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Published in: Seminars in Immunopathology 1/2011

01-01-2011 | Review

Immunopathology of the human pancreas in type-I diabetes

Authors: Sarah J. Richardson, Abby Willcox, Adrian J. Bone, Noel G. Morgan, Alan K. Foulis

Published in: Seminars in Immunopathology | Issue 1/2011

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Abstract

Type 1 diabetes is a chronic autoimmune disease characterised by the selective destruction of pancreatic beta (β) cells. The understanding of the aetiology of this disease has increased dramatically in recent years by the study of tissue recovered from patients, from analysis of the responses of isolated islet and β-cells in tissue culture and via the use of animal models. However, knowledge of the immunopathology of type 1 diabetes in humans is still relatively deficient due largely to the difficulty of accessing appropriate samples. Here we review the state of current knowledge in relation to the histopathological features of the disease in humans. We focus specifically on recent-onset type 1 diabetes cases since in such patients, evidence of the ongoing disease process is still present. We chart the progression of the disease by describing the characteristic features of the pancreas, consider the sequence of immune cell infiltration and discuss the abnormalities of MHC antigen expression. The possibility that these changes might derive from a persistent enteroviral infection of the islet beta cells is examined.
Literature
1.
go back to reference Barnett AH, Eff C, Leslie RD, Pyke DA (1981) Diabetes in identical twins. A study of 200 pairs. Diabetologia 20:87–93PubMedCrossRef Barnett AH, Eff C, Leslie RD, Pyke DA (1981) Diabetes in identical twins. A study of 200 pairs. Diabetologia 20:87–93PubMedCrossRef
2.
3.
go back to reference Redondo MJ, Yu L, Hawa M et al (2001) Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44:354–362PubMedCrossRef Redondo MJ, Yu L, Hawa M et al (2001) Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44:354–362PubMedCrossRef
4.
go back to reference Knip M, Veijola R, Virtanen SM, Hyoty H, Vaarala O, Akerblom HK (2005) Environmental triggers and determinants of type 1 diabetes. Diabetes 54(Suppl 2):S125–136PubMedCrossRef Knip M, Veijola R, Virtanen SM, Hyoty H, Vaarala O, Akerblom HK (2005) Environmental triggers and determinants of type 1 diabetes. Diabetes 54(Suppl 2):S125–136PubMedCrossRef
5.
go back to reference Lally F, Bone AJ (2003) Animal models of type 1 diabetes. Blackwell Science Ltd Lally F, Bone AJ (2003) Animal models of type 1 diabetes. Blackwell Science Ltd
6.
go back to reference Gepts W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619–633PubMed Gepts W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619–633PubMed
7.
go back to reference Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS (1986) The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29:267–274PubMedCrossRef Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS (1986) The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29:267–274PubMedCrossRef
8.
go back to reference 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 26:456–461PubMedCrossRef 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 26:456–461PubMedCrossRef
9.
go back to reference Gepts W, De Mey J (1978) Islet cell survival determined by morphology. An immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus. Diabetes 27(Suppl 1):251–261PubMed Gepts W, De Mey J (1978) Islet cell survival determined by morphology. An immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus. Diabetes 27(Suppl 1):251–261PubMed
10.
go back to reference Fraser PA, Henderson JR (1980) The arrangement of endocrine and exocrine pancreatic microcirculation observed in the living rabbit. Q J Exp Physiol Cogn Med Sci 65:151–158PubMed Fraser PA, Henderson JR (1980) The arrangement of endocrine and exocrine pancreatic microcirculation observed in the living rabbit. Q J Exp Physiol Cogn Med Sci 65:151–158PubMed
11.
go back to reference Greenberg GR, Mitznegg P, Bloom SR (1977) Effect of pancreatic polypeptide on DNA-synthesis in the pancreas. Experientia 33:1332–1333PubMedCrossRef Greenberg GR, Mitznegg P, Bloom SR (1977) Effect of pancreatic polypeptide on DNA-synthesis in the pancreas. Experientia 33:1332–1333PubMedCrossRef
12.
