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Abdel-Samiee M, Youssef MI, Elghamry F, Bazeed M, Al-Shorbagy M, Shalaby H, Shabana H, Abdelsameea E, Lashin HES, El Zamek HMF, Esam T, Alwaseef MAA, Helmy HA, Almarshad F, Khalaf FA, Yossef BWA, Kassem A, Gabr BM, Abdelfattah A, S AboShabaan H, Aboufarrag GA, Omar MM, Bakeer MS, Imam MS, Ibrahim ES, Kamel SY, Allisy T, Mohammed OS, Farahat A, El-Khayat MM, Sekeen MAH, Zaher EM, Said A, Abuamer A, Elmahdi E. A multicentric and nationwide predictive study role of T cell sub-population in the prevalence and prognosis of cryoglobulinemia among genotype 4 chronic hepatitis C patients. J Med Virol 2023; 95:e29248. [PMID: 38108641 DOI: 10.1002/jmv.29248] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/01/2023] [Accepted: 11/11/2023] [Indexed: 12/19/2023]
Abstract
The infection caused by the hepatitis C virus (HCV) is a significant global health concern. The prevailing genotype of HCV in Egypt is 4a, commonly referred to as GT-4a. A significant proportion exceeding 50% of patients infected with HCV experience extrahepatic manifestations (EHMs), encompassing a diverse range of clinical presentations. These manifestations, including essential mixed cryoglobulinemia (MC), can serve as initial and solitary indicators of the disease. The complete understanding of the pathogenesis of EHM remains unclear, with autoimmune phenomena being recognized as the primary causative factor. In this study, we examined the predictive significance of T-cell subpopulations in relation to the occurrence and prognosis of cryoglobulinemia in HCV patients. A total of 450 CHC genotype four treatment naïve patients were enrolled in this analytic cross-sectional study after thorough clinical, laboratory, and radiological examinations. All patients underwent laboratory investigations, including testing for cryoglobulin antibodies and measurements of CD4 and CD8 levels; two groups were described according to their test results: Group 1 consists of patients who have tested positive for cryoglobulin antibodies and Group 2 consists of patients who have tested negative for cryoglobulin antibodies. The exclusion criteria encompassed individuals with HIV infection or chronic HBV infection. Additionally, pelvi-abdominal ultrasonography was performed. Our study included 450 treatment naïve CHC patients (59% male, mean age 50.8 years). The patients were categorized according to their cryoglobulin antibodys test results into two groups: group A, CHC patients with cryoglobulin antibodies (Abs) negative (364 patients), and group B, CHC patients with cryoglobulin Ab positive (86 patients). Group B demonstrated a higher average age, elevated international normalized ratio, more prolonged duration of HCV infection, lower albumin, higher alanine aminotransferase, higher aspartate aminotransferase, higher bilirubin, lower CD8, lower CD4, and lower CD4:CD8 ratio. In contrast, 27 out of 86 (31.40%) patients in group B had symptoms; 85.8% had purpura and arthralgia, 74.3% had paresthesias, 86.7% had weakness, and 12.2% had non-Hodgkin's lymphoma. The levels of CD4 and CD8 were found to be decreased in chronic HCV patients with MC. T-cell subpopulation serves as a reliable indicator for assessing the prevalence and prognosis of MC in individuals with genotype 4 chronic hepatitis C. However, additional research is needed to further understand the development and spread of various emerging infectious diseases. Nevertheless, it is noteworthy that a critical threshold may exist beyond which EHM reaches a point of no return.
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Affiliation(s)
- Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Mohamed I Youssef
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Fathy Elghamry
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mahmoud Bazeed
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohamed Al-Shorbagy
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Helmy Shalaby
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Hossam Shabana
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Department of Internal Medicine, College of Medicine, Shaqra University, Dawadmi, Saudi Arabia
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | | | | | - Tarek Esam
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | | | - Housam Ahmed Helmy
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Feras Almarshad
- Department of Internal Medicine, College of Medicine, Shaqra University, Dawadmi, Saudi Arabia
| | - Fatma A Khalaf
- Department of Clinical Biochemistry, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | | | - Arafat Kassem
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Basant Mostafa Gabr
- Department of Microbiology and Immunology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ahmed Abdelfattah
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Hind S AboShabaan
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Menoufia, Egypt
| | | | - Marwa M Omar
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Mohammed Saied Bakeer
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohammed S Imam
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Shimaa Y Kamel
- Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Talaat Allisy
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Omima Sayed Mohammed
- Department of Microbiology, College of Medicine, Najran University, Najran, Saudi Arabia
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ali Farahat
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohsen M El-Khayat
- Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
| | | | - Eman Mohammed Zaher
- Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Ashraf Said
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Abuamer
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Essam Elmahdi
- Department of Internal Medicine, College of Medicine, Shaqra University, Dawadmi, Saudi Arabia
- Department of Internal medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Liu SQ, Yang YP, Hussain N, Jian YQ, Li B, Qiu YX, Yu HH, Wang HZ, Wang W. Dibenzocyclooctadiene lignans from the family Schisandraceae: A review of phytochemistry, structure-activity relationship, and hepatoprotective effects. Pharmacol Res 2023; 195:106872. [PMID: 37516152 DOI: 10.1016/j.phrs.2023.106872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 07/31/2023]
Abstract
Liver injury is a common pathological process characterized by massive degeneration and abnormal death of liver cells. With increase in dead cells and necrosis, liver injury eventually leads to nonalcoholic fatty liver disease (NAFLD), hepatic fibrosis, and even hepatocellular carcinoma (HCC). Consequently, it is necessary to treat liver injury and to prevent its progression. The drug Bicylol is widely employed in China to treat chronic hepatitis B virus (HBV) and has therapeutic potential for liver injury. It is the derivative of dibenzocyclooctadiene lignans extracted from Schisandra chinensis (SC). The Schisandraceae family is a rich source of dibenzocyclooctadiene lignans, which possesses potential liver protective activity. This study aimed to comprehensively summarize the phytochemistry, structure-activity relationship and molecular mechanisms underlying the liver protective activities of dibenzocyclooctadiene lignans from the Schisandraceae family. Here, we had discussed the analysis of absorption or permeation properties of 358 compounds based on Lipinski's rule of five. So far, 358 dibenzocyclooctadiene lignans have been reported, with 37 of them exhibited hepatoprotective effects. The molecular mechanism of the active compounds mainly involves antioxidative stress, anti-inflammation and autophagy through Kelch-like ECH-associating protein 1/nuclear factor erythroid 2 related factor 2/antioxidant response element (Keap1/Nrf2/ARE), nuclear factor kappa B (NF-кB), and transforming growth factor β (TGF-β)/Smad 2/3 signaling pathways. This review is expected to provide scientific ideas for future research related to developing and utilizing the dibenzocyclooctadiene lignans from Schisandraceae family.
