MGA News January 2001

About one MG patient in ten has a thymoma. These are usually slow-growing tumours with low malignancy; they are nearly always removed as early as possible to prevent local spread. Around 1 in 3 of all thymoma patients get MG; though this myasthenia is a nuisance to the patient, it is also a valuable early warning to the doctor to check for a thymoma, which otherwise might go unnoticed for years.

Thymomas also hold vital clues for us researchers. The 'small cell' lung tumours in some LEMS patients have already taught us valuable lessons for this MG-like condition. The tumour cells clearly have very similar target molecules to those in the nerve endings that are attacked by the antibodies in the LEMS. As Bethan Lang and John Newsom-Davis showed, if the lung tumour can be removed, the antibodies gradually disappear and the LEMS improves. So we all are convinced that these tumours are somehow immunising against the molecules they share with the nerve endings; much of Bethan's current work aims to understand how that comes about.

Things are not so straightforward with thymomas. The patients' MG seems quite typical, but their antibodies are a more complicated mix than in most other myasthenics. They always have the typical antibodies (to the AchR) that attach the ignition system of voluntary muscles. But they also have a variety of different antibodies to other muscle proteins, especially to an 'elastic' molecules called 'titin'.

In 1997, with a colleague in a Biological Standards Institute, Dr Tony Meager, we surprisingly stumbled on a completely different set of antibodies against immune 'messenger' molecules, especially interferon alpha (IFN) (which normally helps to control virus infections: it is not the one used to treat Multiple Sclerosis). Dr Camilla Buckley in our team (no relation) is funded by the Oxford MGA/MDC Centre. She has measured these antibodies in nearly 200 MG patients. Those against titin or IFN occur in about 90% of MG thymoma: we would love to understand why.

Immunisation in Thymomas

We suspect that in the thymoma (large oval area), some mystery cell type immunises some controlling T cells against IFN and others against AchR fragments. These T cells then stimulate B cells to make antibodies. With IFN, this stimulation apparently also occurs in the thymoma: with AchR, we think it happens after the relevant T cells have emigrated through the blood to the lymph glands.

The antibodies to IFN often increase strikingly in the unlucky patients whose thymoma spreads or recurs, and might be a useful early warning. Beyond that, we can see no rhyme or reason in the different levels of all these antibodies in different patients; they seem quite independent of each other, of the exact tumour type and of the patients' genetic factors.

We believe that some cell types(s) in the thymoma are immunising against AChR and IFN at least (see diagram), and that the culprits may be easier to find for the simpler IFN than for the much trickier AChR. Already, Dr Hiro Shiono (a thymectomy surgeon from Osaka in Japan who worked with us for two years) has found that cultured cells from thymomas more often make antibodies against IFN than against AChR or titin. So we suspect that some small fragments of these more complex molecules are immunising just the T cells in the thymoma. IF these 'control freaks' are then exporting to lymph glands, they may start the antibody reaction there against the complete AChR in a second step.

The normal job of the thymus is to educate and export T cells to the rest of the body, where they help B-cells to make antibodies and stimulate other cells to protect against infections. Thymomas are like normal thymus gone crazy, and often generate a vast excess of T cells. Until recently, we never actually knew that these really were exported, a key step in the process mentioned above.

Luckily, Camilla Buckley is a glutton for work; she has adapted a very cunning method for measuring recently exported T cells in the blood. As we predicted, she finds far more of these than normal in most thymoma patients, especially of the damaging type that switch on antibody reactions. These recent emigrants disappear after the thymoma is removed: they also come back if it recurs, perhaps another useful early warning. They are clearly not increased in elderly myasthenics without thymomas, however suspicious their titin and IFN antibodies may seem; these must arise by some different process in these even more puzzling cases.

It is always gratifying to find supporting evidence for one's pet theories. But we are still not satisfied; like 2-year olds, we can't stop asking 'why, why, why?' Why does the MG sometimes start years after a thymoma is removed; why do occasional patients later on develop yet more autoimmune problems - e.g., with twitchy muscles or even with failing blood cell production in the bone marrow? Do the antibodies to IFN (etc) affect the patients' immune reactions to infections?

Most of all, we want to understand the auto immunising process itself - not just for curiosity, but because we hope to find clues about ways of blocking it selectively, without clobbering the whole immune system. We hope that this will shed light on other MG patients without thymoma, or even on quite different autoimmune diseases where there are even fewer clues.

MGA NEWS January 2001

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