go back to reference Henderson JR, Daniel PM, Fraser PA (1981) The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut 22:158–167PubMedCrossRef Henderson JR, Daniel PM, Fraser PA (1981) The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut 22:158–167PubMedCrossRef
13.
go back to reference Salter JM, Davidson IW, Best CH (1957) The pathologic effects of large amounts of glucagon. Diabetes 6:248–252, discussion, 252–245PubMed Salter JM, Davidson IW, Best CH (1957) The pathologic effects of large amounts of glucagon. Diabetes 6:248–252, discussion, 252–245PubMed
14.
go back to reference Rahier J, Wallon J, Loozen S, Lefevre A, Gepts W, Haot J (1983) The pancreatic polypeptide cells in the human pancreas: the effects of age and diabetes. J Clin Endocrinol Metab 56:441–444PubMedCrossRef Rahier J, Wallon J, Loozen S, Lefevre A, Gepts W, Haot J (1983) The pancreatic polypeptide cells in the human pancreas: the effects of age and diabetes. J Clin Endocrinol Metab 56:441–444PubMedCrossRef
15.
go back to reference Stansfield O, Warren S (1928) Inflammation involving the islands of Langerhans in diabetes; report on pathological findings. N Engl J Med 198:686–687CrossRef Stansfield O, Warren S (1928) Inflammation involving the islands of Langerhans in diabetes; report on pathological findings. N Engl J Med 198:686–687CrossRef
16.
go back to reference Warren S, Root HF (1925) The pathology of diabetes, with special reference to pancreatic regeneration. Am J Pathol 1(415–430):411 Warren S, Root HF (1925) The pathology of diabetes, with special reference to pancreatic regeneration. Am J Pathol 1(415–430):411
17.
go back to reference Foulis AK, McGill M, Farquharson MA (1991) Insulitis in type 1 (insulin-dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol 165:97–103PubMedCrossRef Foulis AK, McGill M, Farquharson MA (1991) Insulitis in type 1 (insulin-dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol 165:97–103PubMedCrossRef
18.
go back to reference Somoza N, Vargas F, Roura-Mir C et al (1994) Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol 153:1360–1377PubMed Somoza N, Vargas F, Roura-Mir C et al (1994) Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol 153:1360–1377PubMed
19.
go back to reference 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 313:353–360PubMedCrossRef 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 313:353–360PubMedCrossRef
20.
go back to reference Itoh N, Hanafusa T, Miyazaki A et al (1993) Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 92:2313–2322PubMedCrossRef Itoh N, Hanafusa T, Miyazaki A et al (1993) Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 92:2313–2322PubMedCrossRef
21.
go back to reference Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2009) Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 155:173–181PubMedCrossRef Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2009) Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 155:173–181PubMedCrossRef
22.
go back to reference Uno S, Imagawa A, Okita K et al (2007) Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia 50:596–601PubMedCrossRef Uno S, Imagawa A, Okita K et al (2007) Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia 50:596–601PubMedCrossRef
23.
go back to reference Dotta F, Censini S, van Halteren AG et al (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 104:5115–5120PubMedCrossRef Dotta F, Censini S, van Halteren AG et al (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 104:5115–5120PubMedCrossRef
24.
go back to reference Moriwaki M, Itoh N, Miyagawa J et al (1999) Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus. Diabetologia 42:1332–1340PubMedCrossRef Moriwaki M, Itoh N, Miyagawa J et al (1999) Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus. Diabetologia 42:1332–1340PubMedCrossRef
25.
go back to reference Loweth AC, Williams GT, James RF, Scarpello JH, Morgan NG (1998) Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1beta and Fas ligation. Diabetes 47:727–732PubMedCrossRef Loweth AC, Williams GT, James RF, Scarpello JH, Morgan NG (1998) Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1beta and Fas ligation. Diabetes 47:727–732PubMedCrossRef
26.
