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

Discussion in 'Latest ME/CFS Research' started by snowathlete, Sep 25, 2015.

  1. snowathlete

    snowathlete

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    Loebel, Grabowski, Heidecke, Bauer, Hanitsch, Wittke, Meisel, Reinke, Volk, Fluge Ø, Mella, Scheibenbogen.

    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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  2. Simon

    Simon

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    Note interesting Rituximab connection where elevated autoantibodies at baseline are normalised after treatment for rituximab responders .

    Thanks, @snowathlete

    Broken into paragraphs here to help my fuzzy brain - plus 'highlights'

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

    Highlights
    • β adrenergic and muscarinic acetylcholine receptor autoantibodies are elevated in a subset of patients with Chronic Fatigue Syndrome (CFS).

    • Elevated autoantibodies in CFS correlate with elevated IgG1-3 subclass levels, thyreoperoxidase and ANA antibodies and T cell activation.

    • In CFS patients responding to rituximab treatment, elevated antibody levels detected pre-treatment normalized in the majority of clinical responders post-treatment.


    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.

    Method
    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 [G-protein coupled receptors] 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).

    Results

    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 treatmen
    t 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.

    One for @Jonathan Edwards?
     
    Last edited: Sep 25, 2015
    Wayne, MEMum, SDSue and 18 others like this.
  3. Gijs

    Gijs Senior Member

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    Especially patiënts with POTS/ME will have this problem. I Always have suspected this. This is a breakthrough for a subgroup.
     
  4. Effi

    Effi Senior Member

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    Simon likes this.
  5. Scarecrow

    Scarecrow Revolting Peasant

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    Does the (much) higher than 29.5% response rate in the Phase II trials indicate that there may be more, yet to be discovered, autoantibodies in the other responders?
     
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  6. snowathlete

    snowathlete

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    They're certainly looking in the right place and its a sizeable sample which is good. Would seem to predict half of those who respond to rituximab and suggests more to find in this area to figure out who else will respond. And of course it could significantly focus research efforts into mechanisms, and subsequently causes.
    Look forward to what Prof Edwards makes of it.
     
  7. A.B.

    A.B. Senior Member

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    What are the symptoms typically attributed to β adrenergic and muscarinic acetylcholine receptor autoantibodies?
     
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  8. Sidereal

    Sidereal Senior Member

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    Problems with regulation of vascular tone and heart rate.
     
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  9. ukxmrv

    ukxmrv Senior Member

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    or of POTS maybe?

    "Epinephrine (adrenaline) reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoreceptors because there are more peripheral α1 receptors than β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, producing vasodilation followed by decrease of peripheral vascular resistance."

    https://en.wikipedia.org/wiki/Adrenergic_receptor
     
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  10. Sidereal

    Sidereal Senior Member

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    From the discussion:

     
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  11. A.B.

    A.B. Senior Member

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    MeSci, Never Give Up and Valentijn like this.
  12. Marco

    Marco Grrrrrrr!

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    This is from a blog I wrote on complex regional pain syndrome :

    Read more: From Chronic Regional Pain Syndrome to Fibromyalgia to ME/CFS? The ‘Spreading Neuroinflammation’ Model http://www.cortjohnson.org/blog/201...lgia-mecfs-spreading-neuroinflammation-model/

    These things seem to get around!
     
  13. msf

    msf Senior Member

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    Is this the first evidence we have for how Ritux may be working?
     
  14. msf

    msf Senior Member

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  15. Sidereal

    Sidereal Senior Member

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    They're not antibodies to the same muscarinic receptor. The Japanese study you linked found antibodies to M1 whereas this German/Norwegian collaboration found antibodies to M3 and M4. The Japanese study is cited in their paper.
     
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  16. msf

    msf Senior Member

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    I didn´t say they were...haha, just kidding, I didn´t notice that, thanks for pointing it out.
     
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  17. A.B.

    A.B. Senior Member

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    I find it interesting that the B2 and M3 receptors are involved in insulin release and energy production. This might explain the difficulties that patients tend to have in regulating their blood sugar despite the absence of an identifiable endocrine disease.
     
  18. greeneagledown

    greeneagledown Senior Member

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  19. Rooney

    Rooney Senior Member

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    While I have POTS, I have only had REDUCED IgG subclasses, so I imagine I would be a non-responder.
    Is this a correct interpretation?

    Wow, what an exciting morning!
     
  20. ukxmrv

    ukxmrv Senior Member

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    Would IVIG or steroids (like Predislone) be useful against the antibodies?
     

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