The Immunopathology of Multiple Sclerosis: An Overview

Multiple sclerosis (MS) is traditionally seen as an inflammatory demyelinating disease, characterized by the formation of focal demyelinated plaques in the white matter of the central nervous system. In this review we describe recent evidence that the spectrum of MS pathology is much broader. This includes demyelination in the cortex and deep gray matter nuclei, as well as diffuse injury of the normal‐appearing white matter. The mechanisms responsible for the formation of focal lesions in different patients and in different stages of the disease as well as those involved in the induction of diffuse brain damage are complex and heterogeneous. This heterogeneity is reflected by different clinical manifestations of the disease, such as relapsing or progressive MS, and also explains at least in part the relation of MS to other inflammatory demyelinating diseases.

[1]  J. Charcot Leçons sur les Maladies Du Système Nerveux Faites à La Salpêtrière , 2009 .

[2]  D. Chari,et al.  Remyelination In Multiple Sclerosis , 2007, International Review of Neurobiology.

[3]  Hans Lassmann,et al.  Widespread Demyelination in the Cerebellar Cortex in Multiple Sclerosis , 2007, Brain pathology.

[4]  Hans Lassmann,et al.  Remyelination is extensive in a subset of multiple sclerosis patients. , 2006, Brain : a journal of neurology.

[5]  B. Engelhardt,et al.  Dysferlin Is a New Marker for Leaky Brain Blood Vessels in Multiple Sclerosis , 2006, Journal of neuropathology and experimental neurology.

[6]  Hans Lassmann,et al.  Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. , 2006, Brain : a journal of neurology.

[7]  W. Brück,et al.  A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. , 2006, Brain : a journal of neurology.

[8]  B. Cree Emerging Monoclonal Antibody Therapies for Multiple Sclerosis , 2006, The neurologist.

[9]  B. Weinshenker,et al.  Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. , 2006, Archives of neurology.

[10]  Hans Lassmann,et al.  Cortical demyelination in multiple sclerosis: A substrate for cognitive deficits? , 2006, Journal of the Neurological Sciences.

[11]  M. Krumbholz,et al.  B lineage cells in the inflammatory central nervous system environment: Migration, maintenance, local antibody production, and therapeutic modulation , 2006, Annals of neurology.

[12]  B. Weinshenker,et al.  Revised diagnostic criteria for neuromyelitis optica , 2006, Neurology.

[13]  E. Frohman,et al.  Multiple sclerosis--the plaque and its pathogenesis. , 2006, The New England journal of medicine.

[14]  S. Vukusic,et al.  Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis , 2006, Annals of neurology.

[15]  F. Aloisi,et al.  Lymphoid neogenesis in chronic inflammatory diseases , 2006, Nature Reviews Immunology.

[16]  R. Rudick,et al.  Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients , 2006, Annals of neurology.

[17]  P. Matthews,et al.  Demyelinated neocortical lesions in marmoset autoimmune encephalomyelitis mimic those in multiple sclerosis. , 2005, Brain : a journal of neurology.

[18]  Hans Lassmann,et al.  Cortical demyelination and diffuse white matter injury in multiple sclerosis. , 2005, Brain : a journal of neurology.

[19]  A. Verkman,et al.  The Journal of Experimental Medicine CORRESPONDENCE , 2005 .

[20]  B. Weinshenker,et al.  Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange , 2005, The Lancet.

[21]  L. Fugger,et al.  Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? , 2005, Brain : a journal of neurology.

[22]  Peter K. Stys,et al.  General mechanisms of axonal damage and its prevention , 2005, Journal of the Neurological Sciences.

[23]  Kenneth J. Smith,et al.  Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide , 2005, Brain : a journal of neurology.

[24]  S. Ludwin,et al.  Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis. , 2005, Brain : a journal of neurology.

[25]  L. Bö,et al.  The Pathology of Multiple Sclerosis Is Location-Dependent: No Significant Complement Activation Is Detected in Purely Cortical Lesions , 2005, Journal of neuropathology and experimental neurology.