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Affiliation(s)
- Shi-Qi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yu-Pei Yang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Nusrat Hussain
- Department of Chemistry, University of Baltistan Skardu, Skardu 16100, Pakistan
| | - Yu-Qing Jian
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Bin Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yi-Xing Qiu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Huang-He Yu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hui-Zhen Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
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Rutkowska M, Pokorska-Śpiewak M. Epstein Barr Virus Hepatitis-A Mild Clinical Symptom or a Threat? Vaccines (Basel) 2023; 11:1119. [PMID: 37376507 DOI: 10.3390/vaccines11061119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
The present study aimed to characterize pediatric patients diagnosed with hepatitis associated with primary Epstein-Barr Virus (EBV) infection. We described the changes in liver aminotransferases activity during the disease, and we analyzed the results of abdominal ultrasonography. A retrospective study was performed by analyzing the medical records of 166 immunocompetent children diagnosed with primary EBV hepatitis hospitalized at the Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases in Warsaw, between August 2017 and March 2023. Elevated alanine aminotransferase (ALT) activity was noted in the first three weeks of the disease. In 46.3% of patients, ALT values exceeded five times the upper limit of the laboratory norm in the first week of illness. Aspartate aminotransferase activity increased from the first to fourth week from the onset of symptoms and showed two peaks in the first and third weeks. The changes over time of mean AST activity demonstrated significance. Transient cholestatic liver disease was the predominant type of hepatic involvement in 10.8% of children; 66.6% of them were older than 15 years. Clinical and ultrasound criteria of acute acalculous cholecystitis (AAC) were met in three female patients over 16 years of age. Hepatitis associated with primary EBV infection is usually a mild and self-limiting condition. Significantly elevated values of liver enzymes with features of cholestatic liver disease may occur in patients with a more severe course of the infection.
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Affiliation(s)
- Magdalena Rutkowska
- Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases, 01-201 Warsaw, Poland
| | - Maria Pokorska-Śpiewak
- Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases, 01-201 Warsaw, Poland
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Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
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Piekuse L, Kreile M, Zarina A, Steinberga Z, Sondore V, Keiss J, Lace B, Krumina A. Association between inherited monogenic liver disorders and chronic hepatitis C. World J Hepatol 2014; 6:92-97. [PMID: 24575168 PMCID: PMC3935058 DOI: 10.4254/wjh.v6.i2.92] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/16/2013] [Accepted: 01/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C.
METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing.
RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087).
CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.
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Yang SI, Geong JH, Kim JY. Clinical characteristics of primary Epstein Barr virus hepatitis with elevation of alkaline phosphatase and γ-glutamyltransferase in children. Yonsei Med J 2014; 55:107-12. [PMID: 24339294 PMCID: PMC3874904 DOI: 10.3349/ymj.2014.55.1.107] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
PURPOSE The aim of the present study was to evaluate the clinical characteristics of the primary Epstein-Barr virus (EBV) hepatitis with elevation of both serum alkaline phosphatase (ALP) and γ-glutamyltransferase (γ-GT) levels in children. MATERIALS AND METHODS A retrospective study was performed by reviewing of the medical records of 36 patients who were diagnosed with primary EBV hepatitis. The patients were divided into 2 groups: patients with elevated serum ALP and γ-GT levels (group 1) and patients without (group 2). RESULTS The classic features of infectious mononucleosis (fever, pharyngitis and/or tonsillitis, and cervical lymphadenitis) were seen in 20 (57.1%) of group 1 patients and 18 (50.0%) of group 2 patients. Hepatitis with elevated serum ALP and γ-GT levels were present in 14 (38.9%) of the all patients. Of these patients, Jaundice occurred in only 2 (5.6%). The mean levels of aspartate aminotransferase and alanine aminotransferase (ALT) as well as the number of patients with ALT greater than 400 IU/L were significantly different between the groups (177 IU/L vs. 94 IU/L, 418 IU/L vs. 115 IU/L, and 50.0% vs. 13.6%; p=0.001, p=0.001, p=0.026, respectively). The mean duration of elevated serum ALT levels was 17.5 days in group 1 and 9.0 days in group 2 (p=0.013). All patients recovered fully without any chronic or serious complications. CONCLUSION Primary EBV hepatitis with predominant biochemical abnormalities of the elevation of ALP and γ-GT is frequent and mostly anicteric. This may represent a benign disease, but a delay in recovery of liver function as well.
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Affiliation(s)
- Soo In Yang
- Department of Pediatrics, School of Medicine, Chungnam National University, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Korea.
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Li G, Li K, Lea AS, Li NL, Abdulla NE, Eltorky MA, Ferguson MR. In situ hybridization for the detection of hepatitis C virus RNA in human liver tissue. J Viral Hepat 2013; 20:183-92. [PMID: 23383657 DOI: 10.1111/j.1365-2893.2012.01642.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 05/01/2012] [Indexed: 12/11/2022]
Abstract
In situ hybridization (ISH) enables visualization of specific nucleic acid in morphologically preserved cells and tissue sections. Detection of the HCV genomes in clinical specimens is useful for differential diagnosis, particularly between recurrent HCV infection and acute cellular rejection in transplant specimens. We optimized an ISH protocol that demonstrated sensitivity and specificity for detecting genomic and replicative form of HCV RNA in tissue biopsies. Digoxigenin (Dig)-labelled sense and anti-sense riboprobes were synthesized using a plasmid containing a fragment of the highly conserved HCV noncoding region as a template. The efficiency of the Dig-labelled riboprobes in detecting genomic and replicative-intermediate HCV RNA was analysed in 30 liver biopsies from patients infected or uninfected with HCV in a blinded study. A Huh7 cell line that stably replicates genome-length HCV RNA was developed to be used as a positive control. Negative control riboprobes were used in parallel to evaluate and control for background staining. The anti-sense probe detected HCV RNA in 20/21 specimens from HCV-infected liver tissues obtained from patients and in 0/9 samples from patients with non-HCV-related liver diseases, resulting in a sensitivity and specificity of 95% and 100%, respectively. HCV genomic RNA was variably distributed in tissue sections and was located primarily in the perinuclear regions in hepatocytes. Detection of HCV RNA by our optimized ISH protocol appears to be a sensitive and specific method when processing clinical specimens. It may also be revealing when exploring the pathophysiology of HCV infection by verifying the presence of viral genetic material within heptocytes and other cellular elements of diseased liver tissue. This methodology might also evaluate the response to antiviral therapies by demonstrating the absence or alteration of genetic material in clinical specimens from successfully treated patients.
