Immunopathogenesis: Role of Innate and Adaptive Immune Responses

ABSTRACT

Hepatitis B virus (HBV) infection in immunocompetent adults usually results in a self-limited, transient liver disease and viral clearance, with only a small percentage (5 to 10%) developing chronic hepatitis associated with viral persistence. In contrast, when neonates are infected, more than 90% become persistently infected, suffering differing degrees of chronic liver disease. Activation of immunity plays a central role in host-virus interactions, greatly influencing viral replication and the clinical outcome of infection. Although all of the specific mechanisms and consequences of this interaction have not been elucidated, the purpose of this article is to describe the basic arms of the immune system as they interact with the HBV and describe the present state of knowledge in this area. These arms may be divided broadly into innate and specific immune responses, and they have different roles and responses in acute and chronic infection.

KEYWORDS

Immunoevasion - toll receptors - noncytolytic clearance - antiviral cytokines - interferons - T-cell responses

REFERENCES

• 1 Dandri M, Lutgehetmann M, Volz T, Petersen J. Small animal models for studying hepatitis B virus replication and pathogenesis.  Semin Liver Dis. 2006;  26 181-191
• 2 Zoulim F. In vitro models for studying hepatitis B virus drug resistance.  Semin Liver Dis. 2006;  26 171-180
• 3 Murray J M, Wieland S F, Purcell R H, Chisari F V. Dynamics of hepatitis B virus clearance in chimpanzees.  Proc Natl Acad Sci USA. 2005;  102 17780-17785
• 4 Guidotti L G, Rochford R, Chung J, Shapiro M, Purcell R, Chisari F V. Viral clearance without destruction of infected cells during acute HBV infection.  Science. 1999;  284 825-829
• 5 Webster G J, Reignat S, Maini M K et al.. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.  Hepatology. 2000;  32 1117-1124
• 6 Tang T J, Kwekkeboom J, Laman J D et al.. The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection.  J Viral Hepat. 2003;  10 159-167
• 7 Lascar R M, Lopes A R, Gilson R J et al.. Effect of HIV infection and antiretroviral therapy on hepatitis B virus (HBV)-specific T cell responses in patients who have resolved HBV infection.  J Infect Dis. 2005;  191 1169-1179
• 8 Hoshino K, Takeuchi O, Kawai T et al.. Cutting edge-toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.  J Immunol. 1999;  162 3749-3752
• 9 Nattermann J, Du X, Wei Y, Shevchenko D, Beutler B. Endotoxin-mimetic effect of antibodies against toll-like receptor 4.  J Endotoxin Res. 2000;  6 257-264
• 10 Muzio M, Bosisio D, Polentarutti N et al.. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells.  J Immunol. 2000;  164 5998-6004
• 11 Akira S, Sato S. Toll-like receptors and their signaling mechanisms.  Scand J Infect Dis. 2003;  35 555-562
• 12 Beutler B, Hoebe K, Du X, Ulevitch R J. How we detect microbes and respond to them: the Toll-like receptors and their transducers.  J Leukoc Biol. 2003;  74 479-485
• 13 Haynes L M, Moore D D, Kurt-Jones E A, Finberg R W, Anderson L J, Tripp R A. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus.  J Virol. 2001;  75 10730-10737
• 14 Rassa J C, Meyers J L, Zhang Y, Kudaravalli R, Ross S R. Murine retroviruses activate B cells via interaction with toll-like receptor 4.  Proc Natl Acad Sci USA. 2002;  99 2281-2286
• 15 Katze M G, He Y, Gale Jr M. Viruses and interferon: a fight for supremacy.  Nat Rev Immunol. 2002;  2 675-687
• 16 Wieland S F, Guidotti L G, Chisari F V. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice.  J Virol. 2000;  74 4165-4173
• 17 Kimura K, Kakimi K, Wieland S, Guidotti L G, Chisari F V. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice.  J Immunol. 2002;  169 5188-5195
• 18 Liu S, Khemlani L S, Shapiro R A et al.. Expression of CD14 by hepatocytes: upregulation by cytokines during endotoxemia.  Infect Immun. 1998;  66 5089-5098
• 19 Liu S, Gallo D J, Green A M et al.. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide.  Infect Immun. 2002;  70 3433-3442
• 20 Herkel J, Jagemann B, Wiegard C et al.. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocytes.  Hepatology. 2003;  37 1079-1085
• 21 Isogawa M, Robek M D, Furuichi Y, Chisari F V. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo.  J Virol. 2005;  79 7269-7272
• 22 Wieland S F, Chisari F V. Stealth and cunning: hepatitis B and hepatitis C viruses.  J Virol. 2005;  79 9369-9380
