Treg-related immune suppression theory for ME/CFS and the use of very low dose cyclophosphamide

[sillysocks84]

@Ema hmmm ampk increases tregs, I just got a catalog on ampk from life extension . Also probiotics. Which goes with what adreno had mentioned.

 

[SK2018]

If you give rituximab many sorts of autoantibodies disappear gradually over about 3-6 months - showing what one might call an exponential wash out curve, consistent with gradual dying off of the cells that make them. On the other hand most antibodies to bacteria and viruses stay pretty constant even if the person's B cells do not come back for 4-5 years. That suggests that autoantibodies are produced by short lived plasma cells and that most antimicrobial antibodies are made by long lived plasma cells. The reason for this is probably that when there is an active immune response both short and long lived plasma cells are normally made. Long lived plasma cells may require some extra checking before they are allowed to settle in bone marrow. With an infection the short lived plasma cells disappear after 6 months just leaving long lived ones making antibody. With autoimmunity the active immune response keeps going all the time so short lived plasma cells keep being made. And maybe long lived plasma cells are mostly forbidden from going off to bone marrow, although some long-lived autoantibody remains even years after rituximab so there must be some of these present.

Fascinating comment,so are you saying "memory B cells" are mostly irrelevant in autoimmune auto antibody disorders? And that its short lived plasma cells that keep on being replaced.

 

[Jonathan Edwards]

Fascinating comment,so are you saying "memory B cells" are mostly irrelevant in autoimmune auto antibody disorders? And that its short lived plasma cells that keep on being replaced.

All short lived plasma cells were B cells before they became plasma cells. A memory b cell is just a B cell that is old and mature enough to become a plasma cell but is biding its time for some reason. So both are essential steps in the process.

The key question is whether the 'disease memory' that is responsible for the disease relapsing after months or years following B cell depletion is due to remaining memory B cells or remaining long lived plasma cells. There are arguments for both and the most plausible model is that both contribute but that long lived plasma cells may be the element that we need to tackle in order to get permanent remissions.

 

[SK2018]

All short lived plasma cells were B cells before they became plasma cells. A memory b cell is just a B cell that is old and mature enough to become a plasma cell but is biding its time for some reason. So both are essential steps in the process.

The key question is whether the 'disease memory' that is responsible for the disease relapsing after months or years following B cell depletion is due to remaining memory B cells or remaining long lived plasma cells. There are arguments for both and the most plausible model is that both contribute but that long lived plasma cells may be the element that we need to tackle in order to get permanent remissions.

Just came across this procedure called leukapheresis which removes white blood cells. https://en.m.wikipedia.org/wiki/Leukapheresis
Is this procedure capable of removing antibody secreting plasma cells? I assume it removes B cells also so would that make it as effective as Rituximab without the side effect profile ? And if so as equally long lasting?
It could be very effective if used with plasmapheresis also as one would remove antibodies before the latter removing their source,obviously infection risk would be up though and I imagine it would remove T cells also which would make infection risk even higher.Sorry for all the questions just trying to learn here.

 

[Jonathan Edwards]

Just came across this procedure called leukapheresis which removes white blood cells. https://en.m.wikipedia.org/wiki/Leukapheresis
Is this procedure capable of removing antibody secreting plasma cells? I assume it removes B cells also so would that make it as effective as Rituximab without the side effect profile ? And if so as equally long lasting?
It could be very effective if used with plasmapheresis also as one would remove antibodies before the latter removing their source,obviously infection risk would be up though and I imagine it would remove T cells also which would make infection risk even higher.Sorry for all the questions just trying to learn here.

Lymphocytes spend very little time in blood. Almost all the time they are in spleen or bone marrow or lymph nodes. So leukapheresis would not make a noticeable difference to their numbers.

 

[SK2018]

Lymphocytes spend very little time in blood. Almost all the time they are in spleen or bone marrow or lymph nodes. So leukapheresis would not make a noticeable difference to their numbers.

If a body makes cross reactive antibodies in response to a latent virus eg HSV ,that hit both the virus and NDMA receptors,do you think after RTX B cell depletion that its possible to reset the mistake and let new B cells re process what's in the body or will I be stuck with this mistake for the rest of my life? As obviously herpes viruses don't go away

 

[Jonathan Edwards]

If a body makes cross reactive antibodies in response to a latent virus eg HSV ,that hit both the virus and NDMA receptors,do you think after RTX B cell depletion that its possible to reset the mistake and let new B cells re process what's in the body or will I be stuck with this mistake for the rest of my life? As obviously herpes viruses don't go away

As I have said many times on PR I do not think there is any evidence that the immune system ever makes cross reactive antibodies to viruses in this way. This is a myth that started in the 1960s with rheumatic fever and has proven to be wrong at least in 99% of situations. You will see endless papers referring to 'molecular mimicry' but it has almost never been substantiated (if ever). Autoantibodies arise through the random mutation of immunglobulin genes. The reason why some survive to cause trouble is complex but has nothing to do with similarity to foreign proteins as far as we know.

 

[SK2018]

As I have said many times on PR I do not think there is any evidence that the immune system ever makes cross reactive antibodies to viruses in this way. This is a myth that started in the 1960s with rheumatic fever and has proven to be wrong at least in 99% of situations. You will see endless papers referring to 'molecular mimicry' but it has almost never been substantiated (if ever). Autoantibodies arise through the random mutation of immunglobulin genes. The reason why some survive to cause trouble is complex but has nothing to do with similarity to foreign proteins as far as we know.

Fascinating ,so according to the above it would imply that an initial viral infection could trigger a mutation but not necessarily a "cross reaction" Which would subsequently cause symptomatic disease.
It's also interesting also how some people with anti NMDA can have it shut down after just 2 courses of IVIG while some require B cell depletion ,it's almost like the previous just needed some extra help to allow their body to shut the process down whereas the latter eg "me"are unable to
https://www.hindawi.com/journals/scientifica/2012/215308/

 

[Jonathan Edwards]

Fascinating ,so according to the above it would imply that an initial viral infection could trigger a mutation but not necessarily a "cross reaction" Which would subsequently cause symptomatic disease.
It's also interesting also how some people with anti NMDA can have it shut down after just 2 courses of IVIG while some require B cell depletion ,it's almost like the previous just needed some extra help to allow their body to shut the process down whereas the latter eg "me"are unable to
https://www.hindawi.com/journals/scientifica/2012/215308/

The virus does not trigger a mutation A billion mutations happen every day as a normal part of B cell diversification. The antibodies are not caused by the virus. What may be true is that a viral infection makes it easier for the immune system to make a mistake about not deleting the auto reactive B cell clones. I do not know a lot about the epidemiology of NMDA antibody disease but I suspect most of it occurs without any involvement of any viruses - that is just a story that a lot of immunologists cannot get out of their heads because they do not understand the regulatory signalling mechanism.

 

[M Paine]

I'm not sure if you have been asked this in other places @Jonathan Edwards , but would you mind if I asked if you have any opinion where dysregulation may be most likely to occur in the regulatory framework of auto-immunity in this disease?

Do you have any other musings about what form potential therapy might take moving forward from Rituximab, or how Rituximab therapy may be enhanced to prolong remission? Or perhaps why remission is not permanent?