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Babiker A, Hassan M, Muhammed S, Taylor G, Poonia B, Shah A, Bagchi S. Inflammatory and cardiovascular diseases biomarkers in chronic hepatitis C virus infection: A review. Clin Cardiol 2019; 43:222-234. [PMID: 31785111 PMCID: PMC7068107 DOI: 10.1002/clc.23299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infects 180 million people worldwide and over 4 million people in the United States. HCV infection is a major cause of chronic liver disease and is recognized as a risk factor for clinical cardiovascular disease (CVD). Many studies have shown increased prevalence of cardiac and inflammatory biomarkers in patients with chronic HCV infection (CHC), and though these markers may be used to risk stratify people for cardiac disease in the general population their role in the HCV population is unknown. Patients with CHC have elevated cardiac and inflammatory biomarkers compared to noninfected controls which may play a role in CVD risk stratification. We undertook a systematic review of inflammatory and cardiac biomarkers in people with HCV infection with a focus on the effect of CHC on serum levels of these markers and their utility as predictors of CVD in this population. Medline, EMBASE, and Cochrane databases were searched for relevant articles until June 2019. A total of 2430 results were reviewed with 115 studies included. Our review revealed that HCV infection significantly alters serum levels of markers of inflammation, endothelial function, and cardiac dysfunction prior to HCV treatment, and some of which may change in response to HCV therapy. Current risk stratification tools for development of CVD in the general population may not account for the increased inflammatory markers that appear to be elevated among HCV‐infected patients contributing to increased CVD risk.
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Affiliation(s)
- Ahmed Babiker
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Mohamed Hassan
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Safwan Muhammed
- Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland.,Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gregory Taylor
- Department of Family Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Bhawna Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Anoop Shah
- Division of Cardiology, University of Edinburgh, Little France, Edinburgh
| | - Shashwatee Bagchi
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.,Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland
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Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol 2019; 138:156-171. [PMID: 31092372 DOI: 10.1016/j.critrevonc.2019.04.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.
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Yasuzaki H, Yoshida SI, Hashimoto T, Shibata W, Inamori M, Toya Y, Tamura K, Maeda S, Umemura S. Involvement of the apelin receptor APJ in Fas-induced liver injury. Liver Int 2013; 33:118-26. [PMID: 23121371 DOI: 10.1111/liv.12006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 09/05/2012] [Indexed: 01/05/2023]
Abstract
BACKGROUND Apelin-APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin-APJ signaling and Fas-mediated liver injury in mice. METHODS APJ(-/-) mice and wild type (WT) mice were administered an intraperitoneal injection of an agonistic anti-Fas antibody (clone; Jo2), and sacrificed after 3 or 6 h to assess the liver histology. The expression levels of apelin and APJ, plasma levels of transaminases, activities of hepatic caspases and activations of stress-activated protein kinases were also analysed. RESULTS Before the Jo2 injection, APJ was weakly expressed in the hepatocytes in spots; on the other hand, after the Jo2 injection, it had spread into whole hepatocytes. Moreover, the mRNA expression level of apelin and APJ in the liver increased after Jo2 injection. In the APJ(-/-) mice, the liver injuries and apoptotic changes were significantly inhibited as compared with those in the WT mice. Dramatic increase in JNK activation was observed in the WT mice after Jo2 injection, whereas such activation was completely absent in the APJ(-/-) mice. JNK inhibitor partially, but significantly suppressed Jo2-mediated liver injury in WT mice. CONCLUSION Apelin-APJ signalling may promote Fas-induced liver injury at least partially via JNK activation, and may thus serve as a potential therapeutic target in cases of acute liver injury.
