"Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses" 2015

[halcyon]

http://www.biomedcentral.com/1741-7015/13/28

Background
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

Discussion
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.

Summary
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.

 

[L'engle]

Thanks!

 

[halcyon]

Found this interesting:

Sex effects may also determine responsivity to drug therapy as, for example, in MS. Thus, postmenopausal women are poorer responders to rituximab than men of the same age 390],391]. This might seem a little counter intuitive from the frame of reference that rituximab exerts its effects mainly on the B cell population and that B cell levels do not appear to differ in postmenopausal women and age equivalent men to any significant extent 392]. However rituximab also exerts modulatory effects on the T cell compartment 393]. Numerous researchers have reported that the clinical benefits seen following the use of rituximab in rheumatoid arthritis and other autoimmune conditions are associated with the antibody’s capacity to increase the expression of FOXP3 394], suppress the expression of retanoic acid-like orphan receptors ultimately suppressing the production of Th17 T cells and IL-17 395] and reducing the expression of cytokines by Th1, Th2 and Th17 T cells 396]. It is possible that the Th2 shift in the immune system seen in postmenopausal women negates the benefits of rituximab on a Th1/Th17 biased immune system 392]. The positive benefits of rituximab and natalizumab on MS 84],85] is probably most easily explained by the modulatory effects of rituximab and, likely, natalizumab on the T cell compartment as well as their well-documented effects on B cell depletion.

 

[Valentijn]

This is an open access paper, and seems to be proposing a mechanism for fatigue in autoimmune illnesses and CFS. They haven't made a new discovery, but rather are putting forth a hypothesis.

There's a big section discussing CFS specifically from page 5-6. The entire paper has 14 pages of text, so could be a bit challenging to get through.

Any thoughts, @Jonathan Edwards ?

 

[Jonathan Edwards]

This is an open access paper, and seems to be proposing a mechanism for fatigue in autoimmune illnesses and CFS. They haven't made a new discovery, but rather are putting forth a hypothesis.

There's a big section discussing CFS specifically from page 5-6. The entire paper has 14 pages of text, so could be a bit challenging to get through.

Any thoughts, @Jonathan Edwards ?

This seems to be a gluing together of a variety of fashionable concepts to form a hypothesis about ME by someone who is not actually a laboratory scientist. In my view theories that generalise like this cannot work - because they do not explain the differences between the different diseases. 'Neuroinflammation' in the generic sense implied here is, I think, a bogus idea.

The bit about rituximab is again popular nonsense. It is based on a paper that came out of my old department which does not show anything that suggests that rituximab affect the T cell compartment other than by reducing the TNF produced in response to antibody. I think I have seen this paper before. Immunobabble, again I fear. Everything is thrown in for good measure - which again is a sign of weakness. Good hypotheses are very lean and specific!

 

[halcyon]

The bit about rituximab is again popular nonsense. It is based on a paper that came out of my old department which does not show anything that suggests that rituximab affect the T cell compartment other than by reducing the TNF produced in response to antibody.

It seems like the statement was based on about 4 different papers by different groups so I'm wondering how much nonsense it actually is.

 

[Jonathan Edwards]

It seems like the statement was based on about 4 different papers by different groups so I'm wondering how much nonsense it actually is.

I suspect the one from our department came first and in modern immunology once one person has pub;ished something with buzz words like Treg in then others will follow. I have actually discussed the issue at length with the senior author of the local paper and he is quite clear that he is not saying that T regs have a causal role in RA (despite that not being clear from the way the paper is interpreted).

If B cells were promoting inflammation through antigen presentation to T cells acting other than via antibody production (via help back on the B cells) then rituximab would make people better within a month and very often it takes 3-6 months. It is nonsense, I can absolutely assure you!

 

[halcyon]

If B cells were promoting inflammation through antigen presentation to T cells acting other than via antibody production (via help back on the B cells) then rituximab would make people better within a month and very often it takes 3-6 months. It is nonsense, I can absolutely assure you!

What if it also causes a downregulation of memory T cells that takes some time to manifest as well?

 

[Jonathan Edwards]

What if it also causes a downregulation of memory T cells that takes some time to manifest as well?

Anything is possible but we have no evidence of any excessive activation of T cells in RA anyway, nor any evidence of them being autoreactive - nor anything really. The idea that T cells are important in RA dates back to a paper written by Janossy and Panayi in about 1982, which followed on from work that I had done in Janossy's lab in fact, with Alero Thomas. We showed that inflamed synovium was full of T cells. Janossy and Panayi repeated this on RA samples with Duke and published it to indicate that T cells caused RA. But they omitted to note that the inflammation I had found T cells in was a football injury! T cells will go into anywhere that is injured - their presence means nothing other than a response to injury. We had known for twenty years even then that RA inflammation starts with macrophage activation BEFORE any T cells are found.

And nobody has ever observed autoreactive T cells taking six months to simmer down (partly because nobody has found any autoreactive T cells much). But details of experimental evidence do not tend to worry the immunobabblers.