• 23 Duan X Z, Wang M, Li H W, Zhuang H, Xu D, Wang F S. Decreased frequency and function of circulating plasmocytoid dendritic cells (pDC) in hepatitis B virus infected humans.  J Clin Immunol. 2004;  24 637-646
• 24 Alexopoulou L, Holt A C, Medzhitov R, Flavell R A. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3.  Nature. 2001;  413 732-738
• 25 Sprengers D, Molen R G, Kusters J G et al.. Flow cytometry of fine-needle-aspiration biopsies: a new method to monitor the intrahepatic immunological environment in chronic viral hepatitis.  J Viral Hepat. 2005;  12 507-512
• 26 Chen Y, Wei H, Sun R, Tian Z. Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers.  Int Immunopharmacol. 2005;  5 1839-1852
• 27 Kakimi K, Guidotti L G, Koezuka Y, Chisari F V. Natural killer T cell activation inhibits hepatitis B virus replication in vivo.  J Exp Med. 2000;  192 921-930
• 28 Kimura K, Kakimi K, Wieland S, Guidotti L G, Chisari F V. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice.  J Virol. 2002;  76 10702-10707
• 29 Pasquetto V, Guidotti L G, Kakimi K, Tsuji M, Chisari F V. Host-virus interactions during malaria infection in hepatitis B virus transgenic mice.  J Exp Med. 2000;  192 529-536
• 30 Kakimi K, Lane T E, Chisari F V, Guidotti L G. Cutting edge: inhibition of hepatitis B virus replication by activated NK T cells does not require inflammatory cell recruitment to the liver.  J Immunol. 2001;  167 6701-6705
• 31 Duan Z P, Zhao X Y, Huang D Z et al.. RANTES gene single nucleotide polymorphisms and expression in patients with chronic hepatitis B virus infection.  Chin Med J (Engl). 2005;  118 909-914
• 32 Zhang P A, Li Y, Xu P, Wu J M. Polymorphisms of interleukin-1B and interleukin-1 receptor antagonist genes in patients with chronic hepatitis B.  World J Gastroenterol. 2004;  10 1826-1829
• 33 Godkin A, Davenport M, Hill A V. Molecular analysis of HLA class II associations with hepatitis B virus clearance and vaccine nonresponsiveness.  Hepatology. 2005;  41 1383-1390
• 34 Thimme R, Wieland S, Steiger C et al.. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.  J Virol. 2003;  77 68-76
• 35 Biermer M, Puro R, Schneider R J. Tumor necrosis factor alpha inhibition of hepatitis B virus replication involves disruption of capsid Integrity through activation of NF-kappaB.  J Virol. 2003;  77 4033-4042
• 36 Guidotti L G, Ishikawa T, Hobbs M V, Matzke B, Schreiber R, Chisari F V. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.  Immunity. 1996;  4 25-36
• 37 Feld J J, Heathcote E J. Hepatitis B e Antigen-positive chronic hepatitis B: natural history and treatment.  Semin Liver Dis. 2006;  26 116-129
• 38 Thio C L, Carrington M, Marti D et al.. Class II HLA alleles and hepatitis B virus persistence in African Americans.  J Infect Dis. 1999;  179 1004-1006
• 39 Wu Y F, Wang L Y, Lee T D et al.. HLA phenotypes and outcomes of hepatitis B virus infection in Taiwan.  J Med Virol. 2004;  72 17-25
• 40 Thio C L, Mosbruger T, Astemborski J et al.. Mannose binding lectin genotypes influence recovery from hepatitis B virus infection.  J Virol. 2005;  79 9192-9196
• 41 Maini M K, Boni C, Lee C K et al.. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.  J Exp Med. 2000;  191 1269-1280
• 42 Webster G J, Reignat S, Brown D et al.. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.  J Virol. 2004;  78 5707-5719
• 43 Rossol S, Marinos G, Carucci P, Singer M V, Williams R, Naoumov N V. Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B.  J Clin Invest. 1997;  99 3025-3033
• 44 Ferrari C, Penna A, Bertoletti A et al.. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection.  J Immunol. 1990;  145 3442-3449
• 45 Maini M K, Boni C, Ogg G S et al.. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.  Gastroenterology. 1999;  117 1386-1396
• 46 Rehermann B, Fowler P, Sidney J et al.. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.  J Exp Med. 1995;  181 1047-1058
• 47 Matsumura S, Yamamoto K, Shimada N et al.. High frequency of circulating HBcAg-specific CD8 T cells in hepatitis B infection: a flow cytometric analysis.  Clin Exp Immunol. 2001;  124 435-444
• 48 Hyodo N, Nakamura I, Imawari M. Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection.  Clin Exp Immunol. 2004;  135 462-466
• 49 Penna A, Chisari F V, Bertoletti A et al.. Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.  J Exp Med. 1991;  174 1565-1570
