MGA Annual Report 1997

THE NEUROSCIENCES GROUP
INSTITUTE OF MOLECULAR MEDICINE
JOHN RADCLIFFE HOSPITAL, OXFORD

Report from Prof John Newsom-Davis FRS, Head of Group

Typical Myasthenia Gravis

We are very lucky to get samples of thymus from so many young myasthenics and also specimens of thymomas from other MG patients. In both tissues, Cal MacLennan and David Beeson again find more of the specifically adult subunit of the acetylcholine receptor than any of the other subunits. So Nita Nagvekar, Marguerite Hill and others in the cell culture team are busily testing whether this is sparking off the whole autoimmune response, perhaps by immunising thymic white blood cells (T cells), These T cells normally help to start and maintain antibody responses and are promising targets for 'magic bullet' therapies, which we can adapt when we know exactly what the T cells are attacking. We can now study that by cloning them in the laboratory.

The exciting news is that T cells from nearly all the young myasthenics Marguerite has tested clearly respond well to this adult subunit. Better still, they all recognise exactly the same fragment presented by one particular molecule (DR52a) on specialised presenting cells. That is good news because a soluble complex of this receptor fragment +DR52a might be a widely applicable 'magic bullet' that would selectively turn off the pathogenic T cells in these patients. With another clone, Alison Bond and Louise Corlett have already found that these complexes actually kill many of the pathogenic T cells. That is because they do not receive all the extra signals that they need from the presenting cells, and instead they 'die of unrequited love'. This approach is particularly promising because it has no effect on the rest of the immune system, and should eventually help us to avoid blanket immunosuppression.

Ocular myasthenia : why the eyes?

Many myasthenics will remember that their eye muscles were the first to be affected in their disease, causing double vision. Indeed, over half all MG patients develop double vision or drooping eyelids as their first symptom. There has been much debate as to why this should be so. It had been suggested by an American group that it was because eye muscles contained an excess of the type of acetylcholine receptor found in fetal muscle (see my report last year). However, molecular studies by our Group, particularly Cal MacLennan and David Beeson, have shown that eye muscles contain relatively more adult than fetal acetylcholine receptor. It seems, therefore, that the eye muscles are affected early not because their acetylcholine receptors are different, but because the nerves to the muscle have a very high rate of firing which means that the neuromuscular junction has to work particularly hard. Any impairment of its function caused by myasthenic antibody would quickly cause fatigue at the neuromuscular junctions and double vision as a consequence. Moreover, because normally sighted people are immediately aware when double vision is present, even a small degree of eye muscle weakness will cause double vision.

Penicillamine-induced myasthenia gravis

Some myasthenics first develop MG when they are taking a medication called penicillamine (not to be confused with penicillin) for rheumatoid arthritis. Indeed, it seems that the penicillamine is provoking the disease in their case, since in many (but not all) such patients, stopping the penicillamine results in the MG subsiding and finally disappearing. Marguerite Hill and Nick Willcox have been investigating this, using the blood cells from a friendly and very cooperative patient with penicillamine-induced MG! Marguerite has been able to "clone" T cells (which may "help" the production of the myasthenic antibody) from this patient and to characterise them. The results of her very painstaking and difficult study suggest that penicillamine (which is a very small molecule) may become attached to the muscle acetylcholine receptor, and after it has been processed (chewed up!) by a cell that presents antigens to T cells, it provokes an autoimmune response against this "altered" acetylcholine receptor which was not previously present to the normal acetylcholine receptor. Since penicillamine can also provoke other autoimmune disorders (eg neuromyotonia - see report last year), this finding may be providing us with an important clue to the origin of autoimmunity in a number of different diseases.

Homing-in on the antibodies' target in the
Lambert-Eaton myasthenic syndrome (LEMS)

	Lambert-Eaton Myasthenic Syndrome antibodies to calcium channels reduce release of acetylcholine
	Voltage-Gated Calcium Channel

As LEMS patients may know, their antibodies are attacking calcium channels at the neuromuscular junction. These channels are situated on the nerve terminal (see Figure 1A) and, by allowing the entry of calcium into the nerve terminal, they play a crucial part in triggering the release of acetylcholine on which neuromuscular transmission depends. It turns out that there are several different subtypes of calcium channel. Which one is affected in LEMS? Figure 1B shows a 'cartoon' of the calcium channel, in which you can see that the channel which allows calcium to enter the nerve terminal is in the a1 subunit of the channel.

There are several different a1 subunits (science is never simple!), and the particular a1 subunit defines the subtype of the calcium channel. Each of the different a1 subunits is made by its own special gene. Ashwin Pinto and Bethan Lang, working with colleagues at Eli Lilly (a large Pharmaceutical company), have been able to identify the main targets for the calcium channel antibodies in LEMS using cell lines that have been transfected with the different a1 subunit genes, and which thus express the different a1 subunits. In this study they have shown that the principal target for the autoantibodies in LEMS is the a1A subunit, found in the P/Q-type calcium channel. This is an important step forward in understanding the disease, and is also helping us in its diagnosis.

Clinical work

The Centre at the Radcliffe Infirmary continues to be very busy, with a steady flow of clinics, patient admissions for plasma exchange or intravenous immunoglobulin, and for thymectomies. So life is pretty hectic for Sister Eve Goodger and the rest of the team. There are plans afoot to keep the Centre running after my official retirement, and potential new clinical trials are under discussion. Dr Jackie Palace's previous prednisolone + azathioprime trial is now complete, and the results are to be submitted for publication shortly.

STOP PRESS : More discoveries in congenital myasthenia

I described last year that Rebecca Croxen, Claire Newland and David Beeson had detected mutations in the a subunit of the acetylcholine receptor which caused the "slow channel syndrome". Our paper describing this has now been published in Human Molecular Genetics in May this year. Moreover, our colleagues at the Mayo Clinic (Dr Andrew Engel and Dr Michael Harper) have been testing a medication that may be helpful in patients with this previously untreatable form of congenital myasthenia. So molecular research can sometimes result in new treatments! But that's not all. Our own team have now found mutations in a different subunit (the e subunit: see Figure in the 1996 report) in five families with a different form of myasthenia known as "acetylcholine receptor deficiency". They are working hard to define the functional effects of this - more news next year.

Conclusion

After all of this, you will not need convincing that we are as busy as ever. I promised last year that we would report on our T cell work. Although I have touched on this (in relation to penicillamine MG), we shall be saying a bit more in a report in a future issue of this journal. As ever, we remain very grateful to all those patients who have helped us in our research, and to the MGA itself for its continuing generous support for our research.

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