My Rituximab experience for ME

[Jonathan Edwards]

Chance? I don't even know where to begin with that that. Obviously I'm missing something. (for another thread)

I wasn't aware that the researchers linking virus to autoimmune were even suggesting that...............at least not in the articles that I read.

I think you may indeed be missing the mechanics of the immune response. Antibody species are generated at random - by chance. They are then selected for if antigen is present. That usually makes it look as if you may the antibody species in response to an infection but in fact you do not. If the antigen is self and antibody species are produced randomly then when one escapes the control mechanism - which is what autoimmunity is - it is likely to appear at any random time - which is what we find for almost all autoimmune diseases. To understand the dynamics of autoimmunity one has to factor in how the control mechanisms actually function in molecular terms. We have discussed this on other threads.

I have to admit, however, that many of my rheumatological and immunological colleagues seem to have difficulty getting their heads around immune system dynamics - so you are not alone!

A virus is an environmental factor - i.e. one acting from outside the body - so those researchers are definitely suggesting that.

 

[Eeyore]

This sounds contradictory to me. ..............when you say certain pathogens..........are you saying pathogens that aren't infectious in that they cant spread?

I can see how that would sound confusing, so I'll try to clarify.

Reactive arthritis generally follows an infection. The most common ones are chlamydia trachomatis and bacterial enteric illnesses. However, the infections can be easily cured with antibiotics. They do not persist, and are usually long gone before the symptoms of reactive arthritis occur. They do, however, trigger some abnormal immune response in susceptible individuals (most commonly, those with HLA-B27, a gene that affects antigen presentation to the immune system). Reactive arthritis is not contagious. However, the infection that causes it can be in some cases before it is treated or otherwise cleared. By the time someone has reactive arthritis, the underlying infection is usually gone. In some cases, there is no infection at all and it is caused by a vaccine (such as BCG). The vaccine stimulates the immune system in the same way a live pathogen would - causing the immune dysregulation that produces the symptoms.

The symptoms can persist for a very long time, in some cases forever, after the infection is gone. The symptoms experienced by the patient are not the result of ongoing infection, but of abnormal immune system function that follows exposure to certain pathogens.

 

[Jonathan Edwards]

I think Prof. Edwards will also disagree with you then, I don´t think he believes in molecular mimicry. Negative cultures are not proof that the triggering organism has gone.

http://www.mayoclinic.org/diseases-conditions/guillain-barre-syndrome/basics/causes/con-20025832

You should write to the Mayo clinic and tell them to update their page.

I agree with Eeyore. GBS is the one disease where we do seem to have evidence for molecular mimicry or something very close to that. But it is not a typical autoimmune disease. Most cases are monophasic.

 

[Eeyore]

@Tammy - If you want details, see this for the random processes by which antibodies are generated.

https://en.wikipedia.org/wiki/V(D)J_recombination

 

[msf]

Ah, I thought you were against the theory, Prof. Edwards, I must have misunderstood you.

 

[Jonathan Edwards]

Ah, I thought you were against the theory, Prof. Edwards, I must have misunderstood you.

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.

 

[msf]

It´s unfortunate you picked C. Trachomatis, Eeyore, because that is the one for which there is good evidence for persistence:

http://www.medpagetoday.com/Rheumatology/Arthritis/44666

 

[Eeyore]

I agree with Eeyore. GBS is the one disease where we do seem to have evidence for molecular mimicry or something very close to that. But it is not a typical autoimmune disease. Most cases are monophasic.

I agree with Dr. Edwards - GBS is not typical. It is evidence of molecular mimicry, but not that molecular mimicry is a general phenomenon in autoimmunity. We don't have good evidence for molecular mimicry in autoimmunity in general. Usually in GBS the antibodies do not persist. Once the disease is eliminated, the body stops producing antibodies. This is somewhat similar to celiac disease, although those antibodies are targeted at gliadin, which is not actually a human protein, but causes inflammation. Remove the gliadin and you remove the antibody response, inflammation, and the celiac disease. Similarly, in GBS, remove the campylobacter and the antibodies eventually go away (IgG has a half life of about 3 weeks in serum though, and IgM about 5 days). Chronic cases are more interesting - and are probably partly genetically determined.

 

[Eeyore]

It´s unfortunate you picked C. Trachomatis, Eeyore, because that is the one for which there is good evidence for persistence:

http://www.medpagetoday.com/Rheumatology/Arthritis/44666

It's possible that there are some cases where the pathogen persists. However, we know that it is not the case in general. If the pathogen has the potential to trigger arthritis in a susceptible individual, it does seem reasonable that a chronic infection would continue to prime / re-trigger that individual. However, there are clear cases where there is no pathogen present and there are symptoms. There are cases where it results from non-infectious causes like vaccines. It's primarily an immune phenomenon (not antibody mediated, however). It is beyond any doubt very strongly associated with the HLA-B27 gene, which is similarly associated with ankylosing spondylitis, psoriatic arthritis, and inflammatory bowel disease. These are not generally associated with an antecedent infection - only the reactive arthritis is. Reactive arthritis also follows a more chronic course in people with B27, and a milder course in people without it.

