Institute of Molecular Medicine, Oxford
The antibodies that cause the damage in myasthenia gravis (MG) attack the 'ignition system' in our muscles, so that nerve -> muscle triggering becomes inefficient. Virtually all of them bind to the acetylcholine receptor (AChR) which normally activates the muscle when the nerve endings release the chemical transmitter ACh. Like most other antibodies that help to protect us against different viruses (etc), these antibodies are a very mixed bunch, and vary greatly from patient to patient. For example, some patients' antibodies "cross-react" much better than others with mouse or rat AChR, and some much prefer the AChR of the unborn baby (fetus), whereas others react equally well with AChR from adult muscle. Indeed, the overall antibody levels that we measure in different patients do not accurately reflect the severity of their myasthenia - which implies that some antibodies cause more damage than others. Possibly, some might even be protective - perhaps explaining the very high antibody levels in occasional relatively mild cases. If we could define the exact target sites of individual antibodies, we might be able to interfere with their damaging actions.
For over 15 years, Dr Angela Vincent and I, like many others working on "autoantibodies", have dreamed of being able to clone them. There are many fascinating questions, some concerning their cellular origins. For example, a surprisingly motley mix of different antibodies can arise from a single precursor cell. That is because they normally go through a phase of mutation - which generates a wider range of protective antibodies against infections. If one could nip such precursors in the bud, one might be able to prevent the responses from getting started. We may have even better luck in cloning protective antibodies, which might be valuable for tiding patients over crises. How could we do that ?
In 1976 it became possible to 'immortalise' single antibody-producing cells (from mice); such clones would be ideal for us, but very tantalisingly, this method has never worked well for human cells. In the present decade, however, the ability to clone the antibody genes has proved a promising alternative. If they are sampled from a suitable source - notably the MG thymus - they can be cloned, identified and then mass-produced in bacteria, so that many single antibodies can be compared with each other. Our friends in Maastricht and we in Oxford, both collaborating with Californian teams, have finally started to fulfil these dreams in the last 2 years. These international projects are not easily funded, because they use such futuristic technology; however, both teams have been very fortunate in the support of our sister charity in France, the Association Francaise contre les Myopathies.
Drs Jeremy Farrar and Ian Matthews in our lab, together with Drs Sandra McLachlan and Basil Rapoport in San Francisco, have selected a range of these antibodies from two different patients, and the exciting process of defining their exact structure and target sites is now under way. The first task is to make sure that they are typical of those in the donor patients' blood. Our early results look promising; one antibody greatly prefers fetal AChR, whereas two others recognise adult receptor equally well. They can also bind very avidly to the surface of cultured muscle cells, implying a potential to cause damage, which Ian is now preparing to test in more detail. He is also busily cloning other antibodies (from our unusual patient 2) that seem to cause particularly severe fetal weakness; we are hoping to be able to devise counter-weapons against them to protect subsequent babies.
Even at this early stage, it is already clear that these antibodies must come from many different precursor cells, though the most damaging ones may yet prove to be more restricted. It will be particularly fascinating to pinpoint the exact mutations that target these antibodies to the most vulnerable sites on the AChR; at the moment, however, we need more clones, more work and much number-crunching. When that high noon eventually comes, I, for one, will really be on cloud nine.
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