Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with CFS

[Snow Leopard]

Brain Behav Immun. 2015 Sep 20. pii: S0889-1591(15)30020-9. doi: 10.1016/j.bbi.2015.09.013. [Epub ahead of print]

Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.

Loebel M1, Grabowski P2, Heidecke H3, Bauer S2, Hanitsch LG2, Wittke K2, Meisel C4, Reinke P5, Volk HD6, Fluge Ø7, Mella O8, Scheibenbogen C6.


Abstract
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder. We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

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Please don't share this around the web.

 

[Hip]

Interesting study.

It's worth creating a table showing the autoantibodies that this study and previous ones have found in ME/CFS and its comorbid conditions of POTS, orthostatic hypotension and Sjogren's:

AUTO-ANTIBODIES FOUND IN ME/CFS AND ITS COMORBID CONDITIONS
——————————————————————————————————————————————————————————————————————————————
AUTO-ANTIBODIES                  ME/CFS     POTS     ORTHOSTATIC     SJOGREN'S
OBSERVED                                             HYPOTENSION     SYNDROME
——————————————————————————————————————————————————————————————————————————————
Alpha 1 adrenergic receptor                  Yes
Alpha 2 adrenergic receptor
Beta 1 adrenergic receptor                   Yes         Yes
Beta 2 adrenergic receptor         Yes       Yes         Yes

Muscarinic receptor M1             Yes
Muscarinic receptor M2                                   Yes
Muscarinic receptor M3             Yes                   Yes            Yes
Muscarinic receptor M4             Yes

Dopamine D2 receptor               Yes
Mu-opioid receptor                 Yes
Serotonin 5-HT1A receptor          Yes
Serotonin (neurotransmitter)       Yes

Microtubule-associated protein 2   Yes
Phosphatidylinositol               Yes
Insoluble cellular antigens        Yes
Cardiolipin                        Yes

Study references found here:
Could autoantibodies to muscarinic acetylcholine receptors underpin ME/CFS?
And also here.

Looking at this table, there are lots of autoantibody hits on the muscarinic and adrenergic receptors, especially in ME/CFS patients that have POTS, OH or Sjogren's.

 

[leokitten]

The most interesting remarks I found in this paper are these:

Similar to our findings, in most other diseases autoantibodies are found in only a subset of patients with a wide overlap of levels in patients and controls.

This, of course, does not exclude other autoantibodies (not investigated in the present study) with functional activity in CFS.

There is evidence that a subset of patients experienced major distressing life events before CFS onset and that CFS is frequently triggered by an infection. Thus it is tempting to speculate that chronic adrenergic stimulation may lead to conformational changes of receptors resulting in more immunogenic epitopes and that infection-triggered immune activation induces the autoantibody response.

The main reservation I had at first about this study is that yet again they only find a possible biomarker in a subset of less than 50% of patients. But the authors show us that even in clearly defined autoimmune diseases we only find autoantibodies in a subset and levels do overlap controls.

This study is also beginning to shed light as to why non-responders aren't responding, that it likely isn't because they have a completely different pathophysiology (e.g. chronic infection) but that rituximab treatment did not effectively reduce autoantibody levels.

This paper is a good first step towards biomarker discovery working on Fluge/Mella's theory and samples from their rituximab trials, bravo. I know I've said it a million times, but my opinion as a scientist is that we desperately need a lot more research in this area. I think the major American research groups need to take note that they are spending zero resources on studying the autoimmune pathophysiology of ME/CFS and this theory is not only the quickest and most promising path to effective treatment but also the quickest path to validation that this is a real disease. We patients need this.

The chronic infection theory, in my personal opinion, if it even pans out at all, will only be relevant for a small subset and one could argue that this subset isn't really even ME/CFS, it's an infection by a particular pathogen (e.g. Lyme, Chagas, etc). As we have seen in so many examples, post-Ebola, post-polio, post-sepsis, West Nile induced myasthenia gravis, likely many cases of post-Lyme, and more, that the infection isn't there anymore but it helped to trigger a disease that's now completely driven by the immune system. This is fundamentally different than having a chronic infection and therefore a different disease. Also, when one does pick up infections or has reactivations after their immune system goes into this autoimmune and dysfunctional state we need to make clear that while this does contribute to symptoms it most certainly isn't part of the core pathophysiology of the disease.

