffer skin infection.
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Affiliation(s)
- Corey P Parlet
- Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa
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Lario M, Muñoz L, Ubeda M, Borrero MJ, Martínez J, Monserrat J, Díaz D, Alvarez-Mon M, Albillos A. Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis. J Hepatol 2013; 59:723-30. [PMID: 23742913 DOI: 10.1016/j.jhep.2013.05.042] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 05/09/2013] [Accepted: 05/19/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Depletion of circulating CD4(+) T-helper (Th) lymphocytes, especially naive Th cells, is common in cirrhosis. Little is known about the pathogenetic mechanisms involved in Th-cell depletion in cirrhosis. We investigated the mechanisms involved in circulating Th-cell lymphopenia in cirrhosis. METHODS Circulating naive and memory Th cells were analyzed by flow cytometry in 60 patients with cirrhosis and 40 sex- and age-matched healthy controls. Thymopoiesis, apoptosis, cell activation, and proliferation were assessed through CD31, annexin-V, HLA-DR and Ki-67 expression, respectively. Lipopolysaccharide (LPS)-binding protein (LBP) and spleen size were measured as indicators of bacterial translocation and splenic pooling, respectively. RESULTS Compared to controls, patients showed reduced numbers of Th cells involving a greater depletion of the naive than memory Th-cell compartment (2.7- vs. 1.5-fold, respectively). Recent thymic emigrants were diminished (p < 0.01), and each patient had a lower number of CD31(+) naive Th cells than the matched-control. Spontaneous and induced apoptosis (Annexin-V(+)) of Th cells was increased in patients. Activated (HLA-DR(+)) and proliferating (Ki-67(+)) memory Th cells were increased in patients (p < 0.01), and they directly correlated with plasma LBP (p < 0.05) and negatively with naive Th cells (p < 0.01), respectively. Naive Th cells were inversely correlated (p < 0.01) with their frequencies of apoptosis and of activated memory Th cells, LBP, and spleen size. On multivariate analysis, defective thymic generation of naive Th cells, increased memory Th-cell activation, and splenomegaly were independently associated with Th-cell depletion. CONCLUSIONS Th-cell immunodeficiency in cirrhosis is explained by a universal defect in thymopoiesis exacerbated by splenic pooling and activation-driven cell-death induced by bacterial translocation.
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Affiliation(s)
- Margaret Lario
- Departamento de Medicina, Universidad de Alcalá, Madrid, Spain
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Zhang H, Zhu Z, Meadows GG. Chronic alcohol consumption impairs distribution and compromises circulation of B cells in B16BL6 melanoma-bearing mice. THE JOURNAL OF IMMUNOLOGY 2012; 189:1340-8. [PMID: 22753935 DOI: 10.4049/jimmunol.1200442] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Accumulating research indicates that B cells are involved in anti-tumor immunity. Chronic alcohol consumption is associated with decreased survival of cancer patients. The effect of alcohol consumption on B cells in tumor-bearing hosts is unknown. Results in melanoma-bearing mice showed that chronic alcohol consumption did not alter the percentage and number of B cells in bone marrow, spleen, and lymph nodes but dramatically decreased B cells in the peripheral blood. Alcohol consumption did not alter the development of B cells in the bone marrow and did not affect follicular B cells in the spleen; however, it increased T1 B cells and decreased marginal zone B cells in the spleen. Alcohol consumption also decreased mature B cells in the blood. It did not alter the chemotactic capacity of plasma to facilitate migration of splenocytes or the chemotactic response of splenocytes to CXCL13 and CCL21. However, the response of splenocytes to sphingosine-1-phosphate was impaired in alcohol-consuming, melanoma-bearing mice. The expression of sphingosine-1-phosphate receptor-1 (S1PR1) and sphingosine-1-phosphate lyase-1 (SPL1) in splenocytes was downregulated. Taken together, these results indicate that chronic alcohol consumption decreases peripheral blood B cells by compromising B cell egress from the spleen. The downregulation of S1PR1 and SPL1 expression in alcohol-consuming, melanoma-bearing mice could be associated with compromised egress of B cells from the spleen.