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Affiliation(s)
- Hiroaki Yasuzaki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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ANTONELLI ALESSANDRO, FERRI CLODOVEO, FERRARI SILVIAMARTINA, RUFFILLI ILARIA, COLACI MICHELE, FRASCERRA SILVIA, MICCOLI MARIO, FRANZONI FERDINANDO, GALETTA FABIO, FALLAHI POUPAK. High Serum Levels of CXCL11 in Mixed Cryoglobulinemia Are Associated with Increased Circulating Levels of Interferon-γ. J Rheumatol 2011; 38:1947-52. [DOI: 10.3899/jrheum.110133] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objective.No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with “mixed cryoglobulinemia and chronic hepatitis C infection” (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.Methods.Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.Results.MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8–114.5), 1.4 (range 0.7–2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8–369), 1.1 (range 0.7–3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).Conclusion.Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.
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Cielecka-Kuszyk J, Siennicka J, Jabłońska J, Rek O, Godzik P, Rabczenko D, Madaliński K. Is interleukin-8 an additional to histopathological changes diagnostic marker in HCV-infected patients with cryoglobulinemia? Hepatol Int 2011; 5:934-40. [DOI: 10.1007/s12072-011-9268-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 03/04/2011] [Indexed: 10/18/2022]
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Schiavon LL, Narciso-Schiavon JL, Carvalho-Filho RJ, Sampaio JP, El Batah PN, Silva GA, Carvente CT, Silva AEB, Ferraz MLG. Evidence of a significant role for Fas-mediated apoptosis in HCV clearance during pegylated interferon plus ribavirin combination therapy. Antivir Ther 2011; 16:291-298. [PMID: 21555811 DOI: 10.3851/imp1768] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND The role of apoptosis in treatment-induced HCV clearance is controversial. We sought to assess the kinetics of serum apoptosis-related cytokines during pegylated interferon-α2a or -α2b plus weight-based ribavirin therapy for genotype 1 chronic HCV infection. METHODS Serum levels of soluble Fas (sFas), soluble Fas ligand (sFasL) and soluble tumour necrosis factor receptor I (sTNF-RI) were measured at baseline, week 12 and 24 weeks after the end of therapy. RESULTS Sustained virological response (SVR) was achieved in 46% of the 164 included patients, 29% had a non-response (NR) and 25% had relapse (RR). NR patients presented with higher levels of sFasL at baseline and lower levels of sTNF-RI at week 12 as compared to RR and SVR patients. Lower concentrations of sFas were observed in SVR patients 24 weeks after treatment as compared to RR and NR patients. An increase in sFas at week 12 followed by a significant drop 24 weeks after therapy was observed among SVR patients. An increase in sFasL during and after treatment was observed in RR and SVR patients. NR patients exhibited an earlier drop in sTNF-RI levels as compared to RR and SVR patients. CONCLUSIONS Virological response during HCV therapy was associated with an increase of sFas and sFasL, and maintenance of increased concentrations of sTNF-RI.
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Affiliation(s)
- Leonardo L Schiavon
- Division of Gastroenterology, Hepatitis Section, Federal University of Sao Paulo, Brazil.
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Landau DA, Rosenzwajg M, Saadoun D, Klatzmann D, Cacoub P. The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 2009; 68:337-44. [PMID: 18434450 DOI: 10.1136/ard.2007.085910] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The study aim was to examine the B lymphocyte stimulator (BLyS) receptor-ligand system in hepatitis C virus (HCV)-induced B lymphocyte clonal disorders. METHODS 94 patients with chronic HCV (including 35 with HCV+ mixed cryoglobulinaemia (MC)-vasculitis and nine with HCV+ B cell non-Hodgkin's lymphoma (B-NHL)) and 15 healthy volunteers were included. RESULTS A twofold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a threefold increase with HCV-induced B-NHL, compared with patients that were HCV+, but without vasculitis, or healthy controls (p<0.05). Lower membrane BLyS expression in HCV-induced MC-vasculitis was observed. CD19+ BLyS binding and BLyS receptor 3 (BR3) staining showed a stepwise decrease with highest values in healthy controls and who were HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in VH1-69+ clonal B cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after antiviral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a fivefold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B cells was significantly decreased (p<0.005). CONCLUSIONS The BLyS ligand-receptor activity is increased in HCV-induced B cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor-ligand system.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived
