Chapter 40 : Viruses, Autoimmunity, and Cancer

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Viruses, Autoimmunity, and Cancer, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap40-1.gif /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap40-2.gif


The autoimmune disorder multiple sclerosis (MS) is an instructive example in which several pieces of evidence suggest that a microbial infection is the trigger for disease, with most evidence pointing to viral infections. Initial trigger of an autoimmune response could occur through several mechanisms, including molecular mimicry, bystander activation, epitope spreading, or super-antigen activation. In 1964, Epstein-Barr virus (EBV) was demonstrated to be caused by virus infection by electron microscopy in cells cultured from Burkitt's lymphoma, but it was not until the early 1980s that the causal relationship between other viruses and cancer was acknowledged. Human papillomaviruses (HPV) can be used a model to illustrate how a virus can induce cancer. The molecular pathogenesis of cancer caused by the high-risk HPV types is not fully understood and, although they are self-sufficient to induce carcinogenesis, the infection itself is not able to induce the malignant transformation of infected cells. For a very long time, polyomaviruses (PyV) have been proposed to have a causal link with cancer, because under experimental conditions, cells which are nonpermissive for viral replication can be transformed by PyVs. Over the past decades, more and more viruses have been causally linked to different forms of human and animal cancer. Today, one cancer case in five is caused by an infectious agent. With techniques developing rapidly, more associations between viruses and malignancies can be expected in the coming years.

Citation: Getts M, Bogaert L, Kast W, Miller S. 2011. Viruses, Autoimmunity, and Cancer, p 511-520. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch40
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Mechanisms of infection-induced autoimmunity. Circulating T cells are generally specific for some pathogen-derived or otherwise foreign antigen (virus antigen recognized by a virus-specific T cell, in the example here); however, some circulating T cells also possess a capacity for recognizing self-tissues (autoreactive T cell). A virus infection (for example) could elicit autoimmunity through several mechanisms. Molecular mimicry (A) occurs when T cells are cross-reactive with self and viral antigens, so that a viral infection can activate a T cell that is capable of recognizing a self-antigen as foreign. Bystander activation (B) occurs when tissue damage results in the release of self-antigens that are recognized by autoreactive cells. Such tissue damage could occur due to inflammatory mediators, including cytokines that are released by infected cells and other cells detecting the presence of a pathogen through PAMPs. By extension, epitope spreading can occur when the autoreactive response spreads to other self-antigens, exacerbating the autoimmune process. Superantigen-induced activation of autoreactive cells (C) could occur if autoreactive cells are present within the population of T cells that are nonspecifically activated by a superantigen.

