Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes dramatically suppresses the replication of polioviruses when the human again is infected, thereby keeping that individual safe from crippling polio. There are more than 100 known enterovirus serotypes and each serotype induces immunity in a person that will protect that person from disease caused by future exposure to that same serotype. This means that if one has already experienced an infection by a specific serotype, for example CVB3, one is immune to disease from all variations (strains) of CVB3 when next one may encounter it. However, type-specific immunity does not protect one from infection by a different serotype; protection is serotype-specific. To continue this example, therefore, CVB3 immunity will not protect one against infection by a strain of CVB1 or CVB4, for instance. Therefore, in order to trigger T1D in humans, an ebterovirus must infect a person who has no pre-existing immunity to that specific virus. So in addition to everything else discussed above, one must also experience a new enterovirus infection, against which one has no immunity, in order for T1D to be triggered. From this argument -knowing the various requirements which we can postulate to exist based on our current knowledge - one can see that having T1D initiated by a enterovirus infection such that it 'suddenly' occurs, would be a rare event. In order for T1D to be triggered by a enterovirus infection, therefore, a variety of specific conditions have to be met all at the same time: (1) the right enterovirus species (not all can do this, insulitis needs to be present (and most people likely have none), (2) the virus strain should be one that replicates rapidly (because the average natural infectious dose is very low, the virus has to generate enough progeny virus to cause the damage before the host immune response suppresses the infection), (3) the virus infection must be one never before encountered by the person (otherwise, that person is immune to the virus), and (4) the person's islets must have insulitis ongoing (in order to create the environment that supports productive enterovirus replication in the islets). If T1D onset triggered by an enterovirus requires all these requirements, one can understand why the disease is rarely caused by an enterovirus. 6. What does all of this mean for a cure for T1D? Finding a cure for existing T1D or a preventive measure against as-yet-to-occur T1D are two vital missions. Current work suggests that newly diagnosed T1D patients may profit from an antibody treatment that reduces pathogenic T cells, permitting the patient's own regulatory (good) T cells to expand in number to protect the islets from damage. This is wonderful news. However, we must also stay focused on the issue of preventing T1D completely. We know the value of vaccines: polio, rabies, measles, mumps, rubella and more, all are diseases readily countered and suppressed by vaccine development. Properly designed vaccines work. However, the relationship between enterovirus infections and T1D biology is complex as the foregoing arguments have shown. We can largely prevent T1D in NOD mice with a single injection of CVB at an early age. This means we can prevent the host's own autoimmune disease from killing the beta cells and causing T1D - in most cases. There are those who argue that NOD mice are not a good platform for designing approaches to counteract or suppress T1D, and in most cases, this criticism is valid: nearly every approach that has functioned well in NOD mice does not function in humans. However, human enteroviruses are human viruses and we know they are involved in human T1D. That they mimic much of what we know or surmise occurs when studied in the NOD mouse, is strongly inferential data in support of the hypothesis that certain human enteroviruses can either protect from, or induce, T1D. Enteroviruses are 'a bird in the hand' argument: we know they are involved in human T1D. So while we wait for clinical studies to produce lists of potential infectious candidates involved in the T1D etiology, we ought to be moving ahead to understand how enteroviruses are involved in the disease process. In the final analysis, no matter what list of potential pathogens that are found to be suspected of causing T1D, the human enteroviruses will be at the top of the list. Waiting is not an option anymore, now that we know this story. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 32 of 52

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