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Multiple Sclerosis T Cell Receptor Diversity

Monday June 2nd, 2008 @ 08:55:45 EST

From Category: Un-Categorized

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At we have discussed both in vitro and in vivo evidence for stem cells being able to play a therapeutic effect on multiple sclerosis. The main mechanism by which this occurs is through the ability of stem cells to generate new myelin, and in some cases actually regenerate neurons. However, in multiple sclerosis the main cause of the disease is immunological. It is an immune response that attacks the myelin protein. Theoretically, while stem cells are useful because they can regenerate the damaged tissue, there is still the problem that the tissue will again be damaged by the underlying cause. The video describes a very powerful finding from the group of Eli Sercarz that specific T cell clones are essential for causing disease, while the majority of T cells that respond to myelin are basically innocent bystanders. For a comlete description, one is advised to go to the orginal paper discussed which is freely available at

Here's the transcript of the video.

Multiple sclerosis is an autoimmune disease in which the T cells attack various components of the central nervous system. One main component is called myelin basic protein which lines the nerves it makes up the myelin sheath and its degeneration is causative of MS, we know that this is an important target of the immune response during MS progression because you see responses to this in a lot of MS patients, you can induce an MS-like disease in animals if you immunize with this protein, and more importantly if you use this protein intravenously in a tolerogenic manner you can induce remission in patients with MS, certain subsets of patients

So we are going to discuss a paper that made an important finding regarding the immune response to myelin basic protein. To begin the investigators asked a very basic question. What they induce immune response in a animal to this protein, you get disease. In the specific animal model they used, the MS like disease peaks at day 15. so the first question was, if you immunize with myelin basic protein peptide will you get a same immune response when the disease is at its peak? And will the immune response be lower when the disease is in remission?

As you can see in the figure 1, the immune response to the peptide was pretty much the same, when the animal was at the peak of the disease and when the disease was in remission. So this made the scientists ask what is it that made the pathology come to be. I mean if you are getting proliferative responses in animals that have the disease and animals that are in remission, there must be something different at a qualitative level. So what they did, they looked at the clones, the clonotypes. When you have a proliferative immune response, like I showed you in the figure, there are actually hundreds of different T cell clones that are being activated against that specific peptide. If you look at a large number of animals you see some specific clones get activated, some don’t, there are common clones that get activated in all animals. As you can see in this figure there are two main clones. For simplicity’s sake we will call them the S7 clone and the S5 clone. The difference between these clones is interesting. If you look at how the concentrations of these clones correlated with disease. The S7 clone peaks when you have the highest disease, then in goes down and stays down. This goes against the first figure that I showed you where the proliferation always stays high. This specific clone, even though its recognizing the same antigen, its numbers in vivo decrease after the disease pathology is gone. In the S5 clone you see it increasing with disease, then you see it decreasing, then you see it increasing again even though there is no disease. So what this tells us is that there are 2 types of clones, public clones, in this specific model system that respond to the same antigen, and there is a lot of private and semiprivate clones that are specific to each mouse.

So now lets think about this S7 and S5 clone. Are they qualitatively different besides the genetics of the TCR that allow us to say that they are different? Well they are. If you select for clones that express interferon gamma and cells that do not express IL-4, you see that the large number of clones you purified are S7.

The other reason why it appears that the S7 is causative of the disease is because when you look at the phenotype, at the markers found on clones that have the S7 TCR type, these cells have high expression of FasL, Ox-40, low expressors of CTLA-4. this is a phenotype that other investigators have shown is associated with ability to induce disease.

So that gave the investigators some rationale for why the S7 clone may be causative. But to demonstrate in a black and white manner what they did was 2 interesting experiments. The first one, you can transfer the disease from a diseased animal if you take day 15 T cells and transfer them to a naïve animal, you can transfer disease. If you deplete the BV8.2 family from the T cells that you are transferring, the S7 clone belongs to this family, then you can not transfer disease. If you transfer only BV8.2 cells then you do get disease transfer. So that is more support for the idea that the S7 clone is pathogenic and drives the disease process.

The other supportive argument was that if you actually clone T cells and select for cells that have the DAGGGY motif (which is part of the S7 clone), then you can induce disease in naïve animals.

So what all this is telling us is that of the whole immune response as measured by proliferation, there is actually a whole lot of T cells clones that appear, some clones induce disease, some do not. So on the one hand, one can figure out peptides that stimulate such “driver clones” or clones associated with specific qualities of immunity and stimulate them for treatment of diseases such as cancer or infections, or on the other side of the coin one can attempted to generated altered peptide ligands to selectively inhibit these clones in the context of autoimmunity.

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1 Comment | Add Comment

jonnyboy said...

Created 2008-06-11 23:58:10 EST

These are very complicated matters.  There is still no understanding what exactly induces the formation of these specialized T cell clones that are being refered to as "drivers". 

How interesting that a video would be made for explaining this very difficult concept to the internet scientific community. 

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