Autoantibodies to vasoregulative G-Protein-Coupled receptors correlate with symptom severity, autonomic dysfunction and disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Helma Freitag, Marvin Szklarski, Sebastian Lorenz, Franziska Sotzny, Sandra Bauer, Aurélie Philippe, Claudia Kedor, Patricia Grabowski, Tanja Lange, Gabriela Riemekasten, Harald Heidecke and Carmen Scheibenbogen in J. Clin. Med. 2021, 10(16), 3675; 19 August 2021  (This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)


Research abstract:


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential role of natural regulatory autoantibodies (AAB) to beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS patients comes from a few studies.


Here, we analyzed the correlations of symptom severity with levels of AAB to vasoregulative AdR, AChR and Endothelin-1 type A and B (ETA/B) and Angiotensin II type 1 (AT1) receptor in a Berlin cohort of ME/CFS patients (n = 116) by ELISA. The severity of disease, symptoms and autonomic dysfunction were assessed by questionnaires.


We found levels of most AABs significantly correlated with key symptoms of fatigue and muscle pain in patients with infection-triggered onset. The severity of cognitive impairment correlated with AT1-R- and ETA-R-AAB and severity of gastrointestinal symptoms with alpha1/2-AdR-AAB. In contrast, the patients with non-infection-triggered ME/CFS showed fewer and other correlations.


Correlations of specific AAB against G-protein-coupled receptors (GPCR) with symptoms provide evidence for a role of these AAB or respective receptor pathways in disease pathomechanism.

Excerpts from: 4. Discussion

There is increasing evidence for a role of vascular dysfunction in ME/CFS that shows associations with key symptoms [11]. In this study, we found several remarkable correlations of vasoregulative AAB with clinical symptoms in ME/CFS.

In conclusion, our study provides evidence that AAB and/or the receptor pathways of AdR, AChR as well as AT1-R and ET-R play a role in ME/CFS due to the association with symptom severity. Thus, it is conceivable that various symptoms of ME/CFS, including fatigue, muscle pain, cognitive impairment and autonomic dysregulation, could be mediated or aggravated by these AAB.

Further studies are required to decipher the mechanism and binding specificity of these GPCR-AAB, and their effect of on vascular function in ME/CFS, and how this may be translated into therapeutic concepts. In the case of dysfunctional AAB, therapies targeting AAB, such as immunoadsorption or rituximab, would be warranted and were shown to be effective in a subset of ME/CFS patients (reviewed in [5]).

Further specific targeting of dysfunctional or regulative AAB may be developed as treatment strategies in ME/CFS.

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