Autoantigen- und erregerspezifische T- und B-Zellreaktionen bei multipler Sklerose: „Eine unendliche Geschichte”?

Zusammenfassung

Multiple Sklerose (MS) ist eine chronisch entzündliche Erkrankung des zentralen Nervensystems. Trotz umfangreicher Forschungsarbeiten bleiben die Ursachen der Erkrankung bisher noch immer ungeklärt. Akzeptiert ist, dass es durch eine immunologische Attacke gegen Myelin und wahrscheinlich auch Neurone zu einer zunehmenden Behinderung der Patienten kommt. Auch wenn mehrere Kandidaten-Autoantigene bei MS diskutiert werden, so ist doch bisher kein für die pathologische Immunreaktion verantwortliches Autoantigen wie z. B. der Azetylcholinrezeptor bei Myasthenia gravis sicher identifiziert worden. Unser Labor hat kürzlich Neurofascin, das an den Ranvier'schen Schnürringen konzentriert ist, als Zielstruktur für Autoantikörper identifiziert. In einem Tiermodell verursachten Antikörper gegen Neurofascin einen axonalen Schaden. Die Bedeutung dieser Neurofascin-Autoantikörper für MS-Patienten wird gegenwärtig untersucht. Aktuell ist lediglich die Bestimmung der Aquaporin-4-Antikörper von klinischer Relevanz, durch die die klinische Diagnose einer Neuromyelitis optica (NMO, Morbus Devic) unterstützt werden kann. Eine darüber hinausgehende Bestimmung von Antikörpern gegen Myelinantigene oder infektiöse Erreger ist zum derzeitigen Wissensstand für die klinische Diagnostik nicht sinnvoll. Ähnlich wie bei der humoralen hat sich auch bei der T-zellulären Immunantwort kein Autoantigen oder T-Zellphänotyp als MS-krankheitsspezifisch erwiesen. Die aktuelle Forschung konzentriert sich auf antigenbasierte Therapien, die den theoretischen Vorteil einer hohen Effizienz bei verminderten Nebenwirkungen bieten. Ziel dieses Artikels ist es, einige in der aktuellen Forschung im Vordergrund stehende Antigene zu diskutieren. Die Kenntnis relevanter Antigene bei MS würde neben einem besseren Verständnis für die Pathogenese auch die Möglichkeit eröffnen, Biomarker für den Krankheitsverlauf und das Therapiemonitoring und eventuell antigenbasierte Therapiekonzepte zu entwickeln.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In spite of immense efforts in research the cause of the disease is still unknown. It is well accepted that myelin and probably also neurons are damaged by the immune system. This damage leads to permanent disability in the patients. Unlike myasthenia, in MS the responsible autoantigen for the immune attack has not been discovered so far in spite of extensive research on a variety of candidate autoantigens. We have recently identified neurofascin which is located at the node of Ranvier as a target of autoantibodies. Antibodies against neurofascin induced an axonal damage in an animal model of MS. The relevance of these autoantibodies is currently under investigation. Just recently, it has been found that antibodies against aquaporin 4 are a prominent feature in neuromyelitis optica (NMO). They are currently in clinical use to support the diagnosis of NMO. Beyond this, any antibody testing for myelin antigens or viral antigens is not of clinical utility. Similar to the humoral immune response, no T-cell autoantigen or phenotype has been proven to be MS specific. The current research centres on antigen-based therapies that have the theoretical advantage of a high efficacy while minimising potential adverse effects. The aim of this review is to present some of the recently discussed antigens. More information about relevant antigens in MS would not only lead to a better understanding of the pathogenesis of the disease but would also open new possibilities to develop biomarkers for disease and therapy monitoring and maybe also antigen-based therapies.

