Jonathan Edwards
Senior Member (Voting Rights)
This idea came out of a lengthy chat with Jo Cambridge, who has recently been laid flat by treatment with allogeneic lymphocytes and previously suffered with graft versus host problems. In that situation, a stem cell graft (IV) from another person generates lymphocytes that attack self cells, often gut, skin and blood cells. It occurs because of antigen mismatch, chiefly MHC tissue type antigens.
The idea is that something a bit similar may be happening in ME/CFS except that it is your own lymphocytes that are attacking other immune cells in lymph node and spleen. The attack may be specific to immune cells if it involves signals that are normally used for weeding out unwanted immune cells. For instance CD57+ T cells are thought to weed out disadvantageous B cells in lymphoid follicles as part of the affinity maturation of antibody. Your own cells do not tend to kill other cell types unless they are infected or cancerous but weeding out of lymphoid clones as a normal part of healthy immune function. So it might make sense that a host versus host problem only focused on other immune cells in lymphoid tissue.
This would mean that signals of immune activity were generated and might affect all sorts of organs, including brain or muscle, but being only generated in lymphoid tissue there would be no local inflammatory pathology in other tissues. This model would of course explain symptoms of swollen and tender lymph nodes.
CD38 expression, HLA, NK killing inhibitory receptors, interferons, MAIT and gamma-delta T cells, and various other things we have seen come up, could all be relevant to "host versus host" activity. This would be quite different from autoimmunity and probably not involve any specific autoantibody, although immunoglobulins might get caught up in signalling.
It might be a bit like ankylosing spondylitis. I wondered years back whether there might be a 'fifth' trafficking domain for T and related lymphoid cells. We have 1. skin, 2. gut, 3. other mucosae, 4. general somatic tissues (as in AS, where VCAM-1 is the homing ligand) to which I thought one might add a 'stay at home' domain that involved just recycling through lymph node and spleen. The more I think about it this is what we should expect for cells whose useful function is, for instance, weeding B cells in lymphoid follicles. They have no reason to visit any other tissue. They might not move around much but it would make sense for such cells to redistribute themselves around all the nodes to make sure none were harbouring unwanted cells.
The TSPO tracer studies we saw today seem to me to fit rather well with this idea. Only lymph nodes show a marked uptake as far as I can see. An interesting thing, though, is that uptake is also high in what look like the main feeding lymph tracts. That is where different types of cells trafficking through various tissue will end to "meet up again" as they approach lymph node. If a host versus host response requires some illicit chatting between, say, a T cell or NK subset and some dendritic cells maybe that is what we are seeing building up. It could perhaps just be physical backwash from the nodes but that does not seem very likely to me.
With this sort of model I think there could be quite a range of potential therapeutic strategies. It would probably not be necessary to kill off T cells en masse with Campath-1H. Interfering with activation ligands, especially like CD38 on cell surface, might do rather well.
I only hope that the PET images don't just show where people have been lying on a hard mattress!!
The idea is that something a bit similar may be happening in ME/CFS except that it is your own lymphocytes that are attacking other immune cells in lymph node and spleen. The attack may be specific to immune cells if it involves signals that are normally used for weeding out unwanted immune cells. For instance CD57+ T cells are thought to weed out disadvantageous B cells in lymphoid follicles as part of the affinity maturation of antibody. Your own cells do not tend to kill other cell types unless they are infected or cancerous but weeding out of lymphoid clones as a normal part of healthy immune function. So it might make sense that a host versus host problem only focused on other immune cells in lymphoid tissue.
This would mean that signals of immune activity were generated and might affect all sorts of organs, including brain or muscle, but being only generated in lymphoid tissue there would be no local inflammatory pathology in other tissues. This model would of course explain symptoms of swollen and tender lymph nodes.
CD38 expression, HLA, NK killing inhibitory receptors, interferons, MAIT and gamma-delta T cells, and various other things we have seen come up, could all be relevant to "host versus host" activity. This would be quite different from autoimmunity and probably not involve any specific autoantibody, although immunoglobulins might get caught up in signalling.
It might be a bit like ankylosing spondylitis. I wondered years back whether there might be a 'fifth' trafficking domain for T and related lymphoid cells. We have 1. skin, 2. gut, 3. other mucosae, 4. general somatic tissues (as in AS, where VCAM-1 is the homing ligand) to which I thought one might add a 'stay at home' domain that involved just recycling through lymph node and spleen. The more I think about it this is what we should expect for cells whose useful function is, for instance, weeding B cells in lymphoid follicles. They have no reason to visit any other tissue. They might not move around much but it would make sense for such cells to redistribute themselves around all the nodes to make sure none were harbouring unwanted cells.
The TSPO tracer studies we saw today seem to me to fit rather well with this idea. Only lymph nodes show a marked uptake as far as I can see. An interesting thing, though, is that uptake is also high in what look like the main feeding lymph tracts. That is where different types of cells trafficking through various tissue will end to "meet up again" as they approach lymph node. If a host versus host response requires some illicit chatting between, say, a T cell or NK subset and some dendritic cells maybe that is what we are seeing building up. It could perhaps just be physical backwash from the nodes but that does not seem very likely to me.
With this sort of model I think there could be quite a range of potential therapeutic strategies. It would probably not be necessary to kill off T cells en masse with Campath-1H. Interfering with activation ligands, especially like CD38 on cell surface, might do rather well.
I only hope that the PET images don't just show where people have been lying on a hard mattress!!
