Australian discovery on B Cells and Autoimmunity

[Adster]

http://www.healthcanal.com/infections/33725-How-infection-can-trigger-autoimmune-disease.html

 

[heapsreal]

http://www.healthcanal.com/infections/33725-How-infection-can-trigger-autoimmune-disease.html

Interesting, now we need the bond uni cfs guys to bump into them at a conference

 

[alex3619]

This is not a surprise, its been suspected and discussed as far back as I remember on these issues. However, its the first time apparently that it has been demonstrated, and with more details as to why this happens.

The gene reassortment for antibody production has been known for a very long time. It was obvious there was a failure in suppressing replication of B cells that produce auto-antibodies in autoimmunity, but nobody knew the mechanisms.This reassortment is essentially a shuffling of genes in a very specific region. It is substantially random, though I think not entirely.

This helps our general understanding, and also reinforces the association between immune activation and autoimmunity, especially from pathogens. I do not think it immediately assists us with strategies for coping with this.

Bye, Alex

 

[Mark]

Alex, if I read this correctly, it is saying that the key finding is that the failure occurs when the antigen (infection) is in a specific location, remote from the germinal centre, rather than being a widespread infection throughout the body, and that this is when autoantibodies may be created.

They also go on to mention "cross-reactive autoantibodies that can attack organ-specific targets" and "autoimmune conditions that target particular organs such as the heart or nervous system".

Is this aspect, which they seem to be saying is crucial, also part of what you say has long been suspected: that it must always be a localised infection that exposes the vulnerability to auto-immunity?

Does this also imply that auto-immune conditions will therefore always involve autoantibodies targeting specific organs?

And the main question I'm left with, from reading the article, is whether the specific organs that the autoantibodies attack will (typically/always) be the same organs that the original infection was localised to? Or different organs?

It seems that if this localisation aspect is key to autoimmunity, and if there is a predictable relationship between the organ affected by the initial infection and the organ affected by the autoimmune reaction, then the next question in any given (known or suspected) autoimmune condition would be to identify which specific organ is affected. If this is always the same organ as the organ affected by the initial infection, then there may be clues, both from the current symptomology and the history of infection, which help to identify the organ affected?

And in ME/CFS, I suppose the first guess would be that the organ affected would be the nervous system? Or some particular component of it?

 

[beaverfury]

This is not a surprise, its been suspected and discussed as far back as I remember on these issues. However, its the first time apparently that it has been demonstrated, and with more details as to why this happens.

The gene reassortment for antibody production has been known for a very long time. It was obvious there was a failure in suppressing replication of B cells that produce auto-antibodies in autoimmunity, but nobody knew the mechanisms.This reassortment is essentially a shuffling of genes in a very specific region. It is substantially random, though I think not entirely.

This helps our general understanding, and also reinforces the association between immune activation and autoimmunity, especially from pathogens. I do not think it immediately assists us with strategies for coping with this.

Bye, Alex

Perovyscus mentioned Plasmapheresis on this thread http://forums.phoenixrising.me/inde...-alternatives-to-rituximab.18502/#post-309907

An important use of plasmapheresis is in the therapy of autoimmune disorders, where the rapid removal of disease-causing autoantibodies from the circulation is required in addition to other medical therapy. It is important to note that plasma exchange therapy in and of itself is useful to temper the disease process, where simultaneous medical and immunosuppressive therapy is required for long-term management. Plasma exchange offers the quickest short-term answer to removing harmful autoantibodies; however, the production of autoantibodies by the immune system must also be suppressed, usually by the use of medications such as prednisone, cyclophosphamide, cyclosporine, mycophenolate mofetil, rituximab or a mixture of these.

Wonder how that would go?

I wish B-cells would just develop a bad memory, like me.

 

[taniaaust1]

One area which is obviously under attack is the autonomic nervous system.... maybe the attack could be on the hypothalamus (isnt that what guides the ANS??)

Im excited about this new discovery as I personally believe this may be part of the answer to our illness. At least even if ME/CFS research isnt moving forward much, other reseach which probably is relevant for us is.

 

[Mark]

One area which is obviously under attack is the autonomic nervous system.... maybe the attack could be on the hypothalamus (isnt that what guides the ANS??)

Just what I was thinking...nearly added that at the end of my post above.

Im excited about this new discovery as I personally believe this may be part of the answer to our illness. At least even if ME/CFS research isnt moving forward much, other reseach which probably is relevant for us is.

Yes indeed.

 

[alex3619]

Alex, if I read this correctly, it is saying that the key finding is that the failure occurs when the antigen (infection) is in a specific location, remote from the germinal centre, rather than being a widespread infection throughout the body, and that this is when autoantibodies may be created.

They also go on to mention "cross-reactive autoantibodies that can attack organ-specific targets" and "autoimmune conditions that target particular organs such as the heart or nervous system".

Is this aspect, which they seem to be saying is crucial, also part of what you say has long been suspected: that it must always be a localised infection that exposes the vulnerability to auto-immunity?

Does this also imply that auto-immune conditions will therefore always involve autoantibodies targeting specific organs?