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Affiliation(s)
- Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164, USA.
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Naude CE, Bouic P, Senekal M, Kidd M, Ferrett HL, Fein G, Carey PD. Lymphocyte measures in treatment-naïve 13-15-year old adolescents with alcohol use disorders. Alcohol 2011; 45:507-14. [PMID: 21624786 PMCID: PMC3153431 DOI: 10.1016/j.alcohol.2011.02.307] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Revised: 01/18/2011] [Accepted: 02/12/2011] [Indexed: 12/13/2022]
Abstract
Many adolescents have chronic exposure to hazardous levels of alcohol. This is likely to be a significant predictor of health outcomes, including those related to immunity. We assessed substance use and biochemical immunological parameters in heavy drinking adolescents (meeting DSM-IV criteria for alcohol dependence) and light/nondrinking control adolescents in Cape Town. Lifetime alcohol dose, measured in standard units of alcohol, was orders of magnitude higher in alcohol-dependent (AD) participants than controls. All adolescent AD had a "weekends-only" style of alcohol consumption. The AD group was chosen to represent relatively "pure" AD, with minimal other drug use and no psychiatric diagnoses. With these narrow parameters in place, we found that AD adolescents were lymphopenic compared with controls, with significantly lower mean numbers of absolute circulating CD3+, CD4+, and CD8+ T-lymphocytes. On conclusion, we found that adolescent AD individuals with excessive alcohol intake, in a weekend binge-drinking style but without comorbid drug or psychiatric disorders, may be at increased risk of lymphopenia. This alcohol misuse may increase infectious disease susceptibility (including TB and HIV) by reducing immune system capabilities. Complex interactions of alcohol with other documented high-risk activities may further compound health risks.
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Zhang H, Zhu Z, McKinley JM, Meadows GG. IFN-γ is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice. Clin Exp Metastasis 2011; 28:301-7. [PMID: 21234656 DOI: 10.1007/s10585-011-9372-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Accepted: 12/30/2010] [Indexed: 01/13/2023]
Abstract
We previously found that chronic alcohol consumption (20% w/v in drinking water) that models the level consumed by human alcoholics, when administered to female C57BL/6 mice inhibits B16BL6 melanoma metastasis to the lung; however, the mechanism is not known. Chronic alcohol consumption increases IFN-γ producing NK, NKT, CD4(+), and CD8(+) T cells. To examine the impact of IFN-γ on metastasis, we inoculated B16BL6 melanoma cells i.v. into control and chronic alcohol drinking IFN-γ knockout (KO) mice. Knockout of the ifn-γ gene abrogated the anti-metastatic effects associated with alcohol consumption. We examined metastasis in common gamma-chain (γC) KO mice, which are deficient in NK, NKT and CD8(+) T cells, and in Vα14Jα281(-/-) KO mice, which are deficient in invariant NKT (iNKT) cells, in order to assess the importance of specific IFN-γ producing cell types to this effect. We found that the antimetastatic effect of alcohol was still present in γC KO mice and also in γC KO mice depleted of Gr-1(+) cells. Knockout of iNKT cells reduced the degree but not the antimetastatic effect associated with alcohol. These results indicate that the antimetastatic effect induced by chronic alcohol consumption is IFN-γ dependent and that multiple IFN-γ producing cell types contribute to this effect.
