Chapter 15 : The Possible Role of Enteroviruses in Diabetes Mellitus

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The Possible Role of Enteroviruses in Diabetes Mellitus, Page 1 of 2

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Insulin-dependent diabetes mellitus (IDDM) is the most common severe chronic childhood illness, affecting an estimated 123,000 children in the United States. Picornaviruses have long been examined for their role as the primary etiologic agent in the pathogenesis of IDDM. Encephalomyocarditis virus (EMCV), a murine picornavirus, produces acute lytic infection of pancreatic β cells and diabetes whose severity correlates with the degree of β-cell lysis. An alternative innocent bystander theory proposes that local inflammation in the peri-insular tissue may induce molecules on the surface of β-cells that enteroviruses could use as cellular receptors. Well-established models of persistent viral infection leading to IDDM include reovirus type 1-induced diabetes and lymphocytic choriomeningitis virus (LCMV)-induced diabetes in mice as well as congenital rubella syndrome (CRS) in humans. Much of what is known concerning tropism of enteroviruses to the human pancreas has been learned from autopsy studies of newborns and infants who died of fulminant enteroviral infection. A large prospective study of young children monitored for concurrent development of enteroviral infections and β-cell autoimmunity is needed to test the hypothesis that symptomatic and/or serologically detectable enteroviral infection is associated with development of IDDM or β-cell autoimmunity. At present, it is not known, whether a single pathogenic mechanism is responsible for diabetes induced by various picornaviruses or whether diabetes can result from a spectrum of picornavirus-induced lesions, e.g., acute β-cell lysis, chronic autoimmunity, or insulin secretion defect. The rate of spontaneous mutation for enteroviruses is as high as 10 .

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15

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Image of FIGURE 1

Molecular homology between GAD and coxsackievirus P2-C. Solid lines enclose identical amino acid residues. Dashed lines enclose residues with similar charges, polarities, or hydrophobicities. Reproduced from the ( ), by copyright permission of the American Society for Clinical Investigation.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 2

Incidences of IDDM (thin line) and enteroviral meningitis (EVM) (heavy line) in Wielkopolska, Poland, (a) Children aged 0 through 4 years; (b) children aged 5 through 9 years; (c) children aged 10 through 14 years.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 3

Incidence of IDDM (thin line) and enteroviral meningitis (EVM) (thick line) in Wielkopolska, Poland, 1980 through 1988. The IDDM curve reflects 3-month moving averages. The dominant serotypes of enteroviruses cultured from or determined serologically in the meningitis cases are shown. E, echovirus; B5, CVB5.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 4

Incidence of IDDM in the age group 0 through 14 years in Norway, Colorado, and Poland in 1978 through 1980, showing significant geographic differences in incidence rates.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 5

Age distribution of enteroviral meningitis in Norway, Colorado, and Poland. The high incidence of enteroviral meningitis in the age group 0 through 14 years in Poland (low IDDM risk) compared to those in Colorado (moderate IDDM risk) and Norway (high IDDM .risk) supports the polio model of IDDM etiology.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 6

Age distribution of enteroviral meningitis inWielkopolska, Poland. There was no evidence for a change in distribution during the epidemic year (1982) compared to that in the nonepidemic years (1979 through 1981 and 1983).

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 7

Incidence of IDDM and enteroviral meningitis (AM) in Colorado, 1978 through 1988. The incidence of IDDM paralleled that of enteroviral meningitis in lower-income Hispanics but not in higher-income non-Hispanic white children.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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1. Ahmad, N.,, and A. A. Abraham. 1982. Pancreatic isleitis with coxsackie virus B5 infection. Hum. Pathol. 13:661662.
2. Allen, C.,, M. Paha,, and D. J. D'Alessio. 1991. Risk of diabetes in siblings and other relatives of IDDM subjects. Diabetes 40:831836.
3. Anderson, H. U.,, K. H. Jorgensen,, J. Egeberg,, T. Mandrup-Poulsen,, and J. Nerup. 1994. Nicotinamide prevents interleukin-1 effects on accumulated insulin release and nitric oxide production in rat islets of Langerhans. Diabetes 43:770777.
4. Anderson, O. O.,, M. Christy,, K. Arnung,, K. Buschard,, B. Christau,, H. Kromann,, J. Herup,, P. Platz,, L. P. Ryder,, A. Svejgaard,, and M. Thomsen,. 1977. Viruses and diabetes, p. 294298. In J. S. Baja (ed.), Diabetes. Excerpta Medica, Amsterdam.
5. Archard, L. C.,, N. E. Bowles,, E. G. J. Olsen,, and P.J. Richardson. 1987. Detection of persistent coxsackie B virus RNA in dilated cardiomyopathy and myocarditis. Eur. Heart. J. 8(Suppl. J):437440.
6. Asplin, C. M.,, M. K. Cooney,, J. R. Crossley,, T. L. Dornan,, P. Raghu,, and J. P. Palmer. 1982. Coxsackie B4 infection and islet cell antibodies three years before overt diabetes. J. Pediatr. 101:398400.
6a. Atkinson, M. A., et al. Unpublished observations.
7. Atkinson, M. A.,, M. Bowman,, B. Darrow,,and D. Kaufman. 1994. Cellular immunity to an epitope common to glutamate decarboxylase (GAD) and coxsackie virus in insulin dependent diabetes (IDD). Diabetes 43(Suppl. 1):93A.
8. Atkinson, M. A.,, D. L. Kaufman,, L. Campbell,, A. J. Tobin,, and N. K. Maclaren. 1993. Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin dependent diabetes. J. Clin. Invest. 91:350356.
9. Bae, Y.-S.,, and J.-W. Yoon. 1993. Determination of diabetogenicity attributable to a single amino acid Ala776, on the polyprotein of encephalomyocarditis virus. Diabetes 42:435443.
10. Baekkeskov, S.,, M. Landin,, J. K. Kristensen,, S. Srikanta,, G. J. Bruining,, T. Mandrup-Poulsen,, C. De Beaufort,, J. S. Soeldner,, G. Eisenbarth,, E. Lindgren, et al. 1987. Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes. J. Clin. Invest. 79:926934.
10a. Baekkeskov, S.,, H. Jan-Aanstoot,, S. Christgau,, A. Reetz,, M. Solimena,, M. Cascalho,, E. Folli,, H. Richter-Olesen,, and P. De-Camilli. 1990. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature (London) 347:151156.
11. Baekkeskov, S.,, J. H. Nielsen,, B. T. Marner,, J. Bilde,, Ludvigsson,, and A. Lernmark. 1982. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature (London) 298:167169.
12. Banatvala, J. E. 1987. Insulin-dependent (juvenile-onset, type 1) diabetes mellitus coxsackie B viruses revisited. Prog. Med. Virol. 34:3354.
13. Banatvala, J. E.,, J. Bryant,, G. Schernthaner,, M. Borkenstein,, E. Schober,, D. Brown,, L. M. DeSilva,, M. A. Menser,, and M. Silink. 1985. Coxsackie B, mumps, rubella, and cytomegalovirus specific IgM responses in patients with juvenile-onset insulin-dependent diabetes mellitus in Britain, Austria, and Australia. Lancet i:14091412.
14. Barmeier, H.,, D. K. McCulloch,, J. L. Neifing,, G. Warnock,, R. V. Rajotte,, J. P. Palmer,, and A. Lernmark. 1991. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 34:727733.
15. Barrett-Connor, E. 1985. Is insulin-dependent diabetes mellitus caused by coxsackie virus B infection? A review of the epidemiologic evidence. Rev. Infect. Dis. 7:207215.
