MGA Annual Report 1999

Over the last 8 years, the Myasthenia Gravis Centre has had the services of a research assistant, Mr Leslie Jacobson, to help with the diagnostic assays and other aspects of clinical research. An important study performed by Dr Jackie Palace, Dr Bryan Lecky (Liverpool) and Prof Newsom-Davis, with help from Leslie, was to compare the clinical response and anti-AChR antibody levels in MG patients taking prednisolone with or without azathioprine. The results of this double blind trial were published in the American journal Neurology and showed, very clearly, that azathioprine reduces the need for prednisolone, in many cases allowing it to be withdrawn altogether, and also reduces the number of relapses during immunosuppression. Interestingly, the beneficial effect of azathioprine was not seen until about one year after starting the drug, so it is important to persevere and give it time to take effect.

Last year we described how some women who have babies affected by a serious developmental problem, arthrogryposis multiplex congenita have high levels of antibodies directed against the fetal form of the acetylcholine receptor. Sometimes these women have MG, but in other cases they are asymptomatic or MG is not diagnosed until after several babies have died. Although this condition is quite rare, and not always fatal, about 1 in 3,000 babies is born with some form of arthrogryposis. Leslie's work studying the effects of maternal antibodies in an animal model was reported last year, and has been published in another American journal, J Clinical Investigation. Leslie obtained a DPhil for this work and now has a "Postdoctoral" position in Athens with Prof Socrates Tzartos who has contributed much to our knowledge of the structure of the AChR. Our interest in the role of maternal antibodies in causing other neurological developmental abnormalities, and the techniques that we have established for their study, has led to many paediatricians sending samples for analysis, which we are now studying. We don't expect many to have antibodies to the acetylcholine receptor, but we suspect that some will have antibodies to other muscle or motor nerve proteins.

In those women who do have antibodies to the fetal form of the AChR, the effect on their babies can be catastrophic unless treatment is started. These women appear to make antibodies predominantly to the fetal form, and these antibodies actually prevent it working so that they completely paralyse the baby in the womb. We have looked for similar antibodies in early onset-female MG patients, and they are unusual - explaining why most women with MG do not have babies with these deformities. However, it would obviously be useful if one could identify something special about those women who do have affected babies, allowing one to predict the problem before they get pregnant. Ian Matthews has cloned the antibodies from the thymus of one of these women using an approach called a combinatorial library. He finds that all the antibodies that bind to the fetal AChR seem to come from a single family of antibodies, contrasting with the mixture of antibodies that Jeremy Farrar cloned from a typical MG patient some years ago. These results suggest that women with a bias towards this antibody family may be at risk of developing the antibodies against fetal AChRs if they become pregnant. Ian presented this work at a recent meeting on Autoimmunity in Israel (photograph), thanks to support from the MGA.

Another interest in our group is the patients with typical MG who are negative in the standard test for anti-AChR antibodies. With Dr Bethan Lang and Dr Franz Blaes, we have shown quite clearly that these patients do have antibodies but to another muscle protein. Moreover, when the antibodies bind to this protein on the surface of a muscle cell line in the lab, Paul Plested found that they cause changes inside the cell that lead to inhibition of AChR function. The important thing now is to identify the membrane protein to which they bind, and Dr John McConville, will be joining us from Belfast in September to work on this project.

Following Dr David Beeson's appointment to an MRC Senior Non-Clinical Scientist appointment, his group has expanded and now contains three postdocs (two MGA funded, one MRC) and a Wellcome Training Fellow. One of their novel findings this year, in work by Dr Rebecca Croxen and Dr Phil Nicholls (MRC Clinical Training Fellow), was to demonstrate that a patient with congenital myasthenia has a mutation not in the AChR gene itself but in a 'switch' that controls the amount of the AChR, leading to a marked reduction in AChR made in the muscle. This was published in Annals of Neurology.

Dr Bethan Lang's was the first to show that autoantibodies to calcium channels are responsible for the muscle weakness in patients with the Lambert Eaton myasthenic syndrome (LEMS) who sometimes also have a small cell lung cancer. Her work has benefited particularly from a close collaboration with Eli Lilly and their associates, Sibia. They provided Bethan and Dr Ashwin Pinto with cells that had been engineered to display different sorts of calcium channels on their surface. Ashwin's work with these cells has not only shown that the target for LEMS antibodies is the calcium channel alpha 1a subunit, but also that this subunit is important in certain cells of the cerebellum (published in Proceedings of the National Academy of Sciences of America). The cerebellum is the part of the brain that controls fine movements. Some patients with LEMS have cerebellar problems as well as muscle weakness, suggesting that the antibodies to calcium channels can enter the brain and interfere with function of the cerebellum. Moreover, some small cell lung cancer patients with cerebellar symptoms also have this antibody - even if they don't have obvious muscle weakness. We are now undertaking a survey of many patients who complain of cerebellar problems to see how many of them have the "LEMS" antibody. Interestingly, having this antibody actually improves the long-term prognosis in patients with small cell lung cancer, as Paul Maddison (MGA Clinical Fellow) showed in a short report to the Lancet this year.

These are just some of the recent or ongoing studies that we are performing and which have been published in excellent journals. Thus we feel that the Group is continuing to flourish, and to build further scientific studies based on the clinical material which the MG patients and our many colleagues from the UK and elsewhere provide. We are extremely grateful to the MGA for their continued support of our work.

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