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Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 39716Article in journal (Refereed) Published
Abstract [en]

This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

Place, publisher, year, edition, pages
2017. Vol. 7, article id 39716
National Category
Medical and Health Sciences Neurology
Research subject
Immunology; Neurology
Identifiers
URN: urn:nbn:se:uu:diva-314679DOI: 10.1038/srep39716ISI: 000391148300002PubMedID: 28045063OAI: oai:DiVA.org:uu-314679DiVA, id: diva2:1071417
Funder
Swedish Research Council, 2014-02048Swedish Research Council, 2014-07603Swedish Society of Medicine, SLS-499271Futurum - Academy for Health and Care, Jönköping County Council, Sweden, 520281Available from: 2017-02-04 Created: 2017-02-04 Last updated: 2018-08-01Bibliographically approved
In thesis
1. New Biomarkers for Neuromuscular Function and Myasthenia Gravis
Open this publication in new window or tab >>New Biomarkers for Neuromuscular Function and Myasthenia Gravis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myasthenia gravis (MG) is an autoimmune disorder, which is caused by autoantibodies against the acetylcholine receptor (AChR). The cardinal symptom is muscle fatigue, which can range from slight weakness of the extraocular muscles (causing droopy eyelids or double vision), to paralysis of the respiratory muscles. Antibodies towards other muscle proteins have been discovered, and MG is now considered a very heterogeneous disease with several subgroups. The severity of symptoms in MG patients is often fluctuating, and the antibody titers do not correlate with disease severity or treatment response. Therefore, there is a great need for reliable biomarkers in MG, both for assessing neuromuscular function, but also for clinical aspects such as disease progression and subgrouping.

In Study I, the use of compound motor action potential (CMAP) as a biomarker for muscle status was examined in trained and untrained individuals. We found that trained individuals have a higher CMAP in proximal muscles, and the CMAP value in the biceps correlate with muscle strength in these individuals, indicating that CMAP can be used as a biomarker for muscle function. In Study II, subjects from study I were examined with ultrasound to assess the effect of high-resistance strength training (HRST) on peripheral nerves, and to compare muscle thickness. We did not find a difference in nerve cross-sectional area between the two groups. Trained individuals had thicker biceps muscles. The results from study I and II has led to CMAP and ultrasound being used to evaluate the result of physical exercise as an intervention in MG patients.

In Study III, the expression of inflammatory proteins in the sera of MG patients was compared to healthy controls, in search for possible biomarkers. We found eleven proteins to be elevated, which provide new insight to the inflammatory response in MG and have possible functions as new biomarkers of inflammatory activity.

In Study IV, the effect of thymectomy on the potential microRNA MG biomarkers miR-150-5p and miR-21-5p was examined. A decrease in miR-150-5p was seen 24 months after thymectomy, which further validate the use of miR-150-5p as a disease-specific biomarker for clinical outcome in AChR positive MG patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 84
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1480
Keywords
Biomarkers, myasthenia gravis, neuromuscular function, neurophysiology
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-356116 (URN)978-91-513-0390-1 (ISBN)
Public defence
2018-09-21, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-08-31 Created: 2018-08-01 Last updated: 2018-09-10

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