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Affiliation(s)
- G Li
- Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
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Liver inflammation in a mouse model of Th1 hepatitis despite the absence of invariant NKT cells or the Th1 chemokine receptors CXCR3 and CCR5. J Transl Med 2012; 92:1461-71. [PMID: 22906987 PMCID: PMC3460069 DOI: 10.1038/labinvest.2012.104] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The specific mechanisms that mediate CD4(+) T-cell-mediated liver injury have not been fully elucidated. CD4(+) invariant natural killer T (iNKT) cells are required for liver damage in some mouse models of hepatitis, while the chemokine receptors CXCR3 and CCR5 are considered dominant Th1 chemokine receptors involved in Th1 trafficking in inflammatory conditions. BALB/c-Tgfb1(-/-) mice spontaneously develop Th1 hepatitis. Here, we directly test the hypotheses that iNKT cells or the Th1-cell chemokine receptors CXCR3 and CCR5 are required for development of liver disease in Tgfb1(-/-) mice. Tgfb1(-/-) mouse livers exhibited significant increases in iNKT cells and in ligands for CXCR3 or CCR5. Tgfb1(-/-) mice were rendered deficient in iNKT cells, CXCR3, CCR5, or both CXCR3 and CCR5, by cross-breeding with appropriate knockout mice. Tgfb1(-/-) mice developed severe liver injury, even in the absence of functional CD1d/iNKT cells, CXCR3, CCR5, or both CXCR3 and CCR5. Liver CD4(+) T cells accumulated to high numbers, and spleen CD4(+) T-cell numbers declined, regardless of the functionality of the CXCR3/CCR5 response pathways. Similarly, dendritic cells and macrophages accumulated in Tgfb1(-/-) livers even when CXCR3 and CCR5 were knocked out. Th1-associated cytokines (IFN-γ, TNF-α, IL-2) and chemokines (CXCL9, CXCL10) were strongly overexpressed in Tgfb1(-/-) mice despite knockouts in CD1d, CXCR3, or CCR5. These studies indicate that the cellular and biochemical basis for CD4(+) T-cell-mediated injury in liver can be complex, with myriad pathways potentially involved.
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Li K, Lemon SM. Innate immune responses in hepatitis C virus infection. Semin Immunopathol 2012; 35:53-72. [PMID: 22868377 DOI: 10.1007/s00281-012-0332-x] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2012] [Accepted: 07/05/2012] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV.
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Affiliation(s)
- Kui Li
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
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Coppola N, Pisaturo M, Guastafierro S, Tonziello G, Sica A, Iodice V, Sagnelli C, Ferrara MG, Sagnelli E. Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy. Dig Liver Dis 2012; 44:49-54. [PMID: 21885355 DOI: 10.1016/j.dld.2011.07.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 07/20/2011] [Accepted: 07/25/2011] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate changes in Hepatitis C Virus (HCV) RNA both in plasma and Peripheral Blood Mononuclear Cells (PBMC) in onco-haematological patients. PATIENTS AND METHODS 8 consecutive anti-HCV/HCV RNA-positive patients with onco-haematological diseases (5 with B-cell Non-Hodgkin Lymphoma and 3 with chronic lymphocytic leukaemia) were observed during chemotherapy and after its discontinuation. All were naïve to chemotherapy. HCV RNA was sought by Real Time Polymerase Chain Reaction in Light Cycler 1.5 in plasma and PBMC samples collected before, during and after chemotherapy. RESULTS An increase in HCV RNA of at least 1.5 log IU/mL in plasma and 1.1 log IU/ml in PBMC was observed in all 7 patients undergoing Rituximab-based chemotherapy; these patients showed a hepatic flare after discontinuation, life-threatening in one with cirrhosis. Also the 8th patient had cirrhosis, but was treated with Rituximab-sparing chemotherapy and did not show any increase in HCV RNA or a hepatic flare. CONCLUSION Rituximab-based chemotherapy favours an increase in HCV RNA in onco-haematological patients; this is followed by a hepatic flare, possibly immune-mediated and life threatening in cirrhotic patients.
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MESH Headings
- Aged
- Antibodies, Monoclonal, Murine-Derived/adverse effects
- Antineoplastic Agents/adverse effects
- Female
- Genotype
- Hepacivirus/genetics
- Hepacivirus/isolation & purification
- Hepacivirus/physiology
- Hepatitis C/complications
- Hepatitis C/virology
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/complications
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/virology
- Lymphoma, Non-Hodgkin/complications
- Lymphoma, Non-Hodgkin/drug therapy
- Lymphoma, Non-Hodgkin/virology
- Male
- Middle Aged
- RNA, Viral/blood
- Real-Time Polymerase Chain Reaction
- Rituximab
- Viral Load
- Virus Replication
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Affiliation(s)
- Nicola Coppola
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
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Cripps JG, Wang J, Maria A, Blumenthal I, Gorham JD. Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver. Hepatology 2010; 52:1350-9. [PMID: 20803559 PMCID: PMC2947571 DOI: 10.1002/hep.23841] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Immune-mediated liver injury in hepatitis is due to activated T cells producing interferon-γ (IFN-γ). It is important to identify negative feedback immune mechanisms that can regulate T cell activity. In this study, we demonstrate that liver inflammation mediated by type 1 T helper (Th1) cells can induce the accumulation of myeloid-derived suppressor cells (MDSCs), pleiomorphic cells capable of modulating T cell-mediated immunity, that heretofore have been studied almost exclusively in the context of tumor-associated inflammation. Mice deficient in the gene encoding transforming growth factor-β1 (Tgfb1(-/-) mice) acutely develop liver necroinflammation caused by IFN-γ-producing clusters of differentiation 4-positive (CD4(+)) T cells. Liver Th1 cell accumulation was accompanied by myeloid cells expressing CD11b and Gr1, phenotypic hallmarks of MDSCs. Isolated Tgfb1(-/-) liver CD11b(+)Gr1(+) cells were functional MDSCs, readily suppressing T cell proliferation in vitro. Pharmacologic inhibitors of inducible nitric oxide (NO) synthase completely eliminated suppressor function. Suppressor function and the production of NO were dependent on cell-cell contact between MDSCs and T cells, and upon IFN-γ, and were specifically associated with the "monocytic" CD11b(+)Ly6G(-) Ly6C(hi) subset of liver Tgfb1(-/-) CD11b(+) cells. The rapid accumulation of CD11b(+)Gr1(+) cells in Tgfb1(-/-) liver was abrogated when mice were either depleted of CD4(+) T cells or rendered unable to produce IFN-γ, showing that Th1 activity induces MDSC accumulation. CONCLUSION Th1 liver inflammation mobilizes an MDSC response that, through the production of NO, can inhibit T cell proliferation. We propose that MDSCs serve an important negative feedback function in liver immune homeostasis, and that insufficient or inappropriate activity of this cell population may contribute to inflammatory liver pathology.
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Affiliation(s)
- James G Cripps
- Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA
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12
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Candidate hepatitis C vaccine trials and people who inject drugs: challenges and opportunities. Vaccine 2010; 28:7273-8. [PMID: 20831914 DOI: 10.1016/j.vaccine.2010.08.085] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2010] [Revised: 08/17/2010] [Accepted: 08/24/2010] [Indexed: 12/23/2022]
Abstract
People who inject drugs (PWID) are at high risk of HCV. Limited evidence of the effectiveness of prevention interventions and low uptake of treatment in this group highlight the need for increased investment in biomedical interventions, notably safe and efficacious vaccines. While several candidates are currently in development, field trials in PWID present challenges, including ethical issues associated with trial literacy, informed consent and standards of care. Significant biological and social factors and differences between HIV and HCV suggest that HCV warrants targeted vaccine preparedness research to lay the groundwork for successful implementation of future trials.