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Affiliation(s)
- Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6534, USA
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Tseng YM, Tsai SM, Lin WS, Huang ZR, Lin CC, Yeh WH, Wu YR, Tsai LY. Effects of whey protein concentrate (WPC) on the distributions of lymphocyte subpopulations in rats with excessive alcohol intake. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:12729-12734. [PMID: 21121609 DOI: 10.1021/jf103518u] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
To investigate the effects of whey protein concentrate (WPC) on antioxidant statuses and the lymphocyte subpopulations in the rats with alcohol intake, the antioxidant statuses in the peripheral blood (PB) and the lymphocyte subpopulations in the PB, spleen, and bone marrow (BM) of the rats fed with WPC (0.334 g/kg) and alcohol (6 g/kg) for 3 months were analyzed. Results showed that the effects of WPC on the glutathione peroxidase and glutathione in the PB, the T and B cells in the spleen, and the B cells in the BM were more apparent in the rats with alcohol intake; however, they are not apparent in the controls. Taken together, our results indicated that the immunity of rats might be enhanced by the increased antioxidant ability after WPC supplementation and the effects of WPC on the lymphocyte subpopulations were mainly in the spleen and BM and not in the PB.
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Affiliation(s)
- Yang-Ming Tseng
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Number 386, Ta-chung 1st Road, Kaohsiung 81346, Taiwan
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Riese MJ, Grewal J, Das J, Zou T, Patil V, Chakraborty AK, Koretzky GA. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J Biol Chem 2010; 286:5254-65. [PMID: 21138839 DOI: 10.1074/jbc.m110.171884] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Modulation of T cell receptor signal transduction in CD8(+) T cells represents a novel strategy toward enhancing the immune response to tumor. Recently, levels of guanine exchange factors, RasGRP and SOS, within T cells have been shown to represent a key determinant in the regulation of the analog to the digital activation threshold of Ras. One important for regulating activation levels of RasGRP is diacylglycerol (DAG), and its levels are influenced by diacylglycerol kinase-ζ (DGKζ), which metabolizes DAG into phosphatidic acid, terminating DAG-mediated Ras signaling. We sought to determine whether DGKζ-deficient CD8(+) T cells demonstrated enhanced in vitro responses in a manner predicted by the current model of Ras activation and to evaluate whether targeting this threshold confers enhanced CD8(+) T cell responsiveness to tumor. We observed that DGKζ-deficient CD8(+) T cells conform to most predictions of the current model of how RasGRP levels influence Ras activation. But our results differ in that the EC(50) value of stimulation is not altered for any T cell receptor stimulus, a finding that suggests a further degree of complexity to how DGKζ deficiency affects signals important for Ras and ERK activation. Additionally, we found that DGKζ-deficient CD8(+) T cells demonstrate enhanced responsiveness in a subcutaneous lymphoma model, implicating the analog to a digital conversion threshold as a novel target for potential therapeutic manipulation.
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Affiliation(s)
- Matthew J Riese
- Abramson Family Cancer Research Institute, Department of Medicine, University of Pennsylvania Philadelphia, Pennsylvania 19104, USA
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Zhang H, Zhu Z, Meadows GG. Chronic alcohol consumption decreases the percentage and number of NK cells in the peripheral lymph nodes and exacerbates B16BL6 melanoma metastasis into the draining lymph nodes. Cell Immunol 2010; 266:172-9. [PMID: 20974468 DOI: 10.1016/j.cellimm.2010.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 09/30/2010] [Accepted: 10/04/2010] [Indexed: 01/13/2023]
Abstract
NK cells in the lymph nodes play important roles in inhibiting tumor metastasis into draining lymph nodes. Previously, we reported that chronic alcohol consumption interferes with NK cell trafficking from the bone marrow to the spleen. Herein, we found that alcohol consumption decreases the numbers of NK cells in lymph nodes. Adoptive transfer experiments indicated that continued exposure of donor splenocytes to alcohol inhibits NK but not T cell trafficking to lymph nodes. Alcohol did not negatively affect CCR7(+) and CXCR3(+) NK cells, but decreased the percentage and number of CD62L(+) NK cells in the spleen, which are an important source of NK cell trafficking into the lymph nodes. These data suggest that modulation of the microenvironment associated with alcohol consumption impairs the trafficking of NK cells to lymph nodes. The decreased number of NK cells in the lymph nodes was associated with increased melanoma metastasis into the draining lymph nodes.