16. Bell, G. I.,, S. Horita,, and J. H. Karam. 1984. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176183.
17. Bertrams, J.,, and M. P. Baur,. 1984. Insulin-dependent diabetes mellitus, p. 348358. In E. D. Albert (ed.), Histocompatibility Testing 1984. Springer-Verlag, Berlin.
18. Blom, L.,, L. Nystrom,, and G. Dahlquist. 1991. The Swedish childhood diabetes study. Vaccinations and infections as risk determinants for diabetes in childhood. Diabetologia 34:176181.
19. Bodansky, H. J.,, P. J. Grant,, B. M. Dean,, J. McNally,, G. E Bottazzo,, M. H. Hambling,, and J. K. Wales. 1986. Islet-cell antibodies and insulin autoantibodies in association with common viral infections. Lancet ii:13511353.
20. Boehm, B. O.,, B. Manfras,, J. Seissler,, K. Schoffling,, M. Gluck,, G. Holzberger,, S. Seidl,, P. Kuhnl,, M. Trucco,, and W. A. Scherbaum. 1991. Epidemiology and immunogenetic background of islet cell antibody-positive nondiabetic schoolchildren. Ulm-Frankfurt population study. Diabetes 40:14351439.
21. Bonifacio, E.,, P. J. Bingley,, M. Shattock,, B. M. Dean,, D. Dunger,, E. A. M. Gale,, and G. E Bottazzo. 1990. Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes. Lancet 335:147149.
22. Bonnevie-Nielsen, V.,, M. L. Larsen,, J. J. Frifelt,, B. Michelsen,, and A. Lernmark. 1989. Association of IDDM and attenuated response of 2',5'-oligoadenylate synthetase to yellow fever vaccine. Diabetes 38:16361642.
23. Boucher, D. W.,, K. Hayashi,, J. Rosenthal,, and A. L. Notkins. 1975.Virus-induced diabetes mellitus. III. Influence of sex and strain of the host. J. Infect. Dis. 131:462466.
24. Bouter, K. P.,, R. J. A. Diepersloot,, P. J. Wismans, et al. 1992. Humoral immune response to a yeast-derived hepatitis B vaccine in patients with type 1 diabetes mellitus. Diabetic Med. 9:6669.
25. Bruserud, O.,, J. Jervell,, and E. Thorsby. 1985. HOLA-DR3 and -DR4 control T-lymphocyte responses to mumps and coxsackie B4 virus: studies on patients with type 1 (insulin-dependent) diabetes and healthy subjects. Diabetologia 28:420426.
26. Bruserud, O.,, and E. Thorsby. 1985. T lymphocyte responses to coxsackie B4 and mumps virus. I. Influence of HLA-DR restriction elements. Tissue Antigens 26:4150.
27. Bu, D. E.,, M. G. Erlander,, B. C. Hitz,, N. J. K. Tillakaratne,, D. L. Kaufman,, C. B. Wagner-McPherson,, G. A. Evans,, and A. J. Tobin. 1992. Two human glutamates decarboxylases, GAD 65 and GAD 67, are each en-coded by a single gene. Proc. Natl. Acad. Sci. USA 89:21152119.
28. Buesa-Gomez, J.,, C. J. de la Torre,, T. Dyrberger,, M. Landin-Olsson,, R. S. Mauseth,, A. Lernmark,, and M. B. A. Oldstone. 1994. Failure to detect genomic viral sequences in pancreatic tissues from two children with acute-onset diabetes mellitus.J Med. Virol. 42:193197.
29. Burrows, R. 1966. Studies on the carrier state of cattle exposed to foot-and-mouth disease virus. J. Hyg. Camb. 64:8190.
30. Caggana, M.,, R. Chan,, and A. Ramsingh. 1993. Identification of a single amino acid residue in the capsid protein VP1 of coxsackievirus B4 that determines the virulent phenotype.J. Virol. 67:47974803.
31. Campbell, I. L.,, A. Cutri,, D. Wilkinson,, A. W. Boyd,, and L. C. Harrison. 1989. Intracellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. Proc. Natl. Acad. Sci. USA 86:4282.
32. Cao, Y.,, and D. R Schnurr. 1988. Persistent infection ofYAC-1 cells by coxsackie virus B3. J. Gen. Virol. 69:5965.
33. Champsaur, H. F.,, G. F. Bottazzo,, J. Bertrams,, R. Assan,, and C. Bach. 1982. Virologic, immunologic, and genetic factors in insulin-dependent diabetes mellitus.J. Pediatr. 100:1520.
34. Chase, H. R.,, M. A. Voss,, N. Butler-Simon,, S. Hoops,, D. O'Brien,, and M.J. Doberson. 1987. Diagnosis ofpre-type 1 diabetes.J. Pediatr. 111:807812.
35. Chatterjee, N. K.,, J. Hou,, R. Dockstader,, and T. Charbonneau. 1992. Coxsackievirus B4 infection alters thymic, splenic, and peripheral lymphocyte repertoire preceding onset of hyperglycemia in mice. J. Med. Virol. 38:124131.
36. Chatterjee, N. K.,, C. Nejman,, and I. Gerling. 1988. Purification and characterization of a strain of coxsackievirus B4 of human origin that induces diabetes in mice. J. Med. Virol. 26:5769.
37. Christau, B.,, and A. G. Molbak. 1984. Further epidemiological evidence of a higher incidence level for the insulin-dependent diabetes mellitus in the older age groups. Acta Endocrinol. 95(Suppl. 263):18.
38. Craighead, J. E.,, S. A. Huber,, and S. Sriram. 1990. Animal models of picornavirus-induced autoimmune disease: their possible relevance to human disease. Lab. Invest. 63:432446.
39. Craighead, J. E.,, and M. F. McLane. 1968. Diabetes mellitus: induction in mice by encephalomyocarditis virus. Science 162:913915
40. Craighead, J. E.,, and J. Steinke. 1969. Temporary diabetes in mice caused by encephalomyocarditis virus. Clin. Res. 17:380.
41. Craighead, J. E.,, and J. Steinke. 1971. Diabetes mellitus-hke syndrome in mice infected with encephalomyocarditis virus. Am. J. Pathol. 63:119134.
42. Cudworth, A. G.,, D. R. Gamble,, G. B. B. White,, R. Lendrum,, J. C. Woodrow,, and A. Bloom. 1977. Aetiology of juvenile-onset diabetes: a prospective study. Lancet i:385388.
42a. Dahlquist, G., et al. Unpublished data.
43. D'Alessio, D.J. 1992.A case-control study of group B coxsackievirus immunoglobulin M antibody prevalence and HLA-DR antigens in newly diagnosed cases of insulin-dependent diabetes mellitus. Am.J. Epidemiol. 135:13311338.
44. D'Andrea, B. J.,, G. L. Wilson,, and J. E. Craighead. 1981. Effect of genetic obesity in mice on the induction of diabetes by encephalomyocarditis virus. Diabetes 30:451.
45. delaTorre, J. C.,, M. Davila,, E. Sobrino,, J. Ortin,, and E. Domingo. 1985. Establishment of cell lines persistently infected with foot-and-mouth disease virus. Virology 145:2435.
46.Diabetes Epidemiology Research International Group. 1988. Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes 37:11131119.
47.Diabetes Epidemiology Research International Group. 1990. Secular trends in incidence of childhood IDDM in 10 countries. Diabetes 39:858864.
48. Diepersloot, R. J. A.,, K. R Bouter,, W. E. R Beyer,, J. L. B. Hoekstra,, and N. Masurel. 1987. Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus. Diabetologia 30:97100.
