The possibility of autoimmunity or auto-reactivity in ME/CFS

[Hutan]

T cell cytokines probably operate almost entirely locally over distances of a few microns at most -pretty much with cell contact. Circulating cytokines are probably mostly derived from macrophages and other stroll cells. In psoriasis there isn't necessarily much to find other than the local rash.

I had a couple of flares of Graves Eye Disease prior to developing ME/CFS - seemingly not related to thyroid function in my case. That might be another disease where auto-reactive t-cells can cause their problems quite locally.

Fluge and Mella
reported an association in that region to HLA-DQ and HLA-C I think.

https://www.medscape.com/answers/120619-44486/what-is-the-role-of-genetics-in-graves-disease
HLA-DRB1 and HLA-DQB1 appear to be associated with Graves disease susceptibility.


I was idly googling for any information about Campath (alemtuzumab) helping Graves eye disease. Instead I found that it's reported to be a highly effective treatment for multiple sclerosis, but it's suggested that it causes (autoimmune) thyroid disease including Graves eye disease in an astonishingly high number of people (e.g. 41%).
https://academic.oup.com/jcem/article/103/8/3010/5033322
(disclaimer: this study followed MS patients given alemtuzumab - we aren't told the incidence of thyroid disease in MS patients not given the treatment)

The principal adverse effect of alemtuzumab is development of autoimmunity, occurring most frequently at 16 months following last date of drug administration.

The mechanism of alemtuzumab-induced autoimmunity is not fully understood, but has been attributed to a breakdown in self-tolerance during immune reconstitution post-alemtuzumab, with homeostatically expanding autoreactive T cells driving a humoral autoimmune response

Interestingly the autoimmunity often seems to occur well after the administration of the alemtuzumab. The immune system re-set actually seems to cause autoimmunity problems.

If alemtuzumab causes delayed autoimmunity problems and ME/CFS is an autoimmune problem, then there might not be a clear cut pattern of improvement of ME/CFS following administration of it to people with ME/CFS?

(I totally acknowledge my lack of knowledge about all this)

 

[Marky]

T cells belong to at least four separate trafficking compartments - gut, skin, mucosal and everything else. So we have four T cell arthropathies - Crohn's, psoriatic, Reiter's and ankylosing spondylitis. I think it quite plausible that there is in fact yet another T cell compartment - that does not go out into any of the peripheral tissues but remains confined to lymphoid tissue. B cells remain confined to lymphoid tissue in normal immune responses. For all the functional variants of T cells there are usually 'null' groups. So there might be a 'null-trafficking' group. The interesting implication would be that persistent activation of these cells would not produce any visible local pathology but might still produce systemic symptoms due to signalling mechanisms. These might not be systemic cytokine release but might involve neural signals or other hormonal signals.

[/QUOTE]

Its too bad you are retired, cause your hypophezises are really interesting and theorethically plausible

Any other places than lymphoid tissue that t cell compartments are possible?

 

[Amw66]

Unfortunately it is remarkably difficult to demonstrate exactly what T cells are doing wrong. T cell populations in blood look pretty normal. T cells that traffic to specific compartments show up in those compartments - i.e. in skin for psoriasis and gut for Crohn's disease but nobody knows what is annoying them. If T cells were annoyed just in lymph node and speed, where there are masses of T cells anyway it would be difficult to find the problem I think.

Just possibly it might be that PWME have larger spleens - that would be measurable with MRI. But if there is a difference it must be marginal because someone would have noticed very large spleens by now.

That assumes that they are looked at.
Very little is looked at.

 

[Jonathan Edwards]

I had a couple of flares of Graves Eye Disease prior to developing ME/CFS - seemingly not related to thyroid function in my case. That might be another disease where auto-reactive t-cells can cause their problems quite locally.

As I understand it in autoimmune thyroid disease we only have evidence of B cell autoimmunity. In the common autoimmune diseases there is in general no evidence for T cell autoimmunity or anything wrong with the T cells. Normal T cells are simply hijacked by the autoimmune B cells. The HLA associations with Graves are in Class II (HLA-D) which is relevant to B cell interaction. The T cell disorders have Class I links.

