myelin-oligodendrocyte-glycoprotein-(35-55) and Acute-Disease

Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3

Topics: Acute Disease; Animals; Arginase; Brain-Derived Neurotrophic Factor; Chronic Disease; Connexin 30; Connexin 43; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuroprotection; Peptide Fragments

AKT3, a member of the serine/threonine kinase AKT family, is involved in a variety of biologic processes. AKT3 is expressed in immune cells and is the major AKT isoform in the CNS representing 30% of the total AKT expressed in spinal cord, and 50% in the brain. Myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model in which lymphocytes and monocytes enter the CNS, resulting in inflammation, demyelination, and axonal injury. We hypothesized that during EAE, deletion of AKT3 would negatively affect the CNS of AKT3(-/-) mice, making them more susceptible to CNS damage. During acute EAE, AKT3(-/-)mice were more severely affected than wild type (WT) mice. Evaluation of spinal cords showed that during acute and chronic disease, AKT3(-/-) spinal cords had more demyelination compared with WT spinal cords. Quantitative RT-PCR determined higher levels of IL-2, IL-17, and IFN-γ mRNA in spinal cords from AKT3(-/-) mice than WT. Experiments using bone marrow chimeras demonstrated that AKT3(-/-) mice receiving AKT3-deficient bone marrow cells had elevated clinical scores relative to control WT mice reconstituted with WT cells, indicating that altered function of both CNS cells and bone marrow-derived immune cells contributed to the phenotype. Immunohistochemical analysis revealed decreased numbers of Foxp3(+) regulatory T cells in the spinal cord of AKT3(-/-) mice compared with WT mice, whereas in vitro suppression assays showed that AKT3-deficient Th cells were less susceptible to regulatory T cell-mediated suppression than their WT counterparts. These results indicate that AKT3 signaling contributes to the protection of mice against EAE.

Topics: Acute Disease; Animals; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Genetic Predisposition to Disease; Inflammation Mediators; Lumbosacral Region; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Proto-Oncogene Proteins c-akt; Severity of Illness Index; Signal Transduction; Spinal Cord

Ingested type I IFN and SIRS peptide administered orally inhibit EAE. We examined whether another immunoactive protein, tridecapeptide alpha-MSH, would have similar anti-inflammatory effects in EAE after oral administration. B6 mice were immunized with MOG peptide 35-55 and gavaged with 0.1 ml of control saline or alpha-MSH peptide starting on day -7 preceding active immunization, and continuing through day +14 post-immunization. Alpha-MSH peptide delayed disease onset and decreased inflammatory foci. CNS lymphocytes showed decreases in Th1-like encephalitogenic cytokines IL-2 and IL12p70 in the alpha-MSH fed group compared to the mock fed group. For Th2-like counter-regulatory cytokines, there were increases in peripheral SDF-1 levels comparing alpha-MSH fed vs mock fed groups. There were decreases of chemokines MIP-1-alpha and MIP-1-gamma in the CNS comparing alpha-MSH fed mice vs mock fed mice. Ingested (orally administered) alpha-MSH peptide can reduce clinical disease and inhibit CNS inflammation by decreasing migration of antigen driven CNS Th1 cells into the target organ.

Topics: Acute Disease; Administration, Oral; alpha-MSH; Animals; Anti-Inflammatory Agents; Chemokines; Encephalomyelitis, Autoimmune, Experimental; Female; Glycoproteins; Interferon-gamma; Interleukin-12; Interleukin-2; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments

Experimental autoimmune encephalomyelitis (EAE) is a Tcell-mediated autoimmune disease of the CNS that is widely used as an animal model of multiple sclerosis. In this study, we investigate the role of CXCL13, a chemokine involved in the development and organization of secondary lymphoid tissues, in the pathogenesis of EAE. We detected CXCL13 mRNA and protein in spinal cords of mice with EAE. CXCL13-deficient mice exhibited a mild, self-limited form of disease. CXCL13 appeared to be important for the establishment of chronic white matter lesions. Furthermore, adoptive transfer experiments with CXCL13-deficient hosts indicate that the chemokine plays a distinct role during the effector phase. Our findings raise the possibility that reagents that antagonize or inhibit CXCL13 might be useful for the treatment of neuroinflammatory diseases such as multiple sclerosis.

