Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms

Alexander, J. Steven; Zivadinov, Robert; Maghzi, Amir Hadi; Ganta, Vijay Chaitanya; Harris, Meghan; Minagar, Alireza

doi:10.1016/j.pathophys.2010.04.002

Cited by 33 publications

(31 citation statements)

References 67 publications

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“…3 summarizes IgM serological results obtained in ELISA for all of the compounds analyzed. All compounds presented lower mean values for NBD than for MS populations, except ursolic acid (6). This result highlighted the important role of the glycosylation for specific MS antibody recognition.…”

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confidence: 77%

“…The calculated Spearman r values for compounds 1-4 to the glucopeptide CSF114(Glc) range from 0.499-0.742, demonstrating a good correlation of antibody reactivities (calculated p values < 0.05, two-tailed Spearman Fig. 1 Structure of the triterpene glycosides (1)(2)(3)(4)(5) and ursolic acid (6). test).…”

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confidence: 96%

“…In particular, in the context of multiple sclerosis (MS), the development of serum antibodies as biomarkers to be used for the diagnosis, monitoring, and prognosis of such a heterogeneous disease is a challenge because of the ambiguous identification of antigens (Ags) implicated in the disease. MS pathogenesis has not been yet elucidated but includes viral, immunological, and vascular hypotheses [6]. Most of the putative Ags belong to the myelin protein family (i.e., myelin basic protein, proteolipid lipoprotein, and myelin oligodendrocyte glycoprotein).…”

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confidence: 99%

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Natural Triterpene Glycosides for Antibody Recognition

et al. 2016

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!Multiple sclerosis is an autoimmune disease that affects the central nervous system. The key role of the glycosylation in disease pathogenesis has been previously studied and the synthetic Nglucosylated peptide CSF114(Glc) proved its efficiency in autoantibody recognition in the sera of multiple sclerosis patients. Herein, pure natural triterpene glycosides containing different glycosyl moieties were isolated and tested in multiple sclerosis patientsʼ sera to better understand the role of glycosylation. They were selected taking into account the nature and complexity of their osidic part. Five triterpene glycosides were isolated from several plants with more than 95% purity. The interaction between these glycosides and autoantibodies was evaluated in an enzyme-linked immunosorbent assay measuring IgG and IgM levels in multiple sclerosis patients and healthy blood donors, and the results were compared with those of CSF114(Glc). For each antigen, Mann Whitney and receiver operating characteristic-based analysis were performed to evaluate any statistical significance of the results. The five natural triterpene glycosides showed good capacity to recognize IgMs (sensitivity up to 38 %) with a high specificity (88.9%) for multiple sclerosis patients.Key words multiple sclerosis · triterpene glycosides · autoimmune disease · biomarkers · autoantibody recognition Supporting information available online at http://www.thieme-connect.de/products Complex glycoconjugates, including glycolipids and glycoproteins, are commonly displayed on cell surfaces, where they play crucial roles as intermediaries in extracellular communication and signalling networks [1][2][3]. Therefore, studies on glycan modification patterns of glycoconjugates are a great challenge in medical diagnostic research, offering insight into cellular molecular mechanisms. Moreover, glycoconjugates can be proposed as molecular biomarkers for the disease activity [4,5]. In the field of autoimmunity, different approaches are used to investigate the structures and functions of complex naturally occurring glycoconjugates leading to the identification of autoantigens associated with different autoimmune diseases. In particular, in the context of multiple sclerosis (MS), the development of serum antibodies as biomarkers to be used for the diagnosis, monitoring, and prognosis of such a heterogeneous disease is a challenge because of the ambiguous identification of antigens (Ags) implicated in the disease. MS pathogenesis has not been yet elucidated but includes viral, immunological, and vascular hypotheses [6]. Most of the putative Ags belong to the myelin protein family (i.e., myelin basic protein, proteolipid lipoprotein, and myelin oligodendrocyte glycoprotein). Moreover, pathophysiological post-translational modifications of native Ags can trigger the immune system to generate autoantibodies escaping conventional diagnostic procedures [7]. Thus, autoantibodies against aberrant glycosylations have been hypothesized as diagnostic biomarkers in MS [8,9]. I...

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Natural Triterpene Glycosides for Antibody Recognition

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“…MS patients clearly have an increased prevalence of vascular risk factors (also a function of age), such as reduced physical activity [48], high levels of homocysteine [49,50] and smoking [47] and an increased risk of ischaemic stroke [51,52] and venous thromboembolism [51]. Histopathological similarities have been highlighted comparing the so-called type 3 MS white matter lesions [53,54] (characterized by selective loss of myelin-associated glycoprotein [MAG] and apoptotic-like oligodendrocyte changes) to acute white matter stroke [55] and likely endothelial dysfunction [56]. It has been hypothesized that the thrombotic manifestations in MS patients may be part of the activation of innate immunity [57,58], linking together these two pathological aspects of the disease.…”

Section: Pathological Mechanisms Underlying Disease Progressionmentioning

confidence: 99%

Secondary Progressive Multiple Sclerosis: Definition and Measurement

et al. 2016

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Secondary progressive multiple sclerosis (SPMS) is diagnosed retrospectively and involves a clinical course characterized by a progressive accumulation of neurological disability, independent of relapses, following an initial relapsing-remitting (RR) phase. Our incomplete understanding of the pathological mechanisms underlying neurodegeneration in multiple sclerosis (MS) may explain why, to date, there is no definitive imaging or laboratory test that is able to inform us when the disease is clearly entering into a progressive phase and why the vast majority of clinical trials testing immunosuppressant and immunomodulating drugs in SPMS patients has so far yielded disappointing or mixed results. Here we discuss the definition(s) of SPMS and how it may vary, outcome measurements (current and emerging) and modern trial design.

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“…MS is associated with signifi cant cerebral vascular endothelial cell dysfunction (26)(27)(28)(29). In atherosclerosis, HDL-C plays an important protective role in the immune cellvascular endothelial interactions that mediate lesion formation.…”

Section: Associations Of Csf Variables With Mrimentioning

confidence: 99%

Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients

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et al. 2015

Journal of Lipid Research

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Blood-brain barrier (BBB) injury creates a permissive environment for infl ammation and the extravasation of immune cells ( 1 ) in multiple sclerosis (MS), a chronic infl ammatory and neurodegenerative disease of the CNS ( 2 ). Compromised BBB structural integrity is necessary for the formation of contrast-enhancing lesions (CELs), which are frequently found on brain MRI from MS patients, even in the absence of clinical relapses. CELs represent focal areas with compromised BBB structural integrity and are associated with parenchymal and meningeal infl ammation ( 3 ). Increased BBB water permeability precedes the appearance of CELs and is pervasive in normal-appearing white matter ( 4 ).In CNS regions with loss of BBB structural integrity, there is increased permeability to macromolecules such as proteins, albumin, and immunoglobulins, that are normally Abstract The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS infl ammation following the fi rst clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon ␤ 1-a treatment following the fi rst demyelinating event. Blood and cerebrospinal fl uid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profi le and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P Յ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ ( P < 0.001) and with CSF CD80+CD19+ ( P = 0.007) cell frequencies. Higher serum HDL is associated

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Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms

Cited by 33 publications

References 67 publications

Natural Triterpene Glycosides for Antibody Recognition

Natural Triterpene Glycosides for Antibody Recognition

Secondary Progressive Multiple Sclerosis: Definition and Measurement

Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients

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