New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[BurnA]

A self antigen is never new because it is there in your body all the time. So the time of development of autoantibodies has nothing to do with the time of availability of antigen - it was always there.
.

How would this tie in with molecular mimicry theory ? IF molecular mimicry holds water would the time of developement of autoantibodies be related to time of antigen availability ?

 

[Snow Leopard]

The channel "khan academy" has some nice videos if you tire easily from reading..

Not a recommendation, but:
https://www.khanacademy.org/science/biology/human-biology/immunology

 

[Jonathan Edwards]

How would this tie in with molecular mimicry theory ? IF molecular mimicry holds water would the time of developement of autoantibodies be related to time of antigen availability ?

It doesn't tie in to molecular mimicry, which as I think I have said, does not actually make sense. If the immune system is tolerant to self then the novel presence of something similar to self is no reason to change that. The more similar it is the more you would expect it to be ignored. What does make some sense is if a newly encountered foreign molecule has the ability to bind to some complementary self molecule and present it to the immune system in an aberrant way. That would make sense in coeliac disease where gliadin presumably binds to tissue transglutaminase and presents it to the immune system in such a way that anti-transglutaminase B cells can be expanded to make antibody. Except that in coeliac disease there is not much evidence for the antibodies appearing at the time of first encounter of wheat. So even there it looks as if one has to look for a different rate limiting step.

 

[Eeyore]

@lansbergen - It depends on cross-reactivity. If you are exposed to pathogen A1, and create an antibody response to it, and then eliminate it, you'll have memory B cells that produce only very low levels of antibodies that continue to circulate long term in your body. Should you encounter pathogen A1 again in the future, you'll have a rapid amplification and production of antibodies against it - and you'll already have a raised level to start with (this is why antibody tests work - once exposed, you'll continue to have elevated antibodies to a pathogen for a long time, and in some cases forever).

If you encounter a new strain, say pathogen A2, in the future, then somehow, A2 is different from A1. The question is whether or not the change between them is in the region (epitope) of the pathogen that the antibodies you have react to. If the region is conserved between the 2 strains (the same, or similar enough to not cause problems in recognition by the antibodies), then you'll amplify a response just as quickly as you would have to A1. If the epitope mutates so that your antibodies no longer recognize it, then it's essentially a new pathogen to you, and you won't have any real advantage.

The truth is more nuanced than this - we don't just make one antibody against a pathogen, we make many (what's termed a polyclonal response - each clone makes one type of antibodies, but there are different clones making antibodies to different parts of the pathogen). A simplified example of this would be EBV, where you have the EBV VCA (viral capid antigen - the outside part of the virus) and the EBNA (epstein-barr nuclear antibody - a different part of the virus - not sure exactly what - but one that is expressed during the non-lytic part of the viral life cycle I believe). In reality you make many antibodies to each pathogen, so the closer the 2nd strain is to the first, the more antibodies you'll have that match it, at least reasonably well (all matches are not the same - sometimes they bind very tightly and work very well, and other times it is very loose). Over time, when you continue to be exposed, you tend to produce higher avidity antibodies, which means that you select for the ones that bind the best. This is particular true of viruses like VZV where you are constantly re-exposed, so that you have your life to refine the antibody response. IgM is usually a low avidity antibody - but it does the job early on before your body is able to make better, more specific IgG which confers longer term, superior immunity.

 

[lansbergen]

@Eeyore Good to have it summarized. The way you discripe it is how I remember it.

What I would like to know is if during the disease process of pathogen A1 an autoantibody is made against a cellulair protein and strain A2 and strain A3 etc do that too, how long would it take for the first antibodies to appear.

Do you know the answer to that?

 

[Eeyore]

@lansbergen - The first antibodies are always present at a low level in the serum. B-cells, even unstimulated, continually produce low levels of whatever antibody they are programmed to secrete. If you test normal healthy people for antibodies to just about anything (autoimmune or to a pathogen, or even allergies) - they will pretty much all have some level of antibodies to pretty much everything. In the absence of significant stimulation, B-cells won't produce a lot of any particular antibody though - not enough to cause problems. That's why there's a "normal" range for autoantibodies on tests. My ANA is not negative - it's normal range - and the same is probably true of you and most people.

