@Jonathan Edwards
Thank you for the welcome to the forum. I look forward to many more debates with you, and I have already learned a lot from you. I appreciate your thoughtful answers and the time you put in here. I have a great deal of respect for your viewpoints and how to present them, even when I respectfully disagree, and I think you bring a lot to this forum. My fear with ME forums is always lack of scientific rigor which sends people chasing after hidden pathogens that don’t exist or other environmental triggers that are not at the root of the problem. (Obviously not all patients can be expected to be scientists - we should not have to do that job - I just happened to be headed that direction before I ever got sick). If I were well tomorrow, I’d still find this area of research fascinating, and would likely be doing it professionally.
I think what you are suggesting is that there are subtypes in ME, which is very likely true. Some researchers have attempted to do this rigorously with some partial success (notably Dr. Kerr). You do seem to approach it from a rheumatology background (which isn’t a bad thing - it may very well turn out to be the answer). I will try to find some of your original posts and read through them to get a better idea of your ideas. I’m sure you must be very interested in the rituximab trials - as am I. If that trial goes well, it would be evidence for a rheumatology connection. The chronicity of rheumatic disease and the relapsing/remitting nature is also appealing.
I had never heard that Reiter’s (or Reactive Arthritis as we now say in the states, for PC reasons…) can produce an ME-like syndrome. My understanding is that ReA usually presents with an acute onset post infection with chlamydia or some gram-negative enteric infection, but then follows a somewhat variable course with most patients improving over a year or so - is that your experience? Do you see it frequently produce long term disability or often lead to AS, and if so, is this only in B27 cases?
Yes, antibody genesis is completely random, MHC’s just determine which peptides are presented. Help me a bit here - in RA, the target is the Fc portion of the IgG heavy chain (is it IgG subclass specific (e.g. 1,2,3,4), or is the binding domain conserved across classes, or does this vary? If you could selectively deplete a subclass of IgG’s, would that help, and is the distribution of IgG subclasses aberrant in RA?) Is the connection to joints related to deposition of the immune complex in the synovium? I have a lot to learn on RA. My philosophy in understanding ME has been to try to understand as much of every branch of medicine as I can get my head around - I don’t know where the key discovery will be. Is this an epitope mimicry issue in RA, where a particular peptide is presented by DR4, and if so has any such antigen been identified? I’m not aware of any particular illness being identified as preceding RA onset.
I am also not very attracted to the mitochondrial thesis. I think there may be some secondary mitochondrial dysfunction. There seems to be greater oxidative stress and lipid peroxidation - but I’m not so sure this is at the root. I’ve read Dr. Pall’s work, and while I think there is some merit in the idea of increased oxidative stress, I am not really convinced that, in itself, can create a self perpetuating loop - why doesn’t it just calm down on its own? So, again, I think it’s a piece of the puzzle, but I have questions about whether there can be a self-perpetuating cycle solely based on NO/ONOO-.
The biggest issue for me with the rheum approach is that we cannot find any evidence of inflammation. I don’t know of any autoimmune or auto inflammatory disease where this is the case (MS perhaps - many cases do not show evidence of inflammation - perhaps because of the BBB?). Perhaps my bias is my own illness. Maybe I am in a subtype that does not have inflammatory markers, but for a long time, many ME clinicians have insisted that sed rates are VERY low in their patients, and that they consider it their most replicable finding.
You may very well turn out to be right on T-cell subsets. We’ll have to wait for science to work through these issues. It remains a theory - whether it stands the test of time we won’t know for a while.
Interesting regarding the macrophages and TNF, and good to know. Suggests strongly it’s a local phenomenon - and serum levels aren’t as likely to be useful. Signaling is more paracrine than endocrine. TNF seems likely to be far down the chain, a reactive phenomenon. I understand your point about T-cells being normal and still potentially contributing to the problem - the t-cells themselves are reacting as they should given the stimuli they are receiving, but the stimuli are aberrant. If that’s true, T-cells could be a target, but wouldn’t be the best one, as they are downstream of the root cause. i found a ton of links on treg/th17 balance in RA from a quick pubmed search, but I can’t speak to the quality and I did not go through them in detail.
The seronegative auto inflammatory diseases are interesting to me. I seem to have every conceivable risk factor on genetic screens - but I don’t have the actual illnesses. Is it possible ME is some sort of an auto inflammatory condition? Also, is it possible that this is more common in men? Many auto inflammatory diseases seem to show male predominance, whereas most antibody-mediated autoimmune diseases show a strong female predominance. Dr. Kerr’s work showed some subtypes that were female or male dominated. Is ME different in men and women, and what does this tell us from what we know of well characterized diseases?
I have seen a few small studies on HLA’s in ME patients, and there does not seem to be an overrepresentation of B27. Some MHC II’s were overrepresented I think. This seems like it might be an interesting place to look with some larger, higher powered studies.