Topics: Acute Disease; Amino Acid Sequence; Animals; Cell Movement; Cells, Cultured; Chemokine CXCL13; Chemokines, CXC; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Glycoproteins; Immunity, Active; Leukocytes, Mononuclear; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Receptors, Chemokine; Receptors, CXCR5; Receptors, Cytokine; Recurrence; RNA, Messenger; Spinal Cord; T-Lymphocyte Subsets

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. It also has been identified in constituents of the immune system. Therefore serotonin has been suggested to serve as a mediator of bidirectional interactions between the nervous system and the immune system. We investigated this interaction in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system (CNS) mimicking features of the human disease multiple sclerosis. EAE was induced by immunization with the autoantigens myelin basic protein (MBP) or the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) spanning amino acids 35-55 (MOGp 35-55). We studied EAE in knockout (KO) mice lacking the 5-HT transporter (5-HTT) on a C57.BL/6 background, in comparison with wild-type C57.BL/6 animals. After immunization with MOGp 35-55, or with rat MBP, the disease courses of the 5-HTT knockout mice were attenuated as compared to wildtype control mice. This difference was more pronounced in female animals. To dissect potential immune mechanisms underlying this phenomenon, histological studies of the CNS and cytokine measurements in mononuclear cells from the spleens of 5-HTT KO mice and wild-type controls were performed. We found a reduction of the inflammatory infiltrate in the CNS and of the neuroantigen-specific production of IFN-gamma in splenocytes, again accompanied by a gender difference. These findings suggest a potential role of extracellular 5-HT homeostasis in the fine-tuning of neuroantigen-specific immune responses.

Topics: Acute Disease; Animals; Autoantigens; Cell Division; Central Nervous System; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Glycoproteins; Immunohistochemistry; Interferon-gamma; Interleukins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Rats; Serotonin; Sex Factors; T-Lymphocytes

The scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (SR-PSOX)/CXCL16 is a chemokine expressed on macrophages and dendritic cells, while its receptor expresses on T and NK T cells. We investigated the role of SR-PSOX/CXCL16 on acute and adoptive experimental autoimmune encephalomyelitis (EAE), which is Th1-polarized T cell-mediated autoimmune disease of the CNS. Administration of mAb against SR-PSOX/CXCL16 around the primary immunization decreased disease incidence of acute EAE with associated reduced infiltration of mononuclear cells into the CNS. Its administration was also shown to inhibit elevation of serum IFN-gamma level at primary immune response, as well as subsequent generation of Ag-specific T cells. In adoptive transfer EAE, treatment of recipient mice with anti-SR-PSOX/CXCL16 mAb also induced not only decreased clinical disease incidence, but also diminished traffic of mononuclear cells into the CNS. In addition, histopathological analyses showed that clinical development of EAE correlates well with expression of SR-PSOX/CXCL16 in the CNS. All the results show that SR-PSOX/CXCL16 plays important roles in EAE by supporting generation of Ag-specific T cells, as well as recruitment of inflammatory mononuclear cells into the CNS.

Topics: Acute Disease; Adoptive Transfer; Amino Acid Sequence; Animals; Antibodies, Monoclonal; Chemokine CXCL16; Chemokine CXCL6; Chemokines, CXC; Chemotaxis, Leukocyte; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Glycoproteins; Immunization; Inflammation; Lipoproteins, LDL; Membrane Proteins; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phosphatidylserines; Receptors, Immunologic; Receptors, Scavenger; Spinal Cord; T-Lymphocyte Subsets