My Rituximab experience for ME

[gregh286]

Patients with particular complement deficiencies (often involving impaired opsonization) VERY frequently develop SLE. Interestingly, one of the treatments for many complement deficiencies is androgen therapy. Hormones may have some role here. I am not sure of the mechanisms involved in using androgens to treat SLE resulting from complement deficiency.

Selena Gomez got treated with chemo drugs for SLE. Rituximab maybe?
http://www.dailymail.co.uk/tvshowbi...llness-slams-gossipmongers-claimed-rehab.html

 

[beaker]

Selena Gomez got treated with chemo drugs for SLE. Rituximab maybe?
http://www.dailymail.co.uk/tvshowbi...llness-slams-gossipmongers-claimed-rehab.html

I saw that and thought same thing.

 

[Eeyore]

Autoantibody production probably makes use of antigen presentation by B cells themselves rather than other cells.

Is this generally believed? I'm curious as to why this might be true (or what I should read to learn more about it). I had generally been taught that the role of B-cells in antigen presentation wasn't really all that important compared to macrophages / DC's. MHCII peptides are generally derived from lysosomal degradation, and since macrophages are constantly cleaning up old/dying/dead cell debris, you would expect they might frequently present autoantigens, and more efficiently than B-cells. Why is this not the case?

Is there any reason to believe that cells that do not constitutively express MHCII molecules (i.e. only when stimulated to do so by interferon gamma) play an important role in autoimmunity? This might suggest a role for infection in triggering autoimmunity. i.e. Not via molecular mimicry, but rather by induction of a cytokine response (notably ifn-g) that increases antigen presentation and the expression of MHCII molecules.

This also makes me wonder whether upregulated (macro)autophagy might make cells more vulnerable to autoimmunity, as if so induced, they could present self antigens from the autophagolysosome upon stimulation with ifn-g, or whether cell stress due to autoimmunity triggers the autophagy pathways - or is it a chicken and egg problem that creates a self propagating loop? In Crohns (which is not antibody mediated) defects in ATG16L1 probably have more to do with defective clearance of bacteria in the gut leading to inflammation, but this doesn't seem relevant in antibody mediated autoimmunity (excluding something like celiac where the antibodies are not really self).

Does rapamycin generally increase or decrease the risk of autoimmunity?

 

[lansbergen]

This also makes me wonder whether upregulated (macro)autophagy might make cells more vulnerable to autoimmunity,

On a side. As I understand from the TSE literature with that infection autophagy up to a certain level is beneficial but above that level it is disadvantageous.

 

[Jonathan Edwards]

Is this generally believed? I'm curious as to why this might be true (or what I should read to learn more about it). I had generally been taught that the role of B-cells in antigen presentation wasn't really all that important compared to macrophages / DC's. MHCII peptides are generally derived from lysosomal degradation, and since macrophages are constantly cleaning up old/dying/dead cell debris, you would expect they might frequently present autoantigens, and more efficiently than B-cells. Why is this not the case?

About the first monoclonal antibody to a cell type marker (of the sort that became CDs) was an antibody thought to be specific for B cells. I think it might have been called Ly1, for fairly obvious reasons. It turned out to bind to MHCII. The antigen presentation involved in autoantibody production more or less has to be by B cells because it is part of the help process. The B cell only survives because it gets help from a T cell and it can only get that help if it presents antigen to the T cell with ClassII. If the T cells involved were themselves autoreactive then they could have been primed by othe antigen presenting cells previously but we have no evidence for autoreactive T cells in most forms of autoimmunity. So presumably the T cells doing the help recognise foreign antigens presented 'by mistake' by B cells. That would mean that antigen presentation by other cells was involved historically in the priming of those T cells but in quite a normal way. The abnormal event would be the presentation of the wrong antigen by a B cell in such a way to allow help to the B cell.

The confusion arises because most people simply assume that autoimmunity is driven by autoreactive t cells primed by dendritic cells. However, there are no autoreactive T cells to find and there are good reasons why we should think that is because there are none. If autoimmunity was due to errors in T cell tolerance it should appear during the years of T cell clonal selection - up to age 20. But autoimmunity rarely starts before 20 and gets commoner as time goes by - during the period of continued B cell clonal selection.

