Characterization of residue-specific glutathionylation of CSF proteins in multiple sclerosis – A MS-based approach (original) (raw)
Related papers
Autoimmunity, 2018
During NET formation, the content of neutrophils granules is released into the intercellular milieu. Consisting of many proteases and ROS species, formed NETs were shown to degrade cytokines (Schauer, Nat Med, 2014); while the content of neutrophil's azurophilic granules proved to contain glycosidases, secreted upon activation (Thaysen-Andersen, JBC, 2015), and formation of autoantibodies to neutrophil beta-glucoronidase was connected with the level of anti-MPO antibodies (Ab) (Martensson, Autoimmunity, 1992). Taking into account these facts, we aimed to investigate the possibility of NETrelated changes in glycan composition on circulating IgG molecules and IgG-IgM immune complexes in multiple sclerosis (MS). This autoimmune disorder still has no reliable detection markers or established ways of treatment, besides widely accepted interferon therapy, making it a particularly interesting clinical condition. By applying capture lectin-ELISA, we analysed binding of a2,6 sialyl-specific lectins SNA, PSqL, and core a1,6-fucose specific lectin AAL to circulating IgG and related complexes in five groups of MS patients: untreated (17 persons); undergoing therapy with interferon (IFN) b-1 b (15 persons), corticosteroids (methylprednisolone) (12 persons) and anti-B-cell monoclonal Ab (12 persons: Ocrelizumab, 6 persons and alemtuzumab, 6 persons). A group of 23 healthy donors served as control. Significant increase in neutrophil elastase activity, observed in the group of patients under corticosteroid treatment was also accompanied by sialyl-specific PSqL and SNA lectin binding to captured IgG molecules. Subsequent analysis demonstrated that sialic acid residues were exposed on free IgG and on circulating IgG-IgM immune complexes. Increased lectin binding was not observed for anti-myelin basic protein (one of the major autoAb in MS) Ab compared to total serum Ab. IFN therapy was accompanied by low neutrophil elastase activity and low amount of circulating immune complexes. Incubation of in vitro generated NETs with human serum revealed the digestion of high-molecular weight immune complexes with subsequent exposure of hidden glycoepitops. Obtained data indicate the potential of neutrophil-derived proteases to modify (partially degrade) circulating immune complexes leading to exposure of internal glycoepitops.
Annals of Clinical and Translational Neurology, 2019
Objective: Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS. Methods: We combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load. Results: We identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell-related molecules, such as CXCL13, CXCL12, IL10, and BAFF. Interpretation: Intrathecal dysregulation of iron homeostasis and coagulation pathway as well as B-cell and monocyte activity are strictly correlated with cortical damage at early disease stages.
CSF Proteomics Identifies Specific and Shared Pathways for Multiple Sclerosis Clinical Subtypes
PLOS ONE, 2015
Multiple sclerosis (MS) is an immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) with a heterogeneous clinical presentation and course. There is a remarkable phenotypic heterogeneity in MS, and the molecular mechanisms underlying it remain unknown. We aimed to investigate further the etiopathogenesis related molecular pathways in subclinical types of MS using proteomic and bioinformatics approaches in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS (n=179). Comparison of disease groups with controls revealed a total of 151 proteins that are differentially expressed in clinically different MS subtypes. KEGG analysis using PANOGA tool revealed the disease related pathways including aldosterone-regulated sodium reabsorption (p=8.02x10 -5 ) which is important in the immune cell migration, renin-angiotensin (p=6.88x10 -5 ) system that induces Th17 dependent immunity, notch signaling (p=1.83x10 -10 ) pathway indicating the activated remyelination and vitamin digestion and absorption pathways (p=1.73x10 -5 ). An emerging theme from our studies is that whilst all MS clinical forms share common biological pathways, there are also clinical subtypes specific and pathophysiology related pathways which may have further therapeutic implications.
