[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.142.219. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure.
Proposed mechanisms that appear to be germane to trafficking, inflammation, demyelination, and ultimately axonal dysfunction and loss. According to this model, any of several triggers, including nitric oxide produced as a result of inflammation, can lead to axonal energy rundown with subsequent activation of persistent sodium channels owing to depolarization. Sodium influx through these channels drives reverse Na+ and Ca2+ exchange, thus importing high levels of Ca2+ into the axon, where it can activate injurious enzymes and liberate free radicals that damage axons. CNS indicates central nervous system; APC, antigen-presenting cells; MBP, myelin basic protein; PLP, photolipid protein; and ATPase, adenosine triphosphatase.

Proposed mechanisms that appear to be germane to trafficking, inflammation, demyelination, and ultimately axonal dysfunction and loss. According to this model, any of several triggers, including nitric oxide produced as a result of inflammation, can lead to axonal energy rundown with subsequent activation of persistent sodium channels owing to depolarization. Sodium influx through these channels drives reverse Na+ and Ca2+ exchange, thus importing high levels of Ca2+ into the axon, where it can activate injurious enzymes and liberate free radicals that damage axons. CNS indicates central nervous system; APC, antigen-presenting cells; MBP, myelin basic protein; PLP, photolipid protein; and ATPase, adenosine triphosphatase.