 

[jimells]

George W Bush was not the cause of the French Revolution for reasons that are not too hard to work out. Theories of autoimmunity tend to be at that sort of level of error.

But perhaps the French Revolution was the cause of George W Bush. Surely that is a theory worthy of investigation, no?

 

[Eeyore]

@Jonathan Edwards - On some level, the T-cells that activate the autoimmune inducing B-cells must be autoreactive, and must exist in some quantity to drive the B-cell mediated autoimmunity - unless you are truly implying randomness of activation, although it's hard to see how that would continue longer term. Maybe this is a case of weak interactions, where the T-cell recognizes something sort of close to the B-cell, so that in a small percentage of cases, it is able to bind sufficiently well to activate the B-cell, but not sufficiently strongly to be selected out in the thymus. There is such an abundance of autoantigen that even a weak match could be sufficient to drive an ongoing response, perhaps?

It seems contrary to basic understanding of the immune system that an immune response could be mounted by CD8 effector cells or B-cells in the absence of CD4 cells, other than, perhaps, in malignancy or premalignancy (e.g. anti-MAG) - not a general phenomenon in autoimmunity. I seem to be missing something, and I'm not sure what.

Isn't MS usually considered a T-cell mediated disease? Or do you think this interpretation is incorrect, akin to those chasing after T-cells in RA? How about the seronegatives and IBD (which of course are not antibody mediated)? The latter at least seem to be IL-17 driven, given the success so far of secukinumab (phase 3 trial published recently - looked good) and ustekinumab. Perhaps autoantibodies in MS though are a secondary phenomenon?

 

[Jonathan Edwards]

@Jonathan Edwards - On some level, the T-cells that activate the autoimmune inducing B-cells must be autoreactive, and must exist in some quantity to drive the B-cell mediated autoimmunity - unless you are truly implying randomness of activation, although it's hard to see how that would continue longer term.

Wrong, wrong, wrong, Eeyore. You have not been reading my papers!!!! In simple terms the neatest model is in the paper by Roosnek and Lanzavecchia from 1991. If a B cell picks up its cognate antigen attached to some other molecule (like a rheumatoid factor B cell picking up an IgG attached to a foreign antigen) and then processes and presents the peptides to a T cell it can get help from any T cell recognising peptides in the foreign antigen. There are all sorts of other examples that we have reason to think occur. The production of anti-tissue transglutaminase by B cells helped by T cells recognising gliadin is another good one. There is absolutely no need for autoreactive T cells and in most contexts they have looked for ad nauseam and not found.

It seems contrary to basic understanding of the immune system that an immune response could be mounted by CD8 effector cells or B-cells in the absence of CD4 cells, other than, perhaps, in malignancy or premalignancy (e.g. anti-MAG) - not a general phenomenon in autoimmunity. I seem to be missing something, and I'm not sure what.

Sure, and we know autoantibody production is CD4 dependent - but nobody is suggesting no T cells involved, just no autoreactive T cells. You are not the only one to make this conflation - virtually every immunologist I ever met does, with the exception of a few bright people like Jacob Natvig, David Pisetsky, Hans-Peter Tony are maybe a score of others.

Isn't MS usually considered a T-cell mediated disease? Or do you think this interpretation is incorrect, akin to those chasing after T-cells in RA? How about the seronegatives and IBD (which of course are not antibody mediated)? The latter at least seem to be IL-17 driven, given the success so far of secukinumab (phase 3 trial published recently - looked good) and ustekinumab. Perhaps autoantibodies in MS though are a secondary phenomenon?

Well RA turned out not to be a T cell disease, so why not MS where there has always been equally good evidence for it being a B cell disease. You have to remember that immunologists got bored with antibodies around 1979 and decided to invent theories that all interesting diseases were T cell mediated. They then made T cell mediated animal models and proved it (not). Seronegative arthropathies have always looked like T cell diseases and never had anything to do with antibody and that has turned out right - IL-17.