49. Dippe, S. E.,, R. H. Bennett,, M. Miller,, J. E. Maynard,, and K. R. Berquist. 1975. Lack of causal association between coxsackie B4 virus infection and diabetes. Lancet i:13141317.
49a. Dorman, J. S. 1993. Personal communication.
50. Dronfield, D. M. 1993. Changes in serum insulin and islet cell antibodies following an outbreak of echovirus 4 in Glasgow. Diabetic Med. 10(Suppl. 1):S41.
51. Durruty, O.,, E. Ruiz,, and M. Garcia de los Rios. 1979. Age at diagnosis and seasonal variation in the onset of insulin-dependent diabetes in Chile (southern hemisphere). Diabetologia 17:357360.
52. Eberhardt, M. S.,, D. K. Wagener,, T. J. Orchard,, R. E. LaPorte,, D. E. Cavender,, B. S. Rabin,, R. W. Atchison,, L. H. Kuller,, A. L. Drash,, and D. J. Becker. 1985. HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis. The Pittsburgh IDDM Study. Diabetes 34:12471252.
53. Elias D.,, H. Prigozin,, N. Polak,, M. Rapoport,, A. W. Lohse,, and I. R. Cohen. 1994. Autoimmune diabetes induced by the β cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin. Diabetes 43:992998.
54. Erdo, S. L.,, and J. R. Wolff. 1990. Gamma-aminobutyric acid outside the mammalian brain. J. Neurochem. 54:363372.
55. Fohlman, J.,, J. Bohme,, L. Rask,, G. Frisk,, H. Diderholm,, G. Friman,, and T. Tuvemo. 1987. Matching of host genotype and serotypes of coxsackie B virus in the development of juvenile diabetes. Scand.J. Immunol. 26:105110.
56. Forrest, J. M.,, M. A. Menser,, and J. A. Burgess. 1971. High frequency of diabetes mellitus in young adults with congenital rubella. Lancet ii:332334.
57. Foulis, A. K.,, M. A. Farquharson,, S. O. Cameron,, M. McGill, Schonke, and R. Kandolf. 1990. A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with type 1 (insulin-dependent) diabetes of coxsackieviral myocarditis. Diabetologia 33:290298.
58. Foulis, A. K.,, M. A. Farquharson,, and R. Hardman. 1987. 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 30:333343.
59. Foulis, A. K.,, M. A. Farquharson,, and A. Meager. 1987. Immunoreactive a-interferon in insulin-secreting β cells in type 1 diabetes mellitus. Lancet ii:14231427.
60. Foulis, A. K.,, C. N. Liddle,, M. A. Farquharson,, J. A. Richmond,, and R. S. Weir. 1986. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of death in patients under 20 years of age in the United Kingdom. Diabetologia 20:267274.
61. Foulis, A. K.,, N. D. Francis,, M. A. Farquaharson,, and A. Boylson. 1986. Massive synchronous B-cell necrosis causing type 1 (insulin-dependent) diabetes—a unique histopathological case report. Diabetologia 31:4650.
62. Friedman, A.,, and Y. Lorch. 1985. Theiler's virus infection: a model for multiple sclerosis. Prog. Med. Virol. 31:4348.
63. Friman, G.,, J. Fohlman,, G. Frisk,, H. Diderholm,, U. Ewald,, M. Kobbah,, and T. Tuvemo. 1985. An incidence peak of juvenile diabetes. Relation to coxsackie B virus immune response. Acta Paediatr. Scand. (Suppl. 320):1419.
64. Frisk, G.,, J. Fohlman,, M. Kobbah,, U. Ewald,, T. Tuvemo,, H. Diderholm,, and G. Friman. 1985. High frequency of coxackie-B-virus specific IgM in children developing type I diabetes during a period of high diabetes morbidity.J Med. Virol. 17:219227.
65. Frisk, G.,, G. Friman,, T. Tuvemo,, J. Fohlman,, and H. Diderholm. 1992. Coxsackie B virus IgM in children at onset of type 1 (insulin-dependent) diabetes mellitus: evidence for IgM induction by a recent or current infection. Diabetologia 35:249253.
66. Froeschle, J. E.,, P. M. Feorino,, and H. M. Gelfand. 1966. A continuing surveillance of enterovirus infection in healthy children in six U.S. cities. II. Surveillance enterovirus isolates 1960-1963 and comparison with enterovirus isolates from cases of acute central nervous system disease. Am. J. Epidemiol. 83:455469.
67. Gamble, D. R. 1980. The epidemiology of insulin-dependent diabetes with particular reference to the relationship of virus infection to its etiology. Epidemiol. Rev. 2:4970.
68. Gamble, D.R.,, and H. Cumming. 1985. Coxsackie B virus and juvenile-onset insulin-dependent diabetes. Lancet ii:455456.
69. Gamble, D. R.,, M. L. Kingsley,, M. G. Fitzgerald,, R. Bolton,, and K. W. Taylor. 1969. Viral antibodies in diabetes mellitus. Br. Med. J. 3:627630.
70. Gamble, D. R.,, and K.W. Taylor. 1969. Seasonal incidence of diabetes mellitus. Br. Med. J. 3:631633.
71. Garchon, H.-J.,, P. Bedossa,, L. Eloy,, and J. -E Bach. 1991. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature (London) 353:260262.
72. Garry, D. J.,, H. D. Coulter,, M. G. Garry,, and R. L. Sorenson. 1988. Immunoreactive immunolocalization of L-glutamate decarboxylase in rat pancreatic islets. J. Histochem. Cytochem. 36:573580.
73. Gepts, W. 1965. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619633.
74. Gerling, I.,, and N. K. Chatterjee. 1993. Lack of 64,000-Mt islet autoantigen overexpression and antibody development following coxsackievirus B4 infection in diabetes-resistant mice. Autoimmunity 14:197203.
75. Gerling, I.,, C. Nejman,, and N. K. Chatterjee. 1988. Effect of coxsackievirus B4 infection in mice on expression of 64,000-Mr autoantigen and glucose sensitivity of islets before development of hyperglycemia. Diabetes 37:14191425.
76. Ginsberg-Fellner, F.,, M. E. Witt,, S. Yagihashi,, M. J. Dobersen,, F. Taub,, B. Fedun,, R. C. McEvoy,, S. H. Roman,, R. G. Davies,, L. Z. Cooper, et al. 1984. Congenital rubella syndrome as a model for type 1 (insulin-dependent) diabetes mellitus: increased prevalence of islet cell surface antibodies. Diabetologia 27(Suppl. l):8789.
77. Giron, D. J.,, and S. Yei. 1993. Interference by a non-interferon-inducing subvariant of benign encephalomyelitis virus-B with the ability of EMCV-D to produce insulin-dependent diabetes mellitus in IRC Swiss male mice. J. Interferon Res. 13:363368.
78. Gladish, R.,, W. Hofmann,, and R. Waldherr. 1976. Myocarditis and insulitis in coxsackievirus infection. Z. Kardiol. 65:835849.
79. Gleason, R. E.,, C. B. Kahn,, I. B. Funk,, and J. E. Craighead. 1982. Seasonal incidence of insulin-dependent diabetes in Massachusetts, 1964-1973. Int. J. Epidemiol. 11:3945.
80. Gould, C. L.,, K. G. McMannama,, N. J. Bigley,, and D. J. Giron. 1985. Virus-induced murine diabetes: enhancement by immunosuppression. Diabetes 34:12171221.