Table. 
Examples of Gene Variants That Have Been Associated With Multiple Sclerosis Phenotype
Examples of Gene Variants That Have Been Associated With Multiple Sclerosis Phenotype
1.
Trapp  BDPeterson  JRansohoff  RMRudick  RMork  SBo  L Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338278- 285
PubMedArticle
2.
Bitsch  ASchuchardt  JBunkowski  SKuhlmann  TBrück  W Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;1231174- 1183
PubMedArticle
3.
Kornek  BStorch  MKWeissert  R  et al.  Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000;157267- 276
PubMedArticle
4.
Rivera-Quinones  CMcGavern  DSchmelzer  JHunter  SLow  PRodriguez  M Absence of neurological deficits following extensive demyelination in a class 1-deficient murine model of multiple sclerosis. Nat Med 1998;4187- 193
PubMedArticle
5.
Smith  KJKapoor  RHall  SMDavies  M Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001;49470- 476
PubMedArticle
6.
Yin  XCrawford  TOGriffin  JW  et al.  Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci 1998;181953- 1962
PubMed
7.
Frohman  EMStüve  OHavrdova  E  et al Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations. Arch Neurol200562 In press
8.
Lovett-Racke  AETrotter  JLLauber  JPerrin  PJJune  CHRacke  MK Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients: a marker of activated/memory T cells. J Clin Invest 1998;101725- 730
PubMedArticle
9.
Scholz  CPatton  KTAnderson  DEFreeman  GJHafler  DA Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J Immunol 1998;1601532- 1538
PubMed
10.
van Oosten  BWLai  MHodgkinson  S  et al.  Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997;49351- 357
PubMedArticle
11.
Rep  MHvan Oosten  BWRoos  MTAder  HJPolman  CHvan Lier  RA Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naïve T cells but does not affect IFN-gamma secreting TH1 cells in humans. J Clin Invest 1997;992225- 2231
PubMedArticle
12.
Balashov  KESmith  DRKhoury  SJHafler  DAWeiner  HL Increased IL-12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc Natl Acad Sci U S A 1997;94599- 603
PubMedArticle
13.
Moldovan  IRRudick  RACotleur  AC  et al.  Interferon gamma responses to myelin peptides in multiple sclerosis correlate with a new clinical measure of disease progression. J Neuroimmunol 2003;141132- 140
PubMedArticle
14.
Killestein  JKalkers  NFMeilof  JFBarkhof  Fvan Lier  RAWPolman  CH TNFa production by CD4+ T cells predicts long-term increase in lesion load on MRI in MS. Neurology 2001;571129- 1131
PubMedArticle
15.
Babbe  HRoers  AWaisman  A  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. J Exp Med 2000;192393- 404
PubMedArticle
16.
Skulina  CSchmidt  SDornmair  K  et al.  Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid. Proc Natl Acad Sci U S A 2004;1012428- 2433
PubMedArticle
17.
Tsuchida  TParker  KCTurner  RVMcFarland  HFColigan  JEBiddison  WE Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides. Proc Natl Acad Sci U S A 1994;9110859- 10863
PubMedArticle
18.
Crawford  MPYan  SXOrtega  S  et al.  High prevalence of autoreactive neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 2004;1034222- 4231
PubMedArticle
19.
Allegretta  MNicklas  JASriram  SAlbertini  RJ T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 1990;247718- 721
PubMedArticle
20.
Karandikar  NJCrawford  MPYan  X  et al.  Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest 2002;109641- 649
PubMedArticle
21.
Koh  DRFung-Leung  WPHo  AGray  DAcha-Orbea  HMak  TW Less mortality but more relapses in experimental allergic encephalomyelitis in CD8−/−mice. Science 1992;2561210- 1213
PubMedArticle
22.
Antel  JBania  MNoronha  ANeely  S Defective suppressor cell function mediated by T8+ cell lines from patients with progressive multiple sclerosis. J Immunol 1986;1373436- 3439
PubMed
23.
Shlomchik  MJCraft  JEMamula  MJ From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001;1147- 153
PubMedArticle
24.
Cepok  SJacobsen  MSchock  S  et al.  Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 2001;1242169- 2176
PubMedArticle
25.
Wolf  SDDittel  BNHardarottir  FJaneway  CA  Jr Experimental autoimmune encephalomyelitis in genetically B cell-deficient mice. J Exp Med 1996;1842271- 2278
PubMedArticle
26.
Levin  MCLee  SMKalume  F  et al.  Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 2002;8509- 513
PubMedArticle
27.
Shirai  AAoki  IOtani  MMond  JJKlinman  DM Treatment with dextran-conjugated anti-IgD delays the development of autoimmunity in MRL-lpr/lpr mice. J Immunol 1994;1531889- 1894
PubMed
28.
Nemazee  DHogquist  KA Antigen receptor selection by editing or downregulation of V(D)J recombination. Curr Opin Immunol 2003;15182- 189
PubMedArticle
29.
Owens  GRitchie  ABurgoon  MWilliamson  RCorboy  JGilden  D Single cell repertoire analysis demonstrates clonal expansion is prominent feature of the B cell response in multiple sclerosis spinal fluid. J Immunol 2003;1712725- 2733
PubMedArticle
30.
Anolik  JSanz  ILooney  RJ B cell depletion therapy in systemic lupus erythematosus. Curr Rheumatol Rep 2003;5350- 356
PubMedArticle
31.
Lehmann  PVForsthuber  TMiller  ASercarz  EE Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992;358155- 157
PubMedArticle
32.
Tian  JGregori  SAdorini  LKaufman  DL The frequency of high avidity T cells determines the hierarchy of determinant spreading. J Immunol 2001;1667144- 7150
PubMedArticle
33.
Tuohy  VKYu  MWeinstock-Guttman  BKinkel  RP Diversity and plasticity of self recognition during the development of multiple sclerosis. J Clin Invest 1997;991682- 1690
PubMedArticle
34.
Yu  MKinkel  RPWeinstock-Guttman  BCook  DJTuohy  VK HLA-DP: a class II restriction molecule involved in epitope spreading during the development of multiple sclerosis. Hum Immunol 1998;5915- 24
PubMedArticle
35.
O'Garra  A Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8275- 283
PubMedArticle
36.
Woodland  DLDutton  RW Heterogeneity of CD4(+) and CD8(+) T cells. Curr Opin Immunol 2003;15336- 342
PubMedArticle
37.
Seder  RAPaul  WE Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994;12635- 673
PubMedArticle
38.
Mosmann  TRSad  S The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996;17138- 146
PubMedArticle
39.
Sharief  MKHentges  R Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325467- 472
PubMedArticle
40.
Comabella  MBalashov  KIssazadeh  SSmith  DWeiner  HLKhoury  SJ Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998;102671- 678
PubMedArticle
41.
Steimle  VSiegrist  CAMottet  ALisowska-Grospierre  BMach  B Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 1994;265106- 109
PubMedArticle
42.
Panitch  HSHirsch  RLHaley  ASJohnson  KP Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987;1893- 895
PubMedArticle
43.
Duda  PWSchmied  MCCook  SLKrieger  JIHafler  DA Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000;105967- 976
PubMedArticle
44.
Youssef  SStuve  OPatarroyo  JC  et al.  The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;42078- 84
PubMedArticle
45.
Bielekova  BGoodwin  BRichert  N  et al.  Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000;61167- 1175
PubMedArticle
46.
Kappos  LComi  GPanitch  H  et al. the Altered Peptide Ligand in Relapsing MS Study Group, Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomised phase II trial. Nat Med 2000;61176- 1182
PubMedArticle
47.
Langrish  CLChen  YBlumanschein  WM  et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201233- 240
PubMedArticle
48.
Vajkoczy  PLaschinger  MEngelhardt  B Alpha 4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitic T cell blasts to CNS white matter microvessels. J Clin Invest 2001;108557- 565
PubMedArticle
49.
Yednock  TACannon  LFritz  L  et al.  Prevention of experimental allergic encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;35663- 66
PubMedArticle
50.
Walters  CEPryce  GHankey  DJ  et al.  Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol 2002;1684087- 4094
PubMedArticle
51.
Miller  DHKhan  OASheremata  WA  et al.  A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;34815- 23
PubMedArticle
52.
De Keyser  JWilczak  NLeta  RStreetland  C Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology 1999;531628- 1633
PubMedArticle
53.
De Keyser  JZeinstra  EFrohman  E Are astrocytes central players in the pathophysiology of multiple sclerosis? Arch Neurol 2003;60132- 136
PubMedArticle
54.
Nakamura  AJohns  EJImaizumi  AAbe  TKohsaka  T Regulation of tumour necrosis factor and interleukin-6 gene transcription by beta2-adrenoceptor in the rat astrocytes. J Neuroimmunol 1998;88144- 153
PubMedArticle
55.
Sanchez-Abarca  LITabernero  AMedina  JM Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 2001;36321- 329
PubMedArticle
56.
Tokita  YKeino  HMatsui  F  et al.  Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci 2001;211257- 1264
PubMed
57.
Viehover  AMiller  RHPark  SKFischbach  GVartanian  T Neuregulin: an oligodendrocyte growth factor absent in active multiple sclerosis lesions. Dev Neurosci 2001;23377- 386
PubMedArticle
58.
Ransom  BRWaxman  SGDavis  PK Anoxic injury of CNS white matter: protective effect of ketamine. Neurology 1990;401399- 1404
PubMedArticle
59.
Stys  PKRansom  BRWaxman  SGDavis  PK Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc Natl Acad Sci U S A 1990;874212- 4216
PubMedArticle
60.
Stys  PKWaxman  SGRansom  BR Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+-Ca2+ exchanger. J Neurosci 1992;12430- 439
PubMed
61.
Lassmann  H Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003;206187- 191
PubMedArticle
62.
Kapoor  RDavies  MBlaker  PA  et al.  Blockers of sodium and calcium entry protect axons from nitric oxide mediated degeneration. Ann Neurol 2003;53174- 180
PubMedArticle
63.
Craner  MJNewcombe  JBlack  JAHartle  CCuzner  MLWaxman  SG Molecular changes in neurons in MS: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/C2+ exchanger in the human CNS. Proc Natl Acad Sci U S A 2004;1018168- 8173
PubMedArticle
64.
Lo  ACSaab  CYBlack  JAWaxman  SG Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol 2003;903566- 3571
PubMedArticle
65.
Waxman  SG NO and the axonal death cascade. Ann Neurol 2003;53150- 154
PubMedArticle
66.
Kim  JELi  SGrandPre  TQiu  DStrittmatter  SM Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 2003;38187- 199
PubMedArticle
67.
Domeniconi  MCao  ZSpencer  T  et al.  Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 2002;35283- 290
PubMedArticle
68.
Cai  DDeng  KMellado  WLe  JRatan  RRFilbin  MT Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 2002;35711- 719
PubMedArticle
69.
Kappos  LMoeri  DRadue  EW  et al.  Predictive value of gadolinium-enhanced MRI for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Lancet 1999;353964- 969
PubMedArticle
70.
Filippi  MArnold  DLComi  G Magnetic Resonance Spectroscopy in Multiple Sclerosis.  Milan, Italy: Springer-Verlag; 2001
71.
Filippi  MBozzali  MRovaris  M  et al.  Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003;126433- 437
PubMedArticle
72.
Rovaris  MBozzali  MSantuccio  G  et al.  In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 2001;1242540- 2549