Schlüsselwörter

multiple Sklerose - T-Zellen - Antikörper

Key words

multiple sclerosis - T-cells - antibodies

Literatur

• 1 Kornek B, Lassmann H. Neuropathology of multiple sclerosis-new concepts.  Brain Res Bull. 2003;  61 321-326
• 2 Krumbholz M, Theil D, Derfuss T. et al . BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma.  J Exp Med. 2005;  201 195-200
• 3 Meinl E, Krumbholz M, Hohlfeld R. B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation.  Ann Neurol. 2006;  59 880-892
• 4 Krumbholz M, Theil D, Cepok S. et al . Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.  Brain. 2006;  129 200-211
• 5 Krumbholz M, Theil D, Steinmeyer F. et al . CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions.  J Neuroimmunol. 2007;  190 72-79
• 6 Keegan M, Konig F, McClelland R. et al . Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange.  Lancet. 2005;  366 579-582
• 7 Stuve O, Cepok S, Elias B. et al . Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.  Arch Neurol. 2005;  62 1620-1623
• 8 Hauser S L, Waubant E, Arnold D L. et al . B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.  N Engl J Med. 2008;  358 676-688
• 9 Hemmer B, Hartung H P. Toward the development of rational therapies in multiple sclerosis: what is on the horizon?.  Ann Neurol. 2007;  62 314-326
• 10 Sospedra M, Martin R. Immunology of multiple sclerosis.  Annu Rev Immunol. 2005;  23 683-747
• 11 Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines.  Proc Natl Acad Sci U S A. 2004;  101, Suppl 2 14599-14606
• 12 Olsson T, Sun J, Hillert J. et al . Increased numbers of T cells recognizing multiple myelin basic protein epitopes in multiple sclerosis.  Eur J Immunol. 1992;  22 1083-1087
• 13 Burns J, Rosenzweig A, Zweiman B, Lisak R P. Isolation of myelin basic protein-reactive T-cell lines from normal human blood.  Cell Immunol. 1983;  81 435-440
• 14 Meinl E, Hoch R M, Dornmair K. et al . Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques.  Am J Pathol. 1997;  150 445-453
• 15 Wekerle H, Kojima K, Lannesvieira J. et al . Animal-Models.  Ann Neurol. 1994;  36 S47-S53
• 16 Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.  Brain. 2006;  129 1953-1971
• 17 Madsen L S, Andersson E C, Jansson L. et al . A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor.  Nat Genet. 1999;  23 343-347
• 18 Krogsgaard M, Wucherpfennig K W, Cannella B. et al . Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85 – 99 complex.  J Exp Med. 2000;  191 1395-1412
• 19 Faria A M, Weiner H L. Oral tolerance.  Immunol Rev. 2005;  206 232-259
• 20 Fontoura P, Garren H, Steinman L. Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides.  Int Rev Immunol. 2005;  24 415-446
• 21 Garren H, Ruiz P J, Watkins T A. et al . Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway.  Immunity. 2001;  15 15-22
• 22 Gaur A, Boehme S A, Chalmers D. et al . Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms.  J Neuroimmunol. 1997;  74 149-158
• 23 Benson J M, Stuckman S S, Cox K L. et al . Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis.  J Immunol. 1999;  162 6247-6254
• 24 Weiner H L, Mackin G A, Matsui M. et al . Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis.  Science. 1993;  259 1321-1324
• 25 Panitch H, Francis G. Clinical results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis.  Ann Neurol. 1997;  42 459
• 26 Francis G, Evans A, Panitch H. MRI results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis.  Ann Neurol. 1997;  42 467
• 27 Bielekova B, Goodwin B, Richert 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;  6 1167-1175
• 28 Kappos L, Comi G, Panitch H. et al . 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, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group.  Nat Med. 2000;  6 1176-1182
• 29 Bar-Or A, Vollmer T, Antel J. et al . Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.  Arch Neurol. 2007;  64 1407-1415
