Skip to main content

Viruses in the Human Pancreas

  • Chapter
  • First Online:
Diabetes and Viruses

Abstract

There is extensive epidemiological evidence highlighting a possible ­aetiological role for enteroviral infection in type 1 diabetes. Direct evidence of the presence of enterovirus in the pancreatic islets of type 1 diabetics is, however, limited, due mainly to the paucity of samples from patients diagnosed recently with the disease. This chapter summarises the evidence implicating enteroviral infection in the human pancreas in type 1 diabetes and considers both factors indicating the presence of virus (viral capsid protein, electron microscopic visualisation of viral particles or expression of viral RNA) and the host response to a viral infection (a “viral footprint”). The relationship of these two indicators of viral infection with two apparently different forms of type 1 diabetes (autoimmune versus fulminant) is discussed. It is hypothesised that differing host responses, and perhaps different genetic variation among the viruses involved, may determine whether an enteroviral infection of beta cells causes (1) A rapid lytic cell death—characteristic of fulminant type 1 diabetes and neonatalcoxsackievirus infection, (2) A persistent infection which evokes an autoimmune reaction to beta cells, eventually resulting in their destruction—autoimmune type 1 diabetes, (3) h little host response and little damage.

Overall, it is concluded that the evidence for viral involvement is persuasive but that there is still a long way to go in order to elucidate the precise role of enteroviral infections in the aetiology of type 1 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aida K, Nishida Y, Tanaka S, Maruyama T, Shimada A, Awata T, Suzuki M, Shimura H, Takizawa S, Ichijo M, Akiyama D, Furuya F, Kawaguchi A, Kaneshige M, Itakura J, Fujii H, Endo T, Kobayashi T (2011) RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes. Diabetes 60:884–889

    Article  PubMed  CAS  Google Scholar 

  • Andreoletti L, Hober D, Hober-Vandenberghe C, Belaich S, Vantyghem MC, Lefebvre J, Wattre P (1997) Detection of coxsackie B virus RNA sequences in whole blood samples from adult patients at the onset of type I diabetes mellitus. J Med Virol 52:121–127

    Article  PubMed  CAS  Google Scholar 

  • Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 313:353–360

    Article  PubMed  CAS  Google Scholar 

  • Chehadeh W, Kerr-Conte J, Pattou F, Alm G, Lefebvre J, Wattre P, Hober D (2000) Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J Virol 74:10153–10164

    Article  PubMed  CAS  Google Scholar 

  • Clements GB, Galbraith DN, Taylor KW (1995) Coxsackie B virus infection and onset of childhood diabetes. Lancet 346:221–223

    Article  PubMed  CAS  Google Scholar 

  • Coutant R, Carel JC, Lebon P, Bougneres PF, Palmer P, Cantero-Aguilar L (2002) Detection of enterovirus RNA sequences in serum samples from autoantibody-positive subjects at risk for diabetes. Diabet Med 19:968–969

    Article  PubMed  CAS  Google Scholar 

  • Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC (1990) Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. J Gen Virol 71:1399–1402

    Article  PubMed  Google Scholar 

  • Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Prato SD, Elliott JF, Covacci A, Rappuoli R, Roep BO, Marchetti P (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci USA 104:5115–5120

    Article  PubMed  CAS  Google Scholar 

  • Drescher KM, Kono K, Bopegamage S, Carson SD, Tracy S (2004) Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection. Virology 329:381–394

    Article  PubMed  CAS  Google Scholar 

  • Foulis AK, Stewart JA (1984) The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue. Diabetologia 26:456–461

    Article  PubMed  CAS  Google Scholar 

  • Foulis AK, Farquharson MA, Hardman R (1987a) Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30:333–343

    Article  PubMed  CAS  Google Scholar 

  • Foulis AK, Farquharson MA, Meager A (1987b) Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2:1423–1427

    Article  PubMed  CAS  Google Scholar 

  • Foulis AK, Francis ND, Farquharson MA, Boylston A (1988) Massive synchronous B-cell necrosis causing type 1 (insulin-dependent) diabetes—a unique histopathological case report. Diabetologia 31:46–50

    PubMed  CAS  Google Scholar 

  • Foulis AK, Farquharson MA, Cameron SO, McGill M, Schonke H, Kandolf R (1990) A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with type 1 (insulin-dependent) diabetes and pancreases and hearts of infants who died of coxsackieviral myocarditis. Diabetologia 33:290–298

    Article  PubMed  CAS  Google Scholar 

  • Foulis AK, McGill M, Farquharson MA, Hilton DA (1997) A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia 40:53–61

    Article  PubMed  CAS  Google Scholar 

  • Gladisch R, Hofmann W, Waldherr R (1976) Myocarditis and insulitis following coxsackie virus infection. Z Kardiol 65:837–849