And the main question I'm left with, from reading the article, is whether the specific organs that the autoantibodies attack will (typically/always) be the same organs that the original infection was localised to? Or different organs?

It seems that if this localisation aspect is key to autoimmunity, and if there is a predictable relationship between the organ affected by the initial infection and the organ affected by the autoimmune reaction, then the next question in any given (known or suspected) autoimmune condition would be to identify which specific organ is affected. If this is always the same organ as the organ affected by the initial infection, then there may be clues, both from the current symptomology and the history of infection, which help to identify the organ affected?

And in ME/CFS, I suppose the first guess would be that the organ affected would be the nervous system? Or some particular component of it?

Hi Mark:

"Dr Tyani Chan and Associate Professor Robert Brink from Sydney’s Garvan Institute of Medical Research developed sophisticated mouse models to investigate when and how this happens. They demonstrated that when antigen is abundant and generally available throughout the body, rogue autoantibody-generating B cells are deleted and autoimmunity avoided. Conversely, when target antigen is located only in a tissue or organ remote from the germinal centre, B cells capable of reacting against both antigen and ‘self’ are able to escape the germinal centre and produce autoantibodies. Their finding is published in the prestigious international journal Immunity."

What you are saying Mark appears to be correct. One really good candidate would be a patch on the gut lining, but I would suspect (I don't recall if this is true) that there are lots of germinal centres close to the gut. An infection of lining of the gut that does not go very deep would be a good candidate I think, but if it gets into the blood stream then it wouldn't be.

Any biofilm protected pathogen community would also be a candidate.

Another possibility is if the pathogen gets into an immune privileged organ. Immune privilege refers to the immune system not being able to see the organ. This is important because those organs can get attacked by the immune system if the immune system can find it. These include brain, gonads and eyes. So a brain infection with a partial breakdown of the blood brain barrier would be a candidate for this kind of autoimmune problem.

The other issue is that physical proximity of a germinal centre might not be too relevant. What is relevant is whether or not it is close in terms of direct blood flow or lymph flow.

The strategies for treating autoimmunity are old. Cleaning the blood using antibody specific filters is feasible, but I don't think proven clinically. The other strategies are well known.

If an antibody is attacking, as has been suggested, a part of the hypothalamus, then removal of the antibody producing cells by drugs like Rituximab would produce a delayed response as has been discussed, but the repair of the brain would require an additional recovery period and probably be assisted by specialist nutritional support. All this requires more research though.

Bye, Alex

 

[taniaaust1]

alex.. when are you going to go to medical school? I want u as my doctor . If most of the doctors had just half of your intellegence we wouldnt be where we are now.

 

[natasa778]

Perovyscus mentioned Plasmapheresis on this thread http://forums.phoenixrising.me/inde...-alternatives-to-rituximab.18502/#post-309907

An important use of plasmapheresis is in the therapy of autoimmune disorders, where the rapid removal of disease-causing autoantibodies from the circulation is required in addition to other medical therapy. It is important to note that plasma exchange therapy in and of itself is useful to temper the disease process, where simultaneous medical and immunosuppressive therapy is required for long-term management. Plasma exchange offers the quickest short-term answer to removing harmful autoantibodies; however, the production of autoantibodies by the immune system must also be suppressed, usually by the use of medications such as prednisone, cyclophosphamide, cyclosporine, mycophenolate mofetil, rituximab or a mixture of these.

Wonder how that would go?

There was a nice little study showing plasmapheresis combined with IVIG worked very well for a large number of autoimmune patients, whereas both of those treatments on their own didn't do much. I think they also used steroids in the combo. I posted that study with its own thread, wish I could remember the title now or what condition it was ...

I wish B-cells would just develop a bad memory, like me.

Yes !!

 

[natasa778]

ah, here is one:

In patients with autoimmune autonomic ganglionopathy, combining immunosuppressive medications prednisone and mycophenolate mofetil with plasmapheresis provides substantial and sustained clinical improvement that was not seen using either treatment alone. Multi-agent immunomodulatory therapies may be necessary to satisfactorily treat this immune-mediated disorder.

http://archneur.jamanetwork.com/article.aspx?articleid=795214

 

[natasa778]

another one (good review of IVIG use in variety of conditions):

These studies suggest that combination therapy with IVIg may be effective for treatment of AMBDs. Rituximab can convert partial responders to high responders and these patients, once in remission, maintain a sustained prolonged clinical remission.

... Increasing attention is also being turned to the use of IVIg in combination with other agents, such as immunosuppressive agents or monoclonal antibodies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801038/


wondering if it would go the other way round, if IVIG or plasma exchange would convert partial Rituximab responders to high responders!? Hope Fluge et al have this on their radar !!

 

[Snow Leopard]

Here is the paper by Chan and colleagues:

"Elimination of Germinal Center-Derived Self-Reactive B Cells Is Governed by the Location and Concentration of Self-Antigen"

http://www.cell.com/immunity/abstract/S1074-7613(12)00462-1

 

[free at last]

Hi Everyone as mentioned on the other thread i posted, I belive ME/CFS patients do indeed develop some kind of autoimmunity, ( possibly different types for different patients ) its just too much of a coincedence that antibodie production from a flu vaccine most often occurs 10 days after vaccination.