Your question makes some assumptions that are not necessarily correct. For one, you seem to assume that autoantibodies are a result of epitope mimicry, which may or may not be true (most likely, it's true for some cases, like GBS, and not for others, like RA). I know Dr. Edwards is of the belief that it is rarely relevant. If an epitope is identical to a self epitope, then in theory, you won't amplify any response to it, as autoreactive lymphocytes won't ever get into circulation (they are selected out in the thymus). So A2 and A3 won't amplify a response to an autoantibody - and the more it looks like self the less it will be responded to. When a lymphocyte gets into circulation, it already is programmed with which antigens it will recognize. The only thing that it's waiting for is a signal to proliferate because its particular antigen has been encountered. There is no ability of lymphocytes to "adapt" to a given invader. Rather, there are a wide array of lymphocytes each with a predetermined target. The lymphocyte that will be helpful is selected and proliferates, and the others just hang out waiting for stimulation. They don't participate in the immune response to that antigen.

So there is no real "time for first antibodies to appear." They will predate any infection. The question is more appropriately one of, "at what time will titers against this epitope reach this level" and the answer is a graph, with titers on the y axis and time on the x axis. What you'd observe is that before infection, titers would remain low and relatively constant over long periods. Once the antigen is present and the B-cells are stimulated to make the antibodies, the growth initially looks exponential but then plateaus, and finally begins to decline, and then plateaus again at a lower level (antibodies are continually produced from memory B-cells).

This is for a foreign antigen. The mechanisms that govern autoantibody production are, however, different - and incompletely understood. In a normal immune system, if the antigen looks like self, there should not be any B-cells at all that will react to it. If it looks a bit like self, there might be some that escaped clonal deletion that would make low avidity antibodies to self, but in these cases, you'd have to assume that the self antigens already present would not be sufficient to amplify an immune response, or the immune response would have been amplifying for a long time, as those epitopes are always present.

The immune system is not smart at all in the way it makes different lymphocytes that respond to different antigens. Rather, it takes the approach of making an antigen for every single possible epitope (slight exaggeration). The adaptive nature comes in which clones amplify to significantly greater numbers, and which ones just float around waiting for an antigen they recognize - and in many cases never encounter.

The exact epitopes that we respond to are governed by molecules we have called HLA's, or human leukocyte antigens. They "present" foreign antigens. Which exact epitopes are chosen is very different between different HLA's, and different human beings have extremely different HLA's. When your HLA's match someone else's, you can swap organs (for organ transplantation) or bone marrow. Since they are inherited for the most part in a block on chromosome 6, siblings have a 25% chance of being a perfect match, 50% chance of being haploidentical (sharing one parent's HLA's, but having different HLA's from the other parent), and a 25% chance of being completely different. This is why siblings are generally your only realistic hope of finding a bone marrow match in your family (the registry works by just having hundreds of thousands of people, so that you can match purely based on chance - and even then, many do not match). Parents are almost always 5/10 for bone marrow, maybe 6 or even 7 by chance if parents share HLA's with each other.

HLA's are very important in autoimmunity. MS is strongly linked to HLA-DR3, RA to HLA-DR4 and HLA-DR1, ankylosing spondylitis and the other seronegative arthropathies to HLA-B27 (which is not antibody-mediated autoimmunity, but rather an autoinflammatory condition - but is still the immune system attacking the body), etc. Lupus is strongly tied to the 8.1 haplotype including HLA-DR3. Almost, if not every, autoimmune disease has been linked to HLA's. They are likely the single most important genes in determining autoimmunity, and more specifically, which autoimmune diseases a person might develop. They also affect resistance to microbes. Some HLA's will react quite strongly to key parts of particular microbes. HLA-B27, which increases risk of AS, also reduces rate of progression in HIV. This does suggest that in autoimmunity or autoinflammatory disease, you need to be able to react to certain molecular patterns. I'm not sure if there are any HLA's that completely prevent any autoimmune disease - there might be. There might be some and we don't even know about it.

