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Immunopathology of multiple sclerosis
Calliope A.Dendrou1, Lars Fugger1,2 and Manuel A.Friese3
Abstract | Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine,
John Radcliffe Hospital, University of Oxford,
Oxford OX3 9DS, UK.
Clinical Institute,
Aarhus University Hospital, DK8200 Aarhus, Denmark.
Institut fr Neuroimmunologie und Multiple Sklerose, Zentrum fr Molekulare Neurobiologie Hamburg, Universittsklinikum HamburgEppendorf, 20246 Hamburg, Germany. Correspondence to L.F. email: mailto:lars.fugger%40imm.ox.ac.uk?subject=
Web End [email protected] doi:10.1038/nri3871 Published online 7 August 2015
Approximately 2.5 million people worldwide are afflicted with multiple sclerosis, a chronic neuroinflammatory disease of the brain and spinal cord that is a common cause of serious physical disability in young adults1,
especially women. Multiple sclerosis poses a major personal and socioeconomic burden: the average age of disease onset is 30years a time that is decisive for work and family planning and 25years after diagnosis, approximately 50% of patients require permanent use of a wheelchair. The condition has a heterogeneous presentation (BOX1) that can include sensory and visual disturbances, motor impairments, fatigue, pain and cognitive deficits1. The variation in clinical manifestations correlates with the spatiotemporal dissemination of lesional sites of pathology within the central nervous system (CNS)2. These lesions are a hallmark of multiple sclerosis (BOX2) and are caused by immune cell infiltration across the bloodbrain barrier (BBB) that promotes inflammation, demyelination, gliosis and neuroaxonal degeneration, leading to disruption of neuronal signalling3. Tcells appear early in lesion formation, and the disease is considered to be autoimmune, initiated by autoreactive lymphocytes that mount aberrant responses against CNS autoantigens, the precise nature of which, however, remains enigmatic.
Infiltration of immune cells...