myelin-oligodendrocyte-glycoprotein-(35-55) and Encephalitis

Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

Topics: Animals; Antigens, CD; Central Nervous System; Dendritic Cells; Disease Models, Animal; Encephalitis; Green Fluorescent Proteins; Homeodomain Proteins; Lymph Nodes; Lymphatic Vessels; Male; Meninges; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Photosensitizing Agents; Receptors, CCR7; Spleen; T-Lymphocytes; Tumor Suppressor Proteins

Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently described a model combining noninflammatory cytodegeneration (via cuprizone) with the classic active experimental autoimmune encephalomyelitis (Cup/EAE model), which exhibits inflammatory forebrain lesions. Here, we describe the histopathological characteristics and progression of these Cup/EAE lesions. We show that inflammatory lesions develop at various topographical sites in the forebrain, including white matter tracts and cortical and subcortical grey matter areas. The lesions are characterized by focal demyelination, discontinuation of the perivascular glia limitans, focal axonal damage, and neutrophil granulocyte extravasation. Transgenic mice with enhanced green fluorescent protein-expressing microglia and red fluorescent protein-expressing monocytes reveal that both myeloid cell populations contribute to forebrain inflammatory infiltrates. EAE-triggered inflammatory cerebellar lesions were augmented in mice pre-intoxicated with cuprizone. Gene expression studies suggest roles of the chemokines Cxcl10, Ccl2, and Ccl3 in inflammatory lesion formation. Finally, follow-up experiments in Cup/EAE mice with chronic disease revealed that forebrain, but not spinal cord, lesions undergo spontaneous reorganization and repair. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.

Topics: Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Disease Progression; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Gene Expression; Glial Fibrillary Acidic Protein; Intercellular Adhesion Molecule-1; Luminescent Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Monocytes; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Receptors, CCR2; Receptors, Interleukin-8A; Sesquiterpenes

Month-season of birth (M-SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M-SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M-SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M-SOB with the lowest birth rate were less susceptible to EAE than mice born during the M-SOB with the highest birth rate. We also show that the M-SOB effect on EAE susceptibility is associated with differential production of multiple cytokines/chemokines by neuroantigen-specific T cells that are known to play a role in EAE pathogenesis. Taken together, these results support the existence of an M-SOB effect that may reflect seasonally dependent developmental differences in adaptive immune responses to self-antigens independent of external stimuli, including exposure to sunlight and vitamin D. Moreover, our documentation of an M-SOB effect on EAE susceptibility in mice allows for modeling and detailed analysis of mechanisms that underlie the M-SOB effect in not only MS but in numerous other diseases in which M-SOB impacts susceptibility.-Reynolds, J. D., Case, L. K., Krementsov, D. N., Raza, A., Bartiss, R., Teuscher, C. Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.

Topics: Animals; Birth Rate; Disease Models, Animal; Disease Susceptibility; Encephalitis; Hashimoto Disease; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Retrospective Studies; Risk Factors; Seasons

Multiple Sclerosis, a chronic inflammatory demyelinating disease of the central nervous system, involves an increased expression of monocyte chemotactic protein 1 MCP1-/CCL2. For exerting its chemotactic effects, chemokine binding to glycosaminoglycans (GAGs) is required and therefore this interaction represents a potential target for therapeutic intervention. We have designed an anti-inflammatory decoy variant, Met-CCL2 (Y13A S21K Q23R), embodying increased affinity for GAGs as well as knocked-out GPCR activation properties. This non-signalling dominant-negative mutant is shown here to be able to displace wild type CCL2 from GAGs by which it is supposed to interfere with the chemokine-related inflammatory response. In vivo, the anti-inflammatory properties were successfully demonstrated in a murine model of zymosan-induced peritonitis as well as in an experimental autoimmune encephalomyelitis, a model relevant for multiple sclerosis, where the compound lead to significantly reduced clinical scores due to reduction of cellular infiltrates and demyelination in spinal cord and cerebellum. These findings indicate a promising potential for future therapeutic development.

Topics: Animals; Anti-Inflammatory Agents; Cerebellum; Chemokine CCL2; Dexamethasone; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Glycosaminoglycans; Inhibitory Concentration 50; Male; Mice; Mice, Inbred C57BL; Monocytes; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Peritonitis; Spinal Cord; Zymosan

Cortical lesions are a crucial part of MS pathology and it is critical to determine that new MS therapies have the ability to alter cortical inflammatory lesions given the differences between white and gray matter lesions. We tested lipoic acid (LA) in a mouse focal cortical EAE model. Brain sections were stained with antibodies against CD4, CD11b and galectin-3. Compared with vehicle, treatment with LA significantly decreased CD4+ and galectin-3+ immune cells in the brain. LA treated mice had fewer galectin-3+ cells with no projections indicating decrease in the number of infiltrating monocytes. LA significantly reduces inflammation in a focal cortical model of MS.