81. Greve, J. M.,, G. Davis,, A. M. Meyer,, C. P. Forte,, S. C. Yost,, C. W. Marlor,, M. E. Kamarck,, and A. McClelland. 1989. The major human rhinovirus receptor is ICAM-1. Cell 56:839.
82. Groop, L. C.,, F. B. Bottazzo,, and D. Doniach. 1986. Islet cell antibodies identify latent type I diabetes in patients aged 35-75 at diagnosis. Diabetes 35:237241.
83. Hagopian, W. A.,, S. McGrew,, S. B. Kaliappan,, A. E. Karlsen,, and D. J. D'Allessio. 1993. Recent coxsackie B virus infection associates with glutamic acid decarboxylase autoantibodies (GAD65 Ab) regardless of insulin-dependent diabetes (IDDM) status. Am. Diabetes Assoc. 12th Int. Immunol. Diabetes Workshop.
84. Hamby, B. B.,, M. A. Pallansch,, and O. M. Kew. 1987. Reemergence of an epidemic coxsackievirus B5 genotype. J. Infect. Dis. 156:288292.
85. Harrison, L. C.,, M. G. Honeymoon,, H. J. DeAizpurua,, R. S. Schmidli,, P. G. Colman,, B. D. Tait,, and D. S. Cram. 1993. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 341:13651369.
86. Hartig, P. C.,, G. E. Madge,, and S. R. Webb. 1983. Diversity within a human isolate of coxsackie B4: relationship to viral-induced diabetes. J. Med. Virol. 11:2330.
87. Haskins, K.,, and M. McDuffie. 1990. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249:14331436.
88. Hayashi, K.,, D. W. Boucher,, and A. L. Notkins. 1974. Virus-induced diabetes mellitus. II. Relationship between β-cell damage and hyperglycemia in mice infected with encephalomyocarditis virus. Am. J. Pathol. 75:91102.
89. Hay ward, J. C.,, S. M. Gillespie,, K. M. Kaplan,, R. Packer,, M. Pallansch,, S. Plotkin,, and L. B. Schonberger. 1989. Outbreak of poliomyelitis-like paralysis associated with enterovirus 71. Pediatr. Infect. Dis. 8:611616.
90. Helfand, R. E.,, H. Gary,, C. Freeman,, L. Anderson,, Pittsburgh Diabetes Research Group, and M. Pallansch. 1994. Association between enteroviruses and type 1 diabetes mellitus, Pittsburgh, Pennsylvania. Colo. Dis. Bull. 21:4.
91. Hellqvist, L. N. B.,, K. W. Taylor,, and S. Zaluzny. 1981. Selective disorganisation of biochemical function in B cells of islets of Langerhans infected by EMC-M virus in tissue culture. FEBS Lett. 132:215218.
92. Helmke, K., 1987. In Y. Becker (ed.), Virus Infections and Diabetes Mellitus, p. 127142. Matinus Nijhoff Publishing, Boston.
93. Hierholzer, J. C.,, and W. A. Farris. 1974. Follow-up of children infected in a coxsackievirus B3 and B4 outbreak: no evidence of diabetes mellitus. J. Infect. Dis. 129:741746.
94. Hou, J.,, S. Sheikh,, D. L. Martin,, and N. K. Chatterjee. 1993. Coxsackie virus B4 alters pancreatic glutamate decarboxylase expression in mice soon after infection. J. Autoimmun. 6:529542.
95. Huff, J. C.,, J. C. Hierholzer,, and W. A. Farris. 1974. An "outbreak" of juvenile diabetes mellitus: consideration of a viral etiology. Am. J. Epidemiol. 100:277287.
95a. Hyoty, H., et al. Unpublished data.
96. Hyoty, H.,, M. Hiltunen,, A. Reunanen, et al. 1993. Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Diabetologia 36:13031308.
97. Hyoty, H.,, L. Rasanen,, M. Hiltunen,, M. Lehtinen,, T. Huupponen,, and P. Leinikki. 1991. Decreased antibody reactivity to Epstein-Barr virus capsid antigen in type 1 (insulin-dependent) diabetes mellitus. APMIS 99:359363.
98. Ihm, S. H.,, K. U. Lee,, R. G. McArthur,, and J. W. Yoon. 1990. Predisposing effect of anti-?-cell autoimmune process in NOD mice on the induction of diabetes by environmental insults. Diabetologia 33:709712.
99.Japan, Poland, the Netherlands and Pittsburgh Childhood Diabetes Research Groups. 1990. How frequently do children die at the onset of insulin-dependent diabetes? Analyses of registry data from Japan, Poland, the Netherlands and Allegheny County, Pennsylvania. Diabetes Nutr. Metab. 3:5762.
100. Jenson, A. B.,, H. S. Rosenberg,, and A. L. Notkins. 1980. Pancreatic islet-cell damage in children with fatal viral infections. Lancet ii:354358.
101. Johnston, C.,, B. A. Millward,, P. Hoskins,, R. D. Leslie,, G. F. Bottazzo,, and D. A. Pyke. 1989. Islet-cell antibodies as predictors of the later development of type 1 (insulin-dependent) diabetes. A study in identical twins. Diabetologia 32:382386.
102. Joner, G.,, and O. Sovik. 1991. The incidence of type 1 (insulin-dependent) diabetes mellitus 15-29 years in Norway 1978-1982. Diabetologia 34:271274.
103. Jones, D. B.,, P. J. McLaughlin,, N. Armstrong,, M. Yeung,, and A. Coulson. 1992. Does coxsackie B4 virus infection induce GAD and HSP65 autoreactivity in type 1 diabetes? Diabetic Med. 9(Suppl. 2):524A.
104. Rang, Y.,, and J. W. Yoon. 1993. A genetically determined host factor controlling susceptibility to encephalomyocarditis virus-induced diabetes in mice. J Gen. Virol. 74:12071213.
105. Kaptur, P. E.,, D. C. Thomas,, and D. J. Giron. 1989. Differing attachment of diabetogenic and nondiabetogenic variants of encephalomyocarditis virus to β-cells. Diabetes 38:11031108.
106. Karjalainen, J. K. 1990. Islet cell antibodies as predictive markers for IDDM in children with high background incidence of disease. Diabetes 39:11441150.
107. Karounos, D. G.,, J. S. Wolinsky,, and J. W. Thomas. 1993. Monoclonal antibody to rubella virus capsid protein recognizes a beta-cell antigen. J. Immunol. 150:30803085.
108. Kaufman, D. L.,, M. Clare-Salzler,, J. Tian,, T. Forsthuber,, G. S. P. Ting,, P. Robinson,, M. A. Atkinson,, E. E. Sercarz,, A. J. Tobin,, and P. V. Lehmann. 1993. Spontaneous loss of T cell self tolerance to glutamate decarboxylase is a key event in the pathogenesis of murine insulin-dependent diabetes. Nature (London) 366:6972.
109. Kaufman, D. L.,, M. G. Erlander,, M. Clare-Salzler,, M. A. Atkinson,, N. K. Maclaren,, and A. J. Tobin. 1992. Autoimmunity to two forms of glutamate decarboxylase in insulin dependent diabetes mellitus. J. Clin. Invest. 89:283292.
110. Khoury, M. J.,, W. D. Flanders,, S. Greenland,, and M.J. Adams. 1989. On the measurement of susceptibility in epidemiologic studies. Am. J. Epidemiol. 129:183190.
111. Kim, J. W.,, W. Richter,, H. J. Aanstoot,, Y. Shi,, Q. Fu,, R. Rajotte,, G. Warnock,, and S. Baekkeskov. 1993. Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes 42:17991808.