PubMedArticle
73.
Bozzali  MCercignani  MSormani  MPComi  GFilippi  M Quantification of brain gray matter damage in different MS phenotypes by use of diffusion tensor MR imaging. AJNR Am J Neuroradiol 2002;23985- 988
PubMed
74.
Filippi  MRocca  MA Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging. Curr Opin Neurol 2003;16275- 282
PubMedArticle
75.
Chabas  DBaranzini  SMitchell  D  et al.  The influence of the pro-inflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001;2941731- 1735
PubMedArticle
76.
Lock  CHermans  GPedotti  R  et al.  Gene microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002;8500- 508
PubMedArticle
77.
Steinman  LZamvil  S Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol 2003;3483- 493
PubMedArticle
78.
Vogt  MLopatinskaya  LSmits  MPolman  CHNagelkerken  L Elevated osteopontin levels are associated with disease activity in relapsing-remitting MS patients. Ann Neurol 2003;53819- 822
PubMedArticle
79.
Vollmer  TKey  LDurkalski  V  et al.  Oral simvastatin in relapsing-remitting multiple sclerosis. Lancet 2004;3631607- 1608
PubMedArticle
80.
Doolittle  THMyers  RHLehrich  JR  et al.  Multiple sclerosis sibling pairs: clustered onset and familial predisposition. Neurology 1990;401546- 1552
PubMedArticle
81.
Weinshenker  BGBulman  DCarriere  WBaskerville  JEbers  GC A comparison of sporadic and familial multiple sclerosis. Neurology 1990;401354- 1358
PubMedArticle
82.
Barcellos  LFOksenberg  JRGreen  AJ  et al.  Genetic basis for clinical expression in multiple sclerosis. Brain 2002;125150- 158
PubMedArticle
83.
Bulman  DESadovnick  ADEbers  GC Age of onset in siblings concordant for multiple sclerosis. Brain 1991;114937- 950
PubMedArticle
84.
Butterfield  RJBlankenhorn  EPRoper  RJZachary  JFDoerge  RWTeuscher  C Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am J Pathol 2000;157637- 645
PubMedArticle
85.
Mann  CLDavies  MBBoggild  MD  et al.  Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 2000;54552- 557
PubMedArticle
86.
Schrijver  HMCrusius  JBUitdehaag  BM  et al.  Association of interleukin-lbeta and interleukin-1 receptor antagonist genes with disease severity in MS. Neurology 1999;52595- 599
PubMedArticle
87.
Kantarci  OHAtkinson  EJHebrink  DDMcMurray  CTWeinshenker  BG Association of two variants in IL-1beta and IL-1 receptor antagonist genes with multiple sclerosis. J Neuroimmunol 2000;106220- 227
PubMedArticle
88.
Sciacca  FLFerri  CVandenbroeck  K  et al.  Canal, bi., and Grimaldi, L. M. Relevance of interleukin 1 receptor antagonist intron 2 polymorphism in Italian MS patients. Neurology 1999;521896- 1898
PubMedArticle
89.
Feakes  RSawcer  SBroadley  S  et al.  Interleukin 1 receptor antagonist (IL-lra) in multiple sclerosis. J Neuroimmunol 2000;10596- 101
PubMedArticle
90.
Barcellos  LFSchito  AMRimmler  JB  et al.  Multiple Sclerosis Genetics Group;CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Immunogenetics 2000;51281- 288
PubMedArticle
91.
Kantor  RBakhanashvili  MAchiron  A A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 2003;61238- 240
PubMedArticle
92.
Sellebjerg  FMadsen  HOJensen  CVJensen  JGarred  P CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 2000;10298- 106
PubMedArticle
93.
Haase  CGSchmidt  SFaustmann  PM Frequencies of the G-protein beta3 subunit C825T polymorphism and the delta 32 mutation of the chemokine receptor-5 in patients with multiple sclerosis. Neurosci Lett 2002;330293- 295
PubMedArticle
94.
Schreiber  KOtura  ABRyder  LP  et al.  Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRBl* 1501, CCR5 deletion mutation, apolipoprotein E). Mult Scler 2002;8295- 298
PubMedArticle
95.
Caillier  SBarcellos  LFBaranzini  SE  et al.  Osteopontin polymorphisms and disease course in multiple sclerosis. Genes Immun 2003;4312- 315
PubMedArticle
96.
Niino  MKikuchi  SFukazawa  TYabe  ITashiro  K Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J Neuroimmunol 2003;136125- 129
PubMedArticle
97.
Hensiek  AERoxburgh  RMeranian  M  et al.  Osteopontin gene and clinical severity of multiple sclerosis. J Neurol 2003;250943- 947
PubMedArticle
98.
Vandenbroeck  KMartino  GMarrosu  M  et al.  Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol 1997;76189- 192
PubMedArticle
99.
Kantarci  OHSchaefer-Klein  JLHebrink  DD  et al.  A population-based study of IL4 polymorphisms in multiple sclerosis. J Neuroimmunol 2003;137134- 139
PubMedArticle
100.
Engell  TRaun  NEThomsen  MPlatz  P HLA and heterogeneity of multiple sclerosis. Neurology 1982;321043- 1046
PubMedArticle
101.
Madigand  MOger  JJFauchet  RSabouraud  OGenetet  B HLA profiles in multiple sclerosis suggest two forms of disease and the existence of protective haplotypes. J Neurol Sci 1982;53519- 529
PubMedArticle
102.
Duquette  PDecary  FPleines  J  et al.  Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression. Can J Neurol Sci 1985;12106- 110
PubMed
103.
de la Concha  EGArroyo  RCrusius  JB  et al.  Combined effect of HLA-DRB 1 * 1501 and interleukin- 1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis. J Neuroimmunol 1997;80172- 178
PubMedArticle
104.
Celius  EGHarbo  HFEgeland  TVartdal  FVandvik  BSpurkiand  A Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J Neurol Sci 2000;178132- 135
PubMedArticle
105.
Masterman  TLigers  AOlsson  TAndersson  MOlerup  OHiller  J HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol 2000;48211- 219
PubMedArticle
106.
Hensiek  AESawcer  SJFeakes  R  et al.  HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry 2002;72184- 187
PubMedArticle
107.
Poser  SRitter  GBauer  HJGrosse-Wilde  HKuwert  EKRaun  NE HLA-antigens and the prognosis of multiple sclerosis. J Neurol 1981;225219- 221
PubMedArticle
108.
Runmarker  BMartinsson  TWahlstrom  JAndersen  O HLA and prognosis in multiple sclerosis. J Neurol 1994;241385- 390
PubMedArticle
109.
Weinshenker  BGSantrach  PBissonet  AS  et al.  Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study. Neurology 1998;51742- 747
PubMedArticle
110.
McDonnell  GVMawhinney  HGraham  CAHawkins  SAMiddleton  D A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis. J Neurol Sci 1999;16577- 83
PubMedArticle
111.
Villoslada  PBarcellos  LFRio  J  et al.  The HLA locus and multiple sclerosis in Spain: role in disease susceptibility, clinical course and response to interferon-beta. J Neuroimmunol 2002;130194- 201
PubMedArticle
112.
Kira  JKanai  TNishimura  Y  et al.  Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol 1996;40569- 574
PubMedArticle
113.
Hauser  SLOksenberg  JRLincoln  R  et al. Optic Neuritis Study Group, Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS. Neurology 2000;541859- 1861
PubMedArticle
114.
Olerup  OHillert  JFredrikson  S  et al.  Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A 1989;867113- 7117
PubMedArticle
115.
Kantarci  OHde Andrade  MWeinshenker  BG Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002;123144- 159
PubMedArticle
116.
Zhou  QRammohan  KLin  S  et al.  CD24 is a genetic modifier for risk and progression of multiple sclerosis. Proc Natl Acad Sci U S A 2003;10015041- 15046
PubMedArticle
117.
Kikuchi  SFukazawa  TNiino  M  et al.  Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB 1 * 1501 and disease modulation. J Neuroimmunol 2002;12877- 81
PubMedArticle
118.
Mattila  KMLuomala  MLehtimaki  TLaippala  PKoivula  TElovaara  I Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 2001;561246- 1247
PubMedArticle
119.
Kantarci  OHHebrink  DDAchenbach  SJ  et al.  CD95 polymorphisms are associated with susceptibility to MS in women: a population-based study of CD95 and CD95L in MS. J Neuroimmunol 2004;146162- 170
PubMedArticle
120.
Giess  RMaurer  MLinker  R  et al.  Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol 2002;59407- 409
PubMedArticle
121.
Hoffmann  VHardt  C A null mutation in the CNTF gene is not associated with early onset of multiple sclerosis. Arch Neurol 2002;591974
PubMedArticle
122.
Hoffmann  VPohlau  DPrzuntek  HEpplen  JTHardt  C A null mutation within the ciliary neurotrophic factor (CNTF)-gene: implications for susceptibility and disease severity in patients with multiple sclerosis. Genes Immun 2002;353- 55
PubMedArticle
123.
van Veen  Tvan Winsen  LCrusius  JB  et al.  [Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype. Neurology 2003;611245- 1249
PubMedArticle
124.
Shinar  YLivneh  AVilla  Y  et al.  Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003;4197- 203
PubMedArticle
125.
Evangelou  NJackson  MBeeson  DPalace  J Association of the APOE epsilon4 allele with disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999;67203- 205
PubMedArticle
126.
Fazekas  FStrasser-Fuchs  SSchmidt  H  et al.  Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;6925- 28
PubMedArticle
127.
Hogh  POturai  ASchreiber  K  et al.  Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. Mult Scler 2000;6226- 230
PubMedArticle
128.
Chapman  JVinokurov  SAchiron  A  et al.  APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 2001;56312- 316
PubMedArticle
129.
Fazekas  FStrasser-Fuchs  SKollegger  H  et al.  Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology 2001;57853- 857
PubMedArticle
130.
Enzinger  CRopele  SSmith  S  et al.  Accelerated evolution of brain atrophy and “black holes” in MS patients with APOE-epsilon 4. Ann Neurol 2004;55563- 569
PubMedArticle
131.
Ferri  CSciacca  FLVeglia  F  et al.  APOE epsilon2-4 and -491 polymorphisms are not associated with MS. Neurology 1999;53888- 889
PubMedArticle
132.
Weatherby  SJMann  CLFryer  AA  et al.  No association between the APOE epsilon4 allele and outcome and susceptibility in primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68532Article
133.
Masterman  TZhang  ZHellgren  D  et al.  APOE genotypes and disease severity in multiple sclerosis. Mult Scler 2002;898- 103
PubMedArticle
134.
Savettieri  GAndreoli  VBonavita  S  et al.  Apolipoprotein E genotype does not influence the progression of multiple sclerosis. J Neurol 2003;2501094- 1098
PubMedArticle
135.
Ballerini  CCampani  DRombola  G  et al.  Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis. Neurosci Lett 2000;296174- 176
PubMedArticle
136.
Schmidt  SBarcellos  LFDeSombre  K  et al.  Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002;70708- 717
PubMedArticle
137.
Kantarci  OHHebrink  DDAchenbach  SJ  et al.  Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 2004;62811- 814
PubMedArticle
138.
Green  AJBarcellos  LFRimmler  JB  et al.  Sequence variation in the transforming growth factor-betal (TGFB1) gene and multiple sclerosis susceptibility. J Neuroimmunol 2001;116116- 124
PubMedArticle
139.
Barcellos  LFOksenberg  JRBegovich  AB  et al.  HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003;72710- 716
PubMedArticle
140.
Garcia-Merino  AAlper  CAUsuku  K  et al.  Tumor necrosis factor microsatellite haplotypes in relation to extended haplotypes, susceptibility to diseases associated with the major histocompatibility complex, and TNF secretion. Hum Immunol 1996;5011- 21
PubMedArticle
Neurological Review
September 2005