Topics: Animals; Antioxidants; CD11b Antigen; Cerebral Cortex; Cytokines; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Galectin 3; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Statistics, Nonparametric; Thioctic Acid; Time Factors

We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, an established model of chronic multiple sclerosis. To investigate phenotypic perturbations in neurons in this model, we used apoptotic markers and immunohistochemistry with antibodies to NeuN and other surrogate markers known to be expressed by adult pyramidal Layer V somas, including annexin V, encephalopsin, and Emx1. We found no consistent evidence of chronic loss of Layer V neurons but detected both reversible and chronic decreases in the expression of these markers in conjunction with evidence of cortical demyelination and presynaptic loss. These phenotypic perturbations were present in, but not restricted to, the neocortical Layer V. We also investigated inflammatory responses in the cortex and subcortical white matter of the corpus callosum and spinal dorsal funiculus and found that those in the cortex and corpus callosum were delayed compared with those in the spinal cord. Inflammatory infiltrates initially included T cells, neutrophils, and Iba1-positive microglia/macrophages in the corpus callosum, whereas only Iba1-positive cells were present in the cortex. These data indicate that we have identified a new temporal pattern of subtle phenotypic perturbations in neocortical neurons in this chronic multiple sclerosis model.

Topics: Animals; Caspase 3; Cell Death; Disease Models, Animal; Encephalitis; Freund's Adjuvant; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Motor Neurons; Multiple Sclerosis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neocortex; Peptide Fragments; Phosphopyruvate Hydratase; Synaptophysin; Time Factors

The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-κB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking.. The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS.. We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development.. Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.

Topics: Animals; Antigens, CD; Caspases; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Follow-Up Studies; Lymphocyte Activation; Mice; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neoplasm Proteins; NF-kappa B; Peptide Fragments; Phenothiazines; Spinal Cord; T-Lymphocytes

Fetal neural stem/precursor cells (NPCs) possess powerful immunomodulatory properties which enable them to protect the brain from immune-mediated injury. A major issue in developing neural stem/precursor cell (NPC) therapy for chronic neuroinflammatory disorders such as multiple sclerosis is whether cells maintain their immune-regulatory properties for prolonged periods of time. Therefore, we studied time-associated changes in NPC immunomodulatory properties. We examined whether intracerebrally-transplanted NPCs are able to inhibit early versus delayed induction of autoimmune brain inflammation and whether allogeneic NPC grafts continuously inhibit host rejection responses. In two experimental designs, intraventricular fetal NPC grafts attenuated clinically and pathologically brain inflammation during early EAE relapse but failed to inhibit the disease relapse if induced at a delayed time point. In correlation, long-term cultured neural precursors lost their capacity to inhibit immune cell proliferation in vitro. Loss of NPC immune functions was associated with transition into a quiescent undifferentiated state. Also, allogeneic fetal NPC grafts elicited a strong immune reaction of T cell and microglial infiltration and were rejected from the host brain. We conclude that long-term functional changes in transplanted neural precursor cells lead to loss of their therapeutic immune-regulatory properties, and render allogeneic grafts vulnerable to immunologic rejection. Thus, the immunomodulatory effects of neural precursor cell transplantation are limited in time.

Topics: Adrenergic Agents; Animals; Cell Proliferation; Corpus Striatum; Cytokines; Disease Models, Animal; Embryo, Mammalian; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Glial Fibrillary Acidic Protein; Graft Rejection; Graft Survival; Green Fluorescent Proteins; Interferon-gamma; Lymphocytes; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Myelin-Oligodendrocyte Glycoprotein; Neural Stem Cells; Neurotoxicity Syndromes; Oxidopamine; Peptide Fragments; Pregnancy; Stem Cell Transplantation; Time Factors

Oxidized phospholipids (Ox-PLs) are generated in abundance at sites of inflammation. Recent studies have indicated that Ox-PLs may also exhibit anti-inflammatory activities. In this study, we investigated the beneficial effect of VB-201, a pure synthetic Ox-PL analog that we synthesized, on the development of a central nervous system (CNS) autoimmune inflammatory disease, in vivo. Oral administration of VB-201 ameliorated the severity of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide MOG35-55, and restrained the encephalogenicity of MOG35-55-specific T-cells. Our data presents a novel prospect for the role of Ox-PL analogs in CNS inflammatory diseases.

Topics: Animals; Bone Marrow Cells; Bromodeoxyuridine; CD4 Antigens; Cell Differentiation; Central Nervous System; Cytokines; Dendritic Cells; Disease Models, Animal; Drug Interactions; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Forkhead Transcription Factors; Freund's Adjuvant; Glycerylphosphorylcholine; Glycoproteins; Ionomycin; Ionophores; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Pertussis Toxin; Phosphorylcholine; Polymethacrylic Acids; Severity of Illness Index; T-Lymphocytes; Time Factors