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Affiliation(s)
- Hui Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6534, United States
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D'Souza El-Guindy NB, Kovacs EJ, De Witte P, Spies C, Littleton JM, de Villiers WJS, Lott AJ, Plackett TP, Lanzke N, Meadows GG. Laboratory models available to study alcohol-induced organ damage and immune variations: choosing the appropriate model. Alcohol Clin Exp Res 2010; 34:1489-511. [PMID: 20586763 PMCID: PMC2929290 DOI: 10.1111/j.1530-0277.2010.01234.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The morbidity and mortality resulting from alcohol-related diseases globally impose a substantive cost to society. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, substantial research in the alcohol field is focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most studies are performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium "Methods of Ethanol Application in Alcohol Model-How Long is Long Enough" at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans.
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Affiliation(s)
- Nympha B D'Souza El-Guindy
- Department of Internal Medicine, Division of Digestive Diseases, University of Kentucky and Veterans Affairs Medical Center, Lexington, Kentucky, USA.
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Zhang H, Meadows GG. Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice. Cancer Immunol Immunother 2010; 59:1151-9. [PMID: 20229084 PMCID: PMC2881944 DOI: 10.1007/s00262-010-0837-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2009] [Accepted: 02/18/2010] [Indexed: 12/11/2022]
Abstract
We previously found that chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, we examined the effects of chronic alcohol consumption on the functionality and regulation of these cells in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-gamma producing T cells in the tumor-bearing mice. Foxp3(+)CD4(+)CD25(+) regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation as determined by carboxyfluorescein succinimidyl ester labeling experiments in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-gamma producing CD8(+) T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival.
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MESH Headings
- Alcoholism/complications
- Alcoholism/immunology
- Alcoholism/pathology
- Alcoholism/physiopathology
- Animals
- CD4 Antigens/biosynthesis
- Cell Proliferation/drug effects
- Cells, Cultured
- Ethanol/toxicity
- Forkhead Transcription Factors/biosynthesis
- Immunologic Memory/drug effects
- Immunosuppression Therapy
- Interferon-gamma/metabolism
- Interleukin-2 Receptor alpha Subunit/biosynthesis
- Lymphocyte Activation/drug effects
- Melanoma, Experimental/complications
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Melanoma, Experimental/physiopathology
- Mice
- Mice, Inbred C57BL
- Myeloid Progenitor Cells/drug effects
- Myeloid Progenitor Cells/immunology
- Myeloid Progenitor Cells/metabolism
- Myeloid Progenitor Cells/pathology
- T-Lymphocyte Subsets/drug effects
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- T-Lymphocyte Subsets/pathology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
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Affiliation(s)
- Hui Zhang
- Chronic Illness Research Center, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Box 646534, Pullman, WA 99164-6534, USA
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Xu X, Chen D, Mei L, Deng H. Is ethanol consumption beneficial for oral lichen planus? Med Hypotheses 2009; 72:640-2. [PMID: 19232837 DOI: 10.1016/j.mehy.2008.10.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2008] [Revised: 10/10/2008] [Accepted: 10/11/2008] [Indexed: 11/24/2022]
Abstract
Oral lichen planus (OLP), one of the most common oral mucosa diseases, is an auto-immune disease characterized histologically by basal keratinocyte damage and interface lymphocyte reaction. Previous studies have proved ethanol consumption can suppress immune system in many aspects, including inhibiting lymphocytes proliferation and their function, modifying antigen-presentation, etc. Pathogenesis of the OLP mainly comprises of antigen-presentation, lymphocytes activation and keratinocyte apoptosis, all of which may be inhibited by ethanol consumption. Thus, we put forth our hypothesis that chronic ethanol consumption may decrease OLP incidence and OLP treatment except the erosive type may benefit from ethanol consumption. In the discussion, we also talk about the extent of ethanol consumption. Still ethanol abuse is not commended, for it may increase incidence of many other diseases, and moderate ethanol consumption may be potentially beneficial for other auto-immune diseases.