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13
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Golden-Mason L. Natural killer cells play divergent roles in shaping the outcome of hepatitis C virus recurrence following liver transplantation. Liver Transpl 2009; 15:357-9. [PMID: 19326413 DOI: 10.1002/lt.21701] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/virology
- Disease Progression
- Gene Frequency
- Genotype
- Graft Survival
- HLA-C Antigens/immunology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/surgery
- Histocompatibility
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/virology
- Ligands
- Liver/immunology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/immunology
- Liver Cirrhosis/surgery
- Liver Cirrhosis/virology
- Liver Neoplasms/immunology
- Liver Neoplasms/surgery
- Liver Neoplasms/virology
- Liver Transplantation
- Receptors, KIR2DL3/genetics
- Receptors, KIR2DL3/immunology
- Recurrence
- Risk Assessment
- Risk Factors
- Severity of Illness Index
- Time Factors
- Transplantation, Homologous
- Treatment Outcome
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14
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Robinson RT, Wang J, Cripps JG, Milks MW, English KA, Pearson TA, Gorham JD. End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2009; 182:3278-84. [PMID: 19234226 PMCID: PMC2764282 DOI: 10.4049/jimmunol.0803417] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-gamma-producing T cells. The BALB/c-Tgfb1(-/-) mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-gamma-producing CD4(+) and CD8(+) T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-gamma. In Tgfb1(-/-) liver, CD4(+) T cells were more numerous than CD8(+) T cells and NK cells, and produced more IFN-gamma. Depletion of CD4(+) T cells eliminated both the elevation in plasma IFN-gamma and aspartate aminotransferase, whereas depletion of CD8(+) T cells did not. Rag1(-/-)Tgfb1(-/-) mice exhibited neither IFN-gamma elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-gamma was required for strong overexpression of class II genes but not for CD4(+) T cell activation, oligoclonal expansion, or accumulation in the liver. The T cell inhibitory molecule PD-L1 was strongly expressed in Tgfb1(-/-) livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1(-/-) CD4(+) T cells overexpressed Fas ligand, hepatocellular damage was observed in Fas(lpr/lpr)Tgfb1(-/-) mice, indicating that liver pathology is Fas independent. We conclude that liver damage in this model of fulminant autoimmune hepatitis is driven by CD4(+) T cell production of IFN-gamma, is independent of both CD8(+) T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.
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MESH Headings
- Animals
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Disease Models, Animal
- Fas Ligand Protein/genetics
- Fas Ligand Protein/physiology
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/metabolism
- Hepatitis, Autoimmune/pathology
- Inflammation/immunology
- Inflammation/metabolism
- Inflammation/pathology
- Interferon-gamma/deficiency
- Interferon-gamma/genetics
- Interferon-gamma/physiology
- Liver/immunology
- Liver/metabolism
- Liver/pathology
- Liver Failure, Acute/immunology
- Liver Failure, Acute/metabolism
- Liver Failure, Acute/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Mice, Transgenic
- Transforming Growth Factor beta1/genetics
- fas Receptor/genetics
- fas Receptor/physiology
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Affiliation(s)
- Richard T. Robinson
- Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756
| | - Jing Wang
- Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756
| | - James G. Cripps
- Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756
| | - Michael W. Milks
- Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756
| | | | - Todd A. Pearson
- Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756
| | - James D. Gorham
- Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756
- Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756
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15
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Poncelet L, Coppens A, Peeters D, Bianchi E, Grant CK, Kadhim H. Detection of antigenic heterogeneity in feline coronavirus nucleocapsid in feline pyogranulomatous meningoencephalitis. Vet Pathol 2008; 45:140-53. [PMID: 18424826 DOI: 10.1354/vp.45-2-140] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A new monoclonal antibody (mAb), CCV2-2, was compared with the widely used FIPV3-70 mAb, both directed against canine coronavirus (CCoV), as a diagnostic and research tool. Western blot showed that both anti-CCoV mAbs only reacted with a protein of 50 kD, a weight consistent with the feline coronavirus (FCoV) viral nucleocapsid. A competitive inhibition enzyme-linked immunosorbent assay showed that the 2 recognized epitopes are distinct. Preincubation of CCV2-2 mAb with FCoV antigen suppressed the immunostaining. Formalin-fixed, paraffin-embedded sections from brains of 15 cats with the dry form of feline infectious peritonitis (FIP) were examined by immunohistochemistry. Immunohistochemistry was performed with both anti-CCoV mAbs, either on consecutive or on the same sections. A myeloid-histiocytic marker, MAC 387, was also used to identify FIP virus-infected cells. In all regions where MAC 387-positive cells were present, positive staining with the CCV2-2 mAb was systematically detected, except at some levels in 1 cat. In contrast, none or only a few cells were positive for the FIPV3-70 mAb. Double immunostaining showed macrophages that were immunopositive for either CCV2-2 alone or alternatively for CCV2-2 and FIPV3-70 mAbs. This reveals the coexistence of 2 cohorts of phagocytes whose FIP viral contents differed by the presence or absence of the FIPV3-70-recognized epitope. These findings provide evidence for antigenic heterogeneity in coronavirus nucleocapsid protein in FIP lesions, a result that is in line with molecular observations. In addition, we provide for the first time morphologic depiction of viral variants distribution in these lesions.
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Affiliation(s)
- L Poncelet
- Anatomy/Embryology Department, CP 619, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, Brussels, Belgium.
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16
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Invernizzi P, Bianchi I, Locati M, Bonecchi R, Selmi C. Cytokines in Liver Health and Disease. LIVER IMMUNOLOGY 2008:83-93. [DOI: 10.1007/978-1-59745-518-3_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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17
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Regulation of immune response and inflammatory reactions against viral infection by VCAM-1. J Virol 2008; 82:2952-65. [PMID: 18216105 DOI: 10.1128/jvi.02191-07] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. Here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (VCAM-1) plays a role in regulating T-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (CNS) during viral infection. The ablation of VCAM-1 expression from endothelial and hematopoietic cells using a loxP-Cre recombination strategy had no major effect on the induction or overall tissue distribution of antigen-specific T cells during a systemic infection with lymphocytic choriomeningitis virus (LCMV), except in the case of lung tissue. However, enhanced resistance to lethal LCM and the significantly reduced magnitude and duration of footpad swelling observed in VCAM-1 mutant mice compared to B6 controls suggest a significant role for VCAM-1 in promoting successful local inflammatory reactions associated with efficient viral clearance and even life-threatening immunopathology under particular infection conditions. Interestingly, analysis of the infiltrating populations in the brains of intracerebrally infected mice revealed that VCAM-1 deletion significantly delayed migration into the CNS of antigen-presenting cells (macrophages and dendritic cells), which are critical for optimal stimulation of migrating virus-specific CD8(+) T cells initiating a pathological cascade. We propose that the impaired migration of these accessory cells in the brain may explain the improved clinical outcome of infection in VCAM-1 mutant mice. Thus, these results underscore the potential role of VCAM-1 in regulating the immune response and inflammatory reactions against viral infections.
