Type 1 Diabetes – A Breakdown of Tolerance

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There are several forms of diabetes. The main forms are called Type 1 and Type 2. Here I will try to explain the underlying biology that leads to Type 1 diabetes. In the next post, I’ll tackle Type 2.

Type 1 diabetes is very aggressive. Unlike Type 2, which can take a decade to develop, Type 1 can manifest in months. It is an autoimmune condition in which the insulin secreting cells of the pancreas (organized into structures called islets) are attacked by cells of the patient’s immune system. The reasons for this attack are buried deep within the fundamental design of how the immune system forms.

Military analogies suit discussions about the immune system, since one of its major functions, of course, is to battle pathogens which would really like to feed on us. (It’s comforting to know that we are still part of the food chain.) We are going to focus here on one specific type of immune cell called the T cell. T cells are the generals of the immune system, as they decide what and when to attack. They see the world as antigens.

What are antigens? Well, actually they can be almost anything. The most common sorts of antigens are small fragments of proteins about 7 – 13 amino acids in length. These protein fragments, the remnants of some poor little bacterium, are “presented” to the T cell by something that has the especially creative name of an “antigen presenting cell”.

What is especially important to understand is that the immune system’s ability to recognize a particular string of amino acids; the antigen, as something foreign and dangerous is a very difficult problem for the body. It does not have a store of antigens to practice on. Instead it does something quite beautifully strange. T cells randomly rearrange their antigen recognition receptor gene to create up to a billion different possible receptors. Most of them don’t work right and they are tested on the only thing available…our own proteins. What this means is that every single T cell in your body has the capacity to respond to some self antigen. The mystery, then, is why we aren’t all autoimmune disease patients! This area has been investigated intensively and at present there are several independent processes that we know of that keeps the immune system in check until it is needed. Collectively, these processes are called “tolerance”.

So, now we have it! Type 1 diabetes is a disease caused by a breakdown in one or more of the tolerance processes specifically designed to protect the islets. I will be talking a lot about tolerance mechanisms in future posts as this is one way in which we might be able to stop the immune system from mistakenly destroying the islet cells. We just need to learn how to all get along.

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Jeff Nobles

What an elegant and clear description of current knowledge. Thanks for that.
I’m reading it today, the 36th anniversary of my diagnosis of T1. It brings me some joy to think that my body was doing its job, protecting me in 1973, but trying just a little too hard.

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