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Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes

Dunne, Jessica L.; Richardson, Sarah J.; Atkinson, Mark A.; Craig, Maria E.; Dahl-Jørgensen, Knut; Flodström-Tullberg, Malin; Hyöty, Heikki; Insel, Richard A.; Lernmark, Åke LU and Lloyd, Richard E., et al. (2019) In Diabetologia 62(5). p.744-753
Abstract

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent... (More)

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

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published
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keywords
Antiviral therapy, Autoimmunity, Beta cells, Enterovirus, Pancreas, Prevention, Type 1 diabetes, Vaccine, Virus
in
Diabetologia
volume
62
issue
5
pages
744 - 753
publisher
Springer
external identifiers
  • scopus:85060630556
ISSN
0012-186X
DOI
10.1007/s00125-019-4811-7
language
English
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yes
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36217fce-5457-4b6d-b700-f341b29028c9
date added to LUP
2019-02-07 08:59:29
date last changed
2019-10-15 06:58:09
@article{36217fce-5457-4b6d-b700-f341b29028c9,
  abstract     = {<p>In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.</p>},
  author       = {Dunne, Jessica L. and Richardson, Sarah J. and Atkinson, Mark A. and Craig, Maria E. and Dahl-Jørgensen, Knut and Flodström-Tullberg, Malin and Hyöty, Heikki and Insel, Richard A. and Lernmark, Åke and Lloyd, Richard E. and Morgan, Noel G. and Pugliese, Alberto},
  issn         = {0012-186X},
  keyword      = {Antiviral therapy,Autoimmunity,Beta cells,Enterovirus,Pancreas,Prevention,Type 1 diabetes,Vaccine,Virus},
  language     = {eng},
  month        = {01},
  number       = {5},
  pages        = {744--753},
  publisher    = {Springer},
  series       = {Diabetologia},
  title        = {Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes},
  url          = {http://dx.doi.org/10.1007/s00125-019-4811-7},
  volume       = {62},
  year         = {2019},
}