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18
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19
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Seal KH, Monto A, Dove L, Shen H, Vittinghoff E, Tracy D, Miller E, Lau E, Wright TL. The association of human immunodeficiency virus infection with spontaneously resolved hepatitis C virus infection and level of viremia among injection drug users. Dig Dis Sci 2007; 52:3423-30. [PMID: 17443407 DOI: 10.1007/s10620-006-9277-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2005] [Accepted: 03/01/2006] [Indexed: 12/09/2022]
Abstract
This study aimed to investigate whether HIV and HIV-related factors are associated with spontaneously resolved hepatitis C virus (HCV) infection and levels of hepatitis C viremia. Among 351 anti-HCV(+) injection drug users, with and without HIV infection, multivariate methods were used to evaluate whether HIV status and HIV viral load, CD4 T-cell count, and concurrent HIV antiretroviral therapy were associated with (1) spontaneously resolved HCV infection and (2) HCV RNA levels. In 186 HIV patients, decreased HCV resolution was independently associated with Black race and modestly associated with CD4 T-cell count <200 cells/ml. Among 310 patients with persistent HCV infection, higher HCV RNA levels were independently associated with HIV status but not with other HIV-related factors. HIV may be associated with persistent HCV infection in patients with low CD4 T-cell counts. Moreover, HIV is associated with increased HCV viral load, which may attenuate response to HCV antiviral treatment in coinfected patients.
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Affiliation(s)
- Karen H Seal
- San Francisco Veteran's Administration Medical Center, San Francisco, California 94121, USA.
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20
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Mechanisms of Disease: HCV-induced liver injury. ACTA ACUST UNITED AC 2007; 4:622-34. [DOI: 10.1038/ncpgasthep0961] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2007] [Accepted: 08/20/2007] [Indexed: 02/08/2023]
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21
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Ksiaa L, Ayed-Jendoubi S, Sfar I, Gorgi Y, Najjar HAT, Abdallah TB, Ayed K. Clearance and persistence of hepatitis C virus in a Tunisian population: association with HLA class I and class II. Viral Immunol 2007; 20:312-9. [PMID: 17603847 DOI: 10.1089/vim.2006.0060] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Human leukocyte antigens (HLAs) of class I and class II are reported to influence the outcome of hepatitis C virus (HCV) infection. The aim of this study was to assess the role of HLA class I and class II in influencing spontaneous viral clearance or persistence in HCV-infected patients. HLA class I (A and B) typing was performed by lymphocytotoxicity test and HLA class II (DRB1) was determined by low-resolution PCR-SSP (polymerase chain reaction amplification with sequence-specific primers) for 99 subjects (48 men and 51 women). Of these, 75 had chronic infection and 24 had viral clearance. No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, source of infection, and risk factors. HLAB-w35 and HLA-DRB1*08 occurred more frequently in those with viral clearance (21.7 and 16.6%, respectively) compared with those with chronic infection (5.5 and 2.6%; p < 0.04 and p < 0.01, respectively). DRB1*15 occurred more often in those with chronic infection (29.3%) compared with those with viral clearance (16.66%), but the difference did not reach statistical significance. These results support the hypothesis that specific HLA class I and class II alleles might influence the clearance or persistence of HCV infection. Both Bw35 and DRB1*08 are associated with clearance of circulating HCV whereas DRB1*15 appears to predispose to progression of liver disease in Tunisian patients. Taken together, our results and those previously reported suggest that HLA associations with the outcome of hepatitis C viremia vary in relation to the ethnicity of the population studied. Further prospective studies of larger cohorts of HCV-infected subjects are needed to evaluate, in different populations, the role of specific HLA class I and class II alleles in the outcome of HCV infection.
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Affiliation(s)
- Leila Ksiaa
- Immunology Laboratory, Charles Nicolle Hospital, Tunis, Tunisia
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22
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Cua IHY, Hui JM, Bandara P, Kench JG, Farrell GC, McCaughan GW, George J. Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines. Hepatology 2007; 46:66-73. [PMID: 17596870 DOI: 10.1002/hep.21703] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
UNLABELLED The role of tumor necrosis factor alpha, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV-infected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P = 0.01), TNFalpha (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA-IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFalpha and IL6. Only TNFalpha levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02). CONCLUSION Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV-infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFalpha which correlated with portal/periportal inflammation. HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity.
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Affiliation(s)
- Ian Homer Y Cua
- Storr Liver Unit, Westmead Millennium Institute and Department of Gastroenterology and Hepatology, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia
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23
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Suruki RY, Mueller N, Hayashi K, Harn D, DeGruttola V, Raker CA, Tsubouchi H, Stuver SO. Host immune status and incidence of hepatocellular carcinoma among subjects infected with hepatitis C virus: a nested case-control study in Japan. Cancer Epidemiol Biomarkers Prev 2007; 15:2521-5. [PMID: 17164379 DOI: 10.1158/1055-9965.epi-06-0485] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
A nested case-control study was conducted to examine the association between host immune status, as characterized by serum immune marker levels, and the development of hepatocellular carcinoma (HCC) up to 8 years later in persons with chronic hepatitis C virus (HCV) infection. Cases (n = 39) and matched controls (n = 117) were selected from participants of the Town C HCV Study in Japan between 1996 and 2004 and matched on age at first available sample (+/-1 year), gender, and length of follow-up. Separate analyses were done for each of three serum immune markers: soluble tumor necrosis factor-receptor II (sTNF-R2) and soluble intercellular adhesion molecule-1 (sICAM-1), as indicators of type 1, cell-mediated immune response, and soluble CD30 (sCD30), as an indicator of type 2, humoral immune response. The median concentrations of sTNF-R2, sICAM-1, and sCD30 among controls were 3,170 pg/mL, 305 ng/mL, and 3.0 units/mL, respectively, and were higher among cases (3,870 pg/mL, 372 ng/mL, and 3.3 units/mL, respectively). The risk of developing HCC among subjects with immune marker concentrations above the median levels of the controls was >2-fold greater than among subjects with lower concentrations for all three markers [sTNF-R2: odds ratio (OR), 6.9; 95% confidence interval (95% CI), 2.4-20.5; sICAM-1: OR, 2.0; 95% CI, 0.9-4.1; and sCD30: OR, 2.1; 95% CI, 1.0-4.7]. Simultaneous adjustment for all three markers revealed only sTNF-R2 to be associated with HCC risk (OR, 6.4; 95% CI, 2.0-20.6). Adjustment for alcohol consumption and HCV serotype did not materially alter these associations. Results from this prospective, community-based study suggest that a dysregulation in both type 1-related and type 2-related host immunity contributes to the development of HCV-associated HCC.
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Affiliation(s)
- Robert Y Suruki
- Department of Epidemiology, Harvard School of Public Health, USA.
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24
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Budhu A, Chen Y, Kim JW, Forgues M, Valerie K, Harris CC, Wang XW. Induction of a unique gene expression profile in primary human hepatocytes by hepatitis C virus core, NS3 and NS5A proteins. Carcinogenesis 2007; 28:1552-60. [PMID: 17404395 DOI: 10.1093/carcin/bgm075] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease and hepatitis B and C viruses (HBV and HCV) are considered as major causative factors for the development of HCC. We have conducted gene expression profiling studies to search for potential target genes responsible for HCV-mediated HCC. Adenoviruses encoding core (HCV structural protein), NS3 and NS5A [HCV non-structural (NS) proteins] were generated and infected individually or together in freshly isolated primary human hepatocytes. An adenovirus harboring the oncogenic HBV protein, HBx, was included for comparison. A microarray platform of over 22,000 human oligos was analyzed to seek out significant differentially expressed genes among these viral proteins. We also compared these gene expression profiles with those obtained from HCV-infected liver samples from chronic liver disease (CLD) patients and HCV-related HCC. We found that HCV-related proteins largely induce unique genes when compared with HBx. In particular, interferon-inducible gene 27 (IFI27) was highly expressed in HCV or core-infected hepatocytes and HCV-related CLD or HCC, but was not significantly expressed in HBx-infected hepatocytes or HBV-related CLD or HCC, indicating that IFI27 may play a role in HCV-mediated HCC. In conclusion, our results suggest that HBV and HCV promote HCC development mainly through different mechanisms.
