Development of Type 1 Diabetes in Wild Bank Voles Associated With Islet Autoantibodies and the NovelLjungan Virus

Abstract

Wild bank voles (Clethrionomys glareolus) may develop diabetes in laboratory captivity. The aim of this study was to test whether bank voles develop type 1 diabetes in association with Ljungan virus. Two groups of bank voles were analyzed for diabetes, pancreas histology, autoantibodies to glutamic acid decarboxylase (GAD65), IA-2, and insulin by standardized radioligand-binding assays as well as antibodies to in vitro transcribed and translated Ljungan virus antigens. Group A represented 101 trapped bank voles, which were screened for diabetes when euthanized within 24 hours of capture. Group B represented 67 bank voles, which were trapped and kept in the laboratory for 1 month before being euthanized. Group A bank voles did not have diabetes. Bank voles in group B (22/67; 33%) developed diabetes due to specific lysis of pancreatic islet beta cells. Compared to nondiabetic group B bank voles, diabetic animals had increased levels of GAD65 (P < .0001), IA-2 (P < .0001), and insulin (P = .03) autoantibodies. Affected islets stained positive for Ljungan virus, a novel picorna virus isolated from bank voles. Ljungan virus inoculation of nondiabetic wild bank voles induced beta-cell lysis. Compared to group A bank voles, Ljungan virus antibodies were increased in both nondiabetic (P < .0001) and diabetic (P = .0015) group B bank voles. Levels of Ljungan virus antibodies were also increased in young age at onset of newly diagnosed type 1 diabetes in children (P < .01). These findings support the hypothesis that the development of type 1 diabetes in captured wild bank voles is associated with Ljungan virus. It is speculated that bank voles may have a possible zoonotic role as a reservoir and vector for virus that may contribute to the incidence of type 1 diabetes in humans.

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

“…The population of bank voles in Northern Sweden is known to fluctuate, with multiannual population cycles showing similarities with the T1D incidence fluctuations (29). Levels of LVAb were increased in young age at onset of T1D in children but a possible relationship to the incidence of T1D could either not be determined (28) or was suggestive (31). In our previous investigation, LVAb were studied in children from the Northern part of Sweden where the multiannual population cycles of bank voles now show a trend towards reduced fluctuation pattern (20).…”

“…The Ljungan virus isolate 87-012 (23) was subcloned in the pCRII-TOPOÒ vector (Life technologies, Grand Island, NY) to contain nucleotide positions 301-2685 representing VP0 (VP2), VP3, and VP1 (28). The resulting cDNA clone, pLV1, was verified by sequencing and used in coupled in vitro transcription translation to label the resulting polyprotein (Mr 97K) with 35 S-methionine as described previously (15).…”

“…The first aim of the present study was to test whether LVAb was related to age at clinical diagnosis as reported previously (28,31). Our second aim was to test if HLA types were associated with LVAb levels.…”

“…The LV was first isolated in a bank vole, Myodes glareolus, from the valley of the river Ljungan in Northern Sweden (30). It was also reported that bank voles captured in the wild developed diabetes and had not only Ljungan virus antibodies (LVAb) but also increased levels of autoantibodies against glutamic acid decarboxylase 65 (GADA), islet antigen-2 (IA-2), and insulin (IAA) (28). The population of bank voles in Northern Sweden is known to fluctuate, with multiannual population cycles showing similarities with the T1D incidence fluctuations (29).…”

“…A fluctuating pattern of infectious diseases, including zoonoses (29), has been suggested to contribute to the appearance of either islet autoimmunity, T1D, or both (4,34). The Ljungan virus (LV), a parechovirus, possibly pathogenic to humans (8,23,28) has been proposed to contribute to T1D. The LV was defined (23,29) as a separate species in the family picornaviridae of the parechovirus genus, that formerly was classified as an enterovirus but later reclassified as a separate genus containing both human parechoviruses (HPeV) and the LV.…”