Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 5, 1143-1151

Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Plymouth, UK.
Diabetologia (Impact Factor: 6.67). 04/2009; 52(6):1143-51. DOI: 10.1007/s00125-009-1276-0
Source: PubMed


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.
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.
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.
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.

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    • "Therefore, enterovirus infections in ductal cells may affect also beta-cells and be involved in the induction of type 1 diabetes. Notably, enterovirus genomes/capsid proteins have been detected in ductal cells of type 1 diabetes patients (Richardson et al., 2009; Ylipaasto et al., 2004). "
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    ABSTRACT: Enterovirus infections have been suspected to be involved in the development of type 1 diabetes. However, the pathogenetic mechanism of enterovirus-induced type 1 diabetes is not known. Pancreatic ductal cells are closely associated with pancreatic islets. Therefore, enterovirus infections in ductal cells may affect also beta-cells and be involved in the induction of type 1 diabetes. The aim of this study was to assess the ability of different enterovirus strains to infect, replicate and produce cytopathic effect in human pancreatic ductal cells. Furthermore, the viral factors that affect these capabilities were studied. The pancreatic ductal cells were highly susceptible to enterovirus infections. Both viral growth and cytolysis were detected for several enterovirus serotypes. However, the viral growth and capability to induce cytopathic effect (cpe) did not correlate completely. Some of the virus strains replicated in ductal cells without apparent cpe. Furthermore, there were strain-specific differences in the growth kinetics and the ability to cause cpe within some serotypes. Viral adaptation experiments were carried out to study the potential genetic determinants behind these phenotypic differences. The blind-passage of non-lytic CV-B6-Schmitt strain in HPDE-cells resulted in lytic phenotype and increased progeny production. This was associated with the substitution of a single amino acid (K257E) in the virus capsid protein VP1 and the viral ability to use decay accelerating factor (DAF) as a receptor. This study demonstrates considerable plasticity in the cell tropism, receptor usage and cytolytic properties of enteroviruses and underlines the strong effect of single or few amino acid substitutions in cell tropism and lytic capabilities of a given enterovirus. Since ductal cells are anatomically close to pancreatic islets, the capability of enteroviruses to infect and destroy pancreatic ductal cells may also implications in respect to enterovirus induced type 1 diabetes. In addition, the capability for rapid adaptation to different cell types suggests that, on occasion, enterovirus strains with different pathogenetic properties may arise from less pathogenic ancestors. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 08/2015; 210. DOI:10.1016/j.virusres.2015.08.003 · 2.32 Impact Factor
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    • "al . , 2008 ) , and a number of autoimmune diseases have been linked to infection ; rheumatic fever presents after Streptococcus pyogenes infection ( Fae et al . , 2006 ) , primary anti - phospholipid syndrome patients have high levels of IgM antibodies to rubella and Toxoplasma ( Zinger et al . , 2009 ) , diabetes is associated with Enterovirus ( Richardson et al . , 2009 ) , and active infections with Helicobacter pylori have been observed in autoimmune gastritis ( Annibale et al . , 2001 ) . Chemi - cal / drug exposure , and immunotoxicity of such compounds are linked to autoimmune disease . Chemicals that are commonly found in cosmetics are associated with PBC ( Rieger et al . , 2006 ) , and acetamino"
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    ABSTRACT: Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.
    Frontiers in Neuroendocrinology 04/2014; 35(3). DOI:10.1016/j.yfrne.2014.04.004 · 7.04 Impact Factor
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    • "Another example of associating infection with autoimmune disease is type 1 diabetes. Type 1 diabetes is an autoimmune disease resulting from the destruction of β-islet cells by autoreactive T cells and the concomitant release of various islet cell antigens [21, 25]. The appearance of antibodies against glutamic acid decarboxylase 65 (GAD-65) and tyrosine phosphatase precedes the onset of the disease by 5–10 years [26, 27]. "
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    ABSTRACT: Autoimmune diseases have registered an alarming rise worldwide in recent years. Accumulated evidence indicates that the immune system's ability to distinguish self from nonself is negatively impacted by genetic factors and environmental triggers. Genetics is certainly a factor, but since it normally takes a very long time for the human genetic pattern to change enough to register on a worldwide scale, increasingly the attention of studies has been focused on the environmental factors of a rapidly changing and evolving civilization. New technology, new industries, new inventions, new chemicals and drugs, and new foods and diets are constantly and rapidly being introduced in this fast-paced ever-changing world. Toxicants, infections, epitope spreading, dysfunctions of immune homeostasis, and dietary components can all have an impact on the body's delicate immune recognition system. Although the precise etiology and pathogenesis of many autoimmune diseases are still unknown, it would appear from the collated studies that there are common mechanisms in the immunopathogenesis of multiple autoimmune reactivities. Of particular interest is the citrullination of host proteins and their conversion to autoantigens by the aforementioned environmental triggers. The identification of these specific triggers of autoimmune reactivity is essential then for the development of new therapies for autoimmune diseases.
    02/2014; 2014:437231. DOI:10.1155/2014/437231
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