Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

“…Endothelial dysfunction may result from endothelial β2 receptor attenuation due to chronic sympathetic overstimulation or from abnormal GPCR signaling affecting vascular autoregulation ( Wirth and Scheibenbogen, 2020 ). Many ME/CFS patients have aAB against vasoregulatory GPCR ( Tanaka et al, 2003 ; Loebel et al, 2016 ; Freitag et al, 2021 ). Theoretically, the immune or inflammatory effects of exercise could either aggravate GPCR dysfunction directly or stimulate aAB-production and thus indirectly provoke endothelial dysfunction after exercise.…”

“…aAB against G protein coupled receptors (GPCR) in ME/CFS patients are typically directed against angiotensin type 1 receptors (AT1R), endothelin-1 B receptors (ET1BR), and adrenergic and muscarinic acetylcholine receptors ( Freitag et al, 2021 ), which is reminiscent of the findings in many PASC patients ( Wallukat et al, 2021 ). In ME/CFS, the aAB levels generally correlate with disease severity ( Freitag et al, 2021 ).…”

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

“…Indeed, all of the aabs correlated with ME/CFS so far have been shown to possibly correspond to antigens with functional significance in the CNS. This is true, for instance, for adrenergic receptor aabs which are nowhere more densely packed than in the CNS but also for the aabs against endothelin-1-and angiotension-1-receptors recently identified by Freitag et al 255 The latter two aabs apparently correlate well with both "central" clinical manifestations of ME/CFS like fatigue and cognitive functioning but also with disease severity, global disability and exertion induced symptoms. Also, unlike adrenergic and muscarinergic aabs, these aabs may correlate with disease severity also in the subset of ME/CFS patients with gradual onset.…”

“…In several studies autoantibodies against GPC receptors have been found at increased levels in a subset of ME/CFS patient. 3,255 Unfortunately, the origin, relevance and role of the autoantibodies found in ME/CFS so far remains to be established (if only for the reason that only a limited range of autoantibodies has been investigated in ME/CFS as of yet). After all, such autoantibodies may also be part of the physiologic regulatory repertoire of humans, raising the question if the elevated levels of GPCR autoantibodies found in ME/CFS may be just reflections of an activated tolerance process or part of a preexisting immune signature conferring susceptibility to the development of ME/CFS in some subjects.…”

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach

“…Dyspnea, shortness of breath, and chest pain are frequent symptoms of the post-COVID syndrome (PCS) [ 1 , 2 , 3 ]. Recent studies in PCS suggest that there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which in the majority of patients may be a post-infectious disease, mostly after viral infections [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Both syndromes present with a confusing variety of symptoms with mental and muscular fatigue, cognitive impairment, exertion intolerance with post-exertional malaise (PEM), chronic muscle pain, and headaches, as described for ME/CFS [ 11 ].…”