Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes coxsackie B virus is replicating (shown by the brown color in the upper left corner primarily). The light blue in the remaining area are pathogenic autoimmune lymphocytes. Virus only replicates in the remaining healthy tissue, thus speeding T1D onset by killing insulin-producing beta cells. 4. CVB infection of older, prediabetic mice can, however, trigger T1D, an event linked to the alteration of the islet microenvironment. Older, pre-diabetic mice show massive insulitis in nearly every islet and not surprisingly, soon begin to become sick with T1D due to loss of insulin production. This naturally occurring, genetically driven autoimmune disease kills cells in the islets, including the beta cells, a process that leads to loss of insulin production and thus, T1D onset. This inflammation of islets represents a real change in the biology of the islet, a massive naturallyoccurring change in the islet microenvironment. We therefore asked another simple question: if CVB does not trigger T1D in young mice but instead, protects them, what happens in mice that are about to develop T1D anyway? We knew that IL-4 could let virus replicate in islets: would inflammation permit the same? The answer was yes! Young NOD mice are analogous to humans who are genetically predisposed to developing autoimmune T1D but have yet to do so: they may have little or no insulitis present, just like young NOD mice. Based on our results, we suggest that humans with little or no insulitis, are at low risk from CVBinduced T1D. This is because we have shown that CVB (or in humans, we believe other enteroviruses as well) need to have insulitis in place in order to be able to successfully replicate in islets. However, it is quite difficult to say how advanced insulitis is in a human being; even presuming one knows that one is at risk. Humans are not like mice in a key respect: these mice are highly inbred and so, their own genes drive them to develop T1D in a regular, predictable fashion (the very thing that makes them so useful for this research). Every human is genetically distinct and has a different schedule for developing autoimmune insulitis (if indeed they ever do and of course, by far most do not). By modeling this situation in mice, we mimic the case in humans where a virus infection occurs at a time closely prior to the time when that person would develop T1D anyway from his/her own autoimmune disease. In mice, this is a specific age; in humans, it could be any time. What we found was that pre-diabetic mice - i.e., mice with ongoing insulitis - when inoculated with a virulent strain of CVB, rapidly developed T1D, much faster than the rate of development observed in the control mice in which it is controlled only by the autoimmune disease. When we examined the islets of such mice, we discovered the presence of virus (as shown above). That virus was found replicating within the islets and associated with beta cells prior to the onset of T1D meant that the virus replication was denuding the mouse of intact beta cells, consequently causing early onset T1D[2]. (Stained bright red is an isolated mouse pancreatic islet. It is still associated with some residual pancreatic tissue.) 5. Findings in mice and how they relate to human T1D: connecting the dots. The very great majority of enterovirus infections in humans never trigger T1D, even though enterovirus infections are common in the US from spring through the summer into the fall months and enteroviruses are encountered worldwide. So, if human enteroviruses are causes of human T1D, how is this explained? Using information we have gained by asking key questions of our mouse model and correlating clinical reports of enterovirus-linked T1D, we suggest that there are several reasons. It is very likely that only certain enteroviruses can induce T1D or for that matter, act to protect one from developing T1D. Clearly in NOD mice, the CVB can either protect mice from developing autoimmune T1D (when they are exposed to the virus when young) or CVB can rapidly trigger T1D Invest in ME (Charity Nr. 1114035) www.investinme.org Page 30 of 52

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