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The importance of the stregth of signal view
Avrion Mitchison Scientist
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Katya and Zieper discovered that the cytokine regulation was quite different in the two diseases. Rheumatoid arthritis, within the limits of the data that they collected, was a TH1 disease, which is what is expected of a auto immune disease. Reactive arthritis seemed to be mainly a TH2 disease, but in both cases you could say that the chronic inflammation was the result of cytokine imbalance. And with other students I pursued the same work in- in the setting of mouse model diseases, collagen induced arthritis and I think we were able to substantiate that same disease. The critical point was the breakthrough on mechanism, and I'm still not sure whether it is a real breakthrough or not, but I jolly well hope it is and I believe that the case is getting steadily stronger, and that is that the difference between MHC allele which drives TH1 differentiation and one which drives the opposing TH2 differentiation, is a matter of, or at least substantially a matter of the level of expression. A strong signal, high expression, TH1 differentiation; low expression, low signal, allows TH2 differentiation. And that view has- the strength of signal view has been steadily- I think the case for that has been steadily building up, notably from the work of DNAX, in DNAX, which I mentioned where the strength of signal was adjusted by the DNAX Group, not by changing the level of expression of MHC molecules but by changing the concentration of peptide. They were not the only people to do that, indeed they were not the only people to discover it, but they were the biotech group which pursued the matter with the greatest determination. It led, of course, on to work on other drugs which could- might affect signalling, particularly the signalling inhibitors, and they too seemed to bear out this view. Now, I am giving a rather optimistic point of view because it is not universally accepted. But if you do accept that view, what really matters in the MHC molecules, not only the molecule itself, it binds a peptide and presents the peptide to the B-cell or other cells in the course of regulation, but the level that it is expressed, and that is a matter not of the structural coding sequences but of the promoters. So, at last I was able to- to join in the great rush to molecular genetics. I was delighted with that and I could do so only because Roland Lauster came to join us in Berlin from Basel, The Basel Institute of Immunology where he had been around for a while- he was looking for a job in Germany and he felt able to take this rather temporary sounding, rather uncertain and poor lab facilities still, a budding group rather than an established group, but he took the job there and I am jolly glad he did because he did a number of very good things. But from this point of view, the best thing that he did was he attracted a young Polish scientist who wanted to do molecular genetics, and between them they started sequencing MHC promoters and looking at making substitutions and they were looking at their functional consequences, and bingo, out came what seemed to me like a perfect solution to the findings made two decades before by Lane and Silver. I do not think David Lane understands that at all. I tried once to explain it to him not so long ago and he was completely lost, because his mind is on other things now. But I think we have a molecular understanding of that cross suppression, and I think that is an important part of regulation in the immune system. It's not- it is very unlikely to be the most important part but it is an essential part.

Avrion Mitchison, the British zoologist, is currently Professor Emeritus at University College London and is best known for his work demonstrating the role of lymphocytes in tumour rejection and for the separate and cooperative roles of T- and B-lymphocytes in this and other processes.

Listeners: Martin Raff

Martin Raff is a Canadian-born neurologist and research biologist who has made important contributions to immunology and cell development. He has a special interest in apoptosis, the phenomenon of cell death.



Listen to Martin Raff at Web of Stories



Duration: 4 minutes, 39 seconds

Date story recorded: June 2004

Date story went live: 29 September 2010