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Affiliation(s)
- A Budhu
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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25
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Aggarwal R, Shukla R, Jameel S, Agrawal S, Puri P, Gupta VK, Patil AP, Naik S. T-cell epitope mapping of ORF2 and ORF3 proteins of human hepatitis E virus. J Viral Hepat 2007; 14:283-92. [PMID: 17381721 PMCID: PMC2441432 DOI: 10.1111/j.1365-2893.2006.00796.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Little data are available on cellular immune responses during infection with hepatitis E virus (HEV). We therefore mapped CD4 T-cell epitopes in open reading frame (ORF)2 and ORF3 proteins of HEV using lymphocyte proliferation assays and overlapping peptide libraries. Proliferation of peripheral blood mononuclear cells from 40 patients with acute hepatitis E and 21 healthy controls with recombinant HEV ORF2 protein or pools of overlapping HEV ORF2/ORF3 peptides was measured. HLA-DQB1 and HLA-DRB1 alleles were also determined. Mononuclear cells from patients with hepatitis E more often showed significant proliferation on stimulation with recombinant ORF2 protein than controls (32/40 vs 7/21), and had higher median (range) stimulation indices [2.6 (0.9-15.2) vs 1.3 (0.6-12.9)]. Peptide pools corresponding to amino acids 73-156, 289-372, 361-444 and 505-588 of HEV ORF2 protein were associated with significant proliferation. Individual peptides in these pools did not show a clear pattern of stimulation. HEV ORF3 peptide pools did not induce proliferative responses. Lymphocyte proliferation in response to the peptide pool corresponding to amino acids 289-372 of HEV ORF2 protein was associated with presence of HLA-DRB1 allele 010X. These data on mapping of T-cell epitopes in HEV proteins may prove useful for designing HEV vaccines and for studying the immunopathogenesis of hepatitis E.
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Affiliation(s)
- R Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
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Abstract
Chronic hepatitis B virus infection afflicts 400 million people worldwide and untreated will progress to cirrhosis in 15-40% of individuals, with an associated increased risk for the development of hepatocellular carcinoma. The 'inactive carrier state' carries a benign prognosis with a very low risk of cirrhosis or hepatocellular carcinoma. However, the hepatitis B e antigen (HBeAg)-positive chronic hepatitis state is an active disease state with increased risk for progressing to cirrhosis and hepatocellular carcinoma. The HBeAg-negative mutant variety of chronic hepatitis B has been associated with a higher incidence of cirrhosis at initial presentation and more frequent progression to hepatocellular carcinoma compared with the wild-type hepatitis B. Five medications are currently approved by the US FDA for the treatment of chronic hepatitis B: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir and peginterferon-alpha-2a. Interferon-alpha therapy has been shown to increase the rate of HBeAg and hepatitis B DNA loss with a small chance of hepatitis B surface antigen loss, but has significant adverse effects and is ineffective against the HBeAg-negative mutant. Lamivudine is a safely used, orally administered drug with good efficacy, but is associated with the development of a lamivudine-resistant (Lam-R) mutant in a large proportion of patients after long-term therapy. High relapse rates after lamivudine therapy make this medication less effective in the HBeAg-negative mutant also. Adefovir dipivoxil is a safely used, orally administered drug, which is effective against the Lam-R mutant. Adefovir dipivoxil is effective against the wild-type and HBeAg-negative hepatitis B and has a very low incidence of resistance development. Entecavir is a highly potent and selective new oral drug against hepatitis B. It has demonstrated no resistance development in treatment-naive patients, but a low incidence of resistance in patients infected with prior Lam-R mutants. Peginterferon-alpha-2a is administered once weekly and has improved efficacy compared with standard interferon-alpha and lamivudine. However, it has a similar adverse-effect profile to standard interferon-alpha. Pharmacoeconomic studies have demonstrated a cost benefit in treating chronic hepatitis B patients compared with no therapy. However, results have been conflicting, with earlier studies showing a cost advantage of lamivudine over interferon-alpha and a more recent, comprehensive study favouring interferon-alpha monotherapy in HBeAg-negative patients and adefovir dipivoxil 'salvage' after lamivudine resistance development in HBeAg-positive patients.
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Affiliation(s)
- Steven-Huy B Han
- David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7302, USA.
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27
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Berenguer M, Royuela A, Zamora J. Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis. Liver Transpl 2007; 13:21-9. [PMID: 17192906 DOI: 10.1002/lt.21035] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.
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Affiliation(s)
- Marina Berenguer
- HepatoGastroenterology Service, Hospital Universitari La Fe, Valencia, Spain.
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28
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Kohashi T, Maekawa S, Sakamoto N, Kurosaki M, Watanabe H, Tanabe Y, Chen CH, Kanazawa N, Nakagawa M, Kakinuma S, Yamashiro T, Itsui Y, Koyama T, Enomoto N, Watanabe M. Site-specific mutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication. J Viral Hepat 2006; 13:582-90. [PMID: 16907844 DOI: 10.1111/j.1365-2893.2006.00739.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The number of amino acid substitutions in the interferon sensitivity-determining region (ISDR) in the nonstructural 5A (NS5A) gene of hepatitis C virus (HCV) is closely associated with the interferon (IFN) response and viral load. Several HCV replicon-based studies have reported that ISDR sequences had an influence on viral replication in vitro. However, it is unclear as to how different ISDR sequences affect HCV replication. Various clinically observed ISDR sequences were introduced into HCV replicons and their contribution to viral replication was investigated using a colony formation assay and/or a transient replication assay. A mapping study of the ISDR was performed to identify the amino acid positions that critically affect replication. While no colonies were formed in the colony formation assay using HCV replicons with few mutations (0, 1 and 3) in the ISDR, numerous colonies (>200) appeared when using constructs with six mutations. Introduction of various distinct ISDR sequences with multiple mutations resulted in replication enhancement in transient assays. A mapping study identified several specific sites in the ISDR that critically affected replication, including codon 2209 which, in patients, was closely associated with a strong response to IFN. ISDR sequences associated with a clinical IFN response and viral load modulated the replication of HCV replicons, suggesting the importance of the ISDR sequence in HCV infection.
