The major genetic risk locus for type 1 diabetes controls the presentation of antigens

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It has been estimated that approximately 50% of the genetic risk of developing type 1 diabetes is contributed by a single set of genes called the major histocompatibility complex (MHC). So what are they? Why is it such a major factor in determining the risk of developing this disease? What can we learn about type 1 by considering the MHC?

It turns out that the MHC plays a very important role in the ability of our species to survive a pandemic. Their function is very well understood. They present antigen to T cells. First of all, we have several different genes that code for different MHCs and they all sit next to each other in one location on chromosome 6. Also, just to make things really confusing, researchers have decided to give the human genes their own name: Human Leukocyte Antigen genes (HLA). So for our purposes, HLA and MHC are two different names for the same thing. Antigen presentation is a difficult concept both to teach and to understand. To appreciate the significance of this we need to start with the T cell. (I devoted the last couple of posts to talking about T cells so if you need some review that would be a good place to start). Just to recap, T cells orchestrate the response to infection. They sample the environment, looking for antigen using a special protein called the T cell receptor (TCR). The TCR gene undergoes recombination such that each T cell recognizes a unique antigen.

Now, a TCR binds to antigen but only when it is presented by MHC. Think of the MHC like a trusted friend’s pair of hands offering you a small stick. The hands are the MHC and the stick, nestled comfortably between the two palms is the antigen. This works on a physical level in that antigens are often short strings of amino acids (protein fragments) and they are kinked just like a stick. This physical analogy has some inherent limitations so let’s add another more “relational” analogy. Consider how people get their news each day. We recognize that this is a pretty divided society and that there are different news channels for almost every taste. You might only trust CNN or you might only trust MSNBC or FOX News, or NPR. Now you don’t actually get to see the actual events that are being reported on. You see the events through the eyes of the news agency. Of course, every news agency is completely biased except for your own favorite which is fair and balanced. However, for the sake of argument, let’s assume that all news agencies have some sort of bias. In this analogy, the news agency is the MHC. It presents news items (antigens) to you (the T cell). Given your beliefs you will only accept news as viable from one or perhaps a small set of news agencies. We call the fact that T cells only accept antigen from an MHC that it knows “MHC restriction”. Just as each news agency might give a news item a different spin, each different MHC presents one particular antigen as a slightly different shape. The antigen can assume different shapes because unlike the stick image I used above, each amino acid is attached to the next via a peptide bond that can rotate 360 degrees. Each amino acid side chain that gives the amino acid its unique shape thus can stick out at a different angle. Indeed in this way one peptide string can look completely different when nestled in the cleft of a different MHC. The TCR binds to both the antigen and to the MHC. In fact the TCR cannot recognize the antigen unless it is being presented by MHC.

One of the consequences of this arrangement is that a foreign MHC protein itself will every once in a while be misrecognized as a dangerous antigen and initiate a serious immune response. Where might a foreign MHC come from? Until fairly recently it was an impossible event. Then doctors began to perform organ transplants. It is well known that for a transplant to be accepted it has to either be donated by an identical twin (that has an identical set of MHC) or else 7 out of 8 MHC loci have to match and even then, immunosuppressive drugs must be administered for the rest of the patient’s life. What has happened is that millions of different T cells with different TCR have interacted with this new set of MHC molecules and a few have activated leading to a full blown immune response against the transplanted tissue. So, if nothing else, you can impress your friends with this knowledge. However, to understand how this relates to type 1 diabetes, read on.

There are a great many different proteins in this world and so there are an astronomical number of different protein fragments – or antigens (I performed the actual calculation a couple of posts ago and will not bore you with it again). Amazingly, the slot in the MHC can accommodate many of these different fragments. These peptide fragments are very flexible so the shape of the fragment, the shape seen by the TCR, is determined by the MHC. Consider this because it is of fundamental importance. Your immune system is formed on the basis of the antigens it sees during thymic selection as thymocytes grow up to become T cells. In turn, the shape of the antigens seen by your immune system is strongly affected by the MHC that presents it. This would only be a minor curiosity if there was only one MHC gene. Instead, there exist several hundred different variants (called alleles) for each of our MHC genes. You may have one set of alleles and your mate may only share 1 (or none) of these alleles. This means that you and your mate will present the same antigen as a completely different shape to your respective immune systems. The consequence of this is that everyone in the world will present antigens from, say, the H1N1 virus in a slightly different way. Some shapes are easier to bind to than others so no matter how virulent the virus may be, the chances are that some people in the world will have immune systems that will recognize antigens from this virus. In turn, they will be able to respond so well as to be immune. A different set of people will have an immune system that recognizes antigen from tuberculosis bacteria in such a robust fashion that they will not get sick. In this way the species will always survive.

Now, going back to our analogy, unlike our world where news items are not something you would normally act upon, to the T cell these news items (antigens) are of tremendous importance. Indeed, the T cell decides whether to wage war on the basis of this information. What if a mistake was made such that a T cell was presented a bit of self peptide in a way that caused it to activate? This would be dependent, in part on the shape of the antigen which, in turn, would be partially due to the particular MHC that was doing the presenting. If that self peptide happened to be a fragment of insulin, we would be talking about the onset of type I diabetes.

Which MHC alleles are more likely to make this mistake? Their names are quite esoteric as are most things named by geneticists. The most common MHC class II allele associated with diabetes in Caucasians, for example, is called HLA-DQ-3.2. The important take home message is that we have identified a number of very specific alleles and test for these alleles in children to assess risk.

Returning to the questions with which we started, we see that T cells are restricted to only recognizing antigen when it is presented by an appropriate MHC molecule. The MHC plays a role in establishing the shape of the antigen, ensuring that different MHC will vastly increase the ability of the human race to respond to any one pathogen. What we can learn about type 1 diabetes is surprisingly important. A large share of the genetic risk contributed by the MHC tells us that the process of mistaken antigen recognition plays a major role in this disease. But where is the mistake really made? The autoantibodies found in the blood steam of patients with type I diabetes have helped us to identify the critical antigens associated with the disease. We have not yet identified all of them. Indeed, just recently a colleague of mine identified a new one. She has been searching for it for almost 20 years. I’ll discuss it when her paper gets published. The shape of the antigen leads us to the specificity of the TCR and the specific tolerance mechanisms in place to keep that TCR well behaved. This, in turn leads us deeper and deeper into the complexities of the immune system. It is an evolving news story. Luckily, thanks to the dynamic diabetic duo: Jessica and Michael (the founders of this publication), A Sweet Life is a news organization you can trust!

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[…] these T cells seem to be activated. As you may recall from previous posts, T cells require antigen presented by MHC to become activated. Now, it is not an easy thing to establish what the T cell specificity is for […]

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