• 30 Tang D C, DeVit M, Johnston S A. Genetic immunization is a simple method for eliciting an immune response.  Nature. 1992;  356 152-154
• 31 Lobell A, Weissert R, Storch M K. et al . Vaccination with DNA encoding an immunodominant myelin basic protein peptide targeted to Fc of immunoglobulin G suppresses experimental autoimmune encephalomyelitis.  J Exp Med. 1998;  187 1543-1548
• 32 Berger T, Rubner P, Schautzer F. et al . Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.  N Engl J Med. 2003;  349 139-145
• 33 Kuhle J, Pohl C, Mehling M. et al . Lack of association between antimyelin antibodies and progression to multiple sclerosis.  N Engl J Med. 2007;  356 371-378
• 34 Kuhle J, Lindberg R LP, Regeniter A. et al . Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF.  J Neurol. 2007;  254 160-168
• 35 Rauer S, Euler B, Reindl M, Berger T. Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event.  J Neurol Neurosurg Psychiatry. 2006;  77 739-742
• 36 Litzenburger T, Fassler R, Bauer J. et al . B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.  J Exp Med. 1998;  188 169-180
• 37 Genain C P, Cannella B, Hauser S L, Raine C S. Identification of autoantibodies associated with myelin damage in multiple sclerosis.  Nat Med. 1999;  5 170-175
• 38 O'Connor K C, Appel H, Bregoli L. et al . Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein.  J Immunol. 2005;  175 1974-1982
• 39 Zhou D, Srivastava R, Nessler S. et al . Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis.  Proc Natl Acad Sci U S A. 2006;  103 19057-19062
• 40 Lalive P H, Menge T, Delarasse C. et al . Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis.  Proc Natl Acad Sci U S A. 2006;  103 2280-2285
• 41 O'Connor K C, McLaughlin K A, De Jager P L. et al . Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.  Nat Med. 2007;  13 211-217
• 42 Lennon V A, Kryzer T J, Pittock S J. et al . IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.  J Exp Med. 2005;  202 473-477
• 43 Lennon V A, Wingerchuk D M, Kryzer T J. et al . A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.  Lancet. 2004;  364 2106-2112
• 44 Jarius S, Franciotta D, Bergamaschi R. et al . NMO-IgG in the diagnosis of neuromyelitis optica.  Neurology. 2007;  68 1076-1077
• 45 Wingerchuk D M, Weinshenker B G. Neuromyelitis Optica.  Curr Treat Options Neurol. 2005;  7 173-182
• 46 Watanabe S, Nakashima I, Misu T. et al . Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica.  Mult Scler. 2007;  13 128-132
• 47 Beyer A M, Wandinger K P, Siebert E. et al . Neuromyelitis optica in a patient with an early onset demyelinating episode: clinical and autoantibody findings.  Clin Neurol Neurosurg. 2007;  109 926-930
• 48 Paul F, Jarius S, Aktas O. et al . Antibody to aquaporin 4 in the diagnosis of neuromyelitis optica.  PLoS Med. 2007;  4 e133
• 49 Misu T, Fujihara K, Kakita A. et al . Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis.  Brain. 2007;  130 1224-1234
• 50 Roemer S F, Parisi J E, Lennon V A. et al . Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis.  Brain. 2007;  130 1194-1205
• 51 Wingerchuk D M. Neuromyelitis optica: new findings on pathogenesis.  Int Rev Neurobiol. 2007;  79 665-688
• 52 Ousman S S, Tomooka B H, van Noort J M. et al . Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination.  Nature. 2007;  448 474-479
• 53 Masilamoni J G, Jesudason E P, Baben B. et al . Molecular chaperone alpha-crystallin prevents detrimental effects of neuroinflammation.  Biochim Biophys Acta. 2006;  1762 284-293
• 54 Iwaki T, Wisniewski T, Iwaki A. et al . Accumulation of alpha B-crystallin in central nervous system glia and neurons in pathologic conditions.  Am J Pathol. 1992;  140 345-356
• 55 van Noort J M, Vansechel A C, Bajramovic J J. et al . The Small Heat-Shock Protein Alpha-B-Crystallin As Candidate Autoantigen in Multiple-Sclerosis.  Nature. 1995;  375 798-801
