title: A complex role of herpes viruses in the disease process of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Neither the antigenic target(s) nor the cell population(s) responsible for CNS tissue destruction in MS have been fully defined. The objective of this study was to simultaneously determine the antigen (Ag)-specificity and phenotype of un-manipulated intrathecal CD4+ and CD8+ T cells of patients with relapsing-remitting and progressive MS compared to subjects with other inflammatory neurological diseases. We applied a novel Ag-recognition assay based on co-cultures of freshly obtained cerebrospinal fluid T cells and autologous dendritic cells pre-loaded with complex candidate Ag's. We observed comparably low T cell responses to complex auto-Ag's including human myelin, brain homogenate, and cell lysates of apoptotically modified oligodendroglial and neuronal cells in all cohorts and both compartments. Conversely, we detected a strong intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific (but not cytomegalovirus-specific) reactivities of the Th1-phenotype throughout all patients. Qualitatively, the intrathecal enrichment of herpes virus reactivities was more pronounced in MS patients. This enrichment was completely reversed by long-term treatment with the IL-2 modulating antibody daclizumab, which strongly inhibits MS disease activity. Finally, we observed a striking discrepancy between diminished intrathecal T cell proliferation and enhanced cytokine production of herpes virus-specific T cells among progressive MS patients, consistent with the phenotype of terminally differentiated cells. The data suggest that intrathecal administration of novel therapeutic agents targeting immune cells outside of the proliferation cycle may be necessary to effectively eliminate intrathecal inflammation in progressive MS.
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Simone C
authors.initials: SC
authors.lastname: Wuest
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ina
authors.initials: I
authors.lastname: Mexhitaj
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Noo Ri
authors.initials: NR
authors.lastname: Chai
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Romm
authors.affiliation: Molecular Immunology Section, Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joerg
authors.initials: J
authors.lastname: Scheffel
authors.affiliation: Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Biying
authors.initials: B
authors.lastname: Xu
authors.affiliation: Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lane
authors.affiliation: Clinical Neurosciences Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000956:Antigens, Viral / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D000077561:Daclizumab; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006564:Herpesviridae / Q000276:immunology; D006566:Herpesviridae Infections / Q000150:complications* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000209:etiology*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000956:Antigens, Viral; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000077561:Daclizumab