Even in these cases, it's not clear that epitope mimicry is involved. With HLA

 

[lansbergen]

@Eeyore. Thanks. I will leave the antibodies and go back to the first symptoms I notice are caused by the innate response.

 

[BurnA]

The time frame is random - some fast some slow, some this direction, some that.

You raise an interesting point. We have discussed before that it takes 2 weeks for antibodies to be generated in bulk to a new antigen. Autoantibodies cannot have anything to do with that because the antigen is never new. So it seems that the rate limiting step is quite different. I think it is the rare generation of clones that can subvert negative control. But the interesting point is that getting symptoms 2-3 weeks after a virus is AGAINST new autoimmunity at that time and in favour of some sort of reaction involving a normal antibody response to virus complicated by something else.

The error in logical sequence is to assume that rheumatic fever is autoimmune, which nobody has ever demonstrated satisfactorily. That does occur 2-3 weeks after infection but the tissue injury looks likely to be a side effect of a normal response to a foreign antigen - maybe immune complex deposition. It is a non-autoimmune postinfective reaction. A pre-existing autoimmune process would be just as likely to latch on to the early innate response in the first few days.

Thanks. It seems I might have raised an interesting point without realising it!

In this paper it states that the appearance of new autoantibodies were detected post influenza vaccination. I think I have understood that you are saying the generation of autoantibodies has nothing to do with an infection because the antigen is never new. Does this paper contradict that ? Again, apologies if this makes no sense. If the generation of autoantibodies is not related to antigen presentation, then is it completely random ?

 

[Jonathan Edwards]

Thanks. It seems I might have raised an interesting point without realising it!

In this paper it states that the appearance of new autoantibodies were detected post influenza vaccination. I think I have understood that you are saying the generation of autoantibodies has nothing to do with an infection because the antigen is never new. Does this paper contradict that ? Again, apologies if this makes no sense. If the generation of autoantibodies is not related to antigen presentation, then is it completely random ?

I think we have looked at that paper before. The problem is that whenever you have an antibody response to a new antigen you get a little burst of increase in production of any other antibodies you tend to make. Making autoantibodies is not black and white. We all make low levels of some autoantibodies - that cause no problems. After a vaccination some of these may rise above the reference level in the test. But as far as I know we have essentially no evidence for influenza vaccination precipitating autoimmune disease.

 

[BurnA]

I think we have looked at that paper before. The problem is that whenever you have an antibody response to a new antigen you get a little burst of increase in production of any other antibodies you tend to make. Making autoantibodies is not black and white. We all make low levels of some autoantibodies - that cause no problems. After a vaccination some of these may rise above the reference level in the test. But as far as I know we have essentially no evidence for influenza vaccination precipitating autoimmune disease.

Yes thanks we did look at it, I was curious because it talked of new autoantibodies but I guess if they just raised above a reference level that would explain it.

 

[msf]

Prof. Edwards, does that mean that you think that the molecular mimicry in Gullain-Barre Syndrome is an example of the second type?

 

[msf]

Also, could there be something else that ´sensitizes´ the immune system to antigens that resemble self? Such as an inflammatory response to other antigens that don´t resemble self?

 

[msf]

From the Wikipedia page on Molecular Mimicry:

The HIV-1 virus has been shown to cause diseases of the central nervous system (CNS) in humans through a molecular mimicry apparatus. HIV-1 gp41 is used to bind chemokines on the cell surface of the host so that the virion may gain entrance into the host. Astrocytes are cells of the CNS which are used to regulate the concentrations of K+ and neurotransmitter which enter the cerebrospinal fluid (CSF) to contribute to the blood brain barrier. A twelve amino acid sequence (Leu-Gly-Ile-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys) on gp41 of the HIV-1 virus (immunodominant region) shows sequence homology with a twelve amino acid protein on the surface of human astrocytes. Antibodies are produced for the HIV-1 gp41 protein. These antibodies can cross-react with astrocytes within human CNS tissue and act as autoantibodies. This contributes to many CNS complications found in AIDS patients

My understanding of this is that it isn´t that the body has suddenly lost tolerance for self, it´s just that the two antibodies cross-react.

From the same article:

T cells that bind with low avidity to self-MHC receptors are positively selected for maturation, those that do not die by apoptosis.