Glutathione in multiple sclerosis
British Journal of Biomedical Science, 2013
Introduction Multiple sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterised mainly as an autoimmune neurodegenerative disorder that affects the white matter with infiltration of macrophages and T cells. It causes demyelination, focal lesions with inflammation in various areas of brain and spinal cord, loss of oligodendrocytes, axonal damage and loss of neuronal function, although these processes are not present uniformly in all patients. It manifests clinically with impaired vision, dizziness, muscle fatigue, pain and sensory deficit. 1-9 The geographical distribution of MS reveals predominance in temperate climates, and its prevalence is 4-248 per 100,000, depending on the country. 2 It is estimated that about two million people suffer from MS. It usually begins in those in the 20-40 age group, becoming one of the main causes of disability in young adults, with women at twofold higher risk. 2,5,9 It is a multifactorial disease of unknown cause; however, some studies point to viruses (eg Epstein-Barr virus), toxins or other infectious agents, sun exposure, oxidative stress (OS), proinflammatory cytokines and/or autoimmune response. 2,5,6,9-12 It is also defined by a strong genetic and environmental predisposition, already known to have about 60 risk loci that predispose to disease susceptibility. 13 It has been shown that prognosis and degeneration in the longterm MS patient are genetically influenced by an inability to remove the toxic products of OS. 8,9,13 The diagnosis of MS is clinical and there are several forms of the disease. The most common is the relapsing remitting type (RR; 85%), which is considered a primary early-stage inflammatory disease. The most common symptoms include changes in vision, motor dysfunction and disturbances of urinary and bowel function. Symptoms improve after a few days or weeks, which is called remission. Over time, the recovery from symptoms occurs less frequently, and sometimes changes become permanent, with progression to the secondary progressive (SP) type of the disease. This is characterised by a decrease in inflammatory activity and subsequent brain atrophy due to progressive neuronal loss, seen on magnetic resonance imaging. 1,2,6,9 It is estimated that 90% of people with RR disease converted to the SP type after 20 years. 6 A more aggressive form of MS is the primary progressive (PP) type, which occurs in about 10% of patients. This is characterised by a progressive disability, without relapse or remission. Finally, there is the progressive relapsing (PR) type of MS, which shows continuous progression of disability, with occasional periods of relapse. 2 Thus, MS is characterised not only by inflammatory reactions mediated by the immune system but also by neurodegeneration. It is believed that the inflammatory focus is involved in the RR phase, whereas axonal loss and neurodegeneration are responsible for the progressive symptoms that are the leading cause of disability. 9
Trending Topics in Multiple Sclerosis, 2016
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a focus on inflammation, demyelination, and damage to axons leading to neurological deficits. MS pathology is associated with excessive reactive oxygen species (ROS) and generation of reactive nitrogen species (RNS), causing oxidative/nitrosative stress. Deregulation of glutathione homeostasis and alterations in glutathionedependent enzymes are implicated in MS. Reactive oxygen species enhance both monocyte adhesion and migration across brain endothelial cells. In addition, ROS can activate the expression of the nuclear transcription factor-kappa, which upregulates the expression of many genes involved in MS, such as tumor necrosis factor-α and nitric oxide synthase, among others, leading to mitochondrial dysfunction and energy deficits that result in mitochondrial and cellular calcium overload. Loss of mitochondrial membrane potential can increase the release of cytochrome c, one pathway that leads to neuronal apoptosis. Clinical studies suggest that omega-3 long-chain polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory, antioxidant, and neuroprotective effects in MS and animal models of MS. Here, we review the relationship of oxidative stress, the
Increase of CSF inflammatory profile in a case of highly active multiple sclerosis
BMC Neurology, 2019
Background Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. Case presentation We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory mol...
Scientific reports, 2015
Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal...
Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis
International Journal of Molecular Sciences
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future.
Glutathione in multiple sclerosis: More than just an antioxidant?
Multiple Sclerosis Journal, 2014
Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in multiple sclerosis (MS). In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS. In this review, we provide a comprehensive overview on GSH metabolism in brain cells, with a focus on its involvement in MS. The potential of GSH as an in vivo biomarker in MS is discussed, along with a short overview of improvements in imaging methods that allow non-invasive quantification of GSH in the brain. These methods might be instrumental in providing real-time measures of GSH, allowing the assessment of the oxidative state in MS patients and the monitoring of disease progression. Finally, the therapeutic potential of GSH in MS is discus...