• 56 Moyano J V, Evans J R, Chen F. et al . AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer.  J Clin Invest. 2006;  116 261-270
• 57 Trapp B D, Peterson J, Ransohoff R M. et al . Axonal transection in the lesions of multiple sclerosis.  N Engl J Med. 1998;  338 278-285
• 58 Dutta R, Trapp B D. Pathogenesis of axonal and neuronal damage in multiple sclerosis.  Neurology. 2007;  68 S22-S31
• 59 Wolswijk G, Balesar R. Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis.  Brain. 2003;  126 1638-1649
• 60 Coman I, Aigrot M S, Seilhean D. et al . Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.  Brain. 2006;  129 3186-3195
• 61 Mathey E K, Derfuss T, Storch M K. et al . Neurofascin as a novel target for autoantibody-mediated axonal injury.  J Exp Med. 2007;  204 2363-2372
• 62 Howell O W, Palser A, Polito A. et al . Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.  Brain. 2006;  129 3173-3185
• 63 Shamshiev A, Donda A, Carena I. et al . Self glycolipids as T-cell autoantigens.  Eur J Immunol. 1999;  29 1667-1675
• 64 Ilyas A A, Chen Z W, Cook S D. Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis.  J Neuroimmunol. 2003;  139 76-80
• 65 Kanter J L, Narayana S, Ho P P. et al . Lipid microarrays identify key mediators of autoimmune brain inflammation.  Nat Med. 2006;  12 138-143
• 66 Sriram S, Mitchell W, Stratton C. Multiple sclerosis associated with Chlamydia pneumoniae infection of the CNS.  Neurology. 1998;  50 571-572
• 67 Sriram S, Stratton C W, Yao S. et al . Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis.  Ann Neurol. 1999;  46 6-14
• 68 Yao S Y, Stratton C W, Mitchell W M, Sriram S. CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens.  Neurology. 2001;  56 1168-1176
• 69 Sriram S, Ljunggren-Rose A, Yao S Y, Whetsell Jr W O. Detection of chlamydial bodies and antigens in the central nervous system of patients with multiple sclerosis.  J Infect Dis. 2005;  192 1219-1228
• 70 Du C, Yao S Y, Ljunggren-Rose A, Sriram S. Chlamydia pneumoniae infection of the central nervous system worsens experimental allergic encephalitis.  J Exp Med. 2002;  196 1639-1644
• 71 Lenz D C, Lu L, Conant S B. et al . A Chlamydia pneumoniae-specific peptide induces experimental autoimmune encephalomyelitis in rats.  J Immunol. 2001;  167 1803-1808
• 72 Swanborg R H, Boros D L, Whittum-Hudson J A, Hudson A P. Molecular mimicry and horror autotoxicus: do chlamydial infections elicit autoimmunity?.  Expert Rev Mol Med. 2006;  8 1-23
• 73 Boman J, Roblin P M, Sundstrom P. et al . Failure to detect Chlamydia pneumoniae in the central nervous system of patients with MS.  Neurology. 2000;  54 265
• 74 Hammerschlag M R, Ke Z, Lu F. et al . Is Chlamydia pneumoniae present in brain lesions of patients with multiple sclerosis?.  J Clin Microbiol. 2000;  38 4274-4276
• 75 Ke Z, Lu F, Roblin P. et al . Lack of detectable Chlamydia pneumoniae in brain lesions of patients with multiple sclerosis.  Ann Neurol. 2000;  48 400
• 76 Morre S A, De Groot C J, Killestein J. et al . Is Chlamydia pneumoniae present in the central nervous system of multiple sclerosis patients?.  Ann Neurol. 2000;  48 399
• 77 Pucci E, Taus C, Cartechini E. et al . Lack of Chlamydia infection of the central nervous system in multiple sclerosis.  Ann Neurol. 2000;  48 399-400
• 78 Hammerschlag M R, Apfalter P, Boman J. et al . The role of Chlamydia pneumoniae in multiple sclerosis: real or fictitious?.  J Infect Dis. 2005;  192 1305-1307
• 79 Derfuss T, Gurkov R, Bergh F T. et al . Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.  Brain. 2001;  124 1325-1335
• 80 Woessner R, Grauer M T, Frese A. et al . Long-term antibiotic treatment with roxithromycin in patients with multiple sclerosis.  Infection. 2006;  34 342-344
• 81 Lunemann J D, Kamradt T, Martin R, Munz C. Epstein-barr virus: environmental trigger of multiple sclerosis?.  J Virol. 2007;  81 6777-6784