Characterizing the Mechanisms of Progression in Multiple SclerosisEvidence and New Hypotheses for Future Directions

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Frohman, Karandikar, Monson, and Racke), Ophthalmology (Dr Frohman), and Pathology (Dr Karandikar) and Center for Immunology (Dr Racke), University of Texas Southwestern Medical Center at Dallas; Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy (Dr Filippi); Department of Neurology, Heinrich Heine University, Dusseldorf, Germany (Drs Stuve, Hemmer, and Hartung); Department of Neurology, Yale University, New Haven, Conn (Dr Waxman); Department of Neurology, University of Colorado, Boulder (Dr Corboy); Texas Neurology, Dallas (Dr Phillips); Department of Neurology, Mayo Clinic, Rochester, Minn (Dr Lucchinetti); Division of Neuropsychology, Department of Veterans Affairs, Washington, DC (Dr Wilken); Department of Neurology, University of Groningen, Groningen, the Netherlands (Dr DeKeyser); Department of Neurology, Stanford University, Stanford, Calif (Dr Steinman); and Department of Neurology, University of California, San Francisco (Drs Oksenberg, Cree, Hauser, and Racke).

 

DAVID E.PLEASUREMD

Arch Neurol. 2005;62(9):1345-1356. doi:10.1001/archneur.62.9.1345
Abstract

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

THE PATHOLOGIC MECHANISM OF PROGRESSION IN MULTIPLE SCLEROSIS
Relapse and Progression

Relapses and progression of disability are the 2 basic clinical phenomena of multiple sclerosis (MS). Relapses are considered to be the clinical expression of acute inflammatory demyelination in the central nervous system (CNS), whereas progression is considered to reflect chronic demyelination, gliosis, and axonal loss. Early in the disease, remission of symptoms is likely due to resolution of inflammation, channel redistribution, and remyelination; however, following recurrent attacks, axonal damage is more likely to occur, and axonal loss accumulates. Hence, the balance between injury and repair likely determines the progression of MS.

Recent reports1,2 have emphasized the importance of axonal degeneration in contributing to permanent neurologic deficits in patients with MS. The extent of axonal loss is highly variable, with axonal density within plaques ranging from 20% to 80% of that in the periplaque white matter.

Hypothesis, Evidence, Future Directions

We hypothesize that the accumulation of axonal destruction underlies clinical progression in patients with MS. Support for this contention derives from our understanding that inflammation correlates with the extent of axonal transection in active MS lesions. However, the magnitude of axonal loss in chronic lesions suggests that mechanisms other than inflammatory demyelination may contribute to axonal damage at later stages of the disease.1,2 Axons in MS lesions may be destroyed in 2 different ways.3 During acute demyelination, axons are likely damaged owing to inflammatory mediators, such as proteases, cytokines, and free radicals. An association between the number of CD8 T cells and the extent of axon damage has been reported.2 A CD8 major histocompatibility complex (MHC) class I–mediated pathway of axon destruction has been suggested from experimental studies.4 Inducible nitric oxide may also mediate axon damage.5 This acute phase of massive axonal injury, however, lasts only for a few days to weeks. In contrast, axonal degeneration continues in silent inactive plaques.3 Although merely a few axons are destroyed at a given time point, the accumulation of their destruction can contribute to progression of disability. Chronically demyelinated axons may degenerate owing to the lack of trophic support from myelin and oligodendrocytes. Mice that lack certain myelin proteins (myelin-associated glycoprotein [MAG] and photolipid protein [PLP]) demonstrate late-onset axonal disease, and there is evidence of an increased incidence of wallerian degeneration in MAG-deficient mice.6

Axonal injury and loss of MS lesions have major clinical consequences for the patient. Clinical deficits induced by inflammation and demyelination are principally reversible, whereas functional loss due to axonal degeneration appears to be permanent. Although the CNS has a large reserve capacity, irreversible structural damage accumulates in MS brains. Although substantial damage can be sustained, permanent clinical deficits appear to coincide with a time when the functional reserve capacity is exhausted. Therefore, the need to develop axon-protective therapy for MS will be crucial to our attempt to slow disease progression (see part 27).

THE IMMUNOLOGIC FEATURES OF PROGRESSION IN MS
Role of T Cells in Progression

The clinical characteristics that separate secondary progressive MS from relapsing-remitting disease are better defined than the immunologic differences. It has been suggested that priming of myelin-reactive T cells occurs as part of the disease process in MS.8,9 Primed T cells reactive to myelin antigens may develop a phenotype, making them more resistant to regulatory processes such as programmed cell death. One might expect that these T-cell clones would retain effector functions such as interferon γ secretion but be resistant to the regulatory effects of various therapeutic interventions. It is possible that this resistance to programmed cell death could be an explanation of why interventions such as anti-CD4 therapy were ineffective in patients with MS.10 Studies11 on the immune response in patients who are receiving anti-CD4 therapy have suggested that naive cells, rather than differentiated TH1-like cells, are eliminated.