112. King, M. L.,, D. Bidwell,, A. Voller,, J. Bryant,, and J. E. Banatvala. 1983. Role of coxsackie B viruses in insulin-dependent diabetes mellitus. Lancet ii:915916.
113. Kogon, A.,, I. Spigland,, T. E. Frothingham,, L. Elveback,, C. Williams,, C. E. Hall,, and J. P. Fox. 1969. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VII. Observations on viral excretion, seroimmunity, intrafamiliar spread and illness association in coxsackie and echovirus infections. Am. J. Epidemiol. 89:5161.
114. Kostraba, J. N.,, E. C. Gay,, Y. Cai,, K. J. Cruickshanks,, M. J. Rewers,, G. J. Klingensmith,, H. P. Chase,, and R. F. Hamman. 1992. Incidence of insulin-dependent diabetes mellitus in Colorado. Epidemiology 3:232238.
115. Lampeter, E. F.,, I. Seifert,, D. Lohmann,, J. W. Heise,, J. Bertrams,, M. R. Christie, V Kolb-Bachofen, and H. Kolb. 1994. Inflammatory islet damage in patients bearing HLA-DR3 and/or DR4 haplotypes does not lead to islet autoimmunity. Diabetologia 37:471475.
116. Landin-Olsson, M.,, A. Karlsson,, G. Dahlquist,, L. Blom,, A. Lernmark,, and G. Sundkvist. 1989. Islet cell and other organ specific autoantibodies in all children developing type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children. Diabetologia 32:387395.
117. Lederman, M. M.,, G. Schifman,, and H. M. Rodman. 1981. Pneumococcal immunisation in adult diabetics. Diabetes 30:119121.
118. Lemon, S. M.,, P. C. Murphy,, P. A. Shields,, L. Ping,, S. M. Feinstone,, T. Cromeans,,and R.W. Jansen. 1991. Antigenic and genetic variation in cy topathic hepatitis A virus variants arising during persistent infection: Evidence for genetic recombination. J. Virol. 65:20562065.
119. Lennette, E. H.,, T. T. Shinomoto,, N. J. Schmidt,, and R. L. Magoffin. 1960. Observations on the neutralizing antibody response to group B coxsackie viruses in patients with central nervous system disease. J. Immunol. 86:257266.
120. Levy-Marchal, C.,, J. Tichet,, I. Fajardy,, E. Dubois,, and P. Czernichow. 1992. Follow-up of children from a background population with high ICA titres. Diabetologia 35(Suppl. 1):A32.
121. Libman, I.,, T. Songer,, and R. LaPorte. 1993. How many people in the U.S. have IDDM? Diabetes Care 16:841842.
122. Like, A. A.,, D. L. Guberski,, and L. Butler. 1991. Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes 40:259262.
123. Loria, R. M.,, L. B. Montgomery,, L. Corey,, and V. M. Chinchilli. 1984. Influence of diabetes mellitus heredity on susceptibility to Coxsackie virus B4. Arch. Virol. 81:251262.
124. Lowis, G. W. 1988. Ethnic factors in multiple sclerosis: a review and critique of the epidemiological literature. Int. J. Epidemiol. 17:1420.
125. Ludvigsson, J.,, and A. O. Afoke. 1989. Seasonality of type 1 (insulin-dependent) diabetes mellitus: values of C-peptide, insulin antibodies and haemoglobin Alc show evidence of a more rapid loss of insulin secretion in epidemic patients. Diabetologia 32:8491.
126. Maclaren, N.,, G. Home,, R. Spillar,, L. Brown,, J. Silverstein,, S. Shah,, J. Malone,, and W. Riley. 1990. The feasibility of using ICA to predict IDD in U.S. school children. Diabetes 39(Suppl. 1):122A.
127. Maeda, T.,, T. Sumida,, K. Kurosawa,, H. Tomioka,, I. Itoh,, S. Yoshida,, and T. Koike. 1991. T-lymphocyte receptor repertoire of infiltrating T-lymphocytes into NOD mouse pancreas. Diabetes 40:15801585.
128. Matteucci, D.,, M. Paglianti,, A. M. Giangregorio,, M. R. Capobianchi,, F. Dianzani,, and M. Bendinelli. 1985. Group B coxsackieviruses readily establish persistent infections in human lymphoid cell lines.J. Virol. 56:651654.
128a. McDevitt, H., et al. Unpublished observation.
129. McDuffie, M.,, and A. Ostrowska. 1993. Superantigen-like effects and incidence of diabetes in NOD mice. Diabetes 42:10941098.
130. McKinney, R. E.,, S. L. Katz,, and C. M. Wilfert. 1987. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev. Infect. Dis. 9:334356.
131. Melton, J. L., et al. 1983. Incidence of diabetes mellitus by clinical type. Diabetes Care 6:7586.
132. Mendelsohn, C. L.,, E. Wirtuner,, and V. R. Racaniello. 1989. Cellular receptor for polio-virus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56:855.
133. Menser, M. A.,, J. M. Forrest,, and R.D. Bransby. 1978. Rubella infection and diabetes mellitus. Lancet i:5760.
134. Modlin, J. R.,, and M. Bowman. 1987. Perinatal transmission of coxsackievirus B3 in mice. J. Infect. Dis. 156:2125.
135. Monif, G. R. G.,, G. B. Avery,, S. B. Korones,, and J. L. Sever. 1965. Post-mortem isolation of rubella virus from three children with rubella-syndrome defects. Lancet i:723724.
136. Montgomery, L.,, D. Gordon,, K. George,, and E. Maratos-Flier. 1991. Coxsackie infection of insulinoma cells leads to viral latency and altered insulin and class I MHC expression. Diabetes 40(Suppl. 1):150A.
137. Montgomery, L. B.,, R. M. Loria,, and V. M. Chinchilli. 1990. Immunodeficiency as primary phenotype of diabetes mutation db: studies with coxsackievirus B4. Diabetes 39:675682.
138. Morrow, P. L.,, A. Freedman,, and J. E. Craighead. 1980. Testosterone effect on experimental mellitus in encephalomyocarditis (EMC) virus-infected mice. Diabetologia 18:247.
139. Nakano, N.,, H. Kikutani,, H. Nishimoto,, and T. Kishimoto. 1991. T cell receptor V gene usage of islet β cell-reactive T cells is not restricted in non-obese diabetic mice. J. Exp. Med. 173:10911097.
140. Nathanson, N.,, and J. Martin. 1979. The epidemiology of poliomyelitis: enigmas surrounding its appearance, epidemicity and disappearance. Am. J. Epidemiol. 110:672692.
141. Nicoletti, E.,, G. Scalia,, M. Lunetta,, F. Concorelli,, M. Di Mauro,, W. Barcellini,, S. Stracuzzi,, M. Pagano,, and P. L. Meroni. 1990. Correlation between islet cell antibodies and anti-cytomegalovirus IgM and IgG antibodies in healthy first-degree relatives of type 1 (insulin-dependent) diabetic patients. Clin. Immunol. Immunopathol. 55:139147.
142. Niklasson, B. S.,, M. J. Dobersen,, C. J. Peters,, W. H. Ennis,, and E. Mdller. 1985. An outbreak of coxsackievirus B infection followed by one case of diabetes mellitus. Scand. J. Infect. Dis. 17:1518.
142a. Norris, J. M., et al. Unpublished observations.
143. Notkins, A. L.,, T. Onodera,, and B. S. Prabhakar,. 1984. Virus-induced autoimmunity, p. 210215. In A. L. Notkins (ed.), Concepts in Viral Pathogenesis. Springer, New York.