[26]  M. Esiri,et al.  Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. , 2004, Brain : a journal of neurology.

[27]  J. Hallervorden Die zentralen Entmarkungskrankheiten , 1940, Deutsche Zeitschrift für Nervenheilkunde.

[28]  H. Waldmann,et al.  The window of therapeutic opportunity in multiple sclerosis , 2005, Journal of Neurology.

[29]  Ichiro Nakashima,et al.  A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis , 2004, The Lancet.

[30]  R. Hohlfeld,et al.  Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Lucchinetti,et al.  Evidence for pathogenic heterogeneity in multiple sclerosis , 2004, Annals of neurology.

[32]  B. Serafini,et al.  Detection of Ectopic B‐cell Follicles with Germinal Centers in the Meninges of Patients with Secondary Progressive Multiple Sclerosis , 2004, Brain pathology.

[33]  M. Barnett,et al.  Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion , 2004, Annals of neurology.

[34]  S. McQuaid,et al.  Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination , 2003, The Journal of pathology.

[35]  R. Reynolds,et al.  Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult , 2003, Brain pathology.

[36]  B D Trapp,et al.  Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration , 2003, Multiple sclerosis.

[37]  Frederik Barkhof,et al.  Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. , 2003, Archives of neurology.

[38]  B. Trapp,et al.  Subpial Demyelination in the Cerebral Cortex of Multiple Sclerosis Patients , 2003, Journal of neuropathology and experimental neurology.

[39]  L. Steinman,et al.  Diverse Targets for Intervention during Inflammatory and Neurodegenerative Phases of Multiple Sclerosis , 2003, Neuron.

[40]  P. Adeleine,et al.  Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. , 2003, Brain : a journal of neurology.

[41]  K. Jellinger,et al.  Preferential Loss of Myelin‐Associated Glycoprotein Reflects Hypoxia‐Like White Matter Damage in Stroke and Inflammatory Brain Diseases , 2003, Journal of neuropathology and experimental neurology.

[42]  H. Grossniklaus A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Luchinetti CF,∗ Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuck D, Parisi JE, Lassman H. Brain 2002;125:1450–1461 , 2002 .

[43]  R. Reynolds,et al.  Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? , 2002, Brain : a journal of neurology.

[44]  David H. Miller,et al.  Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. , 2002, Brain : a journal of neurology.

[45]  Hans Lassmann,et al.  A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. , 2002, Brain : a journal of neurology.

[46]  H. Neumann,et al.  Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases , 2002, Trends in Neurosciences.

[47]  H. Lassmann,et al.  CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation , 2002, Nature Medicine.

[48]  C. Elger,et al.  Destruction of neurons by cytotoxic T cells: A new pathogenic mechanism in rasmussen's encephalitis , 2002, Annals of neurology.

[49]  M. Filippi,et al.  Primary Progressive Multiple Sclerosis , 2002, Topics in Neuroscience.

[50]  E. Cho,et al.  Immunopathology of secondary‐progressive multiple sclerosis , 2001, Annals of neurology.

[51]  B. Trapp,et al.  Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions , 2001, Annals of neurology.

[52]  P M Matthews,et al.  Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis. , 2001, Brain : a journal of neurology.

[53]  H. Wekerle,et al.  Myelin Antigen-Specific CD8+ T Cells Are Encephalitogenic and Produce Severe Disease in C57BL/6 Mice1 , 2001, The Journal of Immunology.

[54]  H. Lassmann,et al.  Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. , 2001, Immunity.

[55]  I. V. Allen,et al.  Pathological abnormalities in the normal-appearing white matter in multiple sclerosis , 2001, Neurological Sciences.

[56]  C Confavreux,et al.  Relapses and progression of disability in multiple sclerosis. , 2000, The New England journal of medicine.

[57]  S. Majumder,et al.  Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation , 2000, Immunological reviews.

[58]  P. Matthews,et al.  Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. , 2000, Brain : a journal of neurology.