The pathology of Grave's eye disease is mysterious but the exophthalmos is mostly due to accumulation of mucoid material around eye muscles I think - maybe hyaluronate and proteoglycans. I don't think there is much of a T cell infiltrate although I may be wrong. Normal patrolling T cells wander into any damaged tissue but that should not be confused with infiltrate by abnormal T cells.

I was idly googling for any information about Campath (alemtuzumab) helping Graves eye disease. Instead I found that it's reported to be a highly effective treatment for multiple sclerosis, but it's suggested that it causes (autoimmune) thyroid disease including Graves eye disease in an astonishingly high number of people (e.g. 41%).

I am not sure how good Campath is for MS. Campath does what rituximab does as well as killing B cells because it kills all types of lymphocyte. B cells recover, as after rituximab, but the T cells do not so much. Campath may work temporarily in MS because it kills B cells. Autoimmunity occurs with Campath at the time when B cells return - something seen in transplant cases too.

To be clear, I am not suggesting that ME is a T cell autoimmune problem but might be a problem of excessive T cell activation like psoriasis. The beneficial effects of Campath and the occurrence of rebound B cell autoimmunity are clearly separate things with quite different time courses. We don't have any good evidence for autoimmunity causing ME so I doubt it would be an issue.

 

[Jonathan Edwards]

Any other places than lymphoid tissue that t cell compartments are possible?

Any tissue other than lymphoid tissue would come under the 'everything else' trafficking domain that is associated with ankylosing spondylitis. Lymphoid tissue is unique in that it is normally full of T cells so you cannot tell if has T cells when it shouldn't. It would also be the one place where lymphocytes that never ventured out of lymphoid tissue were found - by definition.

 

[Hoopoe]

The spleen also participates in the regulation of blood volume. If there was some abnormal T cell thing going on in the spleen, would it affect blood volume?

 

[Hutan]

As I understand it in autoimmune thyroid disease we only have evidence of B cell autoimmunity. In the common autoimmune diseases there is in general no evidence for T cell autoimmunity or anything wrong with the T cells. Normal T cells are simply hijacked by the autoimmune B cells.

Because I have had Graves eye disease, I have been keeping an eye (ha) on the papers that come out. There have been hypotheses about T cell involvement for a while now - this is a recent (2019) article:
The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy

It sounds more complicated than autoimmune B cells just hijacking normal T cells, although it's a bit hard to understand what's starting things and if the t-cells are behaving abnormally at any point - as in, would healthy t-cells stop the disease process? I guess the antigen-presenting cells that seem to start things off might be B-cells, although perhaps they are other types of cells too.

The article says that previous studies suggest T cells may be involved in the pathology in three ways:
1. Activating B cells and stimulating the production of autoantibodies

When autoimmune tolerance in TAO is disrupted, antigen-presenting cells that recognize the autoantigen thyroid-stimulating hormone receptor (TSHR) expressed on orbital fibroblasts (OFs) activate T cells. Meanwhile, B cells migrate to the orbit and recognize TSHR through B cell receptor, which is the first signal of B cell activation. The second signal of B cell activation is provided by activated T cells through the combination of CD40L on T cell surface and CD40 on B cell surface. This interplay also stimulates T cells to secrete cytokines such as interleukin (IL)-4, which is essential for further activation of B cells and antibody class switching [5, 13]. Activated B cells undergo clone proliferation and differentiate into plasma cells that produce autoantibodies. These autoantibodies (including stimulating, blocking, and neutralizing subtypes) recognize and attack adipose connective tissues in the orbit.

2. Promote the expression of adhesion molecules.

The interaction of B7 on B cell surface with CD28 on T cell surface provides the second signal for T cell activation [5, 13]. Activated T cells, primarily CD4+ T cells, produce a variety of adhesion molecules. Together with the chemokines and adhesion molecules secreted by stimulated [orbital fibroblasts] OFs, these factors mediate the recruitment of more lymphocytes into orbital tissues and the further interaction between OFs and T cells [14, 15].

3. Produce inflammatory cytokines.

Cytokines produced by CD4+ T cells aggravate the immune responses of TAO by amplifying and maintaining orbital inflammation. They also promote the proliferation and differentiation of OFs, ultimately leading to glycosaminoglycan deposition, orbital fibrosis, and adipose hyperplasia, namely orbital tissue remodeling.