- Antineoplastic Agents/therapeutic use
- Antiviral Agents/therapeutic use
- Apoptosis/immunology
- B-Cell Activating Factor/blood
- B-Cell Activation Factor Receptor/blood
- B-Lymphocytes/immunology
- Cryoglobulinemia/drug therapy
- Cryoglobulinemia/immunology
- Cryoglobulinemia/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Humans
- Ligands
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/virology
- Middle Aged
- Rituximab
- Vasculitis/drug therapy
- Vasculitis/immunology
- Vasculitis/virology
- Young Adult
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Affiliation(s)
- D-A Landau
- Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Sientifique, Universite Pierre et Marrie Curie UMR 7087, Paris, France
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8
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Antonelli A, Ferri C, Fallahi P, Ferrari SM, Sebastiani M, Ferrari D, Giunti M, Frascerra S, Tolari S, Franzoni F, Galetta F, Marchi S, Ferrannini E. High values of CXCL10 serum levels in mixed cryoglobulinemia associated with hepatitis C infection. Am J Gastroenterol 2008; 103:2488-94. [PMID: 18775023 DOI: 10.1111/j.1572-0241.2008.02040.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES No study has evaluated circulating CXCL10 in patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) chronic infection. The aim of this study is to measure inteferon-inducible protein 10 (CXCL10/IP-10), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) (Th1 cytokines) in a series of cryoglobulinemic patients and to correlate this parameter to the clinical phenotype. METHODS Serum CXCL10, IFN-gamma, and TNF-alpha were assayed in 102 patients with hepatitis C-associated cryoglobulinemia (MC + HCV), in 102 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 102 sex- and age-matched controls. RESULTS Cryoglobulinemic patients showed significantly higher mean CXCL10 serum levels than controls (P < 0.0001) or HCV+ patients (P < 0.0001) (397 +/- 132 pg/mL, 92 +/- 53 pg/mL, 280 +/- 149 pg/mL, respectively). Moreover, CXCL10 was significantly increased in 30 cryoglobulinemic patients with active vasculitis compared to those without it (460 +/- 104 pg/mL vs 369 +/- 139 pg/mL, respectively; P < 0.001). Both groups of MC + HCV patients with or without active vasculitis had serum CXCL10 significantly higher than HCV+ patients (P < 0.001, P= 0.02, respectively). IFN-gamma levels were not significantly different in MC + HCV than in HCV+ patients or controls. Serum TNF-alpha levels were significantly higher in MC + HCV than in HCV+ patients or controls (median [interquartile range]: 12.0 [9.8], 5.7 [5.4], 1.3 [2.1] pg/mL, respectively; P < 0.0001). CONCLUSIONS The study demonstrates high CXCL10 and TNF-alpha serum levels in patients with hepatitis C-associated cryoglobulinemia. Moreover, in MC + HCV patients, increased CXCL10 levels were significantly associated with the presence of active vasculitis.
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Affiliation(s)
- Alessandro Antonelli
- Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy
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Landau DA, Saadoun D, Calabrese LH, Cacoub P. The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 2007; 6:581-7. [PMID: 17854753 DOI: 10.1016/j.autrev.2007.03.010] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Accepted: 03/22/2007] [Indexed: 11/20/2022]
Abstract
Hepatitis C virus (HCV) has been shown in epidemiologic studies to be associated with immune system disorders. Primarily disorders that stem from B-cell regulatory control disturbance, such as mixed cryoglobulinemia (MC) and non-Hodgkin's lymphoma (NHL). The causative role of HCV in these disorders is supported by the response to anti-viral treatment. The understanding of the pathophysiological process leading from HCV infection to B-cell clonal expansion has improved significantly. Data supports an antigen-driven indirect stimulation of clonal expansion model, leading from oligoclonal to monoclonal expansion and in some instances to frank malignancy. HCV-E2 antigen has been suggested as a candidate antigen as well as NS3. Binding of the B-cell receptor by viral antigens coupled with direct binding of CD-81 by HCV-E2 has been shown to provide a strong proliferative signal. Additional regulatory elements are also affected in HCV-related B-cell clonal expansion, including the Fas and BLyS signaling mechanisms. Finally, genetic events such as bcl-2 rearrangement may also be involved in clonal expansion. In this review, evidence linking HCV with MC and NHL, as well as known events in the pathophysiological process are described.