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Affiliation(s)
- T Kohashi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Yushima, Bunkyo, Tokyo, Japan
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29
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Wang T, Blatt LM, Seiwert SD. Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections. J Interferon Cytokine Res 2006; 26:473-83. [PMID: 16800786 DOI: 10.1089/jir.2006.26.473] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The standard of care for chronic hepatitis C, pegylated interferon-alpha (IFN-alpha) and ribavirin (RBV), causes a sustained virologic response (SVR) in approximately 50% of patients. SVR is correlated with innate and adaptive immune system responses, such as natural killer (NK) cell activation, production of IFN-alpha from immature plasmocytoid dendritic cells (pDC), and polarization of CD4(+) cells to a T helper 1 (Th1) cell phenotype. To examine how these immunologic responses vary with currently available regimens for chronic hepatitis C, cell populations purified from human peripheral blood mononuclear cells (PBMC) were treated with the clinically available combinations of pegylated IFN-alpha2b (PEG-IFN-alpha2b) + RBV, IFN-alphacon1 + RBV, or IFN- alphacon1 + IFN-gamma1b, and activation of cellular immune system components was monitored. The magnitude of NK cell activation depended on regimen, with IFN-alphacon1 + IFN-gamma1b > IFN-alphacon1 + RBV > PEG-IFN- alphaa2b + RBV. The maximum human serum concentrations of IFN-alphacon1 + IFN-gamma1b saturated NK cell activation, whereas the maximum human serum concentrations of IFN-alphacon1 + RBV or PEG-IFN-alpha2b + RBV did not. IFN-gamma1b also enhanced the production of IFN-alpha from immature pDCs, which are the dominant source of IFN-alpha upon viral infection. The rank order for induction of Th1 cell phenotype and repression of Th2 cell phenotype by the cocktails described was identical to that observed for NK cell activation. Additionally, IFN- gamma1b suppressed the ability of the hepatitis C virus (HCV) NS4 protein to enhance monocyte secretion of interleukin- 10 (IL-10), a cytokine whose expression level is correlated with viral persistence. These results suggest that addition of IFN-gamma1b to HCV treatment regimens may provide unique benefits.
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Affiliation(s)
- Tony Wang
- InterMune Inc., Brisbane, CA 94005, USA
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30
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Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S, Cruz S, Ramirez-Iglesias MT, Gutierrez-Ruiz MC, Sanchez-Avila F, Roldan E, Vargas-Vorackova F, Kershenobich D. Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C. Scand J Immunol 2006; 63:461-467. [PMID: 16764700 DOI: 10.1111/j.1365-3083.2006.001761.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The cellular and humoral natural immune response induced by hepatitis C virus (HCV) is commonly unable to eradicate the virus. HCV is a highly mutable, hepatotropic RNA virus that causes acute and chronic hepatitis, an infection that involves the production of various cytokines. The aim of the study is to analyse the expression of pro-inflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma and the chemokine CXCL8 (IL-8) in liver tissue and their expression and secretion in PBMC of patients with chronic hepatitis C (CHC), in response to pentoxyfilline (PTX). We studied six CHC patients, naive to treatment. Patients received PTX 400 mg twice a day/8 weeks. Pentoxyfilline resulted in decreased expression of mRNA of liver IL-1beta, TNF-alpha and IFN-gamma: 144.2 versus 83.5 molecules of IL-1beta (P < 0.05), TNF-alpha 194.3 versus 17.6 molecules (P = 0.03) and IFN-gamma 26.1 versus 0.5 molecules (P = 0.04). Following PTX, PBMC exhibited a decrease in IFN-gamma mRNA 12.2 versus 1.5 molecules (P = 0.028) and CXCL8 4.2 versus 2.5 molecules (P = 0.027). In PBMC, only the secretion of TNF-alpha was decreased 1109 versus 933.5 pg/ml, P = 0.046. Production of cytokines both locally (within the liver) and systemically (PBMC) may serve as biomarkers of the infection with hepatitis C. PTX inhibits the expression of several pro-inflammatory cytokines in the liver. These results indicate that it is worth exploring PTX in hepatitis in future clinical trials in nonresponders to antiviral treatment.
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Affiliation(s)
- G Gutierrez-Reyes
- Facultad de Medicina, UNAM, Hospital General de México, Mexico City, Mexico
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31
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Callender GG, Rosen HR, Roszkowski JJ, Lyons GE, Li M, Moore T, Brasic N, McKee MD, Nishimura MI. Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition. Hepatology 2006; 43:973-81. [PMID: 16628627 DOI: 10.1002/hep.21157] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) has been reported to elicit B and T cell immunity in infected patients. Despite the presence of antiviral immunity, many patients develop chronic infections leading to cirrhosis, hepatocellular carcinoma, and liver failure that can require transplantation. We have previously described the presence of HLA-A2-restricted, HCV NS3-reactive cytotoxic T lymphocytes (CTL) in the blood of HLA-A2- liver transplantation patients that received an HLA-A2+ liver allograft. These T cells are analogous to the "allospecific" T cells that have been described in hematopoietic stem cell transplantation patients. It has been speculated that allospecific T cells express high-affinity T cell receptors (TCRs). To determine if our HCV-reactive T cells expressed TCRs with relatively high affinity for antigen, we identified and cloned a TCR from an allospecific HLA-A2-restricted, HCV:NS3:1406-1415-reactive CD8+ T cell clone and expressed this HCV TCR in Jurkat cells. Tetramer binding to HCV TCR-transduced Jurkat cells required CD8 expression, whereas antigen recognition did not. In conclusion, based on the reactivity of the TCR-transduced Jurkat cells, we have identified a TCR that transfers anti-HCV reactivity to alternate effectors. These data suggest this high affinity HCV-specific TCR might have potential new immunotherapic implications.
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Affiliation(s)
- Glenda G Callender
- Department of Surgery, University of Chicago Hospitals, Chicago, IL, USA
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32
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Drebber U, Kasper HU, Krupacz J, Haferkamp K, Kern MA, Steffen HM, Quasdorff M, Zur Hausen A, Odenthal M, Dienes HP. The role of Epstein-Barr virus in acute and chronic hepatitis. J Hepatol 2006; 44:879-85. [PMID: 16554102 DOI: 10.1016/j.jhep.2006.02.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2005] [Revised: 01/27/2006] [Accepted: 02/01/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Epstein-Barr virus has a seroprevalence of more than 80% world wide and is known to be associated with hepatitis. However, little is known about the underlying pathogenesis and immunmechanisms and no standard diagnostic criteria to diagnose EBV-hepatitis are available. METHODS We collected liver biopsies (n=21) with the tentative diagnosis of EBV induced hepatitis according to pathological changes and traceable EBV genome by PCR. Correlation with serological data revealed acute in seven cases, convalescent in two cases, past EBV infection in six cases. Viral RNA was visualised by in situ hybridisation within nuclei of lymphocytes. RESULTS In seven of 68 liver biopsies with the diagnosis 'liver disease of unknown aetiology' EBV genome in the tissue was demonstrated indicating a possible role for EBV in the induction of hepatitis or a trapping of infected lymphocytes within the liver. In a control group of 20 EBV-seropositive patients with steatohepatitis EBV-DNA PCR of the liver tissue was negative. Immunohistochemistry identified CD3 and CD8 positive T-lymphocytes as the main lymphocytic infiltrate in EBV hepatitis. CONCLUSIONS EBV hepatitis should be taken into consideration in case of typical histopathological changes and a positive DNA PCR of liver biopsy. Serological confirmation of the diagnosis is inevitable.