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Affiliation(s)
- Xiaomeng Xu
- Department of Oral Prophylaxis and Hygiene, Wenzhou Stomatology Hospital, Wenzhou Medical College, No. 113, West Xueyuan Road, Wenzhou City, Zhejiang 325027, China.
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Zhang H, Meadows GG. Exogenous IL-15 in combination with IL-15R alpha rescues natural killer cells from apoptosis induced by chronic alcohol consumption. Alcohol Clin Exp Res 2008; 33:419-27. [PMID: 19120059 DOI: 10.1111/j.1530-0277.2008.00852.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Chronic alcohol consumption reduces the percentage and number of peripheral natural killer (NK) cells in mice and in humans. The underlying mechanism for these changes is only partly known. We recently found that chronic alcohol consumption inhibits NK cell release from the bone marrow (BM) and that this is associated with a decrease in splenic NK cells. The number of peripheral NK cells is tightly controlled by homeostatic proliferation. It is not known whether this mechanism is initiated in response to the reduction in splenic NK cells, or if so, why the steady state levels of NK cells are not restored. METHODS To examine this mechanism, female C57BL/6 mice were given 20% w/v alcohol in the drinking water for 3 months. NK cell proliferation and apoptosis were determined before and after treatment with IL-15 alone or combined with its alpha receptor. RESULTS Chronic alcohol consumption invoked homeostatic proliferation of splenic NK cells in an attempt to return NK cells to normal levels; however, this did not happen due to enhanced apoptosis of NK cells relative to proliferation. Chronic alcohol consumption decreased IL-15 producing cells in the spleen but not in the BM. The numbers of NK cells in the alcohol-consuming mice returned to normal levels in the spleen and were higher than normal in the BM after 2 daily injections of IL-15; however, the enhanced rate of apoptosis due to alcohol consumption was not decreased in the spleen or BM. Combined IL-15 and IL-15R alpha treatment decreased apoptosis of NK cells from alcohol-consuming mice to levels similar to untreated water-drinking mice and greatly increased the percentage and number of NK cells in both the spleen and BM. CONCLUSION Chronic alcohol consumption causes a self-unrecoverable loss of NK cells in the spleen by compromising NK cell release from the BM and enhancing splenic NK cell apoptosis that can be reversed with IL-15/IL-15R alpha treatment.
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Affiliation(s)
- Hui Zhang
- Cancer Prevention & Research Center, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6713, USA
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Gurung P, Young BM, Coleman RA, Wiechert S, Turner LE, Ray NB, Waldschmidt TJ, Legge KL, Cook RT. Chronic ethanol induces inhibition of antigen-specific CD8+ but not CD4+ immunodominant T cell responses following Listeria monocytogenes inoculation. J Leukoc Biol 2008; 85:34-43. [PMID: 18820175 DOI: 10.1189/jlb.0208101] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic ethanol consumption results in immunodeficiency. Previous work with chronic ethanol-fed mice has shown reduced splenic weight and cellularity, including reduced numbers of CD8+ T cells. However, antigen-specific CD8+ and CD4+ T cell responses in chronic ethanol-fed mice have been studied relatively little. We have used an attenuated Listeria monocytogenes strain DPL 1942 (LM DeltaactA) to inoculate mice and subsequently used CD4+ and CD8+ immunodominant peptides of LM to measure the CD4+ and CD8+ T cell responses after chronic ethanol exposure. We found no major differences between control and ethanol-fed mice in the kinetics and persistence of antigen-specific CD4+ T cells in response to an immunodominant LM peptide, as measured by intracellular IFN-gamma staining. In contrast to CD4+ responses, three methods of in vitro antigen presentation indicated that the primary response of CD8+ T cells to several different epitopes was reduced significantly in mice chronically fed ethanol. Antigen-specific CD8+ T cells were also reduced in chronic ethanol-fed mice during the contraction phase of the primary response, and memory cells evaluated at 29 and 60 days after inoculation were reduced significantly. BrdU proliferation assays showed that in vivo proliferation of CD8+ T cells was reduced in ethanol-fed mice, and IL-2-dependent in vitro proliferation of naive CD8+ T cells was also reduced. In conclusion, these results suggest that antigen-specific CD4+ T cell responses to LM are affected little by chronic ethanol consumption; however, antigen-specific CD8+ T cell responses are reduced significantly, as are in vivo and in vitro proliferation. The reduction of antigen-specific CD8+ T cells may contribute strongly to the immunodeficiency caused by ethanol abuse.
