myelin-oligodendrocyte-glycoprotein-(35-55) and Multiple-Sclerosis--Chronic-Progressive

Topics: Amino Acid Sequence; Amyloid; Amyloidogenic Proteins; Animals; B-Lymphocytes; Benzothiazoles; Callithrix; Cell Line; Citrullination; Dendritic Cells; Herpesvirus 4, Human; Humans; Mice, Inbred C57BL; Multiple Sclerosis, Chronic Progressive; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Aggregation, Pathological; Recombinant Proteins; T-Lymphocytes

Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration.. Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls.. EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules.. These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS.

Topics: Adult; Animals; Cohort Studies; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enhancer of Zeste Homolog 2 Protein; Female; Freund's Adjuvant; Humans; Leukocytes, Mononuclear; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Proto-Oncogene Proteins c-vav; T-Lymphocyte Subsets; Talin; Young Adult

To characterize T cell and antibody responses in remitting-relapsing experimental autoimmune encephalomyelitis (RR-EAE), we compared myelin oligodendrocyte glycoprotein (MOG)-induced RR-EAE in C57BL/6 (B6) x SJL (F1) mice and chronic-progressive EAE (CP-EAE) in B6 mice at week 8 p.i. when clinical scores were comparable. Although these two strains exhibited similar inflammation/demyelination pattern and MOG-induced T cell responses, RR-EAE mice produced significantly higher levels of anti-MOG IgG1/IgG2a antibodies. Further, lymphocytes of RR-EAE mice proliferated vigorously to the secondary epitope myelin basic protein (MBP) 1-11. These results support a potential involvement of anti-MOG antibodies and epitope spreading in T cell responses in the development of MOG-induced RR-EAE model.

Topics: Analysis of Variance; Animals; Antibodies; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glycoproteins; Histological Techniques; Immunization; Immunoglobulin G; Lymphocyte Activation; Mice; Mice, Inbred Strains; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Spinal Cord; T-Lymphocytes; Time Factors