Hypothesis, Evidence, and Future Directions

One could hypothesize that a more inflammatory profile of myelin-reactive T cells correlates with disease progression. Increased CD40 ligand expression on T cells from patients with progressive MS has resulted in increased interleukin (IL) 12 production.12 Increased responses to myelin peptides showed a correlation with disability.13 A correlation between tumor necrosis factor α (TNF-α)–producing CD4 T cells and changes in T2 lesion load has also been reported.14

Both CD8 and CD4 T cells contribute to the cellular infiltrate of demyelinating lesions in patients who have MS with evidence of CD8 T-cell enrichment and clonal expansion.15 Some of these brain-infiltrating CD8 T cells have persisted in the cerebrospinal fluid or blood for longer than 5 years, suggesting that they may play a role in disease progression.16 The CNS-reactive CD8 T-cell responses have been demonstrated in these patients.17 Recent technical advancements in flow cytometric assays allow evaluation of antigen-specific CD4 and CD8 T-cell proliferative responses in patients with MS. These studies demonstrate that CNS-reactive T cells are not restricted to the CD4 T-cell subset. In fact, autoreactive HLA antigen class I–restricted CD8 T-cell responses are widely prevalent in MS.18 A higher prevalence of autoreactive CD8 T-cell responses was noted in patients with relapsing-remitting MS compared with other MS subtypes.18

The CNS-specific T-cell responses are found in patients with MS and healthy subjects. However, the functional attributes of these cells are distinct in the 2 groups, in which CNS-targeted T cells from patients are thought to be more differentiated compared with those from healthy subjects, suggesting that the cells may have experienced self-antigen in vivo.8,19 When CD4 and CD8 T cells were specifically evaluated for their functional profiles, differences were noted in both subsets of cells.18 Although autoreactive CD4 T cells appeared to exhibit a more T helper (TH)1–type profile, autoreactive CD8 T cells showed a mixed functional profile in which higher interferon γ and chemokine receptor 3 expression was accompanied by higher IL-10 expression in patients with MS.

Similar to regulatory subpopulations of CD4 T cells, CD8 T cells have also been implicated as regulatory cells in both experimental autoimmune encephalomyelitis (EAE) and MS.2022 It is possible that the progression of disease in MS depends on a relative lack of regulatory T-cell function. In keeping with this hypothesis, a deficient CD8 T-cell response to glatiramer acetate (Copaxone, Teva Neuroscience, Kansas City, Mo) was found in patients with MS but not in healthy subjects.20 Although patients with MS have widespread, CNS-specific CD8 T-cell responses, glatiramer acetate therapy can restore glatiramer acetate–specific CD8 responses to the levels found in healthy subjects.20 A complex pathogenic and regulatory balance may exist within the CD8 T-cell subset. These findings strengthen the need for defining the role of CD8 T cells in disease progression.

Role of B Cells in Progression

The concept that autoantigens can drive B-cell clonal expansion and generate an autoantibody pool that contributes to autoimmunity has been demonstrated in other autoimmune diseases.23 However, it has been observed that if the B-cell–monocyte ratio is high, progression of MS is more likely to occur.24 In the EAE model, a role of B cells in the recovery from inflammatory demyelination has also been hypothesized.25

Hypothesis, Evidence, and Future Directions

We hypothesize at least 3 different roles that a B cell might play in the progression of MS. The first is through B-cell clonal expansion. If new antigens have been exposed through ongoing myelin damage, B cells that recognize these newly exposed antigens in the CNS may undergo clonal expansion and differentiation, resulting in a larger pool of antigen-presenting cells participating in the immune response. Second, if the patient has recently had an infection that generated a B-cell response in which the resultant antibody not only recognized the viral or bacterial components but also was cross-reactive with some antigen in the CNS, it is possible that such infections may lead to breakthrough disease by indirectly generating antibodies that are cross-reactive to self-antigens in the CNS. This concept is known as molecular mimicry and occurs in some infectious states, such as human T-cell lymphotrophic virus type 1.26 A third possibility relates to the process of immunoglobulin class switching that occurs in B cells. All B cells initially produce IgM, and at a certain point, they are induced to produce IgG instead. In several autoimmune states, the IgG component of the immunoglobulins contains the bulk of autoreactivity rather than the IgM component.27 This switch of self-reactive B cells from IgM to IgG producers could contribute to disease progression.

Each of the mechanisms by which B cells can contribute to progression in MS can potentially be prevented. For example, receptor editing is a phenomenon by which B cells that recognize self-antigens attempt to neutralize their autoreactive potential by replacing the light chain they are currently expressing with a newly rearranged one.28 It has been demonstrated that receptor editing occurs in B cells in the cerebrospinal fluid of patients with MS.29 Receptor editing should discourage further damage to the CNS tissue by autoantibody deposition. However, receptor editing could fail to prevent autoreactivity and instead generate a new antibody with greater self-antigen reactivity or reactivity to more than 1 self-antigen, which could lead to disease progression. In addition, one might be able to prevent B-cell–mediated pathogenesis by depleting the B cells altogether. This approach has led to suppression of autoimmunity in other diseases with known B-cell involvement.27,30

Determinant (Epitope) Spreading

The terms determinant spreading and repertoire broadening describe the same phenomenon. The concept of epitope spreading emerged in the early 1990s to describe 2 phenomena: (1) diversity at the level of the T-cell receptor V gene (variable) use and (2) cellular and humeral immune response diversification from a single to numerous antigenic determinants.31 Epitope spreading is not necessarily a pathogenic immune response but may instead be required for the effective clearing of various infectious agents.32

Hypothesis, Evidence, and Future Directions

Epitope spreading may contribute to the occurrence of disease exacerbations in patients who have MS with a relapsing-remitting phenotype. One group recently showed epitope spreading to overlapping PLP peptides in patients with a clinically isolated demyelinating syndrome.33 The same authors reported that HLA-DP–restricted epitopes may be recognized by initiating or early-driving clones at disease onset.34 We hypothesize, as these processes occur, that specific therapeutic interventions would be less effective and disease progression could occur.

Cytokine Effects on Progression

According to the TH paradigm, activated CD4 lymphocytes are categorized into TH1 or TH2 cells according to their cytokine phenotype.35 Although it is now recognized that activated helper CD8 T cells can also be categorized into T cytotoxic 1 (Tc1) and Tc2 subsets (analogous to CD4 TH1 and TH2 cells, respectively),36 herein we will primarily focus on the role of CD4 Th subsets in progression of MS.

The adaptive immune system induces T cells to change from a naive phenotype to either effector cells or memory cells. The TH1/TH2 phenotype reflects the functional capabilities following T-cell activation.35 In the human immune system, TH1 cells secrete interferon γ, TNF-β, and IL-2, whereas TH2 cells produce IL-4, IL-5, IL-6, and IL-13.37 The role of TH phenotypes (eg, THp, TH0)38 in human diseases has yet to be clearly defined. However, cytokines associated with the TH1 response, such as IL-12 and TNF-α, appear to correlate with disease progression.12,39

Hypothesis, Evidence, and Future Directions

We hypothesize that T helper cells of a TH1 cytokine phenotype contribute to disease progression in MS, whereas self-antigen–specific TH2 cells prevent CNS autoimmune disease. Intracellular cytokine staining confirmed that peripheral blood mononuclear cells from patients with progressive MS express more IL-12 on activation than those from healthy controls.40 Another TH1 cytokine, interferon γ, is a potent inducer of surface MHC class II expression on a variety of antigen-presenting cells.41 The clinical significance of this cytokine in MS pathogenesis was demonstrated when it was shown that the systemic administration of interferon γ caused exacerbations in patients with relapsing-remitting MS.42

Numerous approved and experimental MS pharmacotherapies have been shown to promote a shift or deviation to a TH2 cytokine profile.43,44 Unfortunately, administration of a myelin basic protein peptide (amino acids 83-99) designed as an altered peptide ligand to induce a TH2 cytokine profile in MS was followed by disease exacerbations in several patients.45 However, another study using this altered peptide ligand did not show disease worsening, but some patients experienced adverse allergic responses.46

The view that TH1 cytokines are proinflammatory and TH2 cytokines anti-inflammatory may be oversimplified. Although TH1 cytokines promote the activation of antigen-presenting cells and the clearance of intracellular pathogens, TH2 cytokines support antibody class switching in mice, promote the elimination of blood-borne pathogens, and may contribute to autoimmune disease in humans.35 Finally, cytokines such as IL-17 and IL-23, which are gaining a more prominent role in EAE pathogenesis, will need to be studied for their role in MS disease progression.47

Lymphocyte Trafficking and Progression

Once T cells are activated, these lymphocytes travel through blood vessels in the brain and spinal cord and are captured by molecules on the blood vessel wall that bind to counterreceptors on the activated lymphocyte. After they are firmly bound to the cerebrovascular endothelium, these cells can then elaborate matrix metalloproteinases capable of digesting collagen type IV and fibronectin, which facilitates transmigration.48

Hypothesis, Evidence, and Future Directions

Each step in the process of transendothelial trafficking represents a potential checkpoint. For example, the capture and binding of lymphocytes to the blood vessel wall can be blocked by drugs that interfere with the adhesion molecules on the lymphocyte and endothelial wall, including monoclonal antibodies to α4-integrin.49 The process of transmigration can be stopped by statins that block the addition of lipid moieties on certain molecules in the membrane that are critical for maintaining the shape of the T cell. Statins block the prenylation of ras homology protein molecules on the cell surface that are linked to the migration of lymphocytes into the brain.50

Immunologists hypothesized in the early 1990s that lymphocytes used specific addresses to home to targets like the CNS.49 By identifying the address used to send lymphocytes to a particular organ, it was argued that blocking the particular molecule with an “address-like signature” would thus abolish pathologic homing but would leave lymphocytes free to move elsewhere. One type of molecule, termed α4-integrin, on T lymphocytes allows T cells to recognize vascular cellular adhesion molecule 1 in the brain endothelium.49 The α4-integrin that recognizes vascular cellular adhesion molecule 1 is an essential step required for the capture of lymphocytes. Vascular cellular adhesion molecule 1 usually is not expressed at high levels in blood vessels in the brain, although in animal models and in MS its expression is increased. Administration of α4-integrin antibodies in EAE reversed the paralytic disease and blocked encephalitogenic T-cell clones from entering the brain.49

Antibody to α4-integrin was successful in phase 2 MS clinical trials, in which it reduced the relapse rate by 50% and diminished the number of new gadolinium-enhancing lesions in a 6-month clinical trial by nearly 90%.51 The year 1 results from 2 phase 3 (class I) studies on the use of natalizumab in relapsing MS have been reported. The first (AFFIRM) compared natalizumab with placebo, whereas the second (SENTINEL) compared weekly intramuscular interferon beta-1a (Avonex, Biogen Idec, Cambridge, Mass) and placebo with intramuscular interferon beta-1a and natalizumab. Both investigations show highly statistically significant beneficial effects of natalizumab on clinical (relapses) and radiographic measures of disease activity. The Food and Drug Administration approved natalizumab on November 23, 2004, for the treatment of relapsing forms of MS, yet it was later withdrawn because of the appearance of progressive multifocal leukoencephalopathy in 2 patients in the SENTINEL trial (Food and Drug Administration Web site: http://www.fda.gov/cder/drug/advisory/natalizumab.htm).

