The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

Abstract

Aims/hypothesis Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls. Methods Serial sections of paraffin-embedded pancreatic autopsy samples from 72 recent-onset type 1 diabetes patients and up to 161 controls were immunostained for insulin, glucagon, vp1, double-stranded RNA activated protein kinase R (PKR) and MHC class I. Results vp1-immunopositive cells were detected in multiple islets of 44 out of 72 young recent-onset type 1 diabetic patients, compared with a total of only three islets in three out of 50 neonatal and paediatric normal controls. vp1 staining was restricted to insulin-containing beta cells. Among the control pancreases, vp1 immunopositivity was also observed in some islets from ten out of 25 type 2 diabetic patients. A strong correlation was established between islet cell vp1 positivity and PKR production in insulin-containing islets of both type 1 and type 2 diabetic patients, consistent with a persistent viral infection of the islets. Conclusions/interpretation Immunoreactive vp1 is commonly found in the islets of recent-onset type 1 diabetes patients, but only rarely in normal paediatric controls. vp1 immunostaining was also observed in some islets of type 2 diabetes patients, suggesting that the phenomenon is not restricted to type 1 diabetes patients.

Anti-coxsackievirus B4 (CV-B4) enhancing activity of serum associated with increased viral load and pathology in mice reinfected with CV-B4

“…3 The presence of EV protein in the pancreas of T1D patients has been observed. 4 Prospective studies confirmed the link between EV and the development of pancreas islet autoimmunity. 5 Moreover, experimental studies, in vitro and in vivo animal models, revealed that CV-B4 may be involved in the pathogenesis of T1D through several mechanisms.…”

Case report: type 1 diabetes in monozygotic quadruplets

“…We focused on enteroviruses and coxsackie viruses as they are suspected to have a role in T1D development. [13][14][15] Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms using Aneufast multiplex QF-PCR kit (molGENTIX, S.L., Barcelona, Spain), recommended by CODIS (Combined DNA Index System). 20 …”

“…[9][10][11][12] Notably, and in this context, several recently published findings suggest a strong link between T1D and enteroviral infections. [13][14][15] To prevent the clinical onset of T1D, immuno-intervention should be undertaken in the clinically silent pre-diabetic phase. However, it is difficult to identify suitable candidates for such interventions.…”

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

“…Epidemiological studies have suggested that infections with enteroviruses, in particular those of the coxsackie B virus (CVB) serotypes, may be linked to islet autoimmunity and development of type 1 diabetes [1][2][3][4][5]. Other observations suggesting that infections with these viruses have a causative role in diabetes development come from studies that found enteroviruses more frequently in pancreases [6][7][8] and, in some studies, also gut biopsies [9][10][11], from patients with type 1 diabetes compared with healthy controls. Some enteroviruses, including the CVBs, are pancreatropic and can infect human beta cells in vitro, often with a detrimental outcome (e.g.…”