MGA Annual Report 1998

Prof John Newsom-Davies FRS

The acetylcholine receptor (AChR) is both the site of many genetic mutations in the different forms of congenital myasthenia, and the target of immune attack in myasthenia gravis (MG). One of the principal thrusts of the work that MGA/MDG have supported over the years is the cloning and expression of the genes for each of the five AChR subunits (see Fig). David Beeson's success in cloning the AChR genes, and in defining the mutations that underlie congenital myasthenic syndromes, is summarised in MGA News (July 1998), and has been made possible by the funding that the MGA has supported over the last 13 years. We are delighted to report that he has now been appointed as a Medical Research Council Senior Non-clinical Research Fellow. This achievement, for MGA as well as David, means that the MRC will be taking over support for his work, thereby releasing additional funds for myasthenia research.

This year we want to tell you about some of the immunological work that has been underpinned by David's efforts. 'Autoimmune' Myasthenia is caused by antibodies to the acetylcholine receptor (AChR). These antibodies are produced by 'B cells', and are a very mixed bunch. However, B cells depend on specific messages from other white blood cells, called 'T cells', which come from the thymus. These are less varied and may be more suitable for selective targeting with 'magic bullets'. These T cells are themselves only activated when AChR is broken down by the B cells into fragments that they attach to special 'tissue type' molecules, and then present to the T cells. (These 'tissue type' molecules often differ between individuals and have to be matched in transplant operations). In order to find out more about the T cells, particularly how they can be targeted specifically, we have spent several years identifying the fragments of the AChR that they recognise. Initially we used the AChR alpha subunit, largely because it was thought to be the most important in stimulating the autoimmunity. We obtained some highly specific T cells that we have studied in detail. One of these T cells recognises a small fragment of the alpha subunit. We have previously described how this T cell can be killed by a magic bullet composed of the AChR fragment plus its favourite 'tissue type' molecule. Alison Bond and Louise Corlett have now shown that this method of destroying the offending T cell is much more efficient and long-lasting than just using the AChR fragment alone, or using antibodies that bind to the T cell itself.

These studies have been very encouraging, but unfortunately they used a rare tissue type molecule tailor-made for the original patient. Meanwhile, however, David Beeson continued to clone the other AChR subunits, and Nick Willcox and his team continued to test the patients' T cells which recognised them. The breakthrough came when Marguerite Hill found T cells that recognise a small fragment of the AChR epsilon subunit (see Fig) in four out of the first five patients that she tested. Even more exciting, this fragment was only presented to the T cells by one tissue type molecule, and one that is much commoner in MG patients than in the general population. So at last it looks as if we have found an 'immunodominant T cell epitope' i.e. one that appears to be really important in MG. We now plan to use new technology to assess how common these T cells are in other MG patients. Above all, we hope that we can kill them without affecting the normal healthy T cells. lf we can, then they should be a widely applicable target for treatment in many patients.

Another spin-off of David's work has been studies on adult and fetal AChR. It has been known for several years that the only difference is the presence of a gamma subunit in fetal AChR, which is replaced in late pregnancy by an epsilon subunit in adult AChR (see Fig). Until recently, it was difficult to purify adequate amounts of the two forms. Three years ago, David Beeson introduced the epsilon subunit into a cell line that otherwise only produced the fetal form. This cell line now produces mainly 'adult' AChR; it is very useful in our diagnostic assays, because we no longer miss antibodies that bind only to this form of AChR. In fact, the cell line has been licensed to a British company, RSR Ltd, that markets a diagnostic kit for MG that is used worldwide. (Don't worry, any "royalties" are ploughed back into research).

Using cells that express either fetal or adult AChR, Claire Newland has looked much more carefully at antibodies binding to the two forms of AChR, and their functional consequences. This helped us to recognise the role of maternal antibodies in causing developmental abnormalities in babies. Very rarely, MG mothers have babies that are paralysed in utero, resulting in lack of muscle tone, fixation of the joints, and maldevelopment of the face and lungs. Tragically, these babies are often stillborn or die shortly after birth because of breathing problems. It turns out that these women have many antibodies that inhibit the function of fetal AChR but leave the adult AChR unaffected. These antibodies cross the placenta during pregnancy and prevent normal muscle function, so eventually leading to the characteristic deformities.

In order to prove that the maternal serum antibodies are causing this condition (and are not just a result of it), Leslie Jacobson and Angela Vincent, in work supported partly by the MRC, have injected the serum into pregnant mice. Many of the mouse babies are born paralysed and with deformities that are very similar to those in the human condition. In addition, there are other more subtle deformities that are being characterised with the help of Agata Polizzi, a visiting clinical fellow from the Department of Paediatrics in Catania, Sicily. Because this work clearly indicated that maternal antibodies can cause this devastating fetal condition, with Sister Eve GoodgerÕs help we recently treated a mother, who had previously lost two babies with deformities, with extensive plasma exchange and intravenous immunoglobulin therapy. We were all delighted when, very recently, she gave birth to a healthy baby. This work also makes us wonder whether other deformities might sometimes have similar immune causes, and Angela has just been awarded a grant by Action Research to look at some of the possibilities.

These are just two of the areas that your marvellous efforts have supported and have been keeping us busy over the last year. Both are the subject of major publications that will be submitted shortly.

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