Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1.
OBJECTIVE
Immunohistochemical staining reveals that the enteroviral capsid protein VP1 is present at higher frequency in the insulin-containing islets of patients with recent-onset type 1 diabetes than in controls. This is consistent with epidemiological evidence suggesting that enteroviral infection may contribute to the autoimmune response in type 1 diabetes. However, immunostaining of VP1 is not definitive since the antibody widely used to detect the protein (Clone 5D8/1) might also cross-react with additional proteins under some conditions. Therefore, we sought to verify that VP1 immunopositivity correlates with additional markers of viral infection.


METHODS
Antigen immunoreactivity was examined in formalin-fixed, paraffin-embedded, pancreases from two different collections of type 1 diabetes and control cases: a historical collection from the UK and the nPOD (network of Pancreatic Organ donors with Diabetes) cohort from the USA.


RESULTS
VP1 immunoreactivity was present in ~20% of insulin-containing islets of both cohorts under stringent conditions but was absent from insulin-deficient islets. The presence of VP1 was restricted to beta cells but only a minority of these contained the antigen. The innate viral sensor, protein kinase R (PKR) was upregulated selectively in beta cells that were immunopositive for VP1. The anti-apoptotic protein myeloid cell leukaemia sequence-1 (Mcl-1) was abundant in beta cells that were immunonegative for VP1 but Mcl-1 was depleted in cells containing VP1.


CONCLUSIONS
The presence of immunoreactive VP1 within beta cells in type 1 diabetes is associated with a cellular phenotype consistent with the activation of antiviral response pathways and enhanced sensitivity to apoptosis. However, definitive studies confirming whether viral infections are causal to beta cell loss in human diabetes are still awaited.
Endocrine Pharmacology, University of Exeter Medical School, John Bull Building, Plymouth PL6 8BU, UK. sarah.richardson@pms.ac.uk
S J
SJ
Richardson
P
P
Leete
A J
AJ
Bone
A K
AK
Foulis
N G
NG
Morgan
D000293:Adolescent; D000328:Adult; D000956:Antigens, Viral / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015536:Down-Regulation; D004770:Enterovirus / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D004769:Enterovirus Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004790:Enzyme Induction; D006801:Humans; D007223:Infant; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D006113:United Kingdom; D014481:United States; D019892:eIF-2 Kinase / Q000096:biosynthesis* / Q000378:metabolism
D000956:Antigens, Viral; D015415:Biomarkers; D036022:Capsid Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D019892:eIF-2 Kinase