Citation: Getts M, Bogaert L, Kast W, Miller S. 2011. Viruses, Autoimmunity, and Cancer, p 511-520. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch40
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Barbanti-Brodano, G.,, S. Sabbioni,, F. Martini,, M. Negrini,, A. Corallini, and, M. Tognon. 2004. Simian virus 40 infection in humans and association with human diseases: results and hypotheses. Virology 318: 19.
2. Berkhout, R. J.,, J. N. Bouwes Bavinck, and, J. ter Schegget. 2000. Persistence of human papillomavirus DNA in benign and (pre)malignant skin lesions from renal transplant recipients. J. Clin. Microbiol. 38: 20872096.
3. Christen,, U.,, K. H. Edelmann,, D. B. McGavern,, T. Wolfe,, B. Coon,, M. K. Teague,, S. D. Miller,, M. B. Oldstone, and, M. G. von Herrath. 2004. A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J. Clin. Invest. 114: 12901298.
4. Croxford,, J. L.,, J. K. Olson,, H. A. Anger, and, S. D. Miller. 2005. Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis. J. Virol. 79: 85818590.
5. de Jong, A.,, M. I. van Poelgeest,, J. M. van der Hulst,, J. W. Drijfhout,, G. J. Fleuren,, C. J. Melief,, G. Kenter,, R. Offringa, and, S. H. van der Burg. 2004. Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6. Cancer Res. 64: 54495455.
6. de Martel, C., and, S. Franceschi. 2009. Infections and cancer: established associations and new hypotheses. Crit. Rev. Oncol. Hematol. 70: 183194.
7. Dunn,, G. P.,, A. T. Bruce,, H. Ikeda,, L. J Old, and, R. D. Schreiber. 2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3: 991998.
8. Engels, E. A. 2009. Non-AIDS-defining malignancies in HIV-infected persons: etiologic puzzles, epidemiologic perils, prevention opportunities. AIDS 23: 875885.
9. Fausch,, S. C.,, D. M. Da Silva,, M. P. Rudolf, and, W. M. Kast. 2002. Human papillomavirus virus-like particles do not activate Langerhans cells: a possible immune escape mechanism used by human papillomaviruses. J. Immunol. 169: 32423249.
10. Feng, H.,, M. Shuda,, Y. Chang, and, P. S. Moore. 2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319: 10961100.
11. Fujinami, R. S., and, M. B. Oldstone. 1985. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230: 10431045.
12. Fujinami,, R. S.,, M. B. Oldstone,, Z. Wroblewska,, M. E Frankel, and, H. Koprowski. 1983. Molecular mimicry in virus infection: crossreaction of measles virus phosphoprotein or of herpes simplex virus protein with human intermediate filaments. Proc. Natl. Acad. Sci. USA 80: 23462350.
13. Gauntt, C. J.,, H. M. Arizpe,, A. L. Higdon,, H. J. Wood,, D. F. Bowers,, M. M. Rozek, and, R. Crawley. 1995. Molecular mimicry, anti-coxsackievirus B3 neutralizing monoclonal antibodies, and myocarditis. J. Immunol. 154: 29832995.
14. Giannini, S. L.,, P. Hubert,, J. Doyen,, J. Boniver, and, P. Delvenne. 2002. Influence of the mucosal epithelium microenvironment on Langerhans cells: implications for the development of squamous intraepithelial lesions of the cervix. Int. J. Cancer. 97: 654659.
15. Greene,, M. T.,, A. M. Ercolini,, M. Degutes, and, S. D. Miller. 2008. Differential induction of experimental autoimmune encephalomyelitis by myelin basic protein molecular mimics in mice humanized for HLA-DR2 and an MBP(85-99)-specific T cell receptor. J. Autoimmun. 31: 399407.
16. Grulich,, A. E.,, M. T. van Leeuwen,, M. O. Falster, and, C. M. Vajdic. 2007. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370: 5967.
17. Hildesheim, A., and, S. S. Wang. 2002. Host and viral genetics and risk of cervical cancer: a review. Virus Res. 89: 229240.
18. Ishii,, K. J.,, S. Koyama,, A. Nakagawa,, C. Coban, and, S. Akira. 2008. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 3: 352363.
19. Javier, R. T., and, J. S. Butel. 2008. The history of tumor virology. Cancer Res. 68: 76937706.
20. Kalland, K. H., X. S. Ke, and, A. M. Oyan. 2009. Tumour virology—history, status and future challenges. APMIS 117: 382399.
21. Kanodia, S., L. M. Fahey, and, W. M. Kast. 2007. Mechanisms used by human papillomaviruses to escape the host immune response. Curr. Cancer Drug Tar. 7: 7989.
22. Kurtzke, J. F. 1993. Epidemiologic evidence for multiple sclerosis as an infection. Clin. Microbiol. Rev. 6: 382427.
23. Lawson, C. M. 2000. Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis. Cell. Mol. Life Sci. 57: 552560.
24. Lee, W., and, E. Langhoff. 2006. Polyomavirus in human cancer development. Adv. Exp. Med. Biol. 577: 310318.
25. Lunemann,, J. D.,, I. Jelcic,, S. Roberts,, A. Lutterotti,, B. Tackenberg,, R. Martin, and, C. Munz. 2008. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J. Exp. Med. 205: 17631773.
26. McLaughlin-Drubin, M. E., and, K. Munger. 2008. Viruses associated with human cancer. Biochim. Biophys. Acta 1782: 127150.
27. Miller, S. D.,, C. L. Vanderlugt,, W. S. Begolka,, W. Pao,, R. L. Yauch,, K. L. Neville,, Y. Katz-Levy,, A. Carrizosa, and, B. S. Kim. 1997. Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat. Med. 3: 11331136.