go back to reference Brodie GM, Wallberg M, Santamaria P, Wong FS, Green EA (2008) B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes. Diabetes 57:909–917PubMedCrossRef Brodie GM, Wallberg M, Santamaria P, Wong FS, Green EA (2008) B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes. Diabetes 57:909–917PubMedCrossRef
27.
go back to reference Sia C (2005) Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus. Rev Diabet Stud 2:182–186PubMedCrossRef Sia C (2005) Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus. Rev Diabet Stud 2:182–186PubMedCrossRef
29.
go back to reference Brusko T, Wasserfall C, McGrail K et al (2007) No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 56:604–612PubMedCrossRef Brusko T, Wasserfall C, McGrail K et al (2007) No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 56:604–612PubMedCrossRef
30.
go back to reference Putnam AL, Vendrame F, Dotta F, Gottlieb PA (2005) CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 24:55–62PubMedCrossRef Putnam AL, Vendrame F, Dotta F, Gottlieb PA (2005) CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 24:55–62PubMedCrossRef
32.
go back to reference Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science (New York, NY 306: 1517–1519 Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science (New York, NY 306: 1517–1519
33.
go back to reference Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia
34.
go back to reference Alejandro R, Shienvold FL, Hajek SV, Ryan U, Miller J, Mintz DH (1982) Immunocytochemical localization of HLA-DR in human islets of Langerhans. Diabetes 31(Suppl 4):17–22PubMed Alejandro R, Shienvold FL, Hajek SV, Ryan U, Miller J, Mintz DH (1982) Immunocytochemical localization of HLA-DR in human islets of Langerhans. Diabetes 31(Suppl 4):17–22PubMed
35.
go back to reference Foulis AK, Farquharson MA, Hardman R (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 30:333–343PubMedCrossRef Foulis AK, Farquharson MA, Hardman R (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 30:333–343PubMedCrossRef
36.
go back to reference Imagawa A, Hanafusa T, Itoh N et al (1999) Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus. Diabetologia 42:574–578PubMedCrossRef Imagawa A, Hanafusa T, Itoh N et al (1999) Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus. Diabetologia 42:574–578PubMedCrossRef
37.
go back to reference Gianani R, Campbell-Thompson M, Sarkar SA, et al. Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia Gianani R, Campbell-Thompson M, Sarkar SA, et al. Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia
38.
go back to reference Tanaka S, Nishida Y, Aida K et al (2009) Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes 58:2285–2291PubMedCrossRef Tanaka S, Nishida Y, Aida K et al (2009) Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes 58:2285–2291PubMedCrossRef
39.
go back to reference Lozanoska-Ochser B, Peakman M (2009) Level of major histocompatibility complex class I expression on endothelium in non-obese diabetic mice influences CD8 T cell adhesion and migration. Clin Exp Immunol 157:119–127PubMedCrossRef Lozanoska-Ochser B, Peakman M (2009) Level of major histocompatibility complex class I expression on endothelium in non-obese diabetic mice influences CD8 T cell adhesion and migration. Clin Exp Immunol 157:119–127PubMedCrossRef
40.
go back to reference Thomas HE, Parker JL, Schreiber RD, Kay TW (1998) IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest 102:1249–1257PubMedCrossRef Thomas HE, Parker JL, Schreiber RD, Kay TW (1998) IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest 102:1249–1257PubMedCrossRef
41.
go back to reference von Herrath MG, Oldstone MB (1997) Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. J Exp Med 185:531–539CrossRef von Herrath MG, Oldstone MB (1997) Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. J Exp Med 185:531–539CrossRef
42.
go back to reference Foulis AK, Farquharson MA (1986) Aberrant expression of HLA-DR antigens by insulin-containing beta-cells in recent-onset type I diabetes mellitus. Diabetes 35:1215–1224PubMedCrossRef Foulis AK, Farquharson MA (1986) Aberrant expression of HLA-DR antigens by insulin-containing beta-cells in recent-onset type I diabetes mellitus. Diabetes 35:1215–1224PubMedCrossRef
43.