Moreover, the story going about seems to be that Tregs restore function after B cell depletion and I cannot see why taking away antigen presenting B cells would restore T regs. I may have got that wrong - to be honest I cannot make much of what is in these papers - but either way I cannot see where the theory starts from.

It is a long story and I have been at the middle of it for thirty five years,, one way or another, but immunologists tend to take fifty years to get a new idea. Most of them are still talking about infections causing autoimmunity through molecular mimicry - despite no evidence.

 

[Jonathan Edwards]

Looking at the quote above again, there is talk of reducing TH17 and Th1 cells. But anti-IL-17 had no effect on RA - and nor did depleting all T cells with anti-CD52 to near AIDS levels. There are so many arguments I am beginning to forget them now!

 

[Oredogg]

If I may interject, and perhaps add even more confusion to the issue? Anecdotally, I have seen a number of patients with CLL/SLL (mature B-cell lymphoma/leukemia) treated, presumably solely, with rituxan, who have exhibited absolute T-cell reduction in addition to the anticipated B-cell reduction, by flow cytometry. I do not know the exact nature or course of their treatments, as I see the case from the laboratory end, but have wondered whether rituxan is exerting some degree of T-cell depleting effect, or subset depletion, as well.

Also, a minor subset of T-cells are thought to co-express CD20 to varying degree. In fact, I believe these cells have been implicated in the CNS inflammatory response in patients with MS, and are thought also to secrete IL-17 and Interferon Gamma. Since rituxan targets CD20 antigen, perhaps it is this subset of T-cell that is initially depleted? Perhaps these cells also may be involved in the pathogenesis of ME/CFS? Here's a recent MS publication highlighting these peculiar findings: http://www.msard-journal.com/article/S2211-0348(14)00061-3/abstract

Some food for thought.

 

[Jonathan Edwards]

If I may interject, and perhaps add even more confusion to the issue? Anecdotally, I have seen a number of patients with CLL/SLL (mature B-cell lymphoma/leukemia) treated, presumably solely, with rituxan, who have exhibited absolute T-cell reduction in addition to the anticipated B-cell reduction, by flow cytometry. I do not know the exact nature or course of their treatments, as I see the case from the laboratory end, but have wondered whether rituxan is exerting some degree of T-cell depleting effect, or subset depletion, as well.

Also, a minor subset of T-cells are thought to co-express CD20 to varying degree. In fact, I believe these cells have been implicated in the CNS inflammatory response in patients with MS, and are thought also to secrete IL-17 and Interferon Gamma. Since rituxan targets CD20 antigen, perhaps it is this subset of T-cell that is initially depleted? Perhaps these cells also may be involved in the pathogenesis of ME/CFS? Here's a recent MS publication highlighting these peculiar findings: http://www.msard-journal.com/article/S2211-0348(14)00061-3/abstract

Some food for thought.

I suspect that many CLL or lymphoma patients get rituxan with something like CHOP. That was the pattern when I first started using rituxan in RA (hence using cyclo as well). Rituxan has no effect on T cell numbers (or major subsets) in the circulation in RA patients over the 6-10 month period of B cell depletion. Maria Leandro did detailed kinetics for her PhD. A tiny number of T cells have CD20 - they appear as a little blip on top of the CD20- T cell blob on FACS.

Everyone is trying to find a way of explaining the effect of rituxan by saying it is working on T cells simply because immunologists are obsessed with T cells and think they will only get grants if they write papers on T cells. It is quite bizarre and probably has a lot to do with what you can do in animal models. B cell immunology is now so unfashionable that people have almost forgotten the existence of complement and Fc receptors. One of the reasons I gave up clinical immunology was that since about 2000 it seems to have gone either backwards or nowhere. Almost nothing major new has appeared on the therapeutic horizon.

 

[msf]

Prof. Edwards, I was surprised to hear you say that RA begins with macrophage activation. I don't know why, but I had never thought of this part of the immune system being involved in auto-immune disease. Are there any other auto-immune diseases that you know that start this way?

 

[msf]

I should correct myself, you said RA inflammation, not RA itself, but since the inflammation is the 'visible' part of the illness, this would mean that episodes of RA begin with macrophage activation, wouldn't it?

 

[Jonathan Edwards]

I should correct myself, you said RA inflammation, not RA itself, but since the inflammation is the 'visible' part of the illness, this would mean that episodes of RA begin with macrophage activation, wouldn't it?

Yes, the idea is that autoantibodies are produced in bone marrow and get into the circulation where they bind to antigens and form very small complexes. These complexes are not cleared so can diffuse into tissues. The tissues with macrophages that have receptors that react to small complexes (FcR3 receptors) will then show macrophage activation as the first sign of inflammation. The synovial lining if joints has macrophages with this receptor and the other places are also affected by RA - pleura, pericardium, liver Kuppfer cells, ocular sclera and lymphoid tissue (which gets larger). The important immunology has occurred earlier with the generation of the autoantibodies but the first clinical signs relate to TNF production by macrophages as a response. T cells respond to the call from TNF and arrive in the tissue. They will also arrive in tissue where cytokine is produced in response to a football injury!