THE NEUROSCIENCE OF PROGRESSION IN MS
Role of Astrocytes in Progression

In new MS lesions, astrocytes proliferate and become hypertrophic. In chronic lesions, astroglial scarring can form an obstacle that prevents repair. A primary dysfunction of astrocytes in MS might be involved in lesion formation and progression of disability. A loss of astrocytic β2-adrenergic receptors in MS might explain many of the pathologic changes of the disease and play a role in both inflammation-mediated injury and progressive neurodegeneration.52 Activation of β2-adrenergic receptors by norepinephrine increases intracellular levels of cyclic adenosine monophosphate (cAMP), which controls many astrocytic functions.

Hypothesis, Evidence, and Future Directions

We hypothesize that lack of β2-adrenergic receptors may allow astrocytes to express adhesion, MHC class II, and B7 costimulatory molecules and to act as antigen-presenting cells that can initiate inflammatory reactions.53 During inflammation, lymphocytes, microglia, and macrophages release excessive amounts of glutamate. The lack of β2-adrenergic receptors on astrocytes may impair glutamate uptake and contribute to excitotoxic damage of oligodendrocytes through overactivation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. The receptor defect may also facilitate the release from astrocytes of proinflammatory cytokines such as TNF-α,54 which is involved in myelin and oligodendrocyte destruction, and result in the expression of nitric oxide synthase.52

Evidence is mounting that axons and oligodendrocytes use astrocyte-derived lactate as an energy source. Lactate is generated from astrocytic glycogenolysis that is stimulated by norepinephrine via β2-adrenergic receptor activation. The lack of astrocytic β2-adrenergic receptors in MS might prevent an adequate lactate supply to axons, especially in situations of increased neuronal activity.55 Intracellular cAMP in astrocytes also stimulates the production of various trophic factors, including neuregulin, nerve growth factor, and brain-derived growth factor.56 Neuregulin, which is a survival factor for oligodendrocytes, has been studied in astrocytes of patients with MS and was found to be reduced in active and chronic lesions.57

Potential Role of Sodium Channels in Progressive MS

Although axonal injury is frequent in early stages of MS and contributes to the acquisition of nonremitting deficits, evidence suggests that excitotoxicity is not a principal trigger.58 It has been firmly established that calcium-mediated injury can lead to persistent axonal dysfunction and axonal degeneration within CNS white matter.59 Biophysical evidence indicates, as shown in the Figure, that following a spectrum of insults, reverse sodium-calcium exchange, triggered by sodium influx via voltage-gated sodium channels, can produce injurious sustained calcium influx.60 Pharmacologic block of the sodium-calcium exchanger and of sodium channels is protective, preventing axonal degeneration in response to a spectrum of experimental models of axonal injury.60

On the basis of pathologic examination of MS tissue, it has been suggested that hypoxialike tissue injury is a component of MS lesions.61 Nitric oxide is present at increased concentrations within MS lesions and interferes with mitochondrial function. This observation suggests a role for energy failure in producing axonal injury in MS. Electrically active axons were found to be particularly sensitive to the damaging effects of nitric oxide.5 It has been shown that sodium channel blockers prevent nitric oxide–induced injury of CNS axons, suggesting that inflammatory events (which are associated with nitric oxide production) in MS can also trigger a component of the tissue injury cascade in MS (Figure).62

Irrespective of the trigger, operation of this axon-damaging cascade in MS requires colocalization of sodium channels and the sodium-calcium exchanger in close proximity along axons that are destined to degenerate. This link was shown to be related to the coexpression of the voltage-gated sodium channel, together with the sodium-calcium exchanger, in injured CNS axons (but not in uninjured axons) in both EAE and MS.63

The in vitro studies that demonstrated this axon-damaging cascade have recently been extended by an in vivo study in which the sodium channel blocker phenytoin was shown to have a neuroprotective effect in progressive EAE.64 In that study, phenytoin decreased the degree of axonal degeneration, maintained action potential conduction, and substantially improved clinical outcome.64

Hypothesis, Evidence, and Future Directions

On the basis of these findings, it has been hypothesized that sodium channel blockade may have a neuroprotective effect, preserving axonal integrity and function and thereby preventing nonremitting deficits in MS.65 The putative neuroprotective mechanism of action of these drugs (which appear to target molecules located within neurons) makes them ideal candidates for adjunctive therapy (see part 27).

CNS Repair and Regeneration

Progression in MS is likely the result of impaired axonal regeneration following immune-mediated injury. Understanding the mechanisms of how axonal regeneration is inhibited in the CNS has important clinical implications for MS. Three inhibitor proteins, neurite outgrowth inhibitor (Nogo), MAG, and oligodendrocyte myelin glycoprotein, inhibit CNS neural regeneration through the Nogo receptor and associated p75 neurotrophin receptor and leucine-rich repeat and immunoglobulin domain–containing Nogo receptor–interacting (LINGO) protein. In mice that underwent thoracic cord hemisection, those that were Nogo-A deficient demonstrated increased regrowth of axons after the traumatic injury.66 Both MAG and oligodendrocyte myelin glycoprotein also appear to inhibit axon regeneration through binding of the Nogo receptor complex.67 Once the Nogo receptor is activated, transmission of the signal is mediated by protein kinase C and cAMP. Interestingly, elevated levels of cAMP attenuate the ability of MAG to inhibit axon regeneration in vitro.68

Hypothesis, Evidence, and Future Directions

On the basis of these studies, we hypothesize that cAMP levels might affect axonal regeneration following spinal cord injury. In mice in which the levels of cAMP were increased, axonal regeneration was significantly improved. Cytokines such as IL-6 are also increased in response to increased levels of cAMP. In addition, IL-6 appears to be effective in attenuating MAG inhibition of axon regeneration. Perhaps drugs such as phosphodiesterase inhibitors will be targeted to regulate cAMP levels and reduce MAG inhibition of axon degeneration in immune-mediated CNS injury. Increasing neurite outgrowth, reducing glial scar formation, and increasing functional recovery might influence disease progression in MS.

THE NEURORADIOLOGIC FEATURES OF PROGRESSION IN MS
Neuroradiologic Detection of Tissue Injury in MS Progression

Conventional magnetic resonance imaging (MRI) is widely used for diagnosing and monitoring MS; however, the correlation between conventional MRI and clinical findings of MS is still limited.69 Among the reasons for these radiologic and clinical discrepancies, a major role has been attributed to the low pathologic specificity of the abnormalities seen on conventional MRI studies and the inability of conventional MRI to quantify the extent of the damage of the normal-appearing tissue. In addition, lesion location itself is another variable that plays a significant role in determining the level of disability.

Hypothesis, Evidence, and Future Directions

We hypothesize that application of modern magnetic resonance–based techniques such as magnetization transfer MRI, diffusion tensor MRI, and magnetic resonance spectroscopy to the assessment of patients with MS has significantly changed the notion of MS as a demyelinating disease.70 First, axonal damage, which may be represented by either axonal loss or dysfunction, has been recognized as one of the main contributors to clinical worsening over time. This pathologic process is an early phenomenon in the course of MS; it has been detected even in patients at presentation with clinically isolated syndromes suggestive of MS.71 Second, widespread abnormalities, which go undetected when using conventional MRI, have been demonstrated in the normal-appearing white matter of patients with MS. Such abnormalities are more pronounced in patients with secondary and primary progressive MS72 and tend to worsen over time. Third, it has been shown that the gray matter is not spared by the disease process73 and likely contributes to some of the symptoms of the disease, such as cognitive impairment, mood disorders, and fatigue. Finally, the application of these magnetic resonance techniques is improving our ability to obtain precise estimates of the composition and severity of damaged structures, such as the optic nerves and the spinal cord.

In the case of axonal and neuronal damage, the factors that have traditionally been viewed as potentially able to limit the clinical impact of MS (ie, resolution of inflammation, remyelination, and redistribution of voltage-gated sodium-channels in persistently demyelinated axons) are all likely to have a limited role. Functional MRI studies have demonstrated cortical changes in patients with different disease courses. The relationship found between these changes and magnetic resonance measures of brain and cord damage suggests that brain plasticity might play a major adaptive role in limiting the functional consequences of MS-related widespread tissue damage.74

THE GENETICS OF PROGRESSION IN MS
Analysis of Gene Expression in MS

The development of multiplex analysis of transcripts from MS tissues has advanced our understanding of the disease.75,76 These approaches to decipher the messenger RNA transcripts found at the site of MS lesions have revealed several targets for therapy, as well as increasing our awareness of the complexity of the disease. Large-scale transcriptional analysis of MS brain tissue has revealed that possible targets for therapy include elements of cholesterol metabolism, such as key enzymes involved in cholesterol synthesis, histamine receptors, and various cytokines including TNF, IL-15, IL-17, and osteopontin.75,76 Large-scale robotic sequencing of messenger RNA from complementary DNA libraries derived from MS brain plaques and gene microarray analysis of transcripts from MS lesions of various types75,76 have been performed by several groups.