go back to reference Imagawa A, Hanafusa T, Itoh N et al (1996) Islet-infiltrating t lymphocytes in insulin-dependent diabetic patients express CD80 (B7-1) and CD86 (B7-2). J Autoimmun 9:391–396PubMedCrossRef Imagawa A, Hanafusa T, Itoh N et al (1996) Islet-infiltrating t lymphocytes in insulin-dependent diabetic patients express CD80 (B7-1) and CD86 (B7-2). J Autoimmun 9:391–396PubMedCrossRef
44.
go back to reference Hanninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simell O (1992) Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 90:1901–1910PubMedCrossRef Hanninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simell O (1992) Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 90:1901–1910PubMedCrossRef
45.
go back to reference Lozanoska-Ochser B, Klein NJ, Huang GC, Alvarez RA, Peakman M (2008) Expression of CD86 on human islet endothelial cells facilitates T cell adhesion and migration. J Immunol 181:6109–6116PubMed Lozanoska-Ochser B, Klein NJ, Huang GC, Alvarez RA, Peakman M (2008) Expression of CD86 on human islet endothelial cells facilitates T cell adhesion and migration. J Immunol 181:6109–6116PubMed
46.
go back to reference 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 65:128–139PubMed 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 65:128–139PubMed
47.
go back to reference Foulis AK, Farquharson MA, Meager A (1987) Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2:1423–1427PubMedCrossRef Foulis AK, Farquharson MA, Meager A (1987) Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2:1423–1427PubMedCrossRef
48.
go back to reference Huang X, Yuang J, Goddard A et al (1995) Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44:658–664PubMedCrossRef Huang X, Yuang J, Goddard A et al (1995) Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44:658–664PubMedCrossRef
49.
go back to reference Chehadeh W, Weill J, Vantyghem MC et al (2000) Increased level of interferon-alpha in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J Infect Dis 181:1929–1939PubMedCrossRef Chehadeh W, Weill J, Vantyghem MC et al (2000) Increased level of interferon-alpha in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J Infect Dis 181:1929–1939PubMedCrossRef
50.
go back to reference Hultcrantz M, Huhn MH, Wolf M et al (2007) Interferons induce an antiviral state in human pancreatic islet cells. Virology 367:92–101PubMedCrossRef Hultcrantz M, Huhn MH, Wolf M et al (2007) Interferons induce an antiviral state in human pancreatic islet cells. Virology 367:92–101PubMedCrossRef
51.
go back to reference Roep BO, Kleijwegt FS, van Halteren AG et al (2010) Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol 159:338–43 Roep BO, Kleijwegt FS, van Halteren AG et al (2010) Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol 159:338–43
52.
go back to reference 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 52:1143–1151PubMedCrossRef 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 52:1143–1151PubMedCrossRef
53.
go back to reference Flodstrom-Tullberg M, Hultcrantz M, Stotland A et al (2005) RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J Immunol 174:1171–1177PubMed Flodstrom-Tullberg M, Hultcrantz M, Stotland A et al (2005) RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J Immunol 174:1171–1177PubMed
54.
go back to reference Smyth DJ, Cooper JD, Bailey R et al (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619PubMedCrossRef Smyth DJ, Cooper JD, Bailey R et al (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619PubMedCrossRef
55.
go back to reference Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science (New York, NY 324: 387–389 Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science (New York, NY 324: 387–389
56.
go back to reference Campbell IL, Bizilj K, Colman PG, Tuch BE, Harrison LC (1986) Interferon-gamma induces the expression of HLA-A, B, C but not HLA-DR on human pancreatic beta-cells. J Clin Endocrinol Metab 62:1101–1109PubMedCrossRef Campbell IL, Bizilj K, Colman PG, Tuch BE, Harrison LC (1986) Interferon-gamma induces the expression of HLA-A, B, C but not HLA-DR on human pancreatic beta-cells. J Clin Endocrinol Metab 62:1101–1109PubMedCrossRef
57.
go back to reference Pujol-Borrell R, Todd I, Doshi M et al (1987) HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature 326:304–306PubMedCrossRef Pujol-Borrell R, Todd I, Doshi M et al (1987) HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature 326:304–306PubMedCrossRef
58.
