MGA News Summer 2001

Department of Clinical Neurology
Institute of Molecular Medicine
John Radcliffe Hospital, Oxford

Figure 1a

It is well recognised that most patients with myasthenia gravis (MG) have antibodies to the acetylcholine receptor, and that these antibodies are responsible for the disease symptoms. Normally the acetylcholine receptors are highly concentrated on the muscle membrane, where the long motor nerves communicate with the muscle fibres that they activate (Fig 1a). In MG, the antibodies reach the nerve-muscle junction, where they reduce the numbers of acetylcholine receptors (Fig 1b). This means that the muscle can no longer respond to the acetylcholine 'message' coming from the nerve, and the patients become weak. However, for a long time we and others have realised that about 10-20% of patients with typical symptoms of MG do not have acetylcholine receptor antibodies. We usually call this condition seronegative MG. Applying the rules that we had learnt from studying antibodies in MG, we showed that seronegative MG patients have antibodies, instead, against a different muscle target. Now we have identified the target.

Figure 1b

To give a bit more detail. Firstly, in 1986, John Newsom-Davis showed that the seronegative MG patients got better when they were plasma exchanged; this proved that they had an antibody in their serum that was causing their weakness. Secondly, Stuart Mossman in our lab (at the Royal Free Hospital in those days) injected their antibodies into mice; the mice showed weakness compared with mice injected with antibodies from healthy people. Then a Japanese visiting neurologist, Takeshi Yamamoto, showed in 1991 that the antibodies could reduce the activity of the muscle acetylcholine receptors, but recently another visiting neurologist, Franz Blaes from Germany, showed in 2000 that the antibodies were not sticking directly to the acetylcholine receptor. As you can see, this series of experiments was performed over several years and by a number of different researchers, but we still did not know what the target for the antibodies was.

The breakthrough came last year, when I met a German scientist called Werner Hoch at a basic science meeting in Germany. He had been working on a molecule called MuSK. MuSK is another sort of receptor protein that sits on the surface of muscle cells (Fig 1a). It is very important during development of the nerve muscle junction, because it tells the muscle cell to start pulling all of the acetylcholine receptors together to form a concentrated cluster (see Fig 1a). Because MuSK controls the concentration and number of acetylcholine receptors, we thought it would be a good candidate target for antibodies in patients without acetylcholine receptor antibodies.

Figure 1c

So last April we sent eight serum samples to Werner in Tuebingen and he tested them to see whether they contained antibodies that could fix themselves to MuSK. Five did and three did not. Excitingly, the five sera that fixed themselves to MuSK were from seronegative MG patients and the three that did not were all from healthy lab workers! We then used different techniques to confirm that the antibodies in seronegative MG patients were indeed binding to MuSK (Fig 1c), and found these MuSK antibodies in 17 out of 24 MG patients without AChR antibodies (published in Nature Medicine in March; this is one of the very top journals). In addition, we did not find them in MG patients with acetylcholine receptor antibodies, showing that the two groups of patients have a different form of MG, although they look similar in the clinic. We are now trying to make the test for the MuSK antibody even more reliable and efficient so that it can be used for diagnosis. That will help in sorting out the diagnosis in many patients, and perhaps in identifying more cases – particularly in the elderly. We also need to clarify how the antibodies actually cause the myasthenia symptoms.

MGA NEWS Summer 2001

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