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Affiliation(s)
- Uta Drebber
- Institute of Pathology, University of Cologne, Cologne, Germany.
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Sekiguchi T, Nagamine T, Takagi H, Mori M. Reduction of virus burden-induced splenectomy in patients with liver cirrhosis related to hepatitis C virus infection. World J Gastroenterol 2006; 12:2089-94. [PMID: 16610063 PMCID: PMC4087691 DOI: 10.3748/wjg.v12.i13.2089] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the hepatitis C virus (HCV) levels and immunological markers in cirrhotic patients after splenectomy.
METHODS: HCV RNA titers as well as cellular and humoral immune markers were determined in 20 cirrhotic patients after splenectomy and in 32 cirrhotic controls with an intact spleen.
RESULTS: Serum HCV RNA titers were lower in the splenectomized patients than in the controls (186 ± 225 × 103 copies/mL vs 541 ± 417 × 103 copies/mL, P < 0.01). HCV RNA was judged to have been spontaneously eradicated in 4 splenectomized patients, but in none of the controls. Natural killer cell activity was higher in the splenectomized patients than in the controls (41.2 ± 19.3% vs 24.7 ± 15.3%, P < 0.01), and natural killer cell activity was negatively correlated to HCV RNA titers in the splenectomized patients except in those with serotype 2-related infection. The CD4/CD8 ratio was significantly lower in the splenectomized patients than in the controls.
CONCLUSION: The findings suggest that splenectomy may diminish virus burden in cirrhotic patients with HCV infection at least in part, through augmentation of natural killer cell activity.
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Affiliation(s)
- Tetsuro Sekiguchi
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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Wang J, Sun R, Wei H, Dong Z, Gao B, Tian Z. Poly I:C prevents T cell-mediated hepatitis via an NK-dependent mechanism. J Hepatol 2006; 44:446-54. [PMID: 16310275 DOI: 10.1016/j.jhep.2005.08.015] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2005] [Revised: 08/11/2005] [Accepted: 08/12/2005] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS T cell immune responses play key roles in the pathogenesis of viral hepatitis, and innate immunity is known to be also activated during this process, however, the effects of innate immunity activation on T cell-mediated hepatitis remain obscure. Here we examined the effect of the activation of NK cells induced by toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly I:C), on concanavalin A (Con A)-induced T cell-mediated liver injury. METHODS Mice received nontoxic intraperitoneal poly I:C injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the function of hepatic lymphocytes was detected by FACS analysis. RESULTS Poly I:C pretreatment protected against T cell-mediated hepatitis, as evidenced by decreased mortality, hepatic necrosis, serum transaminase levels and inflammatory cytokines (IL-4, IFN-gamma). The protective effect of poly I:C was diminished in NK-depleted mice, which could be partially restored by adoptive transfer of NK cells. Administration of poly I:C caused NKT and T cell apoptosis via enhancing expression of Fas protein on these cells and expression of Fas ligand on NK cells. CONCLUSIONS These findings suggest that activation of NK cells by poly I:C prevents Con A-induced T cell-hepatitis via downregulation of T/NKT cells and subsequent reduction of inflammatory cytokines.
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Affiliation(s)
- Jing Wang
- School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
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35
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Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl 2006; 12:363-72. [PMID: 16498647 DOI: 10.1002/lt.20708] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Liver cirrhosis and hepatocellular carcinoma secondary to chronic hepatitis C virus (HCV) infection requiring transplantation represents a significant public health problem. The most remarkable feature of hepatitis C virus is the ability to establish chronic infection in the vast majority of cases. Efforts to define clinical correlates of HCV persistence have focused primarily on CD4 and CD8 T cell responses. Until recently, the role of innate immunity in determining the outcome of HCV infection had received relatively little attention. Natural killer (NK) cells are an important antiviral effector population eliminating virus through direct killing and cytokine production. Recent studies highlighting the cross-talk between NK cells, dendritic cells (DCs) and T cells have prompted reevaluation of the important role NK cells play in regulating and maintaining specific immune responses. Like many other viruses, HCV has evolved strategies to evade detection and elimination by NK cells. T cell defects observed in HCV infection may be a consequence of inhibition of NK:DC interactions. We propose a theoretical model for HCV persistence that places the NK cell at the center of HCV immune evasion strategies. While this model is only theoretical, it provides a plausible interpretation of many published observations and a useful working model to test the role of NK cells in HCV persistence. In conclusion, the role of innate immune cells and their regulation of antigen-specific responses by the initial innate response to the virus, in particular NK cells, may prove to be an informative and clinically relevant avenue of investigation.
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Abstract
Transforming growth factor-beta1 (TGF-beta1) is released during the storage of blood components, particularly platelet concentrates, and transfusion recipients are exposed to high levels of TGF-beta1. Because TGF-beta1 is one of the most potent immunosuppressive cytokines known, understanding the immunobiologic functions of TGF-beta1 may be relevant for understanding the immunobiologic effects of transfusion. Our laboratory studies the biologic effects of TGF-beta1 in the immune system. Mice deficient in TGF-beta1 spontaneously develop autoimmunity, confirming the important role of this cytokinean an immune regulator. A few years ago, my laboratory made the observation that genetic background strongly affects the phenotype of TGF-beta1-/- mice. TGF-beta1-/- mice on the BALB/c background rapidly develop an aggressive T-cell-mediated hepatitis, whereas TGF-beta1-/- mice on the 129/CF-1 background do not. In this review, I summarize findings published or in press from our laboratory on disease pathogenesis in TGF-beta1-/- mice and then discuss some of the exciting (as-yet-unpublished) directions our laboratory is currently taking.
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Affiliation(s)
- James D Gorham
- Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
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Giuggio VM, Bonkovsky HL, Rothman AL. Evolution of the Intrahepatic T Cell Repertoire during Chronic Hepatitis C Virus Infection. Viral Immunol 2005; 18:179-89. [PMID: 15802962 DOI: 10.1089/vim.2005.18.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by extensive infiltration of inflammatory cells in the liver, where there is a compartmentalization of HCV-reactive T lymphocytes. Previous studies have demonstrated a broad intrahepatic TCR repertoire; however, there is little information regarding the stability of this intrahepatic T cell population. We studied the T cell repertoires in sequential liver biopsy samples from five individuals with chronic HCV infection using TCR spectratype analysis; four subjects had been treated with IFN-alpha during the interval between biopsies. Transcripts from most TCRBV families were detectable in the liver tissues, and 25-85% of these had skewed spectratype profiles indicative of T cell clonal expansions. Most of the intrahepatic T cell expansions were not evident in an analysis of peripheral blood T cells collected at the same time as the liver biopsy. Detailed analysis using TCRBJ-primed run-off reactions revealed that the intrahepatic TCR repertoires were not stable within an individual, although some TCR clonotypes were maintained for at least 45 months.
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Affiliation(s)
- Vicki M Giuggio
- Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA
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38
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Na D, Park I, Lee KH, Lee D. Integration of Immune Models Using Petri Nets. LECTURE NOTES IN COMPUTER SCIENCE 2004. [DOI: 10.1007/978-3-540-30220-9_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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