Type 1 Diabetes has a long standing history as a largely genetic autoimmune disease passed through families. This is of course supported by looking at the genes of an individual and specifically looking at his or her HLA region to give a percent of risk of diabetes. This was only a potential risk and even with continuing markers for diabetes, antibodies being one, we have yet to be able say for sure whether or not a child will get diabetes until they do. A new component has emerged to identify both a genetic and environmental component to disease progression or, as far as immunology is concerned, a link between adaptive and innate immunity in type 1 Diabetes.
The role of the innate immune system in the development of type 1 diabetes in at risk individuals is currently under investigation and while the complete mechanism is still unclear what is clear is that enterovirus infections are involved. A 2005 paper by Merja Roivainen outlines the potential pathways that EV may take in the destruction of insulin producing β-cells and potential clinical applications. At approximately 80% loss of pancreatic insulin producing β-cells diabetes becomes symptomatic and treatment is required. In previous studies by the same author they were able isolate enterovirus RNA via PCR from the postmortem islet cells of T1D (1). Other studies have also demonstrated a link between enterovirus infection and type 1 diabetes, atherosclerosis disease, myocardial infarction, bronchiolitis and asthma (1). While this may be well established it is unclear as to a mechanism for the virus to ultimately induce or influence disease.
There are three major theories on possible mechanisms for the virus to damage β-cells. First, upon reaching β-cells the virus destroys islet cells and exposes the immune system to “previously hidden self-components” (1). This is similar the case we discussed in class where a researcher accidentally exposed his immune system to brain tissue and his immune attacked his brain, which it otherwise never saw, causing encephalitis. Second, there may be a bystander component to the viral infection where the pancreatic islet cells are damaged by being too close to the viral infection. Lastly there also may be a molecular mimicry component in which the immune system reacts to the virus and, because of similarity between autoantigens such as GAD-65 and HSP-60 and viral proteins 2c and VP0, to the islet cells. An interesting genetic component that is also related is an new SNP that has been associated with diabetes on a protein that is involved in the innate immune response. A single nucleotide polymorphism on the IFIH1 (Inerferon-Induced Helicase 1), a protein that dices incoming viral dsRNA and also is involved in intracellular signaling for the release of cytokines and chemokines in, has been associated with diabetes (2). A viral trigger to diabetes does however provide new hope to potential for clinical applications for prevention.
Clinical immunizations may be the future of diabetes prevention but there are some hurdles to overcome. We know little about what specific strains are causing the progression of diabetes and given that there are currently one hundred known enteroviruses that can infect humans. Also there could be only single amino acid differences between one virus that causes diabetes and one that doesn’t so given that viral RNA replication in a host is error-prone it is likely that an immunization wouldn’t be able to keep-up with the continually mutating virus. While these may be true continued research in viruses my one day both wipe them of the face of the earth and cure disease.
1. Roivainen, Merja. Enertoviruses: New findings on the role of enteroviruses in type 1 diabetes. The Int. J. of Biochem and Cell Bio., 2006. 38:721-725.
2. Smyth, Deborah, Jason Cooper, Rebecca Bailey, Sarah Field, Oliver Burren, Luc Smink, Cristina Guja, Constantin Ionescu-Tirgoviste, Barry Widmer, David Dunger, David Savage, Neil Walker, David Clayton and John A Todd. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genetics, 2006. 38:6, 617-619.
7 comments:
Doesn't this explanation contradict the Hygiene Hypothesis? Even in the field of diabetes, helminths are invoked as the modulators of autoimmunity (although T1D does not seem to be IgE-dependent). How do viruses play into the Hygiene Hypothesis?
Gale, E. 2002. A missing link in the hygiene hypothesis? Diabetologia Volume 45, Number 4. 588-594.
Good question Tonyc7630 and I believe it requires a big answer. Give me some time to answer and I'll post it into a separate blog. I have some ideas I just need to look-up some literature support.
Ok, that was actually me just logged in on a different account.
I had a friend in college with Type I Diabetes. She checked her blood sugar nearly constantly. Once I asked her if her family has a lot of diabetes, and she said, "No, I got diabetes from a virus." At the time I thought, "Yeah, right..." But I guess I shouldn't have dismissed this explanation. Viruses causing diabetes seems pretty scary. T1D is not currently treated as something you can "catch" and getting to the bottom of this might open a whole new world of diabetes prevention.
One thought about how viral infections and the hygeine hypothesis interrelate in T1D pathogenesis is that of competitive inhibition. If a kid is too clean then their guts are not filled with commensal flora and there is more room for pathogenic microbes to move in.
Since T1D is an autoimmune disease and a person's own immune cells are destroying the beta cells in the pancreas, is it a viral infection that is truly causing the person's immune system to destroy itself? With the great increase in T1D there have been many speculations as to what exactly is the cause. In the fall issue of Vivat, a publication of the University of Colorado at Denver and Health Sciences Center, the Director of the Barbara Davis Center for Childhood Diabetes, George Eisenbarth, was quoted as saying that one of the leading theories is the 'hygiene hypothesis'. He says that developed countries are seeing a higher incidence of T1D then underdeveloped countries. Eisenbarth states that the theory is that the immune system has evolved...making it more likely to create autoimmunity, but it is only a hypothesis (1). Even with the hygiene hypothesis, there are many possible triggers that may cause Type 1 Diabetes to develop. Many type 1 diabetics are developing diabetes based on genetic susceptibility. Since there are specific genes that are directly linked to Type I Diabetes, risk for individuals with these genes have a much higher prevalence than individuals with out the diabetes genes. Does a person have a greater chance of developing T1D after a viral infection if they have a high genetic susceptibility to Type 1 Diabetes?
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