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Affiliation(s)
- Dan-Avi Landau
- Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris, F-75013 France
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Bridoux F, Sirac C, Jaccard A, Ayache RA, Goujon JM, Cogné M, Touchard G. Chapter 12 Renal Disease in Cryoglobulinemic Vasculitis. ACTA ACUST UNITED AC 2007. [DOI: 10.1016/s1571-5078(07)07012-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2023]
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Zekri ARN, Ashour MSED, Hassan A, Alam El-Din HM, El-Shehaby AMR, Abu-Shady MA. Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression. World J Gastroenterol 2005; 11:6624-30. [PMID: 16425355 PMCID: PMC4355755 DOI: 10.3748/wjg.v11.i42.6624] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [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 observe the imbalance between T helper cell Th1 and Th2 cytokines in several chronic hepatitis disease at different stages of disease progression.
METHODS: We measured the cytokine levels of Th1 (IL-2 and IL-2R), Th2 (IL-10) and the pro-inflammatory cytokines (IL-6 and IL-6R and TNF and TNF-RI and II) by the ELISA technique in the sera of 33 hepatocellular carcinoma (HCC) patients and 20 chronic liver disease (CLD) patients. In addition, 20 asymptomatic hepatitis C virus carriers and 20 healthy subjects negative for hepatitis C virus(HCV) markers served as controls.
RESULTS: Anti-HCV antibodies were found to be positive in 94% of HCC cases and 75% of CLD cases. On the other hand, HCV viremia was detected using RT-PCR in 67% of HCC cases and 65% of CLD cases. HBsAg was positive in 9% of HCC cases and 30% of CLD cases. Also bilharzial-Ab was positive in 55% of HCC cases, 65% of CLD cases and in 70% of asymptomatic carriers (ASC). HCC patients had significantly higher values of IL-2R, TNF-RII (P<0.001), and TNF-RI (P>0.05), but lower TNFα (P<0.001) and IL-6 (P = 0.032) in comparison to ASC. But, in comparison to non-cancer controls, HCC patients had higher values of IL-2R, IL-6R, TNF-RI and TNF-RII, but lower TNF-α (P<0.001). CLD patients had higher IL-2R, TNF-RI, and TNF-RII (P<0.001) than ASC. But, in comparison to non-cancer controls, CLD patients had higher values of IL-2R, TNF-RI and TNF-RII, but lower TNF-α (P<0.001). IL-10 was higher (though not significantly) in HCC and CLD patients than in symptomatic carriers and non-cancer controls.
CONCLUSION: Liver disease progression from CLD to HCC due to HCV genotype-4 infection is associated with an imbalance between Th1 and Th2 cytokines. IL-2R, TNF-RI, and TNF-RII could be used as potential markers.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Fom El-Khalig, Cairo 11796, Egypt.
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Hooper LC, Chin MS, Detrick B, Hooks JJ. Retinal degeneration in experimental coronavirus retinopathy (ECOR) is associated with increased TNF-alpha, soluble TNFR2 and altered TNF-alpha signaling. J Neuroimmunol 2005; 166:65-74. [PMID: 16039725 PMCID: PMC7112922 DOI: 10.1016/j.jneuroim.2005.05.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2005] [Accepted: 05/23/2005] [Indexed: 12/31/2022]
Abstract
Experimental coronavirus retinopathy (ECOR) is a virally triggered model of retinal degeneration composed of both genetic and autoimmune components. Since TNF-alpha plays a role in immune-mediated processes we evaluated the levels of TNF-alpha/TNF-alpha receptors and the downstream signaling molecule nitric oxide (NO) during disease in both retinal degeneration susceptible BALB/c and degeneration resistant CD-1 mice. Following coronavirus injection, TNF-alpha mRNA was detected at higher levels within the retinas, and concentrations of TNF-alpha (p<0.005) and sTNFR1 (p<0.0005) proteins were increased within the sera of BALB/c but not CD-1 mice. While concentrations of sTNFR2 proteins were elevated in both BALB/c (p<0.00005) and CD-1 (p<0.005) mice compared to controls, concentrations were higher in BALB/c mice (p<0.0005). Gene expression of iNOS while initially high in BALB/c mice decreased during the acute phase of infection, while it increased in CD-1 mice. These trends are attributable to differences in monocyte TNFR2 release (p<0.0005) between the strains since sTNFR2 decreased (p<0.01) levels of NO production. These studies demonstrate that retinal degeneration following viral infection is associated with increased release of TNF-alpha/TNF receptors combined with a down-regulation of NO. Furthermore they suggest that these molecules are involved in alterations in immune response leading to autoimmune reactivity.