@Jonathan Edwards, how is this different to the T-cell arthropathies?

 

[Jonathan Edwards]

The spleen also participates in the regulation of blood volume. If there was some abnormal T cell thing going on in the spleen, would it affect blood volume?

I don't think so. The white pulp and red pulp probably function separately.

Because I have had Graves eye disease, I have been keeping an eye (ha) on the papers that come out. There have been hypotheses about T cell involvement for a while now - this is a recent (2019) article:
The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy

T cell involvement in B cell autoimmunity is not in doubt. All the T cell steps mentioned in your citations are entirely consistent with hijacking of normal T cells. For the T cells to be abnormal or autoimmune themselves we should find abnormal T cell responses but for the thirty years that I was in the field despite almost everyone assuming these cells existed they were never found.

This debate is not new. It goes back to the late 1970s when T cell enthusiasts wanted to show that autoimmunity was T cell driven. Rather like the BPS crowd they collared people's attention and the myth has been 'received wisdom' ever since. Ironically the 'T cell theory' of rheumatoid arthritis was based on some data that Alero Thomas and I had generated at the Royal Free Hospital in 1979 and 'borrowed' by some colleagues. They completely misinterpreted it. The paper you quote comes from a new wave of T cell pundits who claim to have suddenly discovered that B cells contribute by presenting antigen and that T cells contribute with cytokines. We actually knew that in the 1970s, even if we did not know the details of all the molecules.

It was the realisation that it made no sense that was the key to working out that rituximab would be useful. Inducing a die off of plasma cells makes most autoimmune diseases disappear at least temporarily. But the disease does not disappear when the B cells are first removed - which is what a T cell based mechanism would predict.

 

[Jonathan Edwards]

@Jonathan Edwards, how is this different to the T-cell arthropathies?

The situation for T cell arthropathies is completely different. There is no evidence of any B cell involvement. That would predict that the T cells involved were not interacting via Class II (HLA-D) and so are likely to be CD8 rather than CD4 T cells. That fits perfectly with the fact that the seronegative arthropathies have genetic associations to Class I like B27 and Cw6 and not to HLA-D.

Nobody has ever found any evidence of T cells actually recognising self-antigens in these arthropathies as far as I know. So the T cells are overactive but not reacting to self in a specific cognate way. That is not particularly surprising because of the way T cell activity is regulated. For B cells the binding of antibody to antigen is a highly specific high affinity steric interaction if it is to do anything at all. T cell receptor interactions are much lower affinity and only signal if lots of cofactor molecules are arranged around to set the 'sensitivity' right. The corollary of that is that ultimately any T cell can be got to respond to anything if the cofactor environment is racked up high enough. T cells will even respond without any T cell receptor engagement. So having T cells running around being too busy without being autoimmune is not surprising.

 

[FMMM1]

Fascinating few posts Jonathan thank you



Any ideas how we might do that, it sounds very much worth doing?

Perhaps MEA / AfME / MEAction would be willing to put out a call for feedback?

Fascinating few posts Jonathan thank you



Any ideas how we might do that, it sounds very much worth doing?

Perhaps MEA / AfME / MEAction would be willing to put out a call for feedback?

I contacted OMF and Linda replied "We have not looked into Campath". Perhaps they will look at it now. This seems an interesting way to get insight into the disease (ME) mechanism.

@Jonathan Edwards

 

[Snow Leopard]

So there might be a 'null-trafficking' group.

For what reason would this subset become 'null-trafficking'? Are there examples of 'null-trafficking' subsets of other leukocytes?

 

[Jonathan Edwards]

For what reason would this subset become 'null-trafficking'? Are there examples of 'null-trafficking' subsets of other leukocytes?

As I indicated all B cells are essentially null trafficking because they do not function in a peripheral tissue. Their job is to be available for selection and expansion in lymphoid tissue in an environment rich in T cells and NK cells. If they carry useful Ig gene rearrangements they then send off plasma cell daughters to bone marrow - again not to the actual peripheral tissue that is diseased. Plasma cells do get into diseased tissues in the short term to an extent and even B cells may survive in unusual circumstances like myasthenia thymus and rheumatoid synovial but they have no normal immunologic function there.