One just has to stick to the evidence. But one also has to think clearly. It took me twenty years to learn how to do that.

 

[Eeyore]

@Jonathan Edwards - Ok time to read, back later! I don't understand this model yet.

 

[BurnA]

@Jonathan Edwards Do you have any special or unique b cell theories for ME/CFS or how sure are you that there is a b cell theory to be proved. ( If can one ever prove this type of theory ) Would you expect a new theory to be proposed ?

 

[Jonathan Edwards]

But perhaps the French Revolution was the cause of George W Bush. Surely that is a theory worthy of investigation, no?

@Jonathan Edwards - Ok time to read, back later! I don't understand this model yet.

Look at the 1999 paper with Cambridge and Abrahams. I will PM it if I can.

 

[Jonathan Edwards]

@Jonathan Edwards Do you have any special or unique b cell theories for ME/CFS or how sure are you that there is a b cell theory to be proved. ( If can one ever prove this type of theory ) Would you expect a new theory to be proposed ?

I have some special ideas but they are small print really - things like involvement of Fcgamma R1 as an effector mechanism. I would not put good money on them. My main feeling is that 'nothing is ruled out' as the politicians say. Could be anything really. But I do think that at least some intelligent people are now focusing in on narrowing the possibilities down. And quite a few of them are members of PR.

 

[BurnA]

I am indeed against it, but I have had to concede that the evidence for GBS is strong and evidence always wins. That allows me to remain against it for all the other diseases on the grounds that the circumstantial evidence is much more strongly against for typical chronic or relapsing remitting autoimmune states.

Wasnt molecular mimicry suggested / involved in the narcolepsy cases following H1N1pandemic vaccination ?

 

[Jonathan Edwards]

Wasnt molecular mimicry suggested / involved in the narcolepsy cases following H1N1pandemic vaccination ?

It is always suggested. Nobody seems to be able to think of anything else. We still do not really know what the abnormal immune response in narcolepsy is as far as I know.

 

[Marky90]

Really interesting reading this. Thanks!

 

[digital dog]

Can anyone, in VERY simple terms, explain why I no longer get coldsores when I used to get them four or five times a year?
I am also rarely ill with colds or flu.
I was struck down with a short, violent virus in Spain (lots of shivering and sweating) then I had a nasty cold for six months.
Now nothing.
Don't answer if can't be bothered ( I understand). Its just that people mention the herpes virus and Im always puzzled.

 

[gregh286]

Some.suggest immune system is chonically activated as a th2 response. The bulb is always on as opposed to been turned on as required when bacterial or viral insult is detected.
Many of us are sick but never "sick".
Many cfs patients have low nk cell count..indicating a progression away from th1 immune response.

Some of the treatments.used like ldn, ahcc, equilibrant,,etc attempt to normalise immune balance again and calm a chronically active immune heightened state. However, it maybe a futile exercise if there is an active infection or underlying antigen.

If your initial insult was viral maybe worthwhile to speak to your doctor about anti viral course..

 

[sillysocks84]

Many cfs patients have low nk cell count..indicating a progression away from th1 immune response.

Can a gp order a test for nk count? I'd like to test mine, is it expensive?

 

[gregh286]

Doubt gp will do it.
I dont think there is a standard treatment plan for low nk.
Mine was 48 against a 90-360 range.
Redlabs belgium will do it for you over the post.

 

[perrier]

I just wanted to share the following anecdote: I have a contact in Norway. Met him at a clinic and got in touch. This chap now tells me that his doctor, in a small town in Norway, has reversed his position, and has now offered my contact the Rituximab treatment.
Also, this chap tells me he personally knows two people who were in the earlier studies. One was bed bound. Apparently they are " not normal," but " very near to,normal."

If the buzz is going around that this treatment helps, there will be more doctors like this. (I recall that when there were studies on fecal transplants for recalcitrant cdifficile, and the results were so positive, doctors just went ahead and did the fecal transplants for this condition even though the studies were half way done.)