    PubMed  CAS  Google Scholar 

  • Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci USA 89:314–318

    Article  PubMed  CAS  Google Scholar 

  • Lonnrot M, Salminen K, Knip M, Savola K, Kulmala P, Leinikki P, Hyypia T, Akerblom HK, Hyoty H (2000) Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group. J Med Virol 61:214–220

    Article  PubMed  CAS  Google Scholar 

  • Moya-Suri V, Schlosser M, Zimmermann K, Rjasanowski I, Gurtler L, Mentel R (2005) Enterovirus RNA sequences in sera of schoolchildren in the general population and their association with type 1-diabetes-associated autoantibodies. J Med Microbiol 54:879–883

    Article  PubMed  CAS  Google Scholar 

  • Nairn C, Galbraith DN, Taylor KW, Clements GB (1999) Enterovirus variants in the serum of children at the onset of type 1 diabetes mellitus. Diabet Med 16:509–513

    Article  PubMed  CAS  Google Scholar 

  • Oikarinen M, Tauriainen S, Honkanen T, Vuori K, Karhunen P, Vasama-Nolvi C, Oikarinen S, Verbeke C, Blair GE, Rantala I, Ilonen J, Simell O, Knip M, Hyoty H (2008) Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia 51:1796–1802

    Article  PubMed  CAS  Google Scholar 

  • Pujol-Borrell R, Todd I, Doshi M, Gray D, Feldmann M, Bottazzo GF (1986) Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. Clin Exp Immunol 65:128–139

    PubMed  CAS  Google Scholar 

  • Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG (2009) The prevalence of enteroviral capsid protein VP1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 52:1143–1151

    Article  PubMed  CAS  Google Scholar 

  • Richardson SJ, Willcox A, Bone AJ, Morgan NG, Foulis AK (2011) Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol 33:9–21

    Article  PubMed  CAS  Google Scholar 

  • Sarmiento L, Cabrera-Rode E, Lekuleni L, Cuba I, Molina G, Fonseca M, Heng-Hung L, Borroto AD, Gonzalez P, Mas-Lago P, Diaz-Horta O (2007) Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes. Autoimmunity 40:540–545

    Article  PubMed  CAS  Google Scholar 

  • Schulte BM, Bakkers J, Lanke KH, Melchers WJ, Westerlaken C, Allebes W, Aanstoot HJ, Bruining GJ, Adema GJ, Van Kuppeveld FJ, Galama JM (2010) Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. Viral Immunol 23:99–104

    Article  PubMed  CAS  Google Scholar 

  • Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, Okada Y, Uno S, Murase-Mishiba Y, Terasaki J, Makino H, Shimomura I, Hyoty H, Hanafusa T (2010) Expression of Toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr J 57:211–219

    Article  PubMed  CAS  Google Scholar 

  • Tam PE, Messner RP (1999) Molecular mechanisms of coxsackievirus persistence in chronic inflammatory myopathy: viral RNA persists through formation of a double-stranded complex without associated genomic mutations or evolution. J Virol 73:10113–10121

    PubMed  CAS  Google Scholar 

  • Tanaka S, Nishida Y, Aida K, Maruyama T, Shimada A, Suzuki M, Shimura H, Takizawa S, Takahashi M, Akiyama D, Arai-Yamashita S, Furuya F, Kawaguchi A, Kaneshige M, Katoh R, Endo T, Kobayashi T (2009) Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes 58:2285–2291

    Article  PubMed  CAS  Google Scholar 

  • Tauriainen S, Oikarinen S, Oikarinen M, Hyoty H (2011) Enteroviruses in the pathogenesis of type 1 diabetes. Semin Immunopathol 33:45–55

    Article  PubMed  CAS  Google Scholar 

  • Tracy S, Drescher KM, Jackson JD, Kim K, Kono K (2010) Enteroviruses, type 1 diabetes and hygiene: a complex relationship. Rev Med Virol 20:106–116

    Article  PubMed  CAS  Google Scholar 

  • Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2009) Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 155:173–181

    Article  PubMed  CAS  Google Scholar 

  • Willcox A, Richardson SJ, Bone AJ, Foulis A, Morgan NG (2011) Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes. Diabetologia 54:2417–2420

    Article  PubMed  CAS  Google Scholar 

  • Yin H, Berg AK, Tuvemo T, Frisk G (2002) Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset. Diabetes 51:1964–1971

    Article  PubMed  CAS  Google Scholar 

  • Ylipaasto P, Klingel K, Lindberg AM, Otonkoski T, Kandolf R, Hovi T, Roivainen M (2004) Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47:225–239

    Article  PubMed  CAS  Google Scholar 

  • Yoon JW, Austin M, Onodera T, Notkins AL (1979) Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 300:1173–1179

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. J. Richardson Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Richardson, S.J., Willcox, A., Bone, A.J., Morgan, N.G., Foulis, A.K. (2013). Viruses in the Human Pancreas. In: Taylor, K., Hyöty, H., Toniolo, A., Zuckerman, A. (eds) Diabetes and Viruses. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4051-2_17

Download citation

Publish with us

Policies and ethics