B cells traffic from birth in bone marrow to lymphoid tissue of course, but the trafficking domains of interest relate to subsequent movement. Microglia might also be thought of as null trafficking but I think that is not a useful analogy.

B cells carrying the VH4-34 idiotype are even more 'stay at home' in that they do not even move in and out of germinal centres but divide in T cell zones in lymph node or spleen.

I am not suggesting that a T cell subset becomes null trafficking but rather that the differentiation pathways that yields skin, gut, mucosa and everything else traffickers might yield another null trafficking group. It would make perfect sense if for instance these were the CD8+CD57+ cells that sit in germinal centres and kill non-competitive or auto reactive B cells. The only function of these cells is to get rid of B cells within lymphoid tissue as far as we know. There would be no point in them circulating to other peripheral tissues.

In fact now you mention it that would make perfect sense as a candidate subset.

 

[leokitten]

@Jonathan Edwards regarding psoriasis and whether defined as autoimmune or not, the last few years there’s been developing research on the presence of autoantigens and autoantibodies in psoriasis and psoriatic arthritis.

Of course will take more research and time to determine if this is indeed real and a driving mechanism of psoriasis pathology, just putting it out there.

Maybe it’s just semantics and definitions from the immunology community? Are autoantigens and autoreactive T cells not defined as autoimmunity because the traditional definition is autoantibodies and B-cell mediated?

Here’s a recent review paper

Current knowledge on autoantigens and autoantibodies in psoriasis. Ten Bergen et al. Scand J Immunol (2020)

 

[Snow Leopard]

As I indicated all B cells are essentially null trafficking because they do not function in a peripheral tissue.

But the lymph itself is quite diverse and has connections to many parts of the body. What determines whether a B-cell ends up in the Lamina propria and class-switches to IgA for example?

I am not suggesting that a T cell subset becomes null trafficking but rather that the differentiation pathways that yields skin, gut, mucosa and everything else traffickers might yield another null trafficking group. It would make perfect sense if for instance these were the CD8+CD57+ cells that sit in germinal centres and kill non-competitive or auto reactive B cells. The only function of these cells is to get rid of B cells within lymphoid tissue as far as we know. There would be no point in them circulating to other peripheral tissues.

In fact now you mention it that would make perfect sense as a candidate subset.

What would a disease of these T-cells acting in an over-active manner actually look like though?
Lymphadenitis? It still seems different to ME though.

 

[Jonathan Edwards]

ut the lymph itself is quite diverse and has connections to many parts of the body. What determines whether a B-cell ends up in the Lamina propria and class-switches to IgA for example?

I don't know, but that is a different issue. I am discussing re-circulatory trafficking, which applies to T cells and is tissue specific.

What would a disease of these T-cells acting in an over-active manner actually look like though?
Lymphadenitis? It still seems different to ME though.

It would not necessarily look like anything local. Lymphoid tissue is always full of lymphocyte so being full of more active lymphocytes might not be apparent - although many PWME talk of lymph node enlargement or discomfort. Note that more active CD8CD57+T cells would be expected to be associated with a reduction in other lymphocytes because they are cells that remove unwanted clones.

In conditions like Crohn's disease and Reiter's people feel unwell presumably because of some sort of systemic signalling. Some of that may be TNF, which would be associated with raised CRP but in Reiter's the blood markers are often unimpressive. The two patients with identifiable disease that I remember who would fit best with ME/CFS had Reiter's. If a null-trafficking subset of T cells had a particular role like CD8CD57+ killing then systemic signals might be a bit different. (CD8CD57+ cells play a key role in the resolution phase of EBV infection of course.)

I think it is hard to put together a complete story on the basis of what we know and I do not pretend to be able to do that. However, in the absence of other stories that seem to work I think it is at least worth excluding as a mechanism.

 

[Snow Leopard]

It would not necessarily look like anything local. Lymphoid tissue is always full of lymphocyte so being full of more active lymphocytes might not be apparent - although many PWME talk of lymph node enlargement or discomfort. Note that more active CD8CD57+T cells would be expected to be associated with a reduction in other lymphocytes because they are cells that remove unwanted clones.