go back to reference Campbell IL, Oxbrow L, West J, Harrison LC (1988) Regulation of MHC protein expression in pancreatic beta-cells by interferon-gamma and tumor necrosis factor-alpha. Mol Endocrinol 2:101–107PubMedCrossRef Campbell IL, Oxbrow L, West J, Harrison LC (1988) Regulation of MHC protein expression in pancreatic beta-cells by interferon-gamma and tumor necrosis factor-alpha. Mol Endocrinol 2:101–107PubMedCrossRef
59.
go back to reference Rhode A, Pauza ME, Barral AM et al (2005) Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development. J Immunol 175:3516–3524PubMed Rhode A, Pauza ME, Barral AM et al (2005) Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development. J Immunol 175:3516–3524PubMed
60.
go back to reference Nicoletti F, Conget I, Di Mauro M et al (2002) Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease. Diabetologia 45:1107–1110PubMedCrossRef Nicoletti F, Conget I, Di Mauro M et al (2002) Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease. Diabetologia 45:1107–1110PubMedCrossRef
61.
go back to reference Rasschaert J, Liu D, Kutlu B et al (2003) Global profiling of double stranded RNA- and IFN-gamma-induced genes in rat pancreatic beta cells. Diabetologia 46:1641–1657PubMedCrossRef Rasschaert J, Liu D, Kutlu B et al (2003) Global profiling of double stranded RNA- and IFN-gamma-induced genes in rat pancreatic beta cells. Diabetologia 46:1641–1657PubMedCrossRef
62.
go back to reference Ylipaasto P, Kutlu B, Rasilainen S et al (2005) Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48:1510–1522PubMedCrossRef Ylipaasto P, Kutlu B, Rasilainen S et al (2005) Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48:1510–1522PubMedCrossRef
63.
go back to reference Andreoletti L, Hober D, Hober-Vandenberghe C et al (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 52:121–127PubMedCrossRef Andreoletti L, Hober D, Hober-Vandenberghe C et al (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 52:121–127PubMedCrossRef
64.
go back to reference 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 300:1173–1179PubMedCrossRef 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 300:1173–1179PubMedCrossRef
65.
go back to reference Hindersson M, Elshebani A, Orn A, Tuvemo T, Frisk G (2005) Simultaneous type 1 diabetes onset in mother and son coincident with an enteroviral infection. J Clin Virol 33:158–167PubMedCrossRef Hindersson M, Elshebani A, Orn A, Tuvemo T, Frisk G (2005) Simultaneous type 1 diabetes onset in mother and son coincident with an enteroviral infection. J Clin Virol 33:158–167PubMedCrossRef
66.
go back to reference Cabrera-Rode E, Sarmiento L, Molina G et al (2005) Islet cell related antibodies and type 1 diabetes associated with echovirus 30 epidemic: a case report. J Med Virol 76:373–377PubMedCrossRef Cabrera-Rode E, Sarmiento L, Molina G et al (2005) Islet cell related antibodies and type 1 diabetes associated with echovirus 30 epidemic: a case report. J Med Virol 76:373–377PubMedCrossRef
67.
go back to reference Otonkoski T, Roivainen M, Vaarala O et al (2000) Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report. Diabetologia 43:1235–1238PubMedCrossRef Otonkoski T, Roivainen M, Vaarala O et al (2000) Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report. Diabetologia 43:1235–1238PubMedCrossRef
68.
go back to reference Paananen A, Ylipaasto P, Rieder E, Hovi T, Galama J, Roivainen M (2003) Molecular and biological analysis of echovirus 9 strain isolated from a diabetic child. J Med Virol 69:529–537PubMedCrossRef Paananen A, Ylipaasto P, Rieder E, Hovi T, Galama J, Roivainen M (2003) Molecular and biological analysis of echovirus 9 strain isolated from a diabetic child. J Med Virol 69:529–537PubMedCrossRef
69.