So could it be that antibodies produced for the non-self antigen have a low avidity for the self-antigen? Would a low avidity be enough to cause problems if there was a lot of antibody?

 

[BurnA]

You raise an interesting point. We have discussed before that it takes 2 weeks for antibodies to be generated in bulk to a new antigen. Autoantibodies cannot have anything to do with that because the antigen is never new. So it seems that the rate limiting step is quite different. I think it is the rare generation of clones that can subvert negative control. But the interesting point is that getting symptoms 2-3 weeks after a virus is AGAINST new autoimmunity at that time and in favour of some sort of reaction involving a normal antibody response to virus complicated by something else.

Yes, I think the way viruses tinker with cell death and associated danger signal pathways is a good reason to think that a virus might trigger an autoimmune response. I would ditch the idea of cross reactivity though - there is so little evidence that it is relevant despite the fact that immunologists are obsessed with it. I prefer the sort of model we see in coeliac - the T cell recognises the foreign material and the B cell recognises not something that cross reacts with it but an enzyme that binds to the foreign material (tissue transglutaminase).

Apologies if it appears I am nitpicking. The second quote suggests it could be possible for a virus to trigger autoimmunity but the more recent quote above seems to dismiss this idea.

If virus can't cause autoimmunity then is the only way a virus can be linked to autoimmunity is if the autoimmune condition was pre existing ?

 

[wastwater]

Just replying to my earlier question.Is there a third type of Leukemia,there is acute,chronic and smouldering or pre Leukemia,is there any evidence to suggest me/cfs has any thing to do with the smouldering type.

 

[knackers323]

I favor impaired delivery of oxygen, which will of course decrease mitochondrial ATP production, so we will cross the AT earlier when we exercise. I think the push/crash in ME is most interesting re: fatigue. That's not at all common. Fatigue is a nearly universal sign of illness. Heart disease, cancer, PBC (which Julia Newton studies), anemia, FFI (very rare prion disease), sleep apnea, influenza, rheumatoid arthritis, old age, hypothyroidism, etc. all cause fatigue. Most illnesses in fact do.

I think scientists have largely forgotten how to think. We have way too much testing w/o enough formation of coherent hypotheses to test in the first place - as if we've forgotten the first steps of the scientific method! First, create the hypothesis to test. It shouldn't be something dumb like "X chemical is low" - that's now a hypothesis. That's a prediction from a hypothesis that can be tested. There needs to be coherent theory of disease - and this requires long hard thought.

I know this isn't what the thread is about but with all this talk of energy and fatigue, I wanted to ask if anyone's fatigue looks like this.

If rested and at feeling my best I feel really weak with no strength or energy, kind of like how you feel when have the flu or some other illness but without the other symptoms.

Then if I do anything. Any movement at all my head and upper body will become hot, instantly. I also feel the little energy and strength draining from me.

The hot feeling is a bit like how people feel hot when they exercise but I get it without the exertion or sweating.

Could the heat feeling be a problem with the entropy process?

Anyone else's fatigue similar?

 

[perrier]

I know this isn't what the thread is about but with all this talk of energy and fatigue, I wanted to ask if anyone's fatigue looks like this.

If rested and at feeling my best I feel really weak with no strength or energy, kind of like how you feel when have the flu or some other illness but without the other symptoms.

Then if I do anything. Any movement at all my head and upper body will become hot, instantly. I also feel the little energy and strength draining from me.

The hot feeling is a bit like how people feel hot when they exercise but I get it without the exertion or sweating.

Could the heat feeling be a problem with the entropy process?

Anyone else's fatigue similar?

My daughter feels like this too

 

[perrier]

But I don't quite get what happens in a relapse. It can last months. My daughter says she feels when it relapses. This is not PEM. It's a relapse, which means a complete collapse.

 

[worldbackwards]

Spotted this in the latest "ME Essentials" magazine:

The Norwegian studies show benefit but apparently none of the British people with ME who went to the US to join trials there have shown improvement in their condition.

A bit worrying, I thought. Do we have any corroboration of this?

 

[Sidereal]

What "trials"? There are no ongoing US rituximab trials.