Thank you for the welcome to the forum. I look forward to many more debates with you, and I have already learned a lot from you. I appreciate your thoughtful answers and the time you put in here. I have a great deal of respect for your viewpoints and how to present them, even when I respectfully disagree, and I think you bring a lot to this forum. My fear with ME forums is always lack of scientific rigor which sends people chasing after hidden pathogens that don’t exist or other environmental triggers that are not at the root of the problem. (Obviously not all patients can be expected to be scientists - we should not have to do that job - I just happened to be headed that direction before I ever got sick). If I were well tomorrow, I’d still find this area of research fascinating, and would likely be doing it professionally.
I think what you are suggesting is that there are subtypes in ME, which is very likely true. Some researchers have attempted to do this rigorously with some partial success (notably Dr. Kerr). You do seem to approach it from a rheumatology background (which isn’t a bad thing - it may very well turn out to be the answer). I will try to find some of your original posts and read through them to get a better idea of your ideas. I’m sure you must be very interested in the rituximab trials - as am I. If that trial goes well, it would be evidence for a rheumatology connection. The chronicity of rheumatic disease and the relapsing/remitting nature is also appealing.
I had never heard that Reiter’s (or Reactive Arthritis as we now say in the states, for PC reasons…) can produce an ME-like syndrome. My understanding is that ReA usually presents with an acute onset post infection with chlamydia or some gram-negative enteric infection, but then follows a somewhat variable course with most patients improving over a year or so - is that your experience? Do you see it frequently produce long term disability or often lead to AS, and if so, is this only in B27 cases?
Yes, antibody genesis is completely random, MHC’s just determine which peptides are presented. Help me a bit here - in RA, the target is the Fc portion of the IgG heavy chain (is it IgG subclass specific (e.g. 1,2,3,4), or is the binding domain conserved across classes, or does this vary? If you could selectively deplete a subclass of IgG’s, would that help, and is the distribution of IgG subclasses aberrant in RA?) Is the connection to joints related to deposition of the immune complex in the synovium? I have a lot to learn on RA. My philosophy in understanding ME has been to try to understand as much of every branch of medicine as I can get my head around - I don’t know where the key discovery will be. Is this an epitope mimicry issue in RA, where a particular peptide is presented by DR4, and if so has any such antigen been identified? I’m not aware of any particular illness being identified as preceding RA onset.
I am also not very attracted to the mitochondrial thesis. I think there may be some secondary mitochondrial dysfunction. There seems to be greater oxidative stress and lipid peroxidation - but I’m not so sure this is at the root. I’ve read Dr. Pall’s work, and while I think there is some merit in the idea of increased oxidative stress, I am not really convinced that, in itself, can create a self perpetuating loop - why doesn’t it just calm down on its own? So, again, I think it’s a piece of the puzzle, but I have questions about whether there can be a self-perpetuating cycle solely based on NO/ONOO-.
The biggest issue for me with the rheum approach is that we cannot find any evidence of inflammation. I don’t know of any autoimmune or auto inflammatory disease where this is the case (MS perhaps - many cases do not show evidence of inflammation - perhaps because of the BBB?). Perhaps my bias is my own illness. Maybe I am in a subtype that does not have inflammatory markers, but for a long time, many ME clinicians have insisted that sed rates are VERY low in their patients, and that they consider it their most replicable finding.
You may very well turn out to be right on T-cell subsets. We’ll have to wait for science to work through these issues. It remains a theory - whether it stands the test of time we won’t know for a while.
Interesting regarding the macrophages and TNF, and good to know. Suggests strongly it’s a local phenomenon - and serum levels aren’t as likely to be useful. Signaling is more paracrine than endocrine. TNF seems likely to be far down the chain, a reactive phenomenon. I understand your point about T-cells being normal and still potentially contributing to the problem - the t-cells themselves are reacting as they should given the stimuli they are receiving, but the stimuli are aberrant. If that’s true, T-cells could be a target, but wouldn’t be the best one, as they are downstream of the root cause. i found a ton of links on treg/th17 balance in RA from a quick pubmed search, but I can’t speak to the quality and I did not go through them in detail.
The seronegative auto inflammatory diseases are interesting to me. I seem to have every conceivable risk factor on genetic screens - but I don’t have the actual illnesses. Is it possible ME is some sort of an auto inflammatory condition? Also, is it possible that this is more common in men? Many auto inflammatory diseases seem to show male predominance, whereas most antibody-mediated autoimmune diseases show a strong female predominance. Dr. Kerr’s work showed some subtypes that were female or male dominated. Is ME different in men and women, and what does this tell us from what we know of well characterized diseases?
I have seen a few small studies on HLA’s in ME patients, and there does not seem to be an overrepresentation of B27. Some MHC II’s were overrepresented I think. This seems like it might be an interesting place to look with some larger, higher powered studies.