• 82 Swanborg R H, Whittum-Hudson J A, Hudson A P. Infectious agents and multiple sclerosis – are Chlamydia pneumoniae and human herpes virus 6 involved?.  J Neuroimmunol. 2003;  136 1-8
• 83 Ahlqvist J, Fotheringham J, Akhyani N. et al . Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes.  J Neurovirol. 2005;  11 384-394
• 84 Hall C B, Caserta M T, Schnabel K C. et al . Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A.  Clin Infect Dis. 1998;  26 132-137
• 85 Hufner K, Arbusow V, Himmelein S. et al . The prevalence of human herpesvirus 6 in human sensory ganglia and its co-occurrence with alpha-herpesviruses.  J Neurovirol. 2007;  13 462-467
• 86 Campadelli-Fiume G, Mirandola P, Menotti L. Human herpesvirus 6: An emerging pathogen.  Emerg Infect Dis. 1999;  5 353-366
• 87 Wilborn F, Schmidt C A, Brinkmann V. et al . A potential role for human herpesvirus type 6 in nervous system disease.  J Neuroimmunol. 1994;  49 213-214
• 88 Challoner P B, Smith K T, Parker J D. et al . Plaque-associated expression of human herpesvirus 6 in multiple sclerosis.  Proc Natl Acad Sci U S A. 1995;  92 7440-7444
• 89 Tuke P W, Hawke S, Griffiths P D, Clark D A. Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains.  Mult Scler. 2004;  10 355-359
• 90 Opsahl M L, Kennedy P G. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter.  Brain. 2005;  128 516-527
• 91 Goodman A D, Mock D J, Powers J M. et al . Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions.  J Infect Dis. 2003;  187 1365-1376
• 92 Soldan S S, Berti R, Salem N. et al . Association of human herpes virus 6 (HHV-6) with multiple sclerosis: Increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA.  Nat Med. 1997;  3 1394-1397
• 93 Tejada-Simon M V, Zang Y C, Hong J. et al . Detection of viral DNA and immune responses to the human herpesvirus 6 101-kilodalton virion protein in patients with multiple sclerosis and in controls.  J Virol. 2002;  76 6147-6154
• 94 Berti R, Brennan M B, Soldan S S. et al . Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression.  J Neurovirol. 2002;  8 250-256
• 95 Alvarez-Lafuente R, De L H, Bartolome M. et al . Human herpesvirus 6 and multiple sclerosis: a one-year follow-up study.  Brain Pathol. 2006;  16 20-27
• 96 Chapenko S, Millers A, Nora Z. et al . Correlation between HHV-6 reactivation and multiple sclerosis disease activity.  J Med Virol. 2003;  69 111-117
• 97 Akhyani N, Berti R, Brennan M B. et al . Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis.  J Infect Dis. 2000;  182 1321-1325
• 98 Soldan S S, Leist T P, Juhng K N. et al . Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients.  Ann Neurol. 2000;  47 306-313
• 99 Kong H, Baerbig Q, Duncan L. et al . Human herpesvirus type 6 indirectly enhances oligodendrocyte cell death.  J Neurovirol. 2003;  9 539-550
• 100 Gardell J L, Dazin P, Islar J. et al . Apoptotic effects of Human Herpesvirus-6A on glia and neurons as potential triggers for central nervous system autoimmunity.  J Clin Virol. 2006;  37, Suppl 1 S11-S16
• 101 Tejada-Simon M V, Zang Y C, Hong J. et al . Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis.  Ann Neurol. 2003;  53 189-197
• 102 Cirone M, Cuomo L, Zompetta C. et al . Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens.  J Med Virol. 2002;  68 268-272
• 103 Taus C, Pucci E, Cartechini E. et al . Absence of HHV-6 and HHV-7 in cerebrospinal fluid in relapsing-remitting multiple sclerosis.  Acta Neurol Scand. 2000;  101 224-228
• 104 Mirandola P, Stefan A, Brambilla E. et al . Absence of human herpesvirus 6 and 7 from spinal fluid and serum of multiple sclerosis patients.  Neurology. 1999;  53 1367-1368
• 105 Mayne M, Krishnan J, Metz L. et al . Infrequent detection of human herpesvirus 6 DNA in peripheral blood mononuclear cells from multiple sclerosis patients.  Ann Neurol. 1998;  44 391-394
• 106 Martin C, Enbom M, Soderstrom M. et al . Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis.  Acta Neurol Scand. 1997;  95 280-283