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Affiliation(s)
- Prajwal Gurung
- Department of Pathology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
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Waldschmidt TJ, Cook RT, Kovacs EJ. Alcohol and inflammation and immune responses: summary of the 2006 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 2008; 42:137-42. [PMID: 18358993 DOI: 10.1016/j.alcohol.2007.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2007] [Accepted: 11/29/2007] [Indexed: 01/08/2023]
Abstract
The 11th annual meeting of the Alcohol and Immunology Research Interest Group was held at Loyola University Medical Center, Maywood, Illinois on November 17, 2006. The Alcohol and Immunology Research Interest Group meeting is held annually to exchange new findings and ideas that arise from ongoing research examining the effects of alcohol intake on the immune system. The event consisted of five sessions, two of which featured plenary talks from invited speakers, two with oral presentations from selected abstracts, and a final poster session. Participants presented new data on a variety of topics including the effects of ethanol on key cells of the immune system (neutrophils, dendritic cells, NK cells), B cell responses, the capacity to clear infectious agents, and the barrier functions of skin, lung, and intestine.
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Abstract
BACKGROUND Alcohol consumption impairs type 1 cell-mediated adaptive immune responses both in vivo and in vitro. The present study investigated the effect of alcohol consumption on antigen-presenting cell (APC) populations and cytokine production. METHODS BALB/c were fed ethanol-containing, pair-fed isocaloric liquid control, or solid diets for 11 days. Macrophage and dendritic cell (DC) populations were isolated by paramagenetic bead separation and used to present ovalbumin (OVA) to highly purified syngeneic CD4+ T cells derived from DO11.10 T cell receptor transgenic mice in coculture. DC isolated from diet-fed mice were also used to present OVA to highly purified CD4+ T cells derived from antigen-naïve DO11.10Rag2-/- mice that are devoid of memory T cells. In vitro cytokine responses, interleukin (IL) -2, IL-6, IL-12, IL-13, IL-17A, and interferon-gamma (IFN-gamma) were measured by enzyme-linked immunosorbent assay. Flow cytometry measured cell surface molecule expression. RESULTS Alcohol consumption impairs delayed hypersensitivity responses (type 1) and enhances serum IgE levels (type 2). CD11c+ DC, but not F4/80+ macrophages, support cytokine responses by purified CD4+ T cells. CD11c+ DC derived from ethanol consuming BALB/c mice show diminished ability to support IFN-gamma responses by purified CD4+ T cells derived from DO11.10 or DO11.10Rag2-/- mice. Subset analysis indicates that of the 3 "conventional" DC subsets found in mouse spleens, CD11c+CD8(alpha)+ DCs are both responsible for OVA presentation and susceptible to the effects of ethanol. Ethanol consumption does not overtly alter the percent of splenic DC, but does increase the surface density of CD11c on these cells. Data show that cocultures containing purified CD4+ T DO11.10 cells and APC derived from alcohol-consuming mice show decreased IL-6, IL-12, IL-17A, and IFN-gamma and increased IL-13 cytokine production in response to OVA stimulation. CONCLUSIONS Ethanol alters CD11c+CD8(alpha)+ DC function, affecting cytokines responsible for adaptive immune responses. A unifying hypothesis for the underlying mechanism(s) of ethanol's effect upon adaptive immune function is proposed.
