The first thing that we're going to look at is myasthenia gravis, and myasthenia gravis is an autoimmune disease that results in muscle weakness. The reason it results in muscle weakness is that it's going to block the muscle cell here from receiving a stimulus from the nerve cells that would ordinarily stimulate it. So, here at the left, we have a normal situation where the end of a nerve cell is at the neural muscular junction, it is stimulating the cell by releasing the neurotransmitter acetylcholine. So, there's the acetylcholine, acetylcholine is diffusing across the immune synapse. It's binding to the acetylcholine receptor, that's going to trigger a depolarization in the membrane as series of internal changes that will be propagated up and down the muscle and result in release of calcium and the contraction of the actin and myosin actually sliding past each other, leading to the contraction of the muscles. That's the way it's supposed to work. So, here we have, on the right, what happens with myasthenia gravis. In this case, we have antibodies, autoantibodies, and these are autoantibodies that bind to the acetylcholine receptor, and when they bind to the acetylcholine receptor, in this case, they're going to block its receipt of acetylcholine. They're not going to cross-link it and overstimulate it, they're going to prevent it from being stimulated. Now, when that happens, we're also going to then have a buildup of antibodies in this synaptic space, the neuromuscular synaptic space, which is going to lead to complement activation there, which is also going to result in inflammation. So, what we've got here then is something that prevents the brain essentially from communicating with the muscles, because the last stage in this process before the muscles is blocked by a bunch of rogue autoantibodies. Again, this results in some strange symptoms, muscular weakness being the most prominent, and that can have some odd manifestations. One of the diagnostic or very common symptoms you will see with somebody with this problem is that they actually have to tape up their eyelids. The ordinary muscular tone in the eyelid is weakened to the point where they get something called ptosis, P-T-O-S-I-S, and that means their eyelids are drooping. Usually in this case, it's bilateral but it doesn't have to be. There are certainly other ways to keep your eyelids from functioning. But in this case, you've got a situation where you're making extra antibodies, antibodies you shouldn't, and blocking your neural transmission at the neuromuscular junction from the voluntary nerve cells to the muscle itself. Multiple sclerosis has very different ideology. In this case, you're going to actually be killing cells, and those cells are going to be the ones in the myelin sheath around the nerve. So, this is interesting, because in this case, the nerve is fine, the synapse at the end is fine, what's going to happen however is the sheath around the nerve will be damaged. So, here you have a picture of the sheath. The sheath are basically constructed of Schwann cells that wrap around the axons, and they wrap around it and they leave some gaps, and the gaps are called Nodes of Ranvier. In this case, in a nice healthy nerve, the neural transmission will actually leap from gap to gap, and that causes the stimulus to move much faster. If however you damage the myelin, then the neural transmission is slower, was coordinated, and completely compromised in this case. So, anything that involves a myelinated transmission axon, if often in the periphery but it can't happen in the brain, these nerve cells are going to be either blocked or slowed or uncoordinated, and that prevents the person from moving as they would like. So, with a slowdown of nerve conduction, you can lose sensation, including vision, and it can result in paralysis. Again, if you think about it, this is a CTL attack, we're going to actually be killing off those poor Schwann cells, there will of course be antibodies involved in this, but in this case we're not just blocking something or tying it up, we're actually going in and killing off cells. The CTLs can also enter the cerebral spinal fluid, and they can attack the myelin in the brain and in the spinal cord, and you can see that you would get an array of neurological problems with that. So, why would you attack your myelin? Nobody wants to do that. Well, there seems to be genetic factors present, nothing is strong as the binary autosomal, dominant autosomal recessive genes we had with some of our tolerance genes. But if you are an identical twin and you have the disease, there's a two in three chance that your twin will have it as well. Now, you're not only sharing your genes pretty much entirely except for the odd mutation or slip up, but you're also sharing an environment. So, the two together, since they seem to be largely in common, are more likely to result in you contracting this particular disease. So, what things in the environment might give you this problem? One of the more interesting ones is if you were born north of the 37th parallel in the United States, and at similar locations north and south and other parts of the world, then you are more likely to catch the disease than if you were born in the South. So, people looked at that and they said, "Oh well, what could you have here that was doing that?" So, what could be going on in the north, and that's not going on in the south. Well, people suggested various diseases, industrial chemicals, but the probably the most obvious thing is it sunnier in the south than it is in the north. If you live in the south up to age 15, you are less likely to get multiple sclerosis than if you live in the north. Now, I have to say that MS has been found to be associated with vitamin D deficiencies, and vitamin D deficiencies have all kinds of immunological consequences. So, as a potentiating factor, not enough sunlight really is an interesting and likely culprit. Having said that, I would like to also say that we are now in a situation where parents put sunblock on their kids, can spend much more time inside than they used to. The lack of sunlight exposure has been associated with the more likelihood of becoming myopic and needing eyeglasses. So, it would be nice if you would set your kids outside in the sun. But don't neglect the sunblock. Now, this is going to sound really weird, but scientists did some experiments on mice to see if UV light made it less likely that they would develop the mouse equivalent of multiple sclerosis. So, they exposed some of the mice to UV light, and some not. As controls, they turned the lights on some of the mice but they blocked the light with sunblock. Now, these mice should have, by the theory, developed the mouse equivalent of MS. But they didn't. Even though the sunblock block the UV light, these mice remained healthy. So, the next question the scientists asked was, "What the heck is in this sunblock?" It turns out that it has two compounds, homosalate and octisalate. You've already heard of one salate ester acetylsalicylic acid or aspirin, which is a strong anti-inflammatory. So, blocking inflammation may have been the protective element. If you're a religious user of sunblock taking some extra vitamin D is a good idea. In modern societies, a lot of people test is clinically deficient. Too much vitamin D can be toxic, but that's an awful lot of vitamin D to get to that level. Having said that, I will say that vitamin D is clearly not the whole story here. Scientists have found that we have DNA incorporated from a retrovirus on chromosome six or seven, and if you reactivate or replicate this, that is associated with both multiple sclerosis and schizophrenia. Again, excess inflammation and vitamin D deficiency seemed to be involved or perhaps they only set the stage. You need some other stimulus to essentially awaken the immune system against your own tissues. Maybe a retrovirus upregulation, maybe another infection producing tissue damage, some perfect storm of risk factors. The good news is, most autoimmune diseases are treatable. The bad news is they are rarely curable. This is true of many genetic diseases and some cancers. Such chronic medical conditions are expensive, a particular burden in the US, which is the only industrialized country without universal healthcare. I've also mentioned that the US has seen decreased government support for research in recent years, and a very common civic response to this situation is the directed fundraiser. The ice bucket challenge two years ago funded a recent research breakthrough in understanding, and we hope eventually treating ALS. So, as usual, I'm going to present an example, and that example is the MS150, a two day, 150 mile bike ride that takes place in different cities to raise money for treatment and care of people with multiple sclerosis, and research into the underlying causes. The Texas version had 13,000 cyclists and they and their sponsors raised over $20 million. This is one of the more impressive examples of myriads of fun runs and silent auctions and more, that support a variety of research projects and patient care. On the one hand, I wish we didn't have to do this, but on the other, it's very clear that participants enjoy their rides, their fellow riders and the whole satisfaction of making a difference.
