The Humoral and Cellular Immunology of Chronic Hepatitis B and C

Key Learning Objectives

  • viral infections in naive individuals induce a host response that is initially rapid and non-specific and then delayed and specific
  • vaccination leads to rapid and specific responses
  • failure of an adequate immune response can lead to persistence of infection
  • the cellular injury which results from viral infections depends on the host- viral interactions. In general, the more active the host response, the greater the cellular injury.


The “normal” response to viral hepatitis is to induce an immune response which contains or clears infection. Viral infections in naive individuals induce a host response that is initially rapid and non-specific and then delayed and specific. The non-specific initial response to foreign antigen includes immediate production and action of interferons, complement and Fc-receptor bearing cells such as natural killer (NK) cells. The non-specific response occurs within hours of the development of viremia and contains viral loads, while the specific T and B cell responses occur after days and lead to eradication of infection and provide immunity from further infection. Cytokines are important in both specific and non-specific responses, being secreted in response to endogenous or exogenous antigen or bacterial products. Cytokines may kill virally-infected cells. Complement activation is one of the earliest responses to infection. Immune complexes activate the classical pathway of complement leading to recruitment of inflammatory cells including phagocytes which can destroy pathogens. But they can also lead to immune complex damage, as in cryoglobulinemia with vasculitis and glomerulonephritis.

The specific response requires viral antigenic peptides to become associated with HLA self proteins on antigen presenting cells (e.g., hepatocytes, Kupffer Cells or macrophages) and to be recognized by specific receptors on T or B lymphocytes. The type and strength of the immune response determines whether the individual will clear infection, become immune to further infection, or develop chronic disease. The individual’s own genetic background will determine the type and strength of the immune response. The array of cytokines produced may determine whether an individual will respond favorably or unfavorably to an infection. In hepatitis C infection, many infected individuals lack a strong TH1 response, and that is thought to contribute to chronicity of disease. The virus may continually try to evade the immune response by altering its peptides (as shown in hepatitis B) or secreting cytokines or cytokine receptors. The type and strength of the host immune response will also allow spreading or limit the spread of infection. Hepatotrophic viruses are generally not cytopathic and the host immune response is responsible for both viral clearance and cellular injury.

Hepatocyte – Viral Interactions


Virally Induced Cellular Response


Hepatocyte Response

Cell lysisFulminant hepatic failure
Cellular dysfunctionAcute and Chronic Hepatitis
Induce host immune responseAcute and Chronic Hepatitis
Viral multiplication without cell damageInapparent infection- “carrier” state
Integration into host genomeHepatocellular carcinoma

The Host Response to Viral Infection


    1. Interferon
    2. Cytokines
    3. Complement
    4. Fc receptor bearing cells:



Natural Killer cells


    1. Cytotoxic T lymphocytes

Helper T lymphocytes

  1. B lymphocytes: Antibody response

Marion Peters, MD

Suggested Reading

  1. Oldstone MBA. Immune Response to Virus. In: Fields BN, Knipe DM, Howley PM, editors. Field’s Virology. 3rd ed. Philadelphia: Lippincott-Raven, 1997.
  2. Zinkernagel RM, Hengartner H. Viral immunopathology. Introduction. Springer Semin Immunopathol 1995;17:119-20.
  3. Bertoletti A, Costanzo A, Chisari FV, Levrero M, Artini M, Sette A, et al. Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J Exp Med 1994;180:933-43.
  4. Chisari FV. Cytotoxic T cells and viral hepatitis. J Clin Invest 1997;99:1472-7.
  5. Hoffmann RM, Diepolder HM, Zachoval R, Zwiebel FM, Jung MC, Scholz S, et al. Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection. Hepatology 1995;21:632-8.
  6. Peters, M. Immunologic Aspects of Liver Disease. In Schiff’s Diseases of The Liver, editors E. R. Schiff, M. F. Sorrell and W. C. Maddrey Lippincott Raven 1998;37:909-18.


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