It's the immune system, stupid.

 

[lansbergen]

It's the immune system, stupid.

Of course it is. That is almost always the case but that does not rule out chronic infection. .

 

[leokitten]

Of course it is. That is almost always the case but that does not rule out chronic infection. .

No I disagree it's totally different, one is a disease where there is no actual infection and autoimmunity and/or other immune dysfunction are completely driving the disease and the other is a pathogen solely causing and driving the disease and continuously infecting the host which can over time evade and suppress the immune system.

These are two completely different diseases with different pathologies and most importantly completely different treatments.

 

[lansbergen]

No I disagree it's totally different, one is a disease where there is no actual infection and autoimmunity and/or other immune dysfunction are completely driving the disease and the other is a pathogen solely causing and driving the disease and continuously infecting the host which can over time evade and suppress the immune system.

These are two completely different diseases with different pathologies and most importantly completely different treatments.

Why can it not be a chronic infection for which the immune system respones with autoantibodies?

 

[leokitten]

Why can it not be a chronic infection for which the immune system respones with autoantibodies?

This has never been found in any other autoimmune disease. Infections do coexist with and are interrelated to autoimmune disease but for the reasons I've described above not due to the mechanism you describe.

My main point is that instead of all the major American groups spending virtually 100% of resources on the chronic infection theory without any regard for autoimmunity they really need pay attention more to what the Norwegians/Germans/UK groups are doing. These groups are going to get somewhere with this disease.

 

[lansbergen]

This has never been found in any other autoimmune disease. Infections do coexist with and are interrelated to autoimmune disease but for the reasons I've described above not due to the mechanism you describe.

My main point is that instead of all the major American groups spending virtually 100% of resources on the chronic infection theory without any regard for autoimmunity they really need pay attention more to what the Norwegians/Germans/UK groups are doing. These groups are going to get somewhere with this disease.

I am not impresssed.by your arguments.

 

[Hip]

I agree that much more research should be done on the possible autoimmune aspects of ME/CFS. Even if the suspected autoimmunity in ME/CFS is caused by chronic enteroviral infection, if we don't presently have any good antivirals for enterovirus, then we may get better treatment results by tackling autoimmunity by for example rituximab-type approaches, rather than tackling the underlying chronic viral infections.

Any disease involves a long chain of cause-and-effect links that ultimately precipitate and maintain the disease. Whatever link in the chain you can break using current medical technology, doing so will likely help fight disease. And if you can break more than one link in the disease's causal chain, so much the better.


Increased research focus on possible autoimmune mechanisms in ME/CFS should not involve throwing out viral research. In fact, I'd like to see the infectious and autoimmune aspects of ME/CFS synthesized into one grand unifying theory of ME/CFS, not put at odds with each other.

Chronic enterovirus infection can affect several important immune organs in the body, and in addition can cause immune dysfunction by its viral immune evasion tactics. This may conceivably set the stage for the triggering of autoimmunity.

For example, enterovirus infection of the thymus gland, an important immune organ, is being investigated as a factor involved in the precipitation of the autoimmunity in type 1 diabetes. See also: An Enterovirus Attacking the Thymus May Play a Key Role in Triggering Type 1 Diabetes.

Enterovirus infection of the spleen, another important immune organ, has been shown to dramatically alter dendritic cell function, again this may set the stage for immune dysfunction.

Enteroviruses can also directly infect and destroy dendritic cells, which may impede regulation of immune responses.

This has never been found in any other autoimmune disease.

A link between chronic enterovirus infection and the autoimmune disorder of type 1 diabetes certainly has been found in numerous studies, but proving a casual connection of course is much harder to do.

There is also a link between the autoimmune disorder systemic lupus erythematosus and parvovirus B19.

 

[Snow Leopard]

Guys, it's best to take this discussion back to the main thread:

http://forums.phoenixrising.me/index.php?threads/antibodies-to-ß-adrenergic-and-muscarinic-cholinergic-receptors-in-patients-with-cfs.40109