• 107 Enbom M, Wang F Z, Fredrikson S. et al . Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls.  Clin Diagn Lab Immunol. 1999;  6 545-549
• 108 Derfuss T, Hohlfeld R, Meinl E. Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20 % of multiple sclerosis patients and might be linked to a polyspecific B-cell response.  J Neurol. 2005;  252 968-971
• 109 Friedman J E, Zabriskie J B, Plank C. et al . A randomized clinical trial of valacyclovir in multiple sclerosis.  Mult Scler. 2005;  11 286-295
• 110 Hochberg D, Middeldorp J M, Catalina M. et al . Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo.  Proc Natl Acad Sci U S A. 2004;  101 239-244
• 111 Nielsen T R, Rostgaard K, Nielsen N M. et al . Multiple sclerosis after infectious mononucleosis.  Arch Neurol. 2007;  64 72-75
• 112 Thacker E L, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis.  Ann Neurol. 2006;  59 499-503
• 113 Ascherio A, Munger K L, Lennette E T. et al . Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study.  JAMA. 2001;  286 3083-3088
• 114 Bray P F, Bloomer L C, Salmon V C. et al . Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis.  Arch Neurol. 1983;  40 406-408
• 115 Levin L I, Munger K L, Rubertone M V. et al . Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis.  JAMA. 2005;  293 2496-2500
• 116 Sundstrom P, Juto P, Wadell G. et al . An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.  Neurology. 2004;  62 2277-2282
• 117 Villoslada P, Juste C, Tintore M. et al . The immune response against herpesvirus is more prominent in the early stages of MS.  Neurology. 2003;  60 1944-1948
• 118 Wandinger K, Jabs W, Siekhaus A. et al . Association between clinical disease activity and Epstein-Barr virus reactivation in MS.  Neurology. 2000;  55 178-184
• 119 Pariente M, Bartolome J, Lorente S, Crespo M D. [Age distribution of serological profiles of Epstein-Barr virus infection: review of results from a diagnostic laboratory].  Enferm Infecc Microbiol Clin. 2007;  25 108-110
• 120 Alotaibi S, Kennedy J, Tellier R. et al . Epstein-Barr virus in pediatric multiple sclerosis.  JAMA. 2004;  291 1875-1879
• 121 Banwell B, Krupp L, Kennedy J. et al . Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study.  Lancet Neurol. 2007;  6 773-781
• 122 DeLorenze G N, Munger K L, Lennette E T. et al . Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up.  Arch Neurol. 2006;  63 839-844
• 123 Cepok S, Zhou D, Srivastava R. et al . Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis.  J Clin Invest. 2005;  115 1352-1360
• 124 Bray P F, Luka J, Bray P F. et al . Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein.  Neurology. 1992;  42 1798-1804
• 125 Wucherpfennig K W, Strominger J L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein.  Cell. 1995;  80 695-705
• 126 Lang H L, Jacobsen H, Ikemizu S. et al . A functional and structural basis for TCR cross-reactivity in multiple sclerosis.  Nat Immunol. 2002;  3 940-943
• 127 Lunemann J D, Edwards N, Muraro P A. et al . Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis.  Brain. 2006;  129 1493-1506
• 128 Balandraud N, Meynard J B, Auger I. et al . Epstein-Barr virus load in the peripheral blood of patients with rheumatoid arthritis: accurate quantification using real-time polymerase chain reaction.  Arthritis Rheum. 2003;  48 1223-1228
• 129 Kang I, Quan T, Nolasco H. et al . Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus.  J Immunol. 2004;  172 1287-1294
• 130 Serafini B, Rosicarelli B, Magliozzi R. et al . Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis.  Brain Pathol. 2004;  14 164-174
• 131 Serafini B, Rosicarelli B, Franciotta D. et al . Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.  J Exp Med. 2007;  204 2899-2912
• 132 Caldwell R G, Wilson J B, Anderson S J, Longnecker R. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals.  Immunity. 1998;  9 405-411