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Affiliation(s)
- Laura C Hooper
- Laboratory of Immunology, Immunology and Virology Section, National Eye Institute, National Institutes of Health, NIH Bldg 10, Rm 6N228, 10 Center Drive, Bethesda, MD 20892, USA
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Morton LM, Engels EA, Holford TR, Leaderer B, Zhang Y, Zahm SH, Boyle P, Zhang B, Flynn S, Tallini G, Owens PH, Zheng T. Hepatitis C Virus and Risk of Non-Hodgkin Lymphoma: A Population-Based Case-Control Study among Connecticut Women. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.425.13.3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Objective: Previous epidemiologic studies of hepatitis C virus (HCV) infection and B-cell non-Hodgkin lymphoma (B-NHL) have yielded conflicting results, perhaps due to differences in the classification of B-NHL and the choice of non-population-based control groups that may not reflect the background population prevalence of HCV. To further investigate the link between HCV and NHL, we conducted HCV testing on serum samples of 998 women (464 cases; 534 controls) from a population-based case-control study of women in Connecticut. Methods: Serum samples were screened for HCV antibodies using an enzyme immunoassay; positive samples were confirmed by additional testing for HCV antibodies and for serum HCV RNA. Results: Approximately 2% (8 of 464) of cases and 1% (5 of 534) of controls tested positive for HCV. The risk of NHL associated with HCV infection appeared to be concentrated among B-cell lymphomas [odds ratio (OR) 2.0; 95% confidence interval (CI) 0.6, 8.2], particularly among follicular lymphomas (OR 4.1, 95% CI 0.8, 19.4). Conclusion: The primary strength of this study is our use of a population-based study design, although the low prevalence of HCV among women in Connecticut resulted in wide CIs for the estimated association between HCV and B-NHL subtypes. Our study suggests that HCV may be associated with increased risk of development of B-NHL, and that this risk may vary by B-NHL subtype among women. Due to the relatively low prevalence of HCV in our study population and the scarcity of population-based epidemiological research on this subject, our study highlights the need for additional large, population-based studies of the role of HCV in the etiology of B-NHL.
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Affiliation(s)
| | - Eric A. Engels
- 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD; and
| | | | | | - Yawei Zhang
- 1Department of Epidemiology and Public Health and
| | - Shelia Hoar Zahm
- 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD; and
| | - Peter Boyle
- 3Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Bing Zhang
- 5Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - Stuart Flynn
- 2Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Giovanni Tallini
- 2Department of Pathology, Yale University School of Medicine, New Haven, CT
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Casato M, Lilli D, Donato G, Granata M, Conti V, Del Giudice G, Rivanera D, Scagnolari C, Antonelli G, Fiorilli M. Occult hepatitis C virus infection in type II mixed cryoglobulinaemia. J Viral Hepat 2003; 10:455-9. [PMID: 14633180 DOI: 10.1046/j.1365-2893.2003.00462.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Mixed cryoglobulinaemia, when not secondary to other well-defined immunological disorders, is commonly associated with hepatitis C virus (HCV) infection. However, a minority of cases lack evidence of HCV infection and are, therefore, defined as 'true essential' mixed cryoglobulinaemias. We thoroughly investigated three such patients to determine the aetiology of this disorder. Antibodies to HCV (anti-HCV) and HCV RNA, detected by sensitive enzyme-linked immunosorbent and polymerase chain reaction assays in serum and in concentrated cryoglobulins, were repeatedly negative in the three patients. Despite the lack of evidence for HCV infection, two of them were still treated with interferon alpha-2a assuming unrecognized viral infection. Both patients demonstrated excellent clinical and laboratory responses, but cryoglobulinaemia relapsed after the withdrawal of therapy. At the time of relapse, HCV RNA genomic sequences were detected for the first time in the cryoprecipitates of both patients. In the third case, HCV RNA was demonstrated for the first time during a flare of cryoglobulinaemia coincident with varicella infection. In all three patients anti-HCV antibodies remained negative throughout follow-up. We conclude that some apparently 'essential' forms of mixed cryoglobulinaemia can be caused by occult HCV infection. Interferon therapy can be taken into consideration in such HCV-negative cases.