144. Notkins, A. L.,, and J. W. Yoon. 1982. Virus-induced diabetes in mice prevented by a live attenuated vaccine. N. Engl. J. Med. 1:486.
145. Nystrom, L.,, G. Dahlquist,, M. Rewers,, and S. Wall. 1990. The Swedish Childhood Diabetes Study: an analysis of the temporal variation in diabetes incidence 1978-1987. Int. J. Epidemiol. 19:141146.
146. Ohashi, P. S.,, S. Oehen,, P. Aichele,, H. Pricher,, B. Odermatt,, P. Herrera,, Y. Higuchi,, K. Buerki,, H. Hengartner,, and R. M. Zinkernagel. 1993. Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and tumor necrosis factor-a J. Immunol. 150:51855194.
147. 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.
148. Oksenberg, J. R.,, S. Stuart,, A. B. Begovich,, R. B. Bell,, H. A. Erlich,, L. Steinman,, and C. C. A. Bernard. 1990. Limited heterogeneity of rearranged T-cell receptor Va transcripts in brains of multiple sclerosis patients. Nature (London) 345:344346.
149. Oldstone, M. B. A. 1987. Molecular mimicry and autoimmune disease. Cell 50:819820.
150. Oldstone, M. B. A. 1988. Prevention of type 1 diabetes in nonobese diabetic mice by virus infection. Science 239:500502.
151. Oldstone, M. B. A. 1990. Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence. J. Exp. Med. 171:20772089.
152. Oldstone, M. B. A.,, 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.
153. Oldstone, M. B. A.,, P. Southern,, M. Rodriguez,, and P. W. Lampert. 1984. Virus persists in beta-cells and islets of Langerhans and is associated with chemical manifestation of diabetes. Science 224:14401444.
154. O'Leary, L. A.,, J. S. Dorman,, R. E. LaPorte,, T. J. Orchard,, D. J. Becker,, L. H. Kuller,, M. S. Eberhardt,, D. E. Cavender,, B. S. Rabin,, and A. L. Drash. 1991. Familial and sporadic insulin-dependent diabetes: evidence for heterogeneous etiologies? Diabetes Res. Clin. Pract. 14:183190.
155. Onodera, T.,, A. Toniolo,, U. R. Ray,, A. A. Jenson,, R. A. Knazek,, and A. L. Notkins. 1981. Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity. J. Exp. Med. 153:15471573.
156. Onodera, T.,, J. W. Yoon,, K. K. Brown,, and A. L. Notkins. 1978. Evidence for a single locus controlling susceptibility to virus-induced diabetes mellitus. Nature (London) 274:693696.
157. Orchard, T. J.,, R. W. Atchison,, D. Becker,, B. Rabin,, M. Eberhardt,, L. H. Kuller,, R. E. LaPorte,, and D. Cavender. 1983. Coxsackie infection and diabetes. Lancet ii:631. (Letter.)
158. Orchard, T. J.,, D. J. Becker,, R. W. Atchison,, R. E. LaPorte,, D. K. Wagener,, B. S. Rabin,, L. H. Kuller,, and A. L. Drash. 1983. The development of type 1 (insulin-dependent) diabetes mellitus: two contrasting presentations. Diabetologia 25:8992.
159. Owerbach, D.,, and K. H. Gabbay. 1993. Localization of a type 1 diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes 42:17081714.
160. Pacsa, S.,, and J. Werblinska. 1971. Natural immunity of Ghanaian children to polio and coxsackievirus: brief report. Arch. Gesamte Virusforsch. 33:192193.
161. Pak, C. Y.,, E. Hyone-Myong,, R. G. McArthur,, and J. W. Yoon. 1988. Association of cytomegalovirus infection with autoimmune type 1 diabetes. Lancet ii:13.
162. Paliard, X.,, S. G. West,, J. A. Lafferty,, J. R. Clements,, J. W. Kappler,, P. Marrack,, and B. L. Kotzin. 1991. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 253:325329.
163. Palmer, J. P.,, M. K. Cooney,, R. H. Ward,, J. A. Hansen,, J. B. Brodsky,, C. G. Ray,, J. R. Crossley,, C. M. Asplin,, and R. H. Williams. 1982. Reduced coxsackie antibody titres in type I (insulin-dependent) diabetic patients presenting during an outbreak of coxsackie B3 and B4 infection. Diabetologia 22:426429.
164. Petersen, K.-G.,, P. Heilmeyer,, and L. Kerp. 1975. Synthesis of proinsulin and large glucagon immunoreactivity in isolated islets of Langerhans from EMC virus infected mice. Diabetologia 11:2125.
165. Peterson, J. S.,, S. Russel,, M. O. Marshall,, H. Kofod,, K. Buschard,, A. E. Cambon,, A. E. Karlsen,, E. Boel,, W. A. Hagopian,, K. R. Hejnaes,, A. Moody,, T. Dyrberg,, A. E. Lernmark,, O. D. Madsen,, and B. K. Michelsen. 1993. Differential expression of glutamate decarboxylase in rat and human islets. Diabetes 42:484495.
166. Pietropaolo, M.,, and G. S. Eisenbarth. 1994. Biochemical determination of antibodies to three recombinant human autoantigens: high predictive value and stability of patterns. Diabetes 43(Suppl. 1):153A.
167. Pilcher, C. C.,, K. Dickens,, and R. B. Elliott. 1991. ICA only develop in early childhood. Diabetes Res. Clin. Pract. 14(Suppl. I):s82.
168. Pipeleers, D.,, and Z. Ling. 1992. Pancreatic beta cells in insulin-dependent diabetes. Diabetes Metab. Rev. 8:209227.
169. Pociot, E.,, R. Bergholdt,, J. Johannsen,, and J. Nerup. 1994. Genetic susceptibility to IDDM: chromosome 6p versus chromosome 2q. Diabetologia 37(Suppl. 1):A6.
170. Portwood, N. D.,, and K. W. Taylor. 1990. Coxsackie B4 virus-induced changes in mouse pancreatic β-cell mRNAs. Biochem. Soc. Trans. 18:1264.
171. Pozzilli, P.,, P. Arduini,, N. Visalli, et al. 1987. Reduced protection against hepatitis B virus following vaccination in patients with type I (insulin dependent) diabetes. Diabetologia 30:817819.
172. Prabhakar, B. S.,, M. V. Haspel,, P. R. McClintock,, and A. L. Notkins. 1982. High frequency of antigenic variants among naturally occurring human coxsackie B4 virus isolates identified by monoclonal antibodies. Nature (London) 300:374376.
173. Prather, S. L.,, R. Dagan,, J. A. Jenista,, and M. A. Menegus. 1984. The isolation of enteroviruses from blood: a comparison of four processing methods. J. Med. Virol. 14:221227.
174. Ramsingh, A.,, J. Slack,, J. Silkworth,, and A. Hixson. 1989. Severity of disease induced by a pancreatropic coxsackie B4 virus correlates with the H-2Kq locus of the major histocompatibility complex. Virus Res. 14:347358.
175. Ratzmann, K. P.,, J. Strese,, S. Witt,, H. Berling,, H. Kielacker,, and D. Michaelis. 1984. Mumps infection and insulin-dependent diabetes mellitus (IDDM). Diabetes Care 7:170173.
176. Rayfield, E. J.,, and K. Ishimura. 1987. Environmental factors and insulin dependent diabetes mellitus. Diabetes Metab. Rev. 3:925957.
177. Rewers, M.,, R. E. LaPorte,, H. King,, and J. Tuomilehto. 1988. Trends in the prevalence and incidence of diabetes: insulin-dependent diabetes mellitus in childhood. World Health Stat. Q. 41:179189.