It's not completely understood how B27 is related to the seronegative spondyloarthropathies. I think that the best theory right now focuses on abnormalities of protein folding for HLA-B protein molecules with cysteine at residue 45. The molecules form disulfide bonds with other molecules (cysteine is the only amino acid that forms disulfide bonds - which covalently link separate protein monomers), which triggers the unfolded protein response, endoplasmic reticulum stress, and autophagy pathways. However, this is not completely proven yet. There does not appear to be any antibody involved, and not for lack of searching. Also interesting is that these diseases occur more commonly in men, whereas almost all if not all of the antibody mediated autoimmune diseases occur more frequently in women. Women produce a greater diversity of antibodies than men - although the exact reasons why women more commonly contract autoimmune diseases is not known. There is also some evidence it is tied to microchimerism, but again, nothing conclusive.

 

[msf]

´We´ don´t know anything. I have evidence I think is convincing, and you have evidence you think is convincing. I just wanted to point out that the etiology of ReA is controversial, so it´s a bad idea to use it as an analogy for what kind of disease you think ME is.

 

[Tammy]

A virus is an environmental factor - i.e. one acting from outside the body - so those researchers are definitely suggesting that.

I think you misunderstood me. I understand that virus is an environmental factor.................all I was trying to convey is that the issue of causation being genetics vs environmental is not being argued in the articles I've read linking virus to autoimmune...........I can't assume that just because those scientists are researching this.......that it means they don't think genetics can also play a part..............in other words the research is not making an issue of genetics vs. environment. That's all I was trying to say.

 

[Jonathan Edwards]

I think you misunderstood me. I understand that virus is an environmental factor.................all I was trying to convey is that the issue of causation being genetics vs environmental is not being argued in the articles I've read linking virus to autoimmune...........I can't assume that just because those scientists are researching this.......that it means they don't think genetics can also play a part..............in other words the research is not making an issue of genetics vs. environment. That's all I was trying to say.

I was not suggesting that it was genetics vs environment or that anyone was arguing that. The problem is that many researchers think that it must be either one or other or likely both in combination and seem to be unaware that there is at least one other major class of causal factor - internal stochastic events.

 

[jimells]

Reading this thread I am once again thinking just how extraordinarily fortunate we are to have Professor Edwards agree to teach us immunology via the internet. Regular medical students should be green with envy. Or maybe they should join our forum.

 

[Eeyore]

´We´ don´t know anything. I have evidence I think is convincing, and you have evidence you think is convincing. I just wanted to point out that the etiology of ReA is controversial, so it´s a bad idea to use it as an analogy for what kind of disease you think ME is.

Some of the molecular details are still unclear, but it is well accepted that reactive arthritis is not, in general, an ongoing infection, even if a subset may have some ongoing infection. It is an autoinflammatory process and is treated by rheumatologists with immunosuppressive drugs. It has the strongest genetic linkage of any autoimmune/autoinflammatory disease, and the strongest linkage to HLA-I typing of any known disease. This is well established medical science now.

I'm not saying that ReA is a model for ME. I don't even really think the same basic mechanism is involved. It's only given as an example of how a trigger can cause ongoing symptoms w/o ongoing infection. I do not believe that ME is in the family of seronegative spondyloarthropathies, although it's possible that there might be a common risk factor.

I do believe that ME does not involve ongoing infection. I do not believe treating infections will ever prove a useful therapy.

 

[msf]

Well, I believe otherwise. As Cort said, stay tuned.

 

[Eeyore]

I'm curious how you reconcile that with the efficacy of rituximab. Why would immunosuppression / B cell depletion be effective in a chronic infection?

 

[msf]

I think there is an autoimmune component in some too.

 

[Hip]

@Jonathan Edwards

What would be your view on idea that pathogens might trigger autoimmunity by infecting important immune cells or important immune organs such as the thymus, spleen or bone marrow? If a chronic infection occurs in these cells or organs, it may conceivably create an environment which increases the chances of autoimmunity occurring, even if its actual occurrence is due to random factors in antibody production.

If we take enterovirus, this appears to profoundly affect dendritic cells:
Wild-type coxsackievirus infection dramatically alters the abundance, heterogeneity, and immunostimulatory capacity of conventional dendritic cells in vivo

Echovirus infection causes rapid loss-of-function and cell death in human dendritic cells

And coxsackievirus B4 seems to infect the thymus:
How Does Thymus Infection by Coxsackievirus Contribute to the Pathogenesis of Type 1 Diabetes?

And of course we know that Epstein-Barr chronically infects B cells.

 

[nandixon]

@Hip, you can also add the hepatitis C virus to that list. HCV appears to show a significant relationship to the development of autoimmune diseases.

I haven't looked at this in a while, but I think I previously came to the conclusion that the evidence for HCV was likely the strongest against a contention that there's no relationship between (viral) infection and autoimmunity.

This paper from last year gives some good info:

HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases

[From the Discussion section:]
Autoimmune thyroiditis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, autoimmune hepatitis and rheumatoid arthritis etc. could be classified not only as HCV-related diseases but also as Th17-related autoimmune diseases[16]-[19], [34]–[36]. In this study, we clearly demonstrated the relevance of lymphotropic HCV to autoimmune-related diseases including an important role of Th17 cells in CH-C patients.

 

[Hip]

This paper from last year gives some good info:

HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases

That's interesting that the increased risk of autoimmunity due to hepatitis C virus is mediated via this virus's induction of the Th17 response.

Offhand I know that Staphylococcus also induces Th17, and a quick Google check reveals that the risk of developing the autoimmune disease lupus is linked to Staphylococcus bacteria.