What cellular characteristics/signalling would lead to trafficking vs non-trafficking T-cells?

I have not read the following articles in any detail, but besides the obvious role of cytokines/chemokines in homing into specific tissue, they mention that cellular adhesion plays a strong role in T-cell migration. Many of the infectious triggers of ME are known to interact with specific cellular adhesion receptors (such as integrins), is it possible that this signalling could be disturbed leading to a feedback loop between endothelial cells and a subset of T-cells, leading them to remain in the lymph?

T Cell Trafficking through Lymphatic Vessels
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5174098/

T lymphocyte trafficking: molecules and mechanisms
https://pubmed.ncbi.nlm.nih.gov/23276933/

The highway code of T cell trafficking
https://pubmed.ncbi.nlm.nih.gov/18161751/

Introduction: T Cell Trafficking in Inflammation and Immunity
https://pubmed.ncbi.nlm.nih.gov/28349476/

 

[Jonathan Edwards]

they mention that cellular adhesion plays a strong role in T-cell migration. Many of the infectious triggers of ME are known to interact with specific cellular adhesion receptors (such as integrins), is it possible that this signalling could be disturbed leading to a feedback loop between endothelial cells and a subset of T-cells, leading them to remain in the lymph?

The trafficking domains are based on adhesion molecule pairs. I forget but if I remember rightly maybe:
VCAM-1 and VLA-4 (alpha4beta1 integrin) for 'everything else'
MADCAM and alpha4-beta7 for gut
CLA-4 and ligand for skin
E-cadherin and another integrin for mucosa

This is in addition to the general E-selectin and ICAM systems.

Infectious triggers may bind to adhesion molecules but I am not sure how that would play out in terms of affecting T cells. Upregulation of adhesion pairs occurs over 2-48 hours and I am not sure how one would tie that in to. long term post-infective problem. Generally the adhesion systems respond to acute phase cytokines like TNF and IL-1.

These adhesion systems determine emigration of T cells from venule lumen into tissues. Once they are in tissues and recirculate back via lymphatics to nodes I don't think these systems operate, although VCAM-1 is also involved in stromal cell (fibroblast-type) adhesion.

The re-entry from nodes of T cells into blood will follow different signals again.

There is also the issue of entry of T cells into nodes from blood which makes use of some of the systems above like ICAM-11 but I think also CD44 .

One thing I wonder about is why ME does not seem to follow intracellular bacterial infection so much as intracellular virus and what were once called rickettsia. As indicated, Reiter's patients do get fatigue but bacteria seem better at stirring up domain-specific trouble. Interestingly viruses never seem to stir up Reiter's or psoriasis as far as I know.

Maybe stirring up stay-at-home CD8 T cells depends on very specific interactions - maybe involving 'stay-at-home' adhesion systems in lymphoid tissue.

 

[Hoopoe]

Something that seems potentially significant to me was that the onset of the illness felt exactly like the early stage of an infection, when some early immune response has begun but the full response (with fever and more intense symptoms) hasn't kicked in yet. The full response never came, instead that "I'm about to get sick" persisted for at least a week and maybe never went away fully.

I have wondered whether that could reveal something about the root of my illness. What immune responses occur before the ones that produce fever? If these persist and are never turned off, cold they produce ME/CFS? If there is no such thing as an early immune response, maybe what I felt was at vagus nerve or autonomic level.

My brother also had the same onset. Something similar to a mild infection and it went downhill from that point on.

 

[leokitten]

(CD8CD57+ cells play a key role in the resolution phase of EBV infection of course.)

Very interesting didn’t know this

 

[tmrw]

Something that seems potentially significant to me was that the onset of the illness felt exactly like the early stage of an infection, when some early immune response has begun but the full response (with fever and more intense symptoms) hasn't kicked in yet. The full response never came, instead that "I'm about to get sick" persisted for at least a week and maybe never went away fully.

Interesting, I had the same kind of onset. It felt like the infection was about to start. It was intense for about 3 days. And afterwards I just felt sick. Most of the time I feel the worst just after waking up. A lot of the times I think 'oh no, I am going to be really sick' untill I am awake enough to realise that I actually am really sick, but in a worse, chronic type of sick.