178. Rewers, M.,, R. LaPorte,, M. Walczak,, K. Dmochowski,, and E. Bogaczynska. 1987. Apparent epidemic of insulin-dependent diabetes mellitus in midwestern Poland. Diabetes 36:106113.
179. Rewers, M.,, M. A. Pallansch,, E. Bogaczynska,, S. L. Patrick,, L. A. Anderson,, M. Walczak,, and R. E. LaPorte. 1990. Conflicting evidence for enterovirus as the cause of childhood diabetes epidemic in Poland. Diabetologia 33(Suppl. 1):A198.
180. Richter, W.,, T. Mertens,, B. Schoel,, S. Wolfahrt,, P. Muir,, W. A. Scherbaum,, and B. O. Boehm. 1994. Autoantibodies to glutamate decarboxylase detect no molecular mimicry to viral antigens or heat shock protein 60. Diabetologia 37(Suppl. 1):A63.
181. Riley, W. J.,, N. K. MacLaren,, J. Krischer,, R. P. Spillar,, J. H. Silverstein,, D. A. Schatz,, S. Schwartz,, J. Malone,, S. Shah,, C. Vadheim,, and J. I. Rotter. 1990. A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes. N. Engl. J. Med. 323:11671172.
182. Rose, N. R.,, and D. E. Griffin,. 1991. Virus-induced autoimmunity, p. 247272. In N. Talal (ed.), Molecular Autoimmunity. Academic Press Ltd., London.
183. Rossmann, M. G.,, and A. C. Palmenberg. 1988. Conservation of the putative receptor attachment site in picornaviruses. Virology 164:373382.
184. Rotbart, H. A. 1991. Nucleic acid detection systems for enteroviruses. Clin. Microbiol. Rev. 4:156168.
185. Sairenji, T.,, M. Daibata,, C. H. Sorli, et al. 1991. Relating homology between the Epstein-Barr virus BOLF1 and HLA-DQw8 beta chain to recent onset type 1-dependent diabetes mellitus. Diabetologia 34:3339.
186. Salvato, M.,, P. Borrow,, E. Shimomaye,, and M. B. A. Oldstone. 1991. Molecular basis of viral persistence: a single amino acid change in the glycoprotein of lymphocytic choriomeningitis virus is associated with suppression of the antiviral cytotoxic T-lymphocytep response and establishment of persistence. J Virol. 65:18631869.
187. Santamaria, P.,, C. Lewis,, J. Jessurun,, D. E. Sutherland,, and J.J. Barbosa. 1994. Skewed T-cell receptor usage junctional and heterogeneity among isletitis αβ and γσ T-cells in human IDDM. Diabetes 43:599606.
188. Santamaria, P.,, R. E. Nakhleh,, D. E. Sutherland,, and J. J. Barbosa. 1992. Char-acterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes 41:5361.
189. Scherbaum, W. A.,, W. Hampl,, P. Muir,, M. Gluck,, J. SeiBler,, H. Egle,, H. Hauner,, B. O. Boehm,, E. Heinze,, J. E. Banatvala,, and E. E Pfeiffer. 1991. No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7-19 years. Diabetologia 34:835838.
190. Schernthaner, G.,, J. E. Banatvala,, W. Scherbaum,, J. Bryant,, M. Borkenstein,, E. Schober,, and W. R. Mayr. 1985. Coxsackie B virus specific IgM responses, complement-fixing islet cell antibodies, HLA DR antigens, and C-peptide secretion in insulin-dependent diabetes mellitus. Lancet ii:630632.
191. See, D. M.,, and J. G. Tilles. 1993. WIN 54954 treatment of mice infected with a diabetogenic strain of group B coxsackievirus. Antimicrob. Agents Chemother. 37:15931598.
192. Sharief, M. K.,, R. Hentges,, and M. Ciardi. 1991. Intrathecal immune response in patients with the post-polio syndrome. N. Engl. J. Med. 325:749755.
193. Songer, T. J. 1990. Health services and costing in diabetes. Med.J.Aust. 152:115117.
194. Spinas, G. A.,, L. Matter,, T. Wilkin,, O. StafFelbach,, and W. Berger. 1988. Islet-cell and insulin autoantibodies in first-degree relatives of type I diabetics: a 5-year follow-up study in a Swiss population. Adv. Exp. Med. Biol. 246:209214.
195. Stanway, G. 1990. Structure, function and evolution of picornaviruses. J. Gen. Virol. 71:24832501.
196. Staunton, D. E.,, V. J. Merluzzi,, R. Rothlein,, R. Barton,, S. D. Martin,, and T. A. Springer. 1989. A cell adhesion molecule, IAMC-1, is the major surface receptor for rhinoviruses. Cell 56:849.
197. Suenaga, K.,, and J. W. Yoon. 1988. Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse. Diabetes 37:17221726.
198. Sussman, M. L.,, L. Stauss,, and U. L. Hodes. 1959. Fatal coxsackie B virus infections in the newborn. Report of case with necropsy findings and brief review of the literature. Am. J. Dis. Child. 97:483492.
199. Szopa, T. M.,, D. M. Dronfield,, T. Ward,, and K.W. Taylor. 1989. In vivo infection of mice with coxsackie B4 virus induces long-term functional changes in pancreatic islets with minimal alteration in blood glucose. Diabetic Med. 6:314319.
200. Szopa, T. M.,, D. R. Gamble,, and K. W. Taylor. 1986. Coxsackie B4 virus induces short-term changes in the metabolic functions of mouse pancreatic islets in vitro. Cell Biochem. Fund. 4:181189.
201. Szopa, T. M.,, P. A. Titchener,, N. D. Portwood,, and K. W. Taylor. 1993. Diabetes mellitus due to viruses—some recent developments. Diabetologia 36:687695.
202. Szopa, T. M.,, T. Ward,, D. M. Dronfield,, N. D. Portwood,, and K. W. Taylor. 1990. Coxsackie B4 viruses with the potential to damage β-cells of the islets are present in clinical isolates. Diabetologia 33:325328.
203. Szopa, T. M.,, T. Ward,, and K. W. Taylor. 1992. Disturbance of mouse pancreatic β-cell function following echo 4 virus infection. Biochem. Soc. Trans. 20:3155.
204. Thivolet, C.,, B. Beaufrere,, H. Betuel,, L. Gebuhrer,, P. Chatelain,, A. Durand,, J. Tourniaire,, and R. Francois. 1988. Islet cell and insulin autoantibodies in subjects at high risk for development of type 1 (insulin-dependent) diabetes mellitus: the Lyon family study. Diabetologia 31:741746.
204a. Tian, J., et al. Submitted for publication.
205. Tilzey, A. J.,, M. Signy,, and J. E. Banatvala. 1986. Persistent coxsackie B virus specific IgM response in patients with recurrent pericarditis. Lancet i:1491.
206. Tisch, R.,, X. D. Yang,, S. M. Singer,, R. S. Liblau,, L. Fugger,, and H. McDevitt. 1993. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature (London) 366:7275.
207. Todd, J. A. 1990. The role of MHC class II genes in susceptibility to insulin-dependent diabetes mellitus. Curr. Top. Microbiol. Immunol. 164:1740.
208. Tolbert, M.,, and D.J. Giron. 1994. Persistence of the D variant of encephalomyocarditis virus in the ICR-Swiss mouse. Proc. Soc. Exp. Biol. Med. 205:124131.
