IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS

pattismith

Senior Member
Messages
3,651
Likes
7,168
Brain, Behavior, & Immunity - Health
Available online 5 February 2020, 100047


IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS

Author links open overlay panelJelkaHartwiga1FranziskaSotznya1SandraBaueraHaraldHeideckebGabrielaRiemekastencDuskaDragundChristianMeiselaClaudiaDamesaPatriciaGrabowskiaCarmenScheibenbogenae
Show more
https://doi.org/10.1016/j.bbih.2020.100047Get rights and content
Under a Creative Commons license
open access

Highlights


IgG physiologically stimulates β2 AdR signaling.

β2 AdR activation by IgG is attenuated in ME/CFS patients.

First evidence that IgG from ME/CFS patients differentially modulates β2 AdR ligand signaling.

Abstract
Background
There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.


Methods
We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function in vitro. 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AABhigh) and 5 with normal levels (CFS AABnorm) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation in vitro was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.


Results
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect.

The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice.

In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes.

Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28.

IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect.


We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.

Conclusions
We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.
 

Gingergrrl

Senior Member
Messages
16,064
Likes
47,375
@pattismith I'm not sure if I understand this study or if it is similar to another study that you posted a few weeks ago? Are they saying that IVIG reduced beta-adrenergic autoantibodies in ME/CFS patients (or is this not remotely what they are saying)? I wish I was better at understanding all of these studies :bang-head: :xpem:
 

pattismith

Senior Member
Messages
3,651
Likes
7,168
@pattismith I'm not sure if I understand this study or if it is similar to another study that you posted a few weeks ago? Are they saying that IVIG reduced beta-adrenergic autoantibodies in ME/CFS patients (or is this not remotely what they are saying)? I wish I was better at understanding all of these studies :bang-head: :xpem:
no, it's not an IVIG study, but I have some difficulties to understand it myself, so will hardly explain it!

What I understand: they identified some ME patients with high beta2 adrenergic antibody titers, and they took their plasma to test for their ability to activate beta2 cell receptors, and they found no effect.
(Beta2 adrenergic antibodies are supposed to have immune modulation effect)
The thing is that they don't explain why this effect is blunt in these patients, so we can just open the field of questions it raises:

-could it be that these beta2 antibodies are different from the others and may block receptors instead of activating them?

-could it be that another antibody in the plasma is blocking them or is blocking beta2 receptors?

Another study was just published about the beta2 receptors and immunomodulation, showing that beta2 activation is immunosuppressive (below).

Considering that ME patients with high Beta2 titers doesn't show activation of their beta2 receptors, it could be a protective mechanism against infections, and may explain why some patients doesn't catch any cold/flu:


β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection

Elisabeth Wieduwild ... Sophie Ugolini February 11 2020

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.
 

necessary8

Senior Member
Messages
121
Likes
422
I'll ELI5 it for people I guess:
1. There is a subgroup of CFS patients who have autoantibodies to beta2 adrenergic receptors and muscarinic receptors, which are two types of GPCRs. It's about 30% of patients. This is not new, we knew this for a long time.
2. There is new research showing that in healthy people there are "good" autoantibodies which modulate GPCRs.
3. This study shows that in this subset of CFS that I mentioned in point 1, the autoantibodies fail to activate the relevant GPCRs like they do in healthy people.

It's a nice study. Not sure how important in the grand scheme of things. But it's good to have it.
 

pattismith

Senior Member
Messages
3,651
Likes
7,168
I'll ELI5 it for people I guess:
1. There is a subgroup of CFS patients who have autoantibodies to beta2 adrenergic receptors and muscarinic receptors, which are two types of GPCRs. It's about 30% of patients. This is not new, we knew this for a long time.
2. There is new research showing that in healthy people there are "good" autoantibodies which modulate GPCRs.
3. This study shows that in this subset of CFS that I mentioned in point 1, the autoantibodies fail to activate the relevant GPCRs like they do in healthy people.

It's a nice study. Not sure how important in the grand scheme of things. But it's good to have it.
it's important to note that they didn't test the beta2A antibodies but the whole IgG fraction from these patients. It's not exactly the same I think, and they paid a special attention not jumping on the conclusion you mentioned in your point 3.
 

necessary8

Senior Member
Messages
121
Likes
422
it's important to note that they didn't test the beta2A antibodies but the whole IgG fraction from these patients. It's not exactly the same I think, and they paid a special attention not jumping on the conclusion you mentioned in your point 3.
Good point about the whole IgG fraction, but I can't find any part that would contradict my third point. They outright say:
Our data provides evidence that IgG physiologically stimulates the β2 AdR and that this function is attenuated in ME/CFS patients.
Now, I agree that we don't specifically know why its attenuated, there might be multiple mechanisms for it. But it is attenuated. Maybe that's what you meant as well, and we just chose different phrasing.