go back to reference Diaz-Horta O, Bello M, Cabrera-Rode E et al (2001) Echovirus 4 and type 1 diabetes mellitus. Autoimmunity 34:275–281PubMedCrossRef Diaz-Horta O, Bello M, Cabrera-Rode E et al (2001) Echovirus 4 and type 1 diabetes mellitus. Autoimmunity 34:275–281PubMedCrossRef
70.
go back to reference Cabrera-Rode E, Sarmiento L, Tiberti C et al (2003) Type 1 diabetes islet associated antibodies in subjects infected by echovirus 16. Diabetologia 46:1348–1353PubMedCrossRef Cabrera-Rode E, Sarmiento L, Tiberti C et al (2003) Type 1 diabetes islet associated antibodies in subjects infected by echovirus 16. Diabetologia 46:1348–1353PubMedCrossRef
71.
go back to reference (2000) Enterovirus surveillance-United States, 1997–1999. MMWR Morb Mortal Wkly Rep 49: 913–916 (2000) Enterovirus surveillance-United States, 1997–1999. MMWR Morb Mortal Wkly Rep 49: 913–916
72.
go back to reference (2006) Enterovirus surveillance-United States, 2002–2004. MMWR Morb Mortal Wkly Rep 55: 153–156 (2006) Enterovirus surveillance-United States, 2002–2004. MMWR Morb Mortal Wkly Rep 55: 153–156
73.
go back to reference Palacios G, Oberste MS (2005) Enteroviruses as agents of emerging infectious diseases. J Neurovirol 11:424–433PubMedCrossRef Palacios G, Oberste MS (2005) Enteroviruses as agents of emerging infectious diseases. J Neurovirol 11:424–433PubMedCrossRef
74.
go back to reference Gamble DR, Kinsley ML, FitzGerald MG, Bolton R, Taylor KW (1969) Viral antibodies in diabetes mellitus. Br Med J 3:627–630PubMedCrossRef Gamble DR, Kinsley ML, FitzGerald MG, Bolton R, Taylor KW (1969) Viral antibodies in diabetes mellitus. Br Med J 3:627–630PubMedCrossRef
75.
76.
go back to reference Elfaitouri A, Berg AK, Frisk G, Yin H, Tuvemo T, Blomberg J (2007) Recent enterovirus infection in type 1 diabetes: evidence with a novel IgM method. J Med Virol 79:1861–1867PubMedCrossRef Elfaitouri A, Berg AK, Frisk G, Yin H, Tuvemo T, Blomberg J (2007) Recent enterovirus infection in type 1 diabetes: evidence with a novel IgM method. J Med Virol 79:1861–1867PubMedCrossRef
77.
go back to reference 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 51:1964–1971PubMedCrossRef 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 51:1964–1971PubMedCrossRef
78.
go back to reference Clements GB, Galbraith DN, Taylor KW (1995) Coxsackie B virus infection and onset of childhood diabetes. Lancet 346:221–223PubMedCrossRef Clements GB, Galbraith DN, Taylor KW (1995) Coxsackie B virus infection and onset of childhood diabetes. Lancet 346:221–223PubMedCrossRef
79.
go back to reference 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 19:968–969PubMedCrossRef 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 19:968–969PubMedCrossRef
80.
go back to reference 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 16:509–513PubMedCrossRef 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 16:509–513PubMedCrossRef
81.
go back to reference 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 54:879–883PubMedCrossRef 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 54:879–883PubMedCrossRef
82.
go back to reference Drescher KM, Tracy SM (2008) The CVB and etiology of type 1 diabetes. Curr Top Microbiol Immunol 323:259–274PubMedCrossRef Drescher KM, Tracy SM (2008) The CVB and etiology of type 1 diabetes. Curr Top Microbiol Immunol 323:259–274PubMedCrossRef
83.
go back to reference Oikarinen M, Tauriainen S, Honkanen T, et al (2008) Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia 51:1796–802 Oikarinen M, Tauriainen S, Honkanen T, et al (2008) Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia 51:1796–802
84.