And i developed sever bone problems that started exactly 10 days afer this recent vaccine. The effect of this was very pronounced, attacking my feet legs shoulders, and my left ribcage After this antibodie surge 10 days after vaccination,it took a further 4 days for the effect to start to settle down somewhat. my feet and legs have recovered and settled down quite a bit.

However my shoulders ( i am now into 21 days after vaccination ) are still affected quite badly, and can not just be just a short term effect of the vaccine itself, especially when one learns i have been suffereing from these bone problems for at least the last 2 years ( if not earlier ) that seem to flare, and settle down over periods of months.In other words i have a smouldering condition of autoimune bone attack. that was made far worse by the vaccine production of antibodies.

This much seems clear to me. And i can not see any other explanation that comes close to making sense. this is the first direct evidence i have that what is being suggested is intirely correct for some ME/CFS patients
Your thoughts guys

 

[alex3619]

Here is the paper by Chan and colleagues:

"Elimination of Germinal Center-Derived Self-Reactive B Cells Is Governed by the Location and Concentration of Self-Antigen"

http://www.cell.com/immunity/abstract/S1074-7613(12)00462-1

Whoa, this is different. The article is easily misinterpreted I think, or wrong. This abstract makes more sense, but I wonder how more sense the full paper would be - it needs to be read.

Here are the key bits: [My bolding]

"Self-reactive GC B cells not eliminated if target self-antigen is in a distal tissue"

"In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies."

It does not matter where the infection is. It is not about the pathogen. Its about the expression of the epitope. The epitope is the amino acid sequence the antibody binds to. Germinal centers are capable of eliminating auto-antibodies if a similar target exists close to them. If the target is far away they do not eliminate the self-antigen.

What this does to my explanation several posts ago is shift the emphasis. A gut infection could possibly result in auto-antibodies to brain tissue. Similarly a brain infection could possibly result in auto-antibodies to gut tissue. A wide spread viral infection, according to the abstract (the paper might be different to the abstract about this), could still do it. This is because if a B cell is hypermutating in for example a germinal center in the gut, that germinal center will only check for autoimmunity in very close tissue in the gut (though this is not really a purposeful activity, its a function of the biology). Target epitopes in the brain tissue will not be checked for unless they are also expressed in the gut. So the gut germinal center will give an all-clear and the B cell survives. Hello to autoimmunity.

So the apparent co-occurance of gut infection and a brain disorder might actually reflect reality. The whole point is that an infection in one part of the body gives rise to autoimmunity somewhere else. Since the gut is a source of many pathogens, gut infection is likely to be a trigger for many cases of autoimmunity.

However the opposite might be true too. A brain infection (such as measles encephalitis) which I had might induce autoimmunity to the gut. This might weaken the gut, leading to worse infections, which might induce autoimmunity in the brain ... and so the cycle continues.

This implies, but does not prove, that it does not matter where the infection is. Once autoimmune issues start then it becomes a cycle of new autoimmune issues. This is most likely in the case where the original autoimmune target is the gut, in other words when the infection is not in the gut. That infection, which generates gut auto-antibodies, would weaken the gut and a following gut infection would then be more severe, leading to greater risk of autoimmunity.

Of course none of this takes into account autoinflammatory pathways, something which I think will be closely intertwined with this idea.

Just to be clear, when I say pathogen I really mean pathogenic target. This includes vaccines.

Bye, Alex

 

[currer]

wondering if it would go the other way round, if IVIG or plasma exchange would convert partial Rituximab responders to high responders!? Hope Fluge et al have this on their radar !!

Fluge and Mella are already carrying out plasma exchange on their patients, if I remember correctly.

 

[alex3619]

I don't think plasma exchange will have a huge impact on responders vs. non-responders. I do think it will have an impact on speed of response. That faster response might also mean more healing between doses. This will make responders more visible much earlier in treatment.

 

[alex3619]

I would like to clarify something. The autoimmunity issues in a widespread infection are about where the B cells that respond are forming. If they form in the gut, they could make antibodies for brain epitopes that are not expressed in the gut. The location of the germinal center in which the B cell has undergone hypermutation is the key.

 

[Lynne B]

Alex, cheers, Lynne. (After I put in the url I can't seem to go back to normal type so I'm saying goodbye before I begin!)

I was in the middle of a post to you on your other thread where you summarise the findings very clearly, for instance, by explaining what a germinal centre is. Can you bring that over to this thread for others like me? I was saying the Garvan Institute seems to be good value for money because of their other research on things like osteoporosis, which I have, but when I googled the Institute for their website url I lost that thread altogether. Anyway, it's www.garvan.org.au/ .

 

[natasa778]

So would this tie in nicely with lymphoid hyperplasias, (pseudo)lymphomas etc?

http://www.ncbi.nlm.nih.gov/pubmed/15793512