I ask this question after reading this absolutely brilliant article:
Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome
There is a high prevelence between Myalgic enecephalomyelitis (ME) and Postural Orthostatic Tachycardia Syndrome (POTS). Both diseases are of unknown ethiology.
Lipid rafts are microdomains in the cell membrane. These domains are centers for signal transduction, membrane traffiking and regulation of neurotransmission.
Caveolae is a special type of lipid raft, especially found in endothelial cells and adipocytes.
Ganglioside is a molecule composed of a glycosphingolipid and is found in the lipid rafts.
Signal transduction at the cellular level refers to any process by which a cell converts one kind of signal or stimulus into another.
The article give us the information that cardiac lipid raft associated proteins can be a target of autoimmunoreactive IgGs. I suppose lipid raft associated proteins from other tissues also can be a target of autoimmunoreactive IgGs?
Could ME be an autoimmune attack on lipid raft associated proteins after an infection? Are lipid raft associated proteins the target for microorganisms and molecular mimicry? Well, microorganisms do seem to like lipid rafts:
Host-cell lipid rafts: a safe door for micro-organisms?
Viruses, lipid rafts and signal transduction
Epstein-Barr virus LMP1 modulates lipid raft microdomains and the vimentin cytoskeleton for signal transduction and transformation
Guillain-Barré syndrome (GBS) has been connected to Camphylobacter infection. Gangliosides are found in the perifere nerves. GBS paitents have autoantibodies against GM1 ganglioside (GM1). Research strongly suggest that anti-GM1 antibodies directly influence the integrity of the signaling platform, lipid rafts, implicating the importance of lipid rafts in the development of this disorder. Reference: Anti-GM1 antibodies affect the integrity of lipid rafts and this article in Norwegian.
Lipid rafts seem to be involved everywhere:
B-cell antigen receptor acts during B-cell activation both to initiate signalling cascades and to transport antigen into the cell for subsequent processing and presentation and that Lipid rafts and B-cell activation are connected.
Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus
"Something" in the Dorsal Root Ganglion (DRG) is often the subject for ME pathology speculations. Are lipid rafts (proteins?) in DRG target for autoimmunity in ME?
ME is connected to "something with somatosensory perception, neuroplasticity, neuropeptides", and then there is my favorite subject Transient Receptor Potential ion channels. Is there a connection between these buzz-words and lipid rafts?
Yes, I found some exciting articles:
Somatosensory scaffolding structures: "Dynamic changes in somatosensory perception occur as a result of multiple signaling events. In many instances, over-activation of sensory receptors results in the desensitization and subsequent increased threshold for activation of receptors. In other cases, receptor sensitization can occur following tissue injury and/or inflammation. In both cases, signaling mechanisms that control alterations in receptor activities can significantly affect organism response to sensory stimuli, including thermal, mechanical, and chemical."
"Lipid rafts centralize signal transduction through certain receptors, including the μ-opioid receptor (MOR), TRPM8 and TRPV1, via their intracellular association with microdomains concentrated in cholesterol and sphingolipids." (TRPs are found in the trigeminale and dorsale root ganglion.)
A study found autoantibodies against μ-opioid receptor in 15.2% of the CFS patients, and there is Decreased Central-Opioid Receptor Availability in Fibromyalgia.
Here is a review highlighting the importance of lipid rafts for synaptic function and plasticity, as well as their relevance for age or disease-related cognitive impairment.
Do we have a hypothesis? An insult (virus, chemicals, trauma, stress) to the immune systeme triggers an autoimmune repsonse to lipid raft associated proteins in the body - especially in the dorsal root ganglion. Signal transduction get disturbed. TRP channels and other receptors (P2X, G protein coupled receptors....) become dysfunctional. Sound, light, odours are no longer tolerated - something goes bad with neuroplasticity...what about pain and fatigue and μ-opioid receptors...and all the affected receptors we don´t even know....and we need to look into leaky gut and lipd rafts ....further speculations are needed...
...and money for the Rituximab study, MEandYOU:
Im not sure the paper was brilliant - the cohort of patients is only ten for a start and their previous paper included patients with profound orthostatic hypotension, excluding them from the diagnosis of POTS according to the recent consensus statement.SvarSlet
Will be interesting to see if they can employ the same technique to examine adrenergic locations since these mechanisms appear closely linked with the etiology of orthostatic intolerance.
Personally I think evidence has always suggested that CFS/Fibro/POTS and OI syndromes in general are autoimmune in a large portion of patients has been strong; female/male ratio, acute onset after stressor, etc.
Hi FollowMEinDenmark, may I first congratulate you on your excellent blog. I enjoyed reading it, and your past posts.SvarSlet
Yes, this Wang et al paper you refer to is very interesting, the Immune system is likely attacking cardiac tissue which would explain non coronary artery disease chest pain (vasospastic angina), and fluctuating symptoms not associated to postural change and not caused by low blood pressure which many physicians are puzzled by or simply don't believe.
There are other papers in the past showing autoimmunity in POTS and CFS, involving both Ganglionic and Muscaranic antibodies detected in blood. (NB: Not the same 'muscle' acethylcholine antibodies as Myasthenia Gravis). The autoantibodies in ME & CFS effect the autonomic and sympathetic nervous system, both which are deranged in CFS (ME) and POTS.
I would keep a keen eye on PrPC, Endogenous retroviruses and ME and see if you can gather more information on this from your own keen eye.
Prion PrpC in ME (normal prion protein) activity is likely altered through the effects of monoclonal antibodies. Rituximab is a monoclonal antibody depletor of CD20 on B cells.
I think we will find this is why Rituximab 'works' for ME symptoms. Rituximab is likely negatively affecting prion production, which talk to T cells and which talk to B cells. Therefore Rituximab is affecting T cell function, through the effects of B cells, through the administration of a monoclonal antibody drug.
What we need to find out is how to control the cross talk of viruses and PrpC first. Rituximab, although proving the 'cause' (inadvertently, as B cells aren't 'the cause'), is not a realistic long term drug solution.
Getting the unique inflammatory process in ME causing the oxidative stress down in ME patients is the primary goal for future ME research. Inflammation drive by infection. If we can do that, we won't have to use Rituximab at all.
Thank you very much for your comment. I agree, we need to find the cause of the inflammation and better treatment than Rituximab. And I will be very busy the next days reading about PrPc, endogenous retrovirus and lipid rafts. Until a few hours ago, I didn't know anything about prions, but I am learning... :-))Slet