go back to reference Ylipaasto P, Klingel K, Lindberg AM et al (2004) Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47:225–239PubMedCrossRef Ylipaasto P, Klingel K, Lindberg AM et al (2004) Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47:225–239PubMedCrossRef
85.
go back to reference Roivainen M (2006) Enteroviruses: new findings on the role of enteroviruses in type 1 diabetes. Int J Biochem Cell Biol 38:721–725PubMedCrossRef Roivainen M (2006) Enteroviruses: new findings on the role of enteroviruses in type 1 diabetes. Int J Biochem Cell Biol 38:721–725PubMedCrossRef
86.
go back to reference Chehadeh W, Kerr-Conte J, Pattou F et al (2000) Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J Virol 74:10153–10164PubMedCrossRef Chehadeh W, Kerr-Conte J, Pattou F et al (2000) Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J Virol 74:10153–10164PubMedCrossRef
87.
go back to reference Campbell IL, Harrison LC, Ashcroft RG, Jack I (1988) Reovirus infection enhances expression of class I MHC proteins on human beta-cell and rat RINm5F cell. Diabetes 37:362–365PubMedCrossRef Campbell IL, Harrison LC, Ashcroft RG, Jack I (1988) Reovirus infection enhances expression of class I MHC proteins on human beta-cell and rat RINm5F cell. Diabetes 37:362–365PubMedCrossRef
88.
go back to reference von Herrath M, Holz A (1997) Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. J Autoimmun 10:231–238CrossRef von Herrath M, Holz A (1997) Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. J Autoimmun 10:231–238CrossRef
89.
go back to reference Westerholm-Ormio M, Vaarala O, Pihkala P, Ilonen J, Savilahti E (2003) Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes 52:2287–2295PubMedCrossRef Westerholm-Ormio M, Vaarala O, Pihkala P, Ilonen J, Savilahti E (2003) Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes 52:2287–2295PubMedCrossRef
90.
go back to reference Oikarinen M, Tauriainen S, Honkanen T et al (2008) Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin Exp Immunol 151:71–75PubMedCrossRef Oikarinen M, Tauriainen S, Honkanen T et al (2008) Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin Exp Immunol 151:71–75PubMedCrossRef
91.
go back to reference 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(Pt 6):1399–1402PubMedCrossRef 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(Pt 6):1399–1402PubMedCrossRef
92.
go back to reference Klingel K, Hohenadl C, Canu A et al (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 89:314–318PubMedCrossRef Klingel K, Hohenadl C, Canu A et al (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 89:314–318PubMedCrossRef
93.
go back to reference Conaldi PG, Serra C, Mossa A et al (1997) Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis 175:693–696PubMedCrossRef Conaldi PG, Serra C, Mossa A et al (1997) Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis 175:693–696PubMedCrossRef
94.
go back to reference Heim A, Canu A, Kirschner P et al (1992) Synergistic interaction of interferon-beta and interferon-gamma in coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts. J Infect Dis 166:958–965PubMedCrossRef Heim A, Canu A, Kirschner P et al (1992) Synergistic interaction of interferon-beta and interferon-gamma in coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts. J Infect Dis 166:958–965PubMedCrossRef
95.
96.
go back to reference 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 73:10113–10121PubMed 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 73:10113–10121PubMed
97.
go back to reference Kato H, Takeuchi O, Sato S et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRef Kato H, Takeuchi O, Sato S et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRef
98.
go back to reference Pichlmair A, Schulz O, Tan CP et al (2009) Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol 83:10761–10769PubMedCrossRef Pichlmair A, Schulz O, Tan CP et al (2009) Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol 83:10761–10769PubMedCrossRef
Metadata
Title
Immunopathology of the human pancreas in type-I diabetes
Authors
Sarah J. Richardson
Abby Willcox
Adrian J. Bone
Noel G. Morgan
Alan K. Foulis
Publication date
01-01-2011
Publisher
Springer-Verlag
Published in
Seminars in Immunopathology / Issue 1/2011
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-010-0205-0

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