28. Mokhtarian, F.,, Z. Zhang,, Y. Shi,, E. Gonzales, and, R. A. Sobel. 1999. Molecular mimicry between a viral peptide and a myelin oligodendrocyte glycoprotein peptide induces autoimmune demyelinating disease in mice. J. Neuroimmunol. 95: 4354.
29. Munz, C.,, J. D. Lunemann,, M. T. Getts, and, S. D. Miller. 2009. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat. Rev. Immunol. 9: 246258.
30. Ohashi,, P. S.,, S. Oehen,, K. Buerki,, H. Pircher,, C. T Ohashi,, B. Odermatt,, B. Malissen,, R. M. Zinkernagel, and, H. Hengartner. 1991. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65: 305317.
31. Oldstone,, M. B.,, M. Nerenberg,, P. Southern,, J. Price, and, H. Lewicki. 1991. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65: 319331.
32. Oldstone, M. B., M. von Herrath, C. F. Evans, and, M. S. Horwitz. 1996. Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and multiple sclerosis. Curr. Top. Microbiol. Immunol. 206: 6783.
33. Olson,, J. K.,, J. L. Croxford,, M. Calenoff,, M. C. Dal Canto, and, S. D. Miller. 2001. A virus-induced molecular mimicry model of multiple sclerosis. J. Clin. Invest. 108: 311318.
34. Orth, G. 2006. Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin. Immunol. 18: 362374.
35. Parkin, D. M. 2006. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer. 118: 30303044.
36. Patel, S., and, S. Chiplunkar. 2009. Host immune responses to cervical cancer. Curr. Opin. Obstet. Gynecol. 21: 5459.
37. Persing, D. H., and, F. G. Prendergast. 1999. Infection, immunity, and cancer. Arch. Pathol. Lab. Med. 123: 10151022.
38. Salvetti, M., G. Giovannoni, and, F. Aloisi. 2009. Epstein-Barr virus and multiple sclerosis. Curr. Opin. Neurol. 22: 201206.
39. Sheu,, B. C.,, W. C. Chang,, H. H. Lin,, S. N. Chow, and, S. C. Huang. 2007. Immune concept of human papillomaviruses and related antigens in local cancer milieu of human cervical neoplasia. J. Obstet. Gynaecol. Res. 33: 103113.
40. Stanley, M. 2008. Immunobiology of HPV and HPV vaccines. Gynecol. Oncol. 109: S1521.
41. Sterling, J. C. 2005. Human papillomaviruses and skin cancer. J. Clin. Virol. 32: S67S71.
42. Tai,, A. K.,, E. J. O’Reilly,, K. A. Alroy,, K. C. Simon,, K. L. Munger,, B. T. Huber, and, A. Ascherio. 2008. Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis. Mult. Scler. 14: 11751180.
43. Tejada-Simon,, M. V.,, Y. C. Zang,, J. Hong,, V. M Rivera, and, J. Z. Zhang. 2003. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann. Neurol. 53: 189197.
44. Tibbetts,, R. S.,, T. S. McCormick,, E. C. Rowland,, S. D. Miller, and, D. M. Engman. 1994. Cardiac antigen-specific autoantibody production is associated with cardiomyopathy in Trypanosoma cruzi-infected mice. J. Immunol. 152: 14931499.
45. Tindle, R. W. 2002. Immune evasion in human papillomavirus-associated cervical cancer. Nat. Rev. 2: 5965.
46. Vanderlugt, C. L., and, S. D. Miller. 2002. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2: 8595.
47. Visser, J.,, H. W. Nijman,, B. N. Hoogenboom,, P. Jager,, D. van Baarle,, E. Schuuring,, W. Abdulahad,, F. Miedema,, A. G. van der Zee, and, T. Daemen. 2007. Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia. Clin. Exp. Immunol. 150: 199209.
48. Wucherpfennig, K. W. 2001. Mechanisms for the induction of autoimmunity by infectious agents. J. Clin. Invest. 108: 10971104.
49. Wucherpfennig, K. W., and, J. L. Strominger. 1995. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80: 695705.
50. Zhao,, Z. S.,, F. Granucci,, L. Yeh,, P. A. Schaffer, and, H. Cantor. 1998. Molecular mimicry by herpes simplex virustype 1: autoimmune disease after viral infection. Science 279: 13441347.
51. Zipris, D. 2009. Epidemiology of type 1 diabetes and what animal models teach us about the role of viruses in disease mechanisms. Clin. Immunol. 131: 1123.
52. zur Hausen, H. 1999. Viruses in human cancers. Eur. J. Cancer. 35: 18781885.
53. zur Hausen, H. 2002. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. 2: 342350.
54. zur Hausen, H. 2008. Novel human polyomaviruses— re-emergence of a well known virus family as possible human carcinogens. Int. J. Cancer. 123: 247250.


Generic image for table

Selected murine models of infection-induced autoimmune diseases

Citation: Getts M, Bogaert L, Kast W, Miller S. 2011. Viruses, Autoimmunity, and Cancer, p 511-520. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch40
Generic image for table

Selected autoimmune diseases and their proposed viral associations and potential mechanisms

Citation: Getts M, Bogaert L, Kast W, Miller S. 2011. Viruses, Autoimmunity, and Cancer, p 511-520. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch40
Generic image for table

Criteria for defining a causal role for an infection in cancer

Citation: Getts M, Bogaert L, Kast W, Miller S. 2011. Viruses, Autoimmunity, and Cancer, p 511-520. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch40

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error