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Affiliation(s)
- Richard Heinz
- Northwestern University, Feinberg School of Medicine, Department of Microbiology-Immunology, Chicago, Illinois 60611, USA
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48
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Jonsson IM, Verdrengh M, Brisslert M, Lindblad S, Bokarewa M, Islander U, Carlsten H, Ohlsson C, Nandakumar KS, Holmdahl R, Tarkowski A. Ethanol prevents development of destructive arthritis. Proc Natl Acad Sci U S A 2006; 104:258-63. [PMID: 17185416 PMCID: PMC1765445 DOI: 10.1073/pnas.0608620104] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Environmental factors are thought to play a major role in the development of rheumatoid arthritis. Because the use of ethanol is widespread, we assessed the role of ethanol intake on the propensity to develop chronic arthritis. Collagen type II-immunized mice were given water or water containing 10% (vol/vol) ethanol or its metabolite acetaldehyde. Their development of arthritis was assessed, as well as the impact of ethanol on leukocyte migration and activation of intracellular transcription factors. Mice exposed daily to this dose of ethanol did not display any liver toxicity, and the development of erosive arthritis was almost totally abrogated. In contrast, the antibody-mediated effector phase of collagen-induced arthritis was not influenced by ethanol exposure. Also, the major ethanol metabolite, acetaldehyde, prevented the development of arthritis. This antiinflammatory and antidestructive property of ethanol was mediated by (i) down-regulation of leukocyte migration and (ii) up-regulation of testosterone secretion, with the latter leading to decreased NF-kappaB activation. We conclude that low but persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by interaction with innate immune responsiveness.
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Affiliation(s)
| | | | | | - Sofia Lindblad
- *Department of Rheumatology and Inflammation Research and
| | - Maria Bokarewa
- *Department of Rheumatology and Inflammation Research and
| | | | - Hans Carlsten
- *Department of Rheumatology and Inflammation Research and
| | - Claes Ohlsson
- Center for Bone Research at the Sahlgrenska Academy, Göteborg University, SE-405 30 Göteborg, Sweden; and
| | | | - Rikard Holmdahl
- Section for Medical Inflammation Research, Lund University, S-221 00 Lund, Sweden
| | - Andrej Tarkowski
- *Department of Rheumatology and Inflammation Research and
- To whom correspondence should be addressed at:
Department of Rheumatology and Inflammation Research, Guldhedsgatan 10, S-413 45 Göteborg, Sweden. E-mail:
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Waldschmidt TJ, Cook RT, Kovacs EJ. Alcohol and inflammation and immune responses: summary of the 2005 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 2006; 38:121-5. [PMID: 16839859 DOI: 10.1016/j.alcohol.2006.05.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2006] [Revised: 05/04/2006] [Accepted: 05/05/2006] [Indexed: 01/13/2023]
Abstract
The 10th annual meeting of the Alcohol and Immunology Research Interest Group (AIRIG) was held at Loyola University Medical Center, Maywood, Illinois on November 18, 2005. The AIRIG meeting was held to exchange new findings and ideas regarding the profound suppressive effects of alcohol exposure on the immune system. The event consisted of five sessions, two of which featured plenary talks from invited speakers, two with oral presentations from selected abstracts, and a final poster session. Participants presented a range of novel information focused on ethanol-induced effects on innate and adaptive immunity after either acute or chronic exposure. In particular, participants offered insights into the negative effects of ethanol on the innate processes of adhesion, migration, inflammation, wound repair, and bone remodeling. Presentations also focused on the means by which ethanol disrupts activation of macrophages and dendritic cells (DC), especially stimulation mediated by Toll-like receptor ligands. Additional talks provided new data on the means by which ethanol suppresses adaptive immunity, with an emphasis on DC-mediated activation of T cells, effector T cell activity, and T cell-driven B cell responses.
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Affiliation(s)
- Thomas J Waldschmidt
- Department of Pathology, The University of Iowa, Carver College of Medicine, 1038 ML, Iowa City, IA 52242, USA.
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