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Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients - A validation study in plasma and cerebrospinal fluid from two Swedish cohorts.

ABSTRACT: Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated. This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity. We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls. All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1-5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity. Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

SUBMITTER: Bynke A

PROVIDER: S-EPMC8474431 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Recent efforts have described an immunogenic component to the pathobiology of Alzheimer's disease (AD) and Parkinson's disease (PD). However, current methods of studying fluid autoantibodies, such as enzyme-linked immunosorbent assays and immunohistochemistry, are hypothesis-driven and not optimal for discovering new autoantibody biomarkers by proteome-wide screening. Recently, we developed a general mass spectrometry-based approach to identify tissue-specific autoantibodies in serum, at a proteome-wide level. In this study, we adapted the method to explore novel autoantibody biomarkers in the cerebrospinal fluid (CSF) of AD and PD patients. Methods: CSF samples were obtained from 10 headache control individuals, 10 AD patients and 10 PD patients. Antibodies present in the CSF were isolated by immobilization to protein-G magnetic beads. These antibodies were incubated with a brain tissue extract, prepared from frontal cortex, pons, cerebellum and brain stem. Protein antigens captured by the protein-G magnetic bead-bound antibodies were digested with trypsin and analyzed using mass spectrometry. Autoantibody candidates were selected by 1) detection in one or less individuals of the control group and 2) identification in at least half of the patient groups. Results: There were 16 putative autoantibody biomarkers selected from the AD group. Glia-derived nexin autoantibody was detected in eight of ten AD patients and was absent in the control group. Other AD pathology-related targets were also identified, such as actin-interaction protein, quinone oxidoreductase, sushi repeat-containing protein, metalloproteinase inhibitor 2, IP3 receptor 1 and sarcoplasmic/endoplasmic reticulum calcium ATPase 2. An additional eleven autoantibody targets were also identified in the present experiment, although their link to AD is not clear. No autoantibodies in the PD group satisfied our selection criteria. Conclusion: Our unbiased mass spectrometry method was able to detect new putative CSF autoantibody biomarkers of AD. Further investigation into the involvement of humoral autoimmunity in AD and PD pathobiology may be warranted.

Project description:BackgroundThe recent report of gammaretroviruses of probable murine origin in humans, called xenotropic murine retrovirus related virus (XMRV) and human murine leukemia virus related virus (HMRV), necessitated a bioinformatic search for this virus in genomes of the mouse and other vertebrates, and by PCR in humans.ResultsThree major groups of murine endogenous gammaretroviruses were identified. The third group encompassed both exogenous and endogenous Murine Leukemia Viruses (MLVs), and most XMRV/HMRV sequences reported from patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two sensitive real-time PCRs for this group were developed. The predicted and observed amplification range for these and three published XMRV/HMRV PCRs demonstrated conspicuous differences between some of them, partly explainable by a recombinatorial origin of XMRV. Three reverse transcription real-time PCRs (RTQPCRs), directed against conserved and not overlapping stretches of env, gag and integrase (INT) sequences of XMRV/HMRV were used on human samples. White blood cells from 78 patients suffering from ME/CFS, of which 30 patients also fulfilled the diagnostic criteria for fibromyalgia (ME/CFS/FM) and in 7 patients with fibromyalgia (FM) only, all from the Gothenburg area of Sweden. As controls we analyzed 168 sera from Uppsala blood donors. We controlled for presence and amplifiability of nucleic acid and for mouse DNA contamination. To score as positive, a sample had to react with several of the XMRV/HMRV PCRs. None of the samples gave PCR reactions which fulfilled the positivity criteria.ConclusionsXMRV/HMRV like proviruses occur in the third murine gammaretrovirus group, characterized here. PCRs developed by us, and others, approximately cover this group, except for the INT RTQPCR, which is rather strictly XMRV specific. Using such PCRs, XMRV/HMRV could not be detected in PBMC and plasma samples from Swedish patients suffering from ME/CFS/FM, and in sera from Swedish blood donors.

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Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients - A validation study in plasma and cerebrospinal fluid from two Swedish cohorts.

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