Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes inflammation is autoimmune, which is to say, it is a naturally occurring inflammation that targets the host itself. By 12-15 weeks, insulitis is extensive in nearly every islet and it is at this age that the mice begin to develop outright T1D. This is easily observed by measuring the level of glucose (sugar) in the mouse' urine: when normal, there is no glucose detectable but once diabetic, the mice shed more than 20 grams per liter of urine (equal to about an ounce per quart). tube, then resurrect infectious virus in cell cultures, and use such viruses to study their biologies. This is a technique called reverse genetics and uses another key technique, molecular cloning. We have discovered several new aspects of the virus/T1D relationship using the mouse model, all of which are consistent with that which is known from others' human studies. (A picture of a NOD mouse pancreatic islet that is dying due to the infiltration of autoimmune lymphocytes. The pathogenic lymphocytes are the dark cells surrounding the interior, lighter area, which is the remaining intact islet, still able to produce insulin. But not for long...) Our laboratory has a collection of different CVB strains for its studies. A serotype of CVB classifies a group of CVB; we use predominantly the CVB3 because we have spent most of our research characterizing this specific serotype. However, many different enteroviruses are likely able to cause T1D in humans, not just the CVB. It is often mentioned that only CVB4 causes T1D: this is simply not true. Now, within any CVB serotype, there are numerous strains of viruses, which all differ genetically from each other. You can think of a virus strain as a variation on a single theme. Our use of the CVB3 strains has permitted a deeper understanding of how relatively minor variations in the viral genetics can have huge impact on the outcomes of virus infections. We have derived molecular clones of several CVB3 genomes so that we can manipulate the viral genetic stuff in the test 1. The CVB protect diabetes prone mice from developing T1D. Because the CVB are often mentioned as primary infectious causes of human T1D, we asked the simple question: if we inoculate the virus into young, healthy NOD mice, what happens? Does T1D immediately occur? The answer? No! Such CVB-inoculated mice enjoyed a significantly diminished chance of developing T1D compared to control mice (mice which were not inoculated with virus and develop T1D normally)[1]. In some cases following CVB inoculation, no mice developed T1D through 10 months of life. This finding showed that there is no simple link between these viruses and T1D. The NOD mouse is very prone to developing T1D: these data showed, however, that a common virus infection, one linked to human T1D onset, could actually protect these mice. There is the criticism that nearly any treatment of NOD mice will suppress T1D and in large part, this is true. However, this criticism ignores the important fact that alone of all the treatments experimentally used in NOD mice to suppress T1D, inoculation with CVB represents a test of an agent suspected to be the cause - not the cure - of T1D. Our work demonstrated that, in effect, we can vaccinate NOD mice so that they do not develop T1D. This in turn suggests the intriguing possibility that one might be able to be vaccinated against developing T1D. Indeed, we strongly believe that T1D was rare in humans before about 100-200 years ago, simply because humans were commonly exposed naturally to numerous enterovirus infections as a natural part of growing up in a world of contaminated water and poor or absent hygiene [1]. [This was recently reviewed: Enteroviruses, type 1 diabetes, and hygiene: a complex relationship. S. Tracy et al., Reviews in Medical Virology 20:106-116, 2010.] Invest in ME (Charity Nr. 1114035) www.investinme.org Page 28 of 52
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