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Affiliation(s)
- M Casato
- Department of Clinical Medicine, University of Rome La Sapienza, Rome, Italy
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Loffreda S, Muratori P, Muratori L, Mele L, Bianchi FB, Lenzi M. Enhanced monocyte Th1 cytokine production in HCV-infected cryoglobulinemic patients. J Hepatol 2003; 38:230-236. [PMID: 12547413 DOI: 10.1016/s0168-8278(02)00353-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The etiologic link between chronic hepatitis C virus (HCV) infection and mixed cryoglobulinemia is well established, while its prognostic significance within the context of HCV-related hepatitis is not as clear. Patients with an HCV-related cryoglobulinemic syndrome oft have mild liver disease, an aspect that can be influenced by an individual's Th1/Th2 orientation. Our goal was to document stigmata of differentiate cytokine production in this subgroup of patients. METHODS Fifteen patients with chronic HCV-related liver disease (CLD) and a cryoglobulinemic syndrome (CRYO) were compared to age/sex matched CLD controls with negative cryocrit. Cultured monocytes were stimulated with either Staphylococcus aureus (SAC) or lipopolysaccharide (LPS). RESULTS The protein concentrations of TNF-alpha and of the Th1-type cytokines interleukin (IL)-12 and IL-18 were significantly greater in the CRYO group, while IL-10 (a Th2 cytokine) levels were greater in the control group. CONCLUSIONS The clinical distinctiveness of the two groups was reflected at the cytokine level. The cryoglobulinemic patients studied showed a greater Th1 polarization than their cryoglobulin-negative counterparts. This enhanced production of Th1-type cytokines is seemingly not able to rid the host of infection but may account for a milder course of liver disease.
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Affiliation(s)
- Stefano Loffreda
- Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università degli Studi di Bologna, Bologna, Italy.
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Musto P. Hepatitis C virus infection and B-cell non-Hodgkin's lymphomas: more than a simple association. CLINICAL LYMPHOMA 2002; 3:150-60. [PMID: 12521391 DOI: 10.3816/clm.2002.n.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Several studies have reported that the prevalence of the hepatitis C virus (HCV) infection is significantly overrepresented in patients affected by non-Hodgkin's lymphoma (NHL), thus suggesting that besides the well-established link with essential mixed cryoglobulinemia, a possible role for HCV is determining the development of at least some types of B-cell NHL. Such an association, however, seems to be limited to geographic areas where the presence of HCV is more relevant or endemic. According to a multistep pathogenetic model based on a large series of clinical, immunological, histological, and molecular evidences, an HCV antigen-driven polyclonal B-cell lymphoproliferation could be the initial phase of a process leading, in a variable time, into a true clonal disease. Particular genetic and environmental backgrounds could play a role in the development of a malignant phenotype, while specific HCV genotypes do not seem to be relevant in this setting. Hepatitis C virus correlated with NHL often shows some distinctive clinicopathological features, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders, extranodal localizations, and restricted histological subtypes. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant hepatic injury may predict a worse prognosis in these subjects.
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Affiliation(s)
- Pellegrino Musto
- Unit of Hematology and Stem Cell Transplantation, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy.
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