• 50 Mizukoshi E, Sidney J, Livingston B et al.. Cellular immune responses to the hepatitis B virus polymerase.  J Immunol. 2004;  173 5863-5871
• 51 Chang J J, Wightman F, Bartholomeusz A et al.. Reduced HBV-specific CD4+ T-cell responses in HIV-1-HBV co-infected individuals receiving HBV-active antiretroviral therapy.  J Virol. 2005;  79 3038-3051
• 52 Boni C, Bertoletti A, Penna A et al.. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.  J Clin Invest. 1998;  102 968-975
• 53 Malacarne F, Webster G J, Reignat S et al.. Tracking the source of the hepatitis B virus-specific CD8 T cells during lamivudine treatment.  J Infect Dis. 2003;  187 679-682
• 54 Tang T J, de Man R A, Kusters J G et al.. Intrahepatic CD8 T-lymphocytes and HBV core expression in relation to response to antiviral therapy for chronic hepatitis B patients.  J Med Virol. 2004;  72 215-222
• 55 Lai C L, Chien R N, Leung N W et al.. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.  N Engl J Med. 1998;  339 61-68
• 56 Leung N W, Lai C L, Chang T T et al.. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.  Hepatology. 2001;  33 1527-1532
• 57 Marinos G, Torre F, Chokshi S et al.. Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus.  Hepatology. 1995;  22 1040-1049
• 58 Tang T J, Kwekkeboom J, Mancham S et al.. Intrahepatic CD8+ T-lymphocyte response is important for therapy-induced viral clearance in chronic hepatitis B infection.  J Hepatol. 2005;  43 45-52
• 59 Lau G K, Piratvisuth T, Luo K X et al.. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.  N Engl J Med. 2005;  352 2682-2695
• 60 Flink H J, Sprengers D, Hansen B E et al.. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {α}-2b therapy.  Gut. 2005;  54 1604-1609
• 61 Griffith T S, Brunner T, Fletcher S M, Green D R, Ferguson T A. Fas ligand-induced apoptosis as a mechanism of immune privilege.  Science. 1995;  270 1189-1192
• 62 Limmer A, Ohl J, Kurts C et al.. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.  Nat Med. 2000;  6 1348-1354
• 63 Beckebaum S, Cicinnati V, Zhang X et al.. Hepatitis B virus-induced defect of monocyte-derived dendritic cells leads to impaired T helper type 1 response in vitro: mechanisms for viral immune escape.  Immunology. 2003;  109 487-495
• 64 van der Molen R G, Sprengers D, Binda R S et al.. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B.  Hepatology. 2004;  40 738-746
• 65 Murakami S. Hepatitis B virus X protein: a multifunctional viral regulator.  J Gastroenterol. 2001;  36 651-660
• 66 Zhou D X, Taraboulos A, Ou J H, Yen T S. Activation of class I major histocompatibility complex gene expression by hepatitis B virus.  J Virol. 1990;  64 4025-4028
• 67 Milich D, Liang T J. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.  Hepatology. 2003;  38 1075-1086
• 68 Milich D R, Wolf S F, Hughes J L, Jones J E. Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice.  Proc Natl Acad Sci USA. 1995;  92 6847-6851
• 69 Bartholomeusz A, Locarnini S. Hepatitis B virus mutants and fulminant hepatitis B: fitness plus phenotype.  Hepatology. 2001;  34 432-435
• 70 Visvanathan K, Skinner N, Locarnini S, Williams R, Riordan S M. Impaired toll-like receptor expression in chronic hepatitis B.  Gut. 2003;  52 130
• 71 Ribeiro R M, Lo A, Perelson A S. Dynamics of hepatitis B virus infection.  Microbes Infect. 2002;  4 829-835
• 72 Tedder R S, Ijaz S, Gilbert N et al.. Evidence for a dynamic host-parasite relationship in e-negative hepatitis B carriers.  J Med Virol. 2002;  68 505-512
• 73 Bonecchi R, Bianchi G, Bordignon P P et al.. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s.  J Exp Med. 1998;  187 129-134
• 74 Friedman S L. Molecular regulation of hepatic fibrosis: an integrated cellular response to tissue injury.  J Biol Chem. 2000;  275 2247-2250
• 75 Lee J Y, Chae D W, Kim S M et al.. Expression of FasL and perforin/granzyme B mRNA in chronic hepatitis B virus infection.  J Viral Hepat. 2004;  11 130-135
• 76 Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores G J. Apoptotic body engulfment by a human stellate cell line is profibrogenic.  Lab Invest. 2003;  83 655-663
• 77 Akpolat N, Yahsi S, Godekmerdan A, Demirbag K, Yalniz M. Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B.  World J Gastroenterol. 2005;  11 3260-3263
• 78 Akashi S, Shimazu R, Ogata H et al.. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages.  J Immunol. 2000;  164 3471-3475