Continued from the thread: Who tried immunosuppressive treatment/drugs. Do MEs cause CFS? I thought I would set up this thread to discuss two thoughts about what ‘ME’ might be. One is that there are several MEs and the other is that MEs are maybe causes, not effects – which I will deal with first. There is debate about whether ME and CFS are much the same. Many researchers talk of ME/CFS as if they are. Others, like Kermit, may insist that ME and CFS, or at least ‘chronic fatigue’ must not be confused. Something that interested me when teaching students about diseases is that the medical profession often make no clear distinction between causes and effects. One might say ‘this lung damage is due to TB’ and one might also say ‘mycobateria can cause TB of the lung’. Or ‘osteoarthritis causes knee pain’ and football injuries cause osteoarthritis’. There is often some sense lurking in here but often there is also muddling. Which bit of the process is actually ‘the disease’? So my thought is that CFS is an effect – a pattern of symptoms and signs that we find people troubled by. But MEs, especially if we use the plural, are a quite different idea. They are perhaps ‘whatever the processes are that cause the CFS symptom complex in the absence of some other well recognised process’. In this form it seems to me that one cannot deny the existence of MEs, nor can one say that CFS will do instead. Even if one thought (as I do not) that all MEs are ‘bad thinking loops’ based on some entirely internal error in the way the brain sends itself (physical) signals we would have to admit MEs existed. And we would want to find out how they worked. (I think James Baraniuk’s approach is interesting. He has found two different patterns of ‘bad loops’ on fMRI scans.) There is no argument for saying that there is just an effect called CFS with no unknown causes. How many MEs would there be then? I doubt there is ever a precise answer to that sort of question. I am going to suggest that I suspect the existence of at least six. I base this partly on people I have had as patients and partly on what I have come to hear since last year. These groups are purely hunches, so I am not going to be able to give justify all the details. The emphasis is on immune regulation errors, because that is what makes sense to me, but everyone can probably think up some other sorts of MEs based on their own experience. 1. ME1 is due to antibodies to certain nuclear proteins that can enter cells and disturb function on a body-wide basis. ANA is positive and usually speckled in pattern. (The proteins are likely to come under what are called ENA antigens, which are not always strictly nuclear but no matter.) The fatigue of ME1 is basically the same as in primary Sjögren’s syndrome and other ANA-linked illnesses that have names. I have met many people in this group. Some might suggest that they are well enough described to take them out of the ‘unknown causes’ that are MEs but a lot of these people end up labelled as ‘CFS with an ANA’. The fatigue may be a bit different from other groups. 2. ME2 is due to an oversensitive resetting of cells that recognise what are known as Class I proteins, as in HLA-A, B and C. This includes T cells and NK cells. It probably follows a wide range of intracellular infections. As for ME1 it is in a sense a ‘covert’ form of a recognised illness, in this case Reiter’s disease. It may be more common in men and is likely to occur with sudden onset in early adult life. There may be local joint pains and a rise in CRP level but this may subside leaving persistent fatigue. ME2 and ME1 have nothing in common other than the end result. 3. ME3 is not really a subgroup, but a causal component. It may ‘gang up’ with other MEs so that they feed off each other through regulatory pathways. ME3 is a resetting of brain sensitivity to all sorts of ‘noxious’ stimuli. It may well operate through feedback involving the autonomic nervous system. In some cases it may be reduced by the sort of voluntary strategies encouraged by ‘talking therapies’ but very often I suspect it is completely impervious. My own analogy is my tinnitus. Sometimes it seems unbearable and stops me sleeping or enjoying the quiet countryside and at other times I forget I ever had it. When it is there I cannot tell myself to not have it. 4. ME4 is associated with anti-thyroid antibodies. It overlaps with the fatigue that occurs in people with overt autoimmune thyroid disease, which often does not change much when thyroid levels are re-balanced because it is not actually due to the abnormal thyroxine level. There must be complications here, because overt thyroid disease is rarely like severe ME. There may be overlap with e.g. ME1 or ME3 or there may be another unknown ‘partner process’. Anti-thyroid antibodies crop up in people with RA for no reason we can understand and RA itself seems to involve two processes that can feed off each other – one for anti-CCP antibodies and one for rheumatoid factor. 5. ME5 is a speculation rather than something I have evidence for, but the specific autoimmune types I have given so far will not cover the majority. There is at least one more type needed and this is my guess. ME5 involves a sensitisation of the immune signalling mechanisms triggered by viruses. As part of an immune response to a virus the system produces antibodies that sensitise the ‘virus alarm system’ to the extent that even when there is no virus around it may trigger, just with exercise or stress. Two molecules might be particularly important here: gamma interferon and the immunoglobulin receptor FcRI (CD64) which is used to ‘pre-arm’ phagocytes with antibody even before any foreign pathogens have arrived. 6. ME6 is probably a diverse group of MEs due to mitochondrial impairment. There may be an autoimmune process here too but in other cases there may be a major genetic component. So maybe it should be divided up further! Looking back over these my guess is that they might cover 50% of cases with luck, so it cannot be just 6. But at least it seems to me to make a nonsense of a ‘biopsychosocial model for CFS’. All MEs are bio, some may be biopsycho, maybe even some biopsychosocial (maybe the doctor is the 'social' cause here), but you don’t try to put 6 diseases into one model. You try to get to grips with each one on its own terms.