Pathogenesis and treatment of virus-induced autoimmune diabetes: novel insights gained from the RIP-LCMV transgenic mouse model

Herrath, Matthias G. von; Homann, Dirk; Gairin, Jean Edouard; Oldstone, Michael B. A.

doi:10.1042/bst0250630

Cited by 23 publications

(13 citation statements)

References 23 publications

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“…Thus, the disease process would continue even after the invading virus is cleared from the host. A second hypothesis, termed "bystander activation," suggests that viral infection of target tissue may 1) modify surface antigens into immunogenic forms, 2) stimulate the induction of antigen expression, or 3) induce the release of sequestered antigens during target cell lysis (40).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1

Heitmeier

Arnush

Scarim

et al. 2001

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1

Heitmeier

Arnush

Scarim

et al. 2001

Journal of Biological Chemistry

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“…It has been proposed that viral infection of islets may "trigger" or initiate an autoimmune process in genetically predisposed individuals by stimulating the initial destruction of ␤-cells (7)(8)(9)(10)(11). However, few studies have examined the effects of viral infection on the function and viability of isolated islets.…”

Section: Discussionmentioning

confidence: 99%

“…Viruses have been implicated as one environmental factor that may initiate or trigger an autoimmune reaction that targets and destroys ␤-cells in genetically susceptible individuals (7)(8)(9)(10)(11). Mouse models of virus-induced autoimmune diabetes implicate increased cytokine and iNOS expression and nitric oxide production in the development of the disease.…”

mentioning

confidence: 99%

Double-stranded RNA Inhibits β-Cell Function and Induces Islet Damage by Stimulating β-Cell Production of Nitric Oxide

Heitmeier

Scarim

Corbett

1999

Journal of Biological Chemistry

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Viral infection has been implicated as a triggering event that may initiate ␤-cell damage during the development of autoimmune diabetes. In this study, the effects of the viral replicative intermediate, doublestranded RNA (dsRNA) (in the form of synthetic polyinosinic-polycytidylic acid (poly IC)) on islet expression of inducible nitric oxide synthase (iNOS), production of nitric oxide, and islet function and viability were investigated. Treatment of rat islets with poly(IC) ؉ interferon-␥ (IFN-␥) stimulates the time-and concentrationdependent expression of iNOS and production of nitrite by rat islets. iNOS expression and nitrite production by rat islets in response to poly(IC) ؉ IFN-␥ correlate with an inhibition of insulin secretion and islet degeneration, effects that are prevented by the iNOS inhibitor aminoguanidine (AG). We have previously shown that poly ( Insulin-dependent diabetes mellitus is an autoimmune disease characterized by an inflammatory reaction in and around pancreatic islets followed by selective destruction of insulin secreting ␤-cells (1). The mechanisms that lead to the development of autoimmune diabetes are unknown; however, the expression of the inducible form of nitric oxide synthase (iNOS) 1 by ␤-cells and the resulting production of nitric oxide may be one factor that mediates ␤-cell dysfunction and eventual ␤-cell death. We and others (2-4) have shown that treatment of isolated rat islets for 18 h with IL-1 stimulates the time-and concentration-dependent expression of iNOS and production of nitrite that correlates with a potent inhibition of glucose-stimulated insulin secretion. In the presence of IFN-␥, the concentration of IL-1 required to induce iNOS expression by ␤-cells is reduced 10-fold (5). Recently, Okamoto and co-workers (6) have examined the development of diabetes in transgenic mice that express iNOS under control of the rat insulin promotor (6). These mice spontaneously develop diabetes in a nitric oxidedependent manner that occurs in the absence of insulitis. Administration of the iNOS inhibitor, aminoguanidine (AG) (200 mg/kg/2 times daily) prevents the spontaneous development of diabetes in these mice (6). These results support an effector role for nitric oxide in mediating ␤-cell damage during the development of autoimmune diabetes.Viruses have been implicated as one environmental factor that may initiate or trigger an autoimmune reaction that targets and destroys ␤-cells in genetically susceptible individuals (7-11). Mouse models of virus-induced autoimmune diabetes implicate increased cytokine and iNOS expression and nitric oxide production in the development of the disease. Encephalomyocarditis virus-induced diabetes in DBA/2 mice correlates with an increased level of IL-1␤ and TNF mRNA expression in islets as determined by in situ hybridization of pancreatic sections (12). Daily administration of antiserum specific for IL-1␤ or TNF-␣ (0.5 mg/mouse) starting on the day of viral infection attenuates encephalomyocarditis virus-induced diabetes in DBA/2 mice (12). I...

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“…The etiology of human T1D has a genetic component that serves to explain many but not all cases of T1D (114); in identical twins, T1D concordance varies at or Ͻ40% (8,12,30,69,88). Consequently, an environmental contribution to the etiology has been proposed to account for the overall observed T1D incidence (37,63,111), although the mechanism(s) by which this occurs is not known. Various putative environmental agents have been suggested, among the most common of which are viral infections (55).…”

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confidence: 99%

Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence

Tracy

Drescher

Chapman

et al. 2002

J Virol

147

164

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Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4-or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2-to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four-to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.The group B coxsackieviruses (CVB; family Picornaviridae, genus Enterovirus, species group B coxsackievirus; six serotypes, CVB1 to -6) are among the best studied of human enteroviruses (102). The CVB genome is a single strand of positive sense RNA 7,400 nucleotides in length that encodes 11 proteins in a single open reading frame (89). The CVB have been associated with diverse human diseases, among the more serious of which are myocarditis, pancreatitis, and aseptic meningitis. The CVB have been soundly implicated as causes of human myocarditis (1, 26, 42, 60-62, 73, 74, 108, 109) and pancreatitis (2,41,54,58,66,107) and, furthermore, cause these diseases readily i...

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Pathogenesis and treatment of virus-induced autoimmune diabetes: novel insights gained from the RIP-LCMV transgenic mouse model

Cited by 23 publications

References 23 publications

Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1

Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1

Double-stranded RNA Inhibits β-Cell Function and Induces Islet Damage by Stimulating β-Cell Production of Nitric Oxide

Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence

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