Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?

Brian DellaValle*, Alba Manresa-Arraut, Henrik Hasseldam, Allan Stensballe, Jørgen Rungby, Agnete Larsen, Casper Hempel

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

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    Abstract

    Introduction: Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS.
    Methods: Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.
    Results: All animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.
    Discussion: In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.
    Original languageEnglish
    Article number1254
    JournalFrontiers in Immunology
    Volume9
    Number of pages9
    ISSN1664-3224
    DOIs
    Publication statusPublished - 2018

    Keywords

    • Glycocalyx
    • Multiple sclerosis
    • Precision medicine
    • Biomarkers
    • Glycosaminoglycans
    • Proteoglycans
    • EAE
    • BBB

    Cite this

    DellaValle, B., Manresa-Arraut, A., Hasseldam, H., Stensballe, A., Rungby, J., Larsen, A., & Hempel, C. (2018). Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers? Frontiers in Immunology, 9, [1254]. https://doi.org/10.3389/fimmu.2018.01254
    DellaValle, Brian ; Manresa-Arraut, Alba ; Hasseldam, Henrik ; Stensballe, Allan ; Rungby, Jørgen ; Larsen, Agnete ; Hempel, Casper. / Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?. In: Frontiers in Immunology. 2018 ; Vol. 9.
    @article{3e45006a3af1413b825ef50066b8b941,
    title = "Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?",
    abstract = "Introduction: Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS.Methods: Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.Results: All animals receiving EAE emulsion developed fulminant EAE (100{\%} penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.Discussion: In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.",
    keywords = "Glycocalyx, Multiple sclerosis, Precision medicine, Biomarkers, Glycosaminoglycans, Proteoglycans, EAE, BBB",
    author = "Brian DellaValle and Alba Manresa-Arraut and Henrik Hasseldam and Allan Stensballe and J{\o}rgen Rungby and Agnete Larsen and Casper Hempel",
    year = "2018",
    doi = "10.3389/fimmu.2018.01254",
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    DellaValle, B, Manresa-Arraut, A, Hasseldam, H, Stensballe, A, Rungby, J, Larsen, A & Hempel, C 2018, 'Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?', Frontiers in Immunology, vol. 9, 1254. https://doi.org/10.3389/fimmu.2018.01254

    Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers? / DellaValle, Brian; Manresa-Arraut, Alba; Hasseldam, Henrik; Stensballe, Allan; Rungby, Jørgen; Larsen, Agnete; Hempel, Casper.

    In: Frontiers in Immunology, Vol. 9, 1254, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?

    AU - DellaValle, Brian

    AU - Manresa-Arraut, Alba

    AU - Hasseldam, Henrik

    AU - Stensballe, Allan

    AU - Rungby, Jørgen

    AU - Larsen, Agnete

    AU - Hempel, Casper

    PY - 2018

    Y1 - 2018

    N2 - Introduction: Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS.Methods: Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.Results: All animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.Discussion: In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.

    AB - Introduction: Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS.Methods: Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.Results: All animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.Discussion: In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.

    KW - Glycocalyx

    KW - Multiple sclerosis

    KW - Precision medicine

    KW - Biomarkers

    KW - Glycosaminoglycans

    KW - Proteoglycans

    KW - EAE

    KW - BBB

    U2 - 10.3389/fimmu.2018.01254

    DO - 10.3389/fimmu.2018.01254

    M3 - Journal article

    C2 - 29915593

    VL - 9

    JO - Frontiers in Immunology

    JF - Frontiers in Immunology

    SN - 1664-3224

    M1 - 1254

    ER -

    DellaValle B, Manresa-Arraut A, Hasseldam H, Stensballe A, Rungby J, Larsen A et al. Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers? Frontiers in Immunology. 2018;9. 1254. https://doi.org/10.3389/fimmu.2018.01254