A potential role for osteopontin (also known as Eta-1) in the progression of MS was identified.75 In the present study, more than 11 000 clones were sequenced from libraries prepared from brain plaques in patients with MS and controls. Elucidated were 423 genes, including 26 novel genes that were present only in MS plaques and absent in control material. Transcripts for αB-crystallin, an inducible heat shock protein localized in the myelin sheath and targeted by T cells in MS, were the most abundant transcripts unique to MS plaques. The next 5 most abundant transcripts included those for prostaglandin D synthase, prostatic binding protein, ribosomal protein L17, and osteopontin.

Hypothesis, Evidence, and Future Directions

We hypothesize that mining of the data sets will reveal new targets in MS.75,76 Osteopontin is a secreted molecule that is critical in the polarization of cytokines toward a TH1 bias, driving increases in interferon γ and IL-12, which may be necessary in the pathogenesis of MS.77 Levels of osteopontin are elevated in the plasma during relapses of MS and may serve as an important surrogate marker for disease activity.78 Levels of novel cytokines, including IL-15 and IL-17, were shown to be elevated in MS lesions and may be targets for therapy.76 Elevated levels of transcripts for immunoglobulin and Fc receptor make therapy directed to removal of B cells an attractive possibility in MS.

Transcriptional profiling of MS tissue revealed many changes in genes involved in lipid and cholesterol metabolism.76 Expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was down-regulated in MS tissue, as were the expression levels of other genes encoding critical pathways in lipid metabolism. Recently, promising results in clinical studies have ignited interest in the potential application of the cholesterol-lowering HMG-CoA reductase inhibitors statins in MS therapy79 (see part 27).

Genetic Modifiers of Progression

Although little is known about the underlying cause of disease variability, concordance for early and late clinical features has been observed in families with multiple cases of MS, suggesting that in addition to susceptibility, genes influence disease progression and other aspects of the clinical phenotype.8082

Hypothesis, Evidence, and Future Directions

We hypothesize that disease progression in MS is influenced by genetic and nongenetic factors. The genomic determinants of MS heterogeneity are most likely single-nucleotide polymorphisms. It is also important to recognize that the aggregate contribution of germline genetic variants to the disease course of a given patient with MS may be modest. This is highlighted by observations that the clinical expression of MS may be very different even between monozygotic twin siblings who both have the disease. It is therefore likely that several postgermline events influence the clinical expression of MS.

Earlier studies8083 have reported intrafamilial concordance for disease course, disease severity, and age at onset. The clinical course and severity of MS may also differ between ethnic groups. This phenotypic aggregation is due to genetic sharing. In EAE, it appears that MHC genes primarily influence penetrance, whereas other loci modulate specific phenotypes, such as topographic location of lesions in the brain or spinal cord, demyelination, and severity of inflammation.84 Similar interplay of genetic factors may apply to human disease.

To assess the state of genotype-phenotype research in MS, we have identified from the literature a set of gene polymorphisms that have been significantly associated with phenotypic end points (Table). The list omits many reports and probably includes a few type I errors due to small sample sizes. In addition, series are retrospective, some phenotypic end points are questionable or not validated, and the confounding effects of drug treatment and/or stratification generally have not been considered. The effect of HLA genotypes (ie, both alleles at the HLA locus) on clinical phenotypes is particularly instructive.139 In a mildly affected group of patients with MS, HLA-DRB1*1501 homozygotes were significantly less frequent compared with patients classified as having nonmild MS. When a more stringent definition of mild MS was applied in which disease duration of at least 15 years was imposed, no HLA-DRB1*1501 homozygotes were present in this subgroup. Furthermore, HLA-DRB1*1501 homozygotes were observed more frequently among patients with a severe disease course in contrast to patients classified as having nonsevere disease. The observed dose effect could conceivably result from a perturbation in the balance of TH1 and TH2 cytokines influenced by other genes in the HLA region, such as TNF. For example, HLA-DRB1*1501 haplotypes are associated with a TNF promoter polymorphism that modulates levels of expression of this proinflammatory TH1 cytokine.140 The observation of an HLA genotypic effect on disease outcome is also consistent with a model of protection mediated by HLA-DRB1*1501-negative haplotypes.

THE FUTURE

The past few years have seen real progress in the development of laboratory and analytical approaches to study complex genetic disorders on a genome-wide scale and in defining the pathologic basis of demyelination. There is widespread enthusiasm that the deconstruction of the MS-prone genotype may lead to novel diagnostics and, more important, better therapeutic options for our patients. Unexpected overlap between genomic variations associated with MS and other medical disorders might be uncovered, such as a role for APOE4 as a modifier in both Alzheimer disease and MS. The development of reliable and predictive genomic profiles will not be trivial because of experimental constraints and practical economical and ethical considerations.

Identification of genomic variants that predispose patients to a discrete phenotype might also reveal novel disease-associated biochemical pathways and new therapeutic targets. The demonstration of even a modest genetic effect of a known gene on the course of MS could represent a major therapeutic opportunity.

Back to top
Article Information

Correspondence: Elliot M. Frohman, MD, PhD, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235 (elliot.frohman@utsouthwestern.edu).

Accepted for Publication: June 10, 2005.

Author Contributions:Study concept and design: Frohman, Filippi, Stuve, Waxman, Corboy, Phillips, Lucchinetti, Wilken, Karandikar, DeKeyser, Hartung, Steinman, Oksenberg, Hauser, and Racke. Acquisition of data: Frohman, Waxman, DeKeyser, and Hauser. Analysis and interpretation of data: Frohman, Phillips, Wilken, Hemmer, Monson, DeKeyser, Hartung, Cree, and Hauser. Drafting of the manuscript: Frohman, Filippi, Stuve, Waxman, Phillips, Wilken, Karandikar, Hemmer, Monson, DeKeyser, Steinman, Oksenberg, Hauser, and Racke. Critical revision of the manuscript for important intellectual content: Frohman, Stuve, Corboy, Phillips, Lucchinetti, DeKeyser, Hartung, Oksenberg, Cree, Hauser, and Racke. Statistical analysis: Wilken, Cree, and Hauser. Obtained funding: Waxman, DeKeyser, and Steinman. Administrative, technical, and material support: Frohman, Filippi, Stuve, Waxman, Hemmer, and Hartung. Study supervision: Frohman, Stuve, Corboy, Phillips, and Hartung.

Funding/Support: This study was supported by the Once Upon a Time Foundation, Fort Worth, Tex (Dr Frohman) and the National Institutes of Health, Bethesda, Md (Dr Racke). Dr Cree is a Sylvia Lawry Fellow of the National Multiple Sclerosis Society.

