chondroitin-sulfates and Multiple-Sclerosis

It remains uncertain how brain glycosaminoglycans (GAGs) contribute to the progression of inflammatory disorders like multiple sclerosis (MS). We investigated here neuroinflammation-mediated changes in GAG composition and metabolism using the mouse model of experimental autoimmune encephalomyelitis (EAE) and sham-immunized mice as controls. Cerebellum, mid- and forebrain at different EAE phases were investigated using gene expression analysis (microarray and RT-qPCR) as well as HPLC quantification of CS and hyaluronic acid (HA). The cerebellum was the most affected brain region showing a downregulation of Bcan, Cspg5, and an upregulation of Dse, Gusb, Hexb, Dcn and Has2 at peak EAE. Upregulation of genes involved in GAG degradation as well as synthesis of HA and decorin persisted from onset to peak, and diminished at remission, suggesting a severity-related decrease in CS and increments in HA. Relative disaccharide quantification confirmed a 3.6 % reduction of CS-4S at peak and a normalization during remission, while HA increased in both phases by 26.1 % and 17.6 %, respectively. Early inflammatory processes led to altered GAG metabolism in early EAE stages and subsequent partially reversible changes in CS-4S and in HA. Targeting early modifications in CS could potentially mitigate progression of EAE/MS.

Topics: Animals; Chondroitin Sulfates; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Glycosaminoglycans; Hyaluronic Acid; Mice; Multiple Sclerosis

The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.. APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.. APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.. Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.

Topics: Adult; Aged; Animals; Astrocytes; B-Cell Activating Factor; Cell Proliferation; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Immunohistochemistry; Interleukin-10; Macrophages; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Tumor Necrosis Factor Ligand Superfamily Member 13

Chondroitin sulfate proteoglycans (CSPGs) are a constituent of the matrix of the central nervous system (CNS), likely participating as regulatory molecules in the process of demyelination, remyelination, axonal degeneration and regeneration in the CNS. ChGn-1 is a key enzyme for production of CSPGs and knock-out mice of this gene showed better recovery from spinal cord injury. We hypothesized that the clinical course of multiple sclerosis (MS) is influenced by the level of expression of ChGn-1 gene. We recruited 147 patients with MS and 181 healthy control subjects and analyzed single nucleotide polymorphisms (SNPs) of this gene. We found the coding SNP (cSNP: rs140161612) in approximately 10% of patients with MS as well as normal controls. The cSNP is changed from serine to leucine at position 126 (p.S126L). The expressed ChGn-1 mutant proteins exhibited no enzyme activities in COS-1 cells. In men, patients who had MS with S126L had a slower disease progression. This cSNP might be associated with the sex differences in clinical course of MS.

Topics: Adolescent; Adult; Aged; Animals; Case-Control Studies; Chlorocebus aethiops; Chondroitin Sulfates; COS Cells; Disease Progression; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Multiple Sclerosis; Mutation, Missense; N-Acetylgalactosaminyltransferases; Polymorphism, Single Nucleotide; Recurrence; Sex Factors; Young Adult

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS.

Topics: Animals; Antigens; Axons; Biocompatible Materials; Cell Differentiation; Chondroitin Sulfates; Cytokines; Drug Delivery Systems; Gold; Leukemia Inhibitory Factor; Lysophosphatidylcholines; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Multiple Sclerosis; Myelin Sheath; Nanoparticles; Neural Stem Cells; Oligodendroglia; Proteoglycans; Rats; Rats, Sprague-Dawley

Chondroitin sulfate proteoglycans (CSPGs) are the main component of the extracellular matrix in the central nervous system (CNS) and influence neuroplasticity. Although CSPG is considered an inhibitory factor for nerve repair in spinal cord injury, it is unclear whether CSPG influences the pathogenetic mechanisms of neuroimmunological diseases. We induced experimental autoimmune encephalomyelitis (EAE) in chondroitin 6-O-sulfate transferase 1-deficient (C6st1(-/-)) mice. C6ST1 is the enzyme that transfers sulfate residues to position 6 of N-acetylgalactosamine in the sugar chain of CSPG. The phenotypes of EAE in C6st1(-/-) mice were more severe than those in wild-type (WT) mice were. In adoptive-transfer EAE, in which antigen-reactive T cells from WT mice were transferred to C6st1(-/-) and WT mice, phenotypes were significantly more severe in C6st1(-/-) than in WT mice. The recall response of antigen-reactive T cells was not significantly different among the groups. Furthermore, the number of pathogenic T cells within the CNS was also not considerably different. When EAE was induced in C6ST1 transgenic mice with C6ST1 overexpression, the mice showed considerably milder symptoms compared with those in WT mice. In conclusion, the presence of sulfate at position 6 of N-acetylgalactosamine of CSPG may influence the effecter phase of EAE to prevent the progression of pathogenesis. Thus, modification of the carbohydrate residue of CSPG may be a novel therapeutic strategy for neuroimmunological diseases such as multiple sclerosis.

Topics: Acetylglucosamine; Animals; Carbohydrate Sulfotransferases; Chondroitin Sulfates; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation, Enzymologic; Mice; Mice, Knockout; Multiple Sclerosis; Sulfotransferases; T-Lymphocytes

46-year-old woman developed painful ulcers over her lower abdomen in the form of reticulate erythema after injecting interferon beta-1b subcutaneously for multiple sclerosis. Skin biopsy revealed multiple superficial thrombosed vessels with focal epidermal necrosis as well as prominent interstitial mucinosis. Treatment with low-molecular-weight heparin followed by a heparinoid resulted in slow healing of the ulcers but also allowed the subcutaneous interferon injections to be continued.

Topics: Abdominal Wall; Adjuvants, Immunologic; Chondroitin Sulfates; Dermatan Sulfate; Enoxaparin; Female; Fibrinolytic Agents; Heparitin Sulfate; Humans; Injections, Subcutaneous; Interferon beta-1b; Interferon-beta; Middle Aged; Mucinoses; Multiple Sclerosis; Thrombosis; Treatment Outcome; Ulcer

Anti-chondroitin sulfates (ChSs) antibodies have been reported in neuropathy and neurodegenerative diseases. Differences in specificities may account for their association with different diseases. Sera from 303 neurological patients were tested for antibodies to ChSs A, B, C. Titers >/=51,200 were found in 16 patients (eight peripheral neuropathy, three motor neuron disease, four multiple sclerosis, one myelitis). Three patients also had anti-sulfatides antibodies, which in two cases cross-reacted with ChSs. By indirect immunofluorescence, positive sera stained nuclei on normal human peripheral nerve sections. These findings indicate that human anti-ChSs antibodies are broadly reactive and not specific to any neurological disease.

Topics: Absorption; Antibodies; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immune Sera; Motor Neuron Disease; Multiple Sclerosis; Myelitis; Nervous System Diseases; Statistics as Topic; Sulfoglycosphingolipids