209. Toniolo, A.,, T. Onodera,, G. Jordan,, J. W. Yoon,, and A. L. Notkins. 1982. Virus-induced diabetes mellitus. Glucose abnormalities produced in mice by the six members of the coxsackie B virus group. Diabetes 31:496499.
210. Toniolo, A.,, T. Onodera,, J. W. Yoon,, and A. L. Notkins. 1980. Induction of diabetes by cumulative environmental insults from viruses and chemicals. Nature (London) 288:383385.
210a. Trucco, M. Unpublished observations.
211. Trucco, M.,, C. Ricordi,, E. Weidmann,, H. Rodriquez-Rio,, G. Trucco,, and D. Finegold. 1993. Involvement of superantigensin the etiology of IDDM. Diabetes 42(Suppl. 1):4A.
212. Tuomi, T.,, L. C. Groop,, P. Z. Zimmet,, M. J. Rowley,, W. Knowles,, and I. R. Mackay. 1993. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359362.
213. Tuvemo, T.,, G. Dahlquist,, G. Frisk,, L. Blom,, G. Friman,, M. Landin-Olsson,, and H. Dierholm. 1989. The Swedish childhood diabetes study. III. IgM against coxsackie B viruses in newly diagnosed type 1 (insulin-dependent) diabetic children—no evidence of increased antibody frequency. Diabetologia 32:745747.
214. Tuvemo, T.,, G. Frisk,, G. Friman,, J. Ludvigsson,, and H. Diderholm. 1988. IgM against coxsackie B viruses in children developing type I diabetes mellitus—a seven year retrospective study. Diabetes Res. 9:125129.
215. Ujevich, M. M.,, and R. Jane. 1980. Pancreatic cell damage. Its occurrence in neonatal coxsackie virus encephalomyocarditis. Arch. Pathol. Lab. Med. 104:438441.
216. Uriarte, A.,, E. Cabrera,, R. Ventura,, and J. Vargas. 1987. Islet cell antibodies and ECHO-4 virus infection. Diabetologia 30(Suppl. 1):590A.
217. Vadheim, C. M.,, A. Zeidler,, J. I. Rotter,, M. Langbaum,, I. A. Shulman,, M. R. Spencer,, G. Costin,, W. J. Riley,, and N. K. MacLaren. 1989. Different HLA haplotypes in Mexican Americans with IDDM. Diabetes Care 12:497500.
218. Vella, C.,, A. J. Easton,, P. R. Eglin,, C. L. Brown,, and L. Perry. 1991. Coxsackie virus B4 infection of the mouse pancreas. I. Detection of virus-specific RNA in the pancreas by in situ hybridization. J. Med. Virol. 35:4649.
219. Vento, S.,, T. Garofano,, G. DiPerri,, L. Dolci,, E. Concia,, and D. Bassetti. 1991. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet 337:11811187.
220. Vialettes, B.,, P. Demicco,, C. Badier,, J. Niccoline, and V Lassmann-Vague. 1987. Anti-coxsackie B IgG and IgM antibodies in first degree relatives of type 1 (insulin-dependent) diabetic patients: lack of association with islet cell antibodies. Diabetologia 30(Suppl. 1):594A.
221. Wagener, D. K.,, J. M. Sacks,, R. E. LaPorte,, and J. M. MacGregor. 1982. The Pittsburgh study of insulin-dependent diabetes mellitus. Risk for diabetes among relatives of IDDM. Diabetes 31:136144.
222. Wagenknecht, L. E.,, J. M. Roseman,, and W. H. Herman. 1991. Increased incidence of insulin-dependent diabetes mellitus following an epidemic of coxsackievirus B5. Am. J. Epidemiol. 133:10241031.
223. Ward, T.,, J. Clemens,, and K. W. Taylor. 1990. Effects of a diabetogenic strain of encephalomyocarditis virus on protein synthesis in mouse islets of langerhans. Biochem.J. 270:777781.
224. Warram, J. H.,, B. C. Martin,, and A. S. Krolewski. 1991. Risk of IDDM in children of diabetic mothers decreases with increasing maternal age at pregnancy. Diabetes 40:16791984.
225. Waters, S. H.,, J. J. O'Neil,, D. T. Melican,, and M. C. Appel. 1992. Multiple TCR VB usage by infiltrates of young NOD mouse islets of Langerhans. Diabetes 41:308312.
226. Webb, S. R.,, R. M. Loria,, G. E. Madge,, and S. Kibrick. 1976. Susceptibility of mice to group B coxsackie virus is influenced by diabetic gene. J. Exp. Med. 143:12391248.
227. Wegner, V.,, A. Kewitsch,, M. Madauss,, L. Dohner,, and H. Ziihlke. 1985. Hyperglycemia in BALB/c mice after pretreatment with one subdiabetogenic dose of streptozotocin and subsequent infection with a coxsackie B4 strain. Biomed. Biochem. Acta 44:2127.
228. Weinberg, C. R.,, T. L. Dornan,, J. A. Hansen,, R. K. Raghu,, and J. P. Palmer. 1984. HLA-related heterogeneity in seasonal patterns of diagnosis in type 1 (insulin-dependent) diabetes. Diabetologia 26:199202.
229. Werner, S.,, W. M. Klump,, H. Schdnke,, P. H. Hofscheider,, and R. Kandolf. 1988. Expression of coxsackievirus B 3 capsid proteins in Escherichia coli and generation of virus-specific antisera. DNA 7:307316.
230.WHOS tudy Group. 1985. Diabetes Mellitus. Technical Report Series 727. World Health Organization, Geneva.
231. Wilberz, S.,, H. J. Partke,, F. Dagnaes-Hansen,, and L. Herberg. 1991. Persistent MHV (mouse hepatitis virus) infection reduces the incidence of diabetes mellitus in non-obese diabetic mice. Diabetologia 34:25.
232. Wilfert, C. M.,, R. H. Buckley,, T. Mohanakumar,, J. K. Griffiths,, S. L. Katz,, J. K. Whisnant,, and P. A. Eggleston. 1977. Persistent and fatal central system echovirus infection in agammaglobulinaemia. N. Engl. J. Med. 296:1485.
233. Wyatt, H. V. 1973. Poliomyelitis in hypogammaglobuhnemics.J. Infect. Dis. 128:802806.
234. Yagi, S.,, D. Schnurr,, and J. Lin. 1992. Spectrum of monoclonal antibodies to coxsackievirus B-3 includes type- and group-specific antibodies J. Clin. Microbiol. 30:24982501.
235. Yoon, J.W. 1990. The role of viruses and environmental factors in the induction of diabetes. Curt Top. Microbiol. Immunol. 164:95123.
236. Yoon, J. W.,, M. Austin,, T. Onodera,, and A. L. Notkins. 1979. Virus-induced diabetes mellitus: isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N. Engl. J. Med. 300:11731179.
237. Yoon, J. W.,, T. L. London,, L. Curfman,, R. L. Brown,, and A. L. Notkins. 1986. Coxsackie virus B4 produces transient diabetes in nonhuman primates. Diabetes 35:712716.
238. Yoon, J. W.,, P. R. McClintock,, C. J. Bachurski,, J. D. Longstreth,, and A. L. Notkins. 1985. Virus-induced diabetes mellitus: no evidence for immune mechanisms in the destruction of p-cells by the D-variant of encephalomyocarditis virus. Diabetes 34:922925.
239. Yoon, J. W.,, P. R. McClintock,, T. Onodera,, and A. L. Notkins. 1980. Virus-induced diabetes mellitus. XVIII. Inhibition by a non-diabetogenic variant of encephalomyocarditis virus J. Exp. Med. 152:878892.