References
1.
Trapp  BDPeterson  JRansohoff  RMRudick  RMork  SBo  L Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338278- 285
PubMedArticle
2.
Bitsch  ASchuchardt  JBunkowski  SKuhlmann  TBrück  W Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;1231174- 1183
PubMedArticle
3.
Kornek  BStorch  MKWeissert  R  et al.  Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000;157267- 276
PubMedArticle
4.
Rivera-Quinones  CMcGavern  DSchmelzer  JHunter  SLow  PRodriguez  M Absence of neurological deficits following extensive demyelination in a class 1-deficient murine model of multiple sclerosis. Nat Med 1998;4187- 193
PubMedArticle
5.
Smith  KJKapoor  RHall  SMDavies  M Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001;49470- 476
PubMedArticle
6.
Yin  XCrawford  TOGriffin  JW  et al.  Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci 1998;181953- 1962
PubMed
7.
Frohman  EMStüve  OHavrdova  E  et al Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations. Arch Neurol200562 In press
8.
Lovett-Racke  AETrotter  JLLauber  JPerrin  PJJune  CHRacke  MK Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients: a marker of activated/memory T cells. J Clin Invest 1998;101725- 730
PubMedArticle
9.
Scholz  CPatton  KTAnderson  DEFreeman  GJHafler  DA Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J Immunol 1998;1601532- 1538
PubMed
10.
van Oosten  BWLai  MHodgkinson  S  et al.  Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997;49351- 357
PubMedArticle
11.
Rep  MHvan Oosten  BWRoos  MTAder  HJPolman  CHvan Lier  RA Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naïve T cells but does not affect IFN-gamma secreting TH1 cells in humans. J Clin Invest 1997;992225- 2231
PubMedArticle
12.
Balashov  KESmith  DRKhoury  SJHafler  DAWeiner  HL Increased IL-12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc Natl Acad Sci U S A 1997;94599- 603
PubMedArticle
13.
Moldovan  IRRudick  RACotleur  AC  et al.  Interferon gamma responses to myelin peptides in multiple sclerosis correlate with a new clinical measure of disease progression. J Neuroimmunol 2003;141132- 140
PubMedArticle
14.
Killestein  JKalkers  NFMeilof  JFBarkhof  Fvan Lier  RAWPolman  CH TNFa production by CD4+ T cells predicts long-term increase in lesion load on MRI in MS. Neurology 2001;571129- 1131
PubMedArticle
15.
Babbe  HRoers  AWaisman  A  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. J Exp Med 2000;192393- 404
PubMedArticle
16.
Skulina  CSchmidt  SDornmair  K  et al.  Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid. Proc Natl Acad Sci U S A 2004;1012428- 2433
PubMedArticle
17.
Tsuchida  TParker  KCTurner  RVMcFarland  HFColigan  JEBiddison  WE Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides. Proc Natl Acad Sci U S A 1994;9110859- 10863
PubMedArticle
18.
Crawford  MPYan  SXOrtega  S  et al.  High prevalence of autoreactive neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 2004;1034222- 4231
PubMedArticle
19.
Allegretta  MNicklas  JASriram  SAlbertini  RJ T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 1990;247718- 721
PubMedArticle
20.
Karandikar  NJCrawford  MPYan  X  et al.  Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest 2002;109641- 649
PubMedArticle
21.
Koh  DRFung-Leung  WPHo  AGray  DAcha-Orbea  HMak  TW Less mortality but more relapses in experimental allergic encephalomyelitis in CD8−/−mice. Science 1992;2561210- 1213
PubMedArticle
22.
Antel  JBania  MNoronha  ANeely  S Defective suppressor cell function mediated by T8+ cell lines from patients with progressive multiple sclerosis. J Immunol 1986;1373436- 3439
PubMed
23.
Shlomchik  MJCraft  JEMamula  MJ From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001;1147- 153
PubMedArticle
24.
Cepok  SJacobsen  MSchock  S  et al.  Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 2001;1242169- 2176
PubMedArticle
25.
Wolf  SDDittel  BNHardarottir  FJaneway  CA  Jr Experimental autoimmune encephalomyelitis in genetically B cell-deficient mice. J Exp Med 1996;1842271- 2278
PubMedArticle
26.
Levin  MCLee  SMKalume  F  et al.  Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 2002;8509- 513
PubMedArticle
27.
Shirai  AAoki  IOtani  MMond  JJKlinman  DM Treatment with dextran-conjugated anti-IgD delays the development of autoimmunity in MRL-lpr/lpr mice. J Immunol 1994;1531889- 1894
PubMed
28.
Nemazee  DHogquist  KA Antigen receptor selection by editing or downregulation of V(D)J recombination. Curr Opin Immunol 2003;15182- 189
PubMedArticle
29.
Owens  GRitchie  ABurgoon  MWilliamson  RCorboy  JGilden  D Single cell repertoire analysis demonstrates clonal expansion is prominent feature of the B cell response in multiple sclerosis spinal fluid. J Immunol 2003;1712725- 2733
PubMedArticle
30.
Anolik  JSanz  ILooney  RJ B cell depletion therapy in systemic lupus erythematosus. Curr Rheumatol Rep 2003;5350- 356
PubMedArticle
31.
Lehmann  PVForsthuber  TMiller  ASercarz  EE Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992;358155- 157
PubMedArticle
32.
Tian  JGregori  SAdorini  LKaufman  DL The frequency of high avidity T cells determines the hierarchy of determinant spreading. J Immunol 2001;1667144- 7150
PubMedArticle
33.
Tuohy  VKYu  MWeinstock-Guttman  BKinkel  RP Diversity and plasticity of self recognition during the development of multiple sclerosis. J Clin Invest 1997;991682- 1690
PubMedArticle
34.
Yu  MKinkel  RPWeinstock-Guttman  BCook  DJTuohy  VK HLA-DP: a class II restriction molecule involved in epitope spreading during the development of multiple sclerosis. Hum Immunol 1998;5915- 24
PubMedArticle
35.
O'Garra  A Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8275- 283
PubMedArticle
36.
Woodland  DLDutton  RW Heterogeneity of CD4(+) and CD8(+) T cells. Curr Opin Immunol 2003;15336- 342
PubMedArticle
37.
Seder  RAPaul  WE Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994;12635- 673
PubMedArticle
38.
Mosmann  TRSad  S The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996;17138- 146
PubMedArticle
39.
Sharief  MKHentges  R Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325467- 472
PubMedArticle
40.
Comabella  MBalashov  KIssazadeh  SSmith  DWeiner  HLKhoury  SJ Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998;102671- 678
PubMedArticle
41.
Steimle  VSiegrist  CAMottet  ALisowska-Grospierre  BMach  B Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 1994;265106- 109
PubMedArticle
42.
Panitch  HSHirsch  RLHaley  ASJohnson  KP Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987;1893- 895
PubMedArticle
43.
Duda  PWSchmied  MCCook  SLKrieger  JIHafler  DA Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000;105967- 976
PubMedArticle
44.
Youssef  SStuve  OPatarroyo  JC  et al.  The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;42078- 84
PubMedArticle
45.
Bielekova  BGoodwin  BRichert  N  et al.  Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000;61167- 1175
PubMedArticle
46.
Kappos  LComi  GPanitch  H  et al. the Altered Peptide Ligand in Relapsing MS Study Group, Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomised phase II trial. Nat Med 2000;61176- 1182
PubMedArticle
47.
Langrish  CLChen  YBlumanschein  WM  et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201233- 240
PubMedArticle
48.
Vajkoczy  PLaschinger  MEngelhardt  B Alpha 4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitic T cell blasts to CNS white matter microvessels. J Clin Invest 2001;108557- 565
PubMedArticle
49.
Yednock  TACannon  LFritz  L  et al.  Prevention of experimental allergic encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;35663- 66
PubMedArticle
50.
Walters  CEPryce  GHankey  DJ  et al.  Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol 2002;1684087- 4094
PubMedArticle
51.
Miller  DHKhan  OASheremata  WA  et al.  A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;34815- 23
PubMedArticle
52.
De Keyser  JWilczak  NLeta  RStreetland  C Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology 1999;531628- 1633
PubMedArticle
53.
De Keyser  JZeinstra  EFrohman  E Are astrocytes central players in the pathophysiology of multiple sclerosis? Arch Neurol 2003;60132- 136
PubMedArticle
54.
Nakamura  AJohns  EJImaizumi  AAbe  TKohsaka  T Regulation of tumour necrosis factor and interleukin-6 gene transcription by beta2-adrenoceptor in the rat astrocytes. J Neuroimmunol 1998;88144- 153
PubMedArticle
55.
Sanchez-Abarca  LITabernero  AMedina  JM Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 2001;36321- 329
PubMedArticle
56.
Tokita  YKeino  HMatsui  F  et al.  Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci 2001;211257- 1264
PubMed
57.
Viehover  AMiller  RHPark  SKFischbach  GVartanian  T Neuregulin: an oligodendrocyte growth factor absent in active multiple sclerosis lesions. Dev Neurosci 2001;23377- 386
PubMedArticle
58.
Ransom  BRWaxman  SGDavis  PK Anoxic injury of CNS white matter: protective effect of ketamine. Neurology 1990;401399- 1404
PubMedArticle
59.
Stys  PKRansom  BRWaxman  SGDavis  PK Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc Natl Acad Sci U S A 1990;874212- 4216
PubMedArticle
60.
Stys  PKWaxman  SGRansom  BR Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+-Ca2+ exchanger. J Neurosci 1992;12430- 439
PubMed
61.
Lassmann  H Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003;206187- 191
PubMedArticle
62.
Kapoor  RDavies  MBlaker  PA  et al.  Blockers of sodium and calcium entry protect axons from nitric oxide mediated degeneration. Ann Neurol 2003;53174- 180
PubMedArticle
63.
Craner  MJNewcombe  JBlack  JAHartle  CCuzner  MLWaxman  SG Molecular changes in neurons in MS: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/C2+ exchanger in the human CNS. Proc Natl Acad Sci U S A 2004;1018168- 8173
PubMedArticle
64.
Lo  ACSaab  CYBlack  JAWaxman  SG Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol 2003;903566- 3571
PubMedArticle
65.
Waxman  SG NO and the axonal death cascade. Ann Neurol 2003;53150- 154
PubMedArticle
66.
Kim  JELi  SGrandPre  TQiu  DStrittmatter  SM Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 2003;38187- 199
PubMedArticle
67.
Domeniconi  MCao  ZSpencer  T  et al.  Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 2002;35283- 290
PubMedArticle
68.
Cai  DDeng  KMellado  WLe  JRatan  RRFilbin  MT Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 2002;35711- 719
PubMedArticle
69.
Kappos  LMoeri  DRadue  EW  et al.  Predictive value of gadolinium-enhanced MRI for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Lancet 1999;353964- 969
PubMedArticle
70.
Filippi  MArnold  DLComi  G Magnetic Resonance Spectroscopy in Multiple Sclerosis.  Milan, Italy: Springer-Verlag; 2001
71.
Filippi  MBozzali  MRovaris  M  et al.  Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003;126433- 437
PubMedArticle
72.
Rovaris  MBozzali  MSantuccio  G  et al.  In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 2001;1242540- 2549
PubMedArticle
73.
Bozzali  MCercignani  MSormani  MPComi  GFilippi  M Quantification of brain gray matter damage in different MS phenotypes by use of diffusion tensor MR imaging. AJNR Am J Neuroradiol 2002;23985- 988
PubMed
74.
Filippi  MRocca  MA Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging. Curr Opin Neurol 2003;16275- 282
PubMedArticle
75.
Chabas  DBaranzini  SMitchell  D  et al.  The influence of the pro-inflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001;2941731- 1735
PubMedArticle
76.
Lock  CHermans  GPedotti  R  et al.  Gene microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002;8500- 508
PubMedArticle
77.
Steinman  LZamvil  S Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol 2003;3483- 493
PubMedArticle
78.
Vogt  MLopatinskaya  LSmits  MPolman  CHNagelkerken  L Elevated osteopontin levels are associated with disease activity in relapsing-remitting MS patients. Ann Neurol 2003;53819- 822
PubMedArticle
79.
Vollmer  TKey  LDurkalski  V  et al.  Oral simvastatin in relapsing-remitting multiple sclerosis. Lancet 2004;3631607- 1608
PubMedArticle
80.
Doolittle  THMyers  RHLehrich  JR  et al.  Multiple sclerosis sibling pairs: clustered onset and familial predisposition. Neurology 1990;401546- 1552
PubMedArticle
81.
Weinshenker  BGBulman  DCarriere  WBaskerville  JEbers  GC A comparison of sporadic and familial multiple sclerosis. Neurology 1990;401354- 1358
PubMedArticle
82.
Barcellos  LFOksenberg  JRGreen  AJ  et al.  Genetic basis for clinical expression in multiple sclerosis. Brain 2002;125150- 158
PubMedArticle
83.
Bulman  DESadovnick  ADEbers  GC Age of onset in siblings concordant for multiple sclerosis. Brain 1991;114937- 950
PubMedArticle
84.
Butterfield  RJBlankenhorn  EPRoper  RJZachary  JFDoerge  RWTeuscher  C Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am J Pathol 2000;157637- 645
PubMedArticle
85.
Mann  CLDavies  MBBoggild  MD  et al.  Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 2000;54552- 557
PubMedArticle
86.
Schrijver  HMCrusius  JBUitdehaag  BM  et al.  Association of interleukin-lbeta and interleukin-1 receptor antagonist genes with disease severity in MS. Neurology 1999;52595- 599
PubMedArticle
87.
Kantarci  OHAtkinson  EJHebrink  DDMcMurray  CTWeinshenker  BG Association of two variants in IL-1beta and IL-1 receptor antagonist genes with multiple sclerosis. J Neuroimmunol 2000;106220- 227
PubMedArticle
88.
Sciacca  FLFerri  CVandenbroeck  K  et al.  Canal, bi., and Grimaldi, L. M. Relevance of interleukin 1 receptor antagonist intron 2 polymorphism in Italian MS patients. Neurology 1999;521896- 1898
PubMedArticle
89.
Feakes  RSawcer  SBroadley  S  et al.  Interleukin 1 receptor antagonist (IL-lra) in multiple sclerosis. J Neuroimmunol 2000;10596- 101
PubMedArticle
90.
Barcellos  LFSchito  AMRimmler  JB  et al.  Multiple Sclerosis Genetics Group;CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Immunogenetics 2000;51281- 288
PubMedArticle
91.
Kantor  RBakhanashvili  MAchiron  A A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 2003;61238- 240
PubMedArticle
92.
Sellebjerg  FMadsen  HOJensen  CVJensen  JGarred  P CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 2000;10298- 106
PubMedArticle
93.
Haase  CGSchmidt  SFaustmann  PM Frequencies of the G-protein beta3 subunit C825T polymorphism and the delta 32 mutation of the chemokine receptor-5 in patients with multiple sclerosis. Neurosci Lett 2002;330293- 295
PubMedArticle
94.
Schreiber  KOtura  ABRyder  LP  et al.  Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRBl* 1501, CCR5 deletion mutation, apolipoprotein E). Mult Scler 2002;8295- 298
PubMedArticle
95.
Caillier  SBarcellos  LFBaranzini  SE  et al.  Osteopontin polymorphisms and disease course in multiple sclerosis. Genes Immun 2003;4312- 315
PubMedArticle
96.
Niino  MKikuchi  SFukazawa  TYabe  ITashiro  K Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J Neuroimmunol 2003;136125- 129
PubMedArticle
97.
Hensiek  AERoxburgh  RMeranian  M  et al.  Osteopontin gene and clinical severity of multiple sclerosis. J Neurol 2003;250943- 947
PubMedArticle
98.
Vandenbroeck  KMartino  GMarrosu  M  et al.  Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol 1997;76189- 192
PubMedArticle
99.
Kantarci  OHSchaefer-Klein  JLHebrink  DD  et al.  A population-based study of IL4 polymorphisms in multiple sclerosis. J Neuroimmunol 2003;137134- 139
PubMedArticle
100.
Engell  TRaun  NEThomsen  MPlatz  P HLA and heterogeneity of multiple sclerosis. Neurology 1982;321043- 1046
PubMedArticle
101.
Madigand  MOger  JJFauchet  RSabouraud  OGenetet  B HLA profiles in multiple sclerosis suggest two forms of disease and the existence of protective haplotypes. J Neurol Sci 1982;53519- 529
PubMedArticle
102.
Duquette  PDecary  FPleines  J  et al.  Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression. Can J Neurol Sci 1985;12106- 110
PubMed
103.
de la Concha  EGArroyo  RCrusius  JB  et al.  Combined effect of HLA-DRB 1 * 1501 and interleukin- 1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis. J Neuroimmunol 1997;80172- 178
PubMedArticle
104.
Celius  EGHarbo  HFEgeland  TVartdal  FVandvik  BSpurkiand  A Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J Neurol Sci 2000;178132- 135
PubMedArticle
105.
Masterman  TLigers  AOlsson  TAndersson  MOlerup  OHiller  J HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol 2000;48211- 219
PubMedArticle
106.
Hensiek  AESawcer  SJFeakes  R  et al.  HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry 2002;72184- 187
PubMedArticle
107.
Poser  SRitter  GBauer  HJGrosse-Wilde  HKuwert  EKRaun  NE HLA-antigens and the prognosis of multiple sclerosis. J Neurol 1981;225219- 221
PubMedArticle
108.
Runmarker  BMartinsson  TWahlstrom  JAndersen  O HLA and prognosis in multiple sclerosis. J Neurol 1994;241385- 390
PubMedArticle
109.
Weinshenker  BGSantrach  PBissonet  AS  et al.  Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study. Neurology 1998;51742- 747
PubMedArticle
110.
McDonnell  GVMawhinney  HGraham  CAHawkins  SAMiddleton  D A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis. J Neurol Sci 1999;16577- 83
PubMedArticle
111.
Villoslada  PBarcellos  LFRio  J  et al.  The HLA locus and multiple sclerosis in Spain: role in disease susceptibility, clinical course and response to interferon-beta. J Neuroimmunol 2002;130194- 201
PubMedArticle
112.
Kira  JKanai  TNishimura  Y  et al.  Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol 1996;40569- 574
PubMedArticle
113.
Hauser  SLOksenberg  JRLincoln  R  et al. Optic Neuritis Study Group, Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS. Neurology 2000;541859- 1861
PubMedArticle
114.
Olerup  OHillert  JFredrikson  S  et al.  Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A 1989;867113- 7117
PubMedArticle
115.
Kantarci  OHde Andrade  MWeinshenker  BG Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002;123144- 159
PubMedArticle
116.
Zhou  QRammohan  KLin  S  et al.  CD24 is a genetic modifier for risk and progression of multiple sclerosis. Proc Natl Acad Sci U S A 2003;10015041- 15046
PubMedArticle
117.
Kikuchi  SFukazawa  TNiino  M  et al.  Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB 1 * 1501 and disease modulation. J Neuroimmunol 2002;12877- 81
PubMedArticle
118.
Mattila  KMLuomala  MLehtimaki  TLaippala  PKoivula  TElovaara  I Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 2001;561246- 1247
PubMedArticle
119.
Kantarci  OHHebrink  DDAchenbach  SJ  et al.  CD95 polymorphisms are associated with susceptibility to MS in women: a population-based study of CD95 and CD95L in MS. J Neuroimmunol 2004;146162- 170
PubMedArticle
120.
Giess  RMaurer  MLinker  R  et al.  Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol 2002;59407- 409
PubMedArticle
121.
Hoffmann  VHardt  C A null mutation in the CNTF gene is not associated with early onset of multiple sclerosis. Arch Neurol 2002;591974
PubMedArticle
122.
Hoffmann  VPohlau  DPrzuntek  HEpplen  JTHardt  C A null mutation within the ciliary neurotrophic factor (CNTF)-gene: implications for susceptibility and disease severity in patients with multiple sclerosis. Genes Immun 2002;353- 55
PubMedArticle
123.
van Veen  Tvan Winsen  LCrusius  JB  et al.  [Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype. Neurology 2003;611245- 1249
PubMedArticle
124.
Shinar  YLivneh  AVilla  Y  et al.  Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003;4197- 203
PubMedArticle
125.
Evangelou  NJackson  MBeeson  DPalace  J Association of the APOE epsilon4 allele with disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999;67203- 205
PubMedArticle
126.
Fazekas  FStrasser-Fuchs  SSchmidt  H  et al.  Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;6925- 28
PubMedArticle
127.
Hogh  POturai  ASchreiber  K  et al.  Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. Mult Scler 2000;6226- 230
PubMedArticle
128.
Chapman  JVinokurov  SAchiron  A  et al.  APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 2001;56312- 316
PubMedArticle
129.
Fazekas  FStrasser-Fuchs  SKollegger  H  et al.  Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology 2001;57853- 857
PubMedArticle
130.
Enzinger  CRopele  SSmith  S  et al.  Accelerated evolution of brain atrophy and “black holes” in MS patients with APOE-epsilon 4. Ann Neurol 2004;55563- 569
PubMedArticle
131.
Ferri  CSciacca  FLVeglia  F  et al.  APOE epsilon2-4 and -491 polymorphisms are not associated with MS. Neurology 1999;53888- 889
PubMedArticle
132.
Weatherby  SJMann  CLFryer  AA  et al.  No association between the APOE epsilon4 allele and outcome and susceptibility in primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68532Article
133.
Masterman  TZhang  ZHellgren  D  et al.  APOE genotypes and disease severity in multiple sclerosis. Mult Scler 2002;898- 103
PubMedArticle
134.
Savettieri  GAndreoli  VBonavita  S  et al.  Apolipoprotein E genotype does not influence the progression of multiple sclerosis. J Neurol 2003;2501094- 1098
PubMedArticle
135.
Ballerini  CCampani  DRombola  G  et al.  Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis. Neurosci Lett 2000;296174- 176
PubMedArticle
136.
Schmidt  SBarcellos  LFDeSombre  K  et al.  Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002;70708- 717
PubMedArticle
137.
Kantarci  OHHebrink  DDAchenbach  SJ  et al.  Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 2004;62811- 814
PubMedArticle
138.
Green  AJBarcellos  LFRimmler  JB  et al.  Sequence variation in the transforming growth factor-betal (TGFB1) gene and multiple sclerosis susceptibility. J Neuroimmunol 2001;116116- 124
PubMedArticle
139.
Barcellos  LFOksenberg  JRBegovich  AB  et al.  HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003;72710- 716
PubMedArticle
140.
Garcia-Merino  AAlper  CAUsuku  K  et al.  Tumor necrosis factor microsatellite haplotypes in relation to extended haplotypes, susceptibility to diseases associated with the major histocompatibility complex, and TNF secretion. Hum Immunol 1996;5011- 21
PubMedArticle
×