[59]  Hans Lassmann,et al.  Clonal Expansions of Cd8+ T Cells Dominate the T Cell Infiltrate in Active Multiple Sclerosis Lesions as Shown by Micromanipulation and Single Cell Polymerase Chain Reaction , 2000, The Journal of experimental medicine.

[60]  H. Lassmann,et al.  Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. , 2000, The American journal of pathology.

[61]  J. Parisi,et al.  Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination , 2000, Annals of neurology.

[62]  T. Tabira [Concentric sclerosis (Baló)]. , 2000, Ryoikibetsu shokogun shirizu.

[63]  B. Scheithauer,et al.  A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. , 1999, Brain : a journal of neurology.

[64]  W. Brück,et al.  Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination , 1999, Multiple sclerosis.

[65]  F. Barkhof,et al.  Cortical lesions in multiple sclerosis. , 1999, Brain : a journal of neurology.

[66]  H. Lassmann,et al.  Multiple sclerosis: In situ evidence for antibody‐ and complement‐mediated demyelination , 1998, Annals of neurology.

[67]  R. Rudick,et al.  Axonal transection in the lesions of multiple sclerosis. , 1998, The New England journal of medicine.

[68]  M. Esiri,et al.  The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. , 1997, Brain : a journal of neurology.

[69]  J M Land,et al.  Nitric Oxide‐Mediated Mitochondrial Damage in the Brain: Mechanisms and Implications for Neurodegenerative Diseases , 1997, Journal of neurochemistry.

[70]  V. Perry,et al.  Axonal damage in acute multiple sclerosis lesions. , 1997, Brain : a journal of neurology.

[71]  C. Raine,et al.  The adhesion molecule and cytokine profile of multiple sclerosis lesions , 1995, Annals of neurology.

[72]  K. Jellinger,et al.  Patterns of oligodendroglia pathology in multiple sclerosis. , 1994, Brain : a journal of neurology.

[73]  J. Prineas,et al.  Blood‐Brain Barrier Abnormalities in Longstanding Multiple Sclerosis Lesions. An Immunohistochemical Study , 1994, Journal of neuropathology and experimental neurology.

[74]  E. Cho,et al.  Multiple sclerosis: Remyelination of nascent lesions: Remyelination of nascent lesions , 1993 .

[75]  E. Cho,et al.  Multiple sclerosis: remyelination of nascent lesions. , 1993, Annals of neurology.

[76]  A. Thompson,et al.  Major differences in the dynamics of primary and secondary progressive multiple sclerosis , 1991, Annals of neurology.

[77]  J. Benjamins,et al.  Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. , 1989, Laboratory investigation; a journal of technical methods and pathology.

[78]  C. Morimoto,et al.  Dual‐label immunocytochemistry of the active multiple sclerosis lesion: Major histocompatibility complex and activation antigens , 1988, Annals of neurology.

[79]  H. Lassmann,et al.  Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. , 1988, The American journal of pathology.

[80]  G. Moore,et al.  Balo's concentric sclerosis: New observations on lesion development , 1985, Annals of neurology.

[81]  E. Cho,et al.  Continual Breakdown and Regeneration of Myelin in Progressive Multiple Sclerosis Plaques a , 1984, Annals of the New York Academy of Sciences.

[82]  M. Esiri,et al.  Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis , 1983, Journal of the Neurological Sciences.

[83]  Y. P. Guo,et al.  Concentric sclerosis. , 1983, Clinical and experimental neurology.

[84]  L. Scheinberg,et al.  Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. , 1981, Laboratory investigation; a journal of technical methods and pathology.

[85]  I. Allen,et al.  A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis , 1979, Journal of the Neurological Sciences.

[86]  K. Jellinger,et al.  Einige morphologische Aspekte der Multiplen Sklerose , 1969 .

[87]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[88]  R. Adams,et al.  The morbid anatomy of the demyelinative diseases , 1952 .

[89]  J. Baló ENCEPHALITIS PERIAXIALIS CONCENTRICA , 1928 .

[90]  A. Jakob,et al.  Zur pathologie der multiplen sklerose mit besonderer berücksichtigung der akuten formen , 1913 .