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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EWith evidence accumulating that the \u03b2-cells of patients with type 1 diabetes (T1DM) can be infected with enterovirus [Richardson SJ et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2009], the question if enterovirus could cause \u03b2-cell damage and T1DM has become increasingly relevant [Tauriainen S et al. \u003Cem\u003ESemin Immunopathol\u003C\/em\u003E 2011]. This article discusses the evidence of viral infection in the pancreas of patients with T1DM.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EViral Infections\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EVaccinations\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EWith evidence accumulating that the \u03b2-cells of patients with type 1 diabetes (T1DM) can be infected with enterovirus [Richardson SJ et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2009], the question if enterovirus could cause \u03b2-cell damage and T1DM has become increasingly relevant [Tauriainen S et al. \u003Cem\u003ESemin Immunopathol\u003C\/em\u003E 2011]. Noel G. Morgan, PhD, University of Exeter, Exeter, United Kingdom, discussed the evidence of viral infection in the pancreas of patients with T1DM.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EA systematic review and meta-analysis recently found a clinically significant association between enterovirus infection detected with molecular methods and autoimmunity\/T1DM [Yeung WC et al. \u003Cem\u003EBMJ\u003C\/em\u003E 2011]. While observational studies cannot assign causation, the results provide additional support to direct evidence of enterovirus infection in pancreatic tissues of individuals with T1DM [Dotta F et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2007].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EWillcox et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2010] found that \u03b1-and \u03b2-cells undergo a marked increase in proliferation during the progression of T1DM in humans (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). These results imply that islet cell proliferation is re-initiated in response to the autoimmune attack associated with T1DM.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/16\/24\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Islet Cell Proliferation Is Increased in Response to Insulitis.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1642557877\u0022 data-figure-caption=\u0022Islet Cell Proliferation Is Increased in Response to Insulitis.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/16\/24\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/16\/24\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/16\/24\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13062\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003EIslet Cell Proliferation Is Increased in Response to Insulitis.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReprinted from Willcox A et al. Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2010;3(9):2020\u20132028, with permission from Springer Verlag.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EIn 2007, Dotta et al. [\u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2007] found direct evidence that the enterovirus can infect \u03b2-cells in patients with T1DM, and infection is associated with inflammation and functional impairment. Two years later, Richardson et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2009] demonstrated that the immunoreactive enteroviral capsid protein vp1 is commonly found in the islets of recent-onset diabetes patients but only rarely in normal pediatric controls. A strong correlation was also seen between islet cell vp1 positivity and protein kinase R (PKR) production in insulin-containing islets of type 1 and type 2 diabetic patients.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe antiapoptotic protein Mcl-1 is also expressed in \u03b2-cells [Richardson SJ et al. In press]. PKR activation leads to degradation of Mcl-1, thereby enhancing the sensitivity of cells to proapoptotic stimuli. In the \u03b2-cells of patients with T1DM, double-stranded ribonucleic acid (dsRNA), which forms during replication of enteroviruses, has also been detected and appears to be associated with elevated levels of MDA5 (a cellular sensor for dsRNA). Prof. Morgan said, \u201cThis is consistent with the possibility that \u03b2-cells can sustain an enteroviral infection in patients with T1DM.\u201d\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe Possible Roles of Viral Infections and Diabetes\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EMatthias von Herrath, MD, La Jolla Institute for Allergy and Immunology, San Diego, California, USA, discussed whether viral infection enhances or abrogates T1DM.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EViral infections have been implicated in the etiology of T1DM for more than 100 years [Knip M, Simell O. \u003Cem\u003ECold Spring Harb Perspect Med\u003C\/em\u003E 2012]. Recent data from Ylipaasto et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2012] suggest that a distinct, virus-strain-specific, gene expression pattern leads to pancreatic islet destruction and proinflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely, the combined effect of these, and possibly cellular energy depletion, is behind the enterovirus-induced necrosis of islets.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EDr. Herrath reported that viral infections cause strong inflammation and\/or upregulation of major histocompatibility complex (MHC) molecule 1 and interferons. In animal models for virally induced T1DM, MHC class 1 upregulation of \u03b2-cells is a prerequisite for their recognition and demise by CD8+ (killer) T cells [Seewaldt S et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2000]. Dr. Herrath said that even without an inflammatory infiltrate, human islets can express MHC 1\u2014often many years after diagnosis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EUpregulation of MHC 1 is not uniform; it is patchy, almost in a vitiligo-like fashion. Thus, infections might act as providers of a \u201cfertile field\u201d to facilitate destruction of \u03b2-cells by autoreactive CD8s that are detected in human islets.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EConversely, viruses might prevent T1DM through various mechanisms. These are usually operational to curb immunopathology following infections. These mechanisms comprise apoptosis of antiviral and autoreactive (as bystanders) lymphocytes via programmed death ligand-1 and tumor necrosis factor-\u03b2 mechanisms as well as enhancement of regulatory T cells function and expansion.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EToll-like receptor (TLR) 2 and TLR9 are involved but TLR4 and 7 are not. Viruses that replicate to high levels in their hosts are more likely to accelerate T1DM, whereas lower-level infections are more likely to stop T1DM. Therefore, development of vaccinations against entero- and rota-viruses might help prevent some T1DM in children at risk.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EProspects for a Preventive Enterovirus Vaccine for T1DM\u003C\/h2\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EHeikki Hy\u00f6ty, MD, PhD, University of Tampere, Tampere, Finland, discussed the evidence and prospects for a preventive vaccine against T1DM.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EViruses cause diabetes in animals, including the Coxsackie B and encephalomyocarditis viruses in mice, the Ljungan virus in voles, the Kilham virus in rats, and bovine viral diarrhea in cattle. In humans, enteroviruses have tropism to pancreatic islets.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EEnterovirus proteins and RNA are both found in islets but much less so in the exocrine pancreas. Fatal Coxsackie B virus infections cause severe islet cell damage. Coxsackievirus and adenovirus receptor (CAR) is the major receptor for Coxsackie B viruses and is strongly expressed in the islets. Moreover, islet cells are permissive for enteroviruses \u003Cem\u003Ein vitro.\u003C\/em\u003E\n         \u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EYlipaasto et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2004] found a definite islet-cell tropism of enteroviruses in the human pancreas. Oikarinen et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2008] determined that, in children, positivity of islet cell antibodies alone, even when lasting for more than a year, was not associated with inflammatory changes in the islets. However, it was likely the pancreatic islets were infected by an enterovirus.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EEpidemiological studies also show an association between enterovirus infections and T1DM. As mentioned previously, Yeung WC et al. [\u003Cem\u003EBMJ\u003C\/em\u003E 2011] identified a clinically significant association between enterovirus infection detected with molecular methods and autoimmunity\/T1DM. Changes in the epidemiology of enterovirus infections can explain the increasing incidence of T1DM, variation in diabetes incidence between countries, and seasonal onset of the disease. Prof. Hy\u00f6ty said that the possibilities to develop a vaccine against enteroviruses should be fully explored. The first such studies are currently in progress. The identification of the exact subtypes of enteroviruses that show association with T1DM is an important goal in these studies. If these subtypes can be identified, the production of the vaccine would become technically possible.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/16\/24.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzn902\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn902\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}