Advertisement

B- and T-cell responses in multiple sclerosis: Novel approaches offer new insights

      Abstract

      In experimental autoimmune encephalomyelitis (EAE), several target antigens of encephalitogenic T- and B-cell responses have been identified. However, in human multiple sclerosis (MS) the target antigens of pathogenic T and B cells have remained conjectural. Here we discuss how recent methodological advances have offered new insights into the nature of B- and T-cell receptor repertoires expressed in MS tissues, and how novel approaches have helped to identify neurofascin as a target of anti-axonal autoantibodies in MS and EAE.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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
        • Steinman L.
        Optic neuritis, a new variant of experimental encephalomyelitis, a durable model for all seasons, now in its seventieth year.
        J Exp Med. 2003; 197: 1065-1071
        • Ben-Nun A.
        • Wekerle H.
        • Cohen I.R.
        The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis.
        Eur J Immunol. 1981; 11: 195-199
        • Schluesener H.J.
        • Sobel R.A.
        • Linington C.
        • Weiner H.L.
        A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease.
        J Immunol. 1987; 139: 4016-4021
        • Linington C.
        • Bradl M.
        • Lassmann H.
        • Brunner C.
        • Vass K.
        Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.
        Am J Pathol. 1988; 130: 443-454
        • Huseby E.S.
        • Liggitt D.
        • Brabb T.
        • Schnabel B.
        • Öhlén C.
        • Goverman J.
        A pathogenic role for myelin specific CD8+ T cells in a model for multiple sclerosis.
        J Exp Med. 2001; 194: 669-676
        • Sun D.M.
        • Whitaker J.N.
        • Huang Z.G.
        • Liu D.
        • Coleclough C.
        • Wekerle H.
        • et al.
        Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice.
        J Immunol. 2001; 166: 7579-7587
        • Friese M.A.
        • Fugger L.
        Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?.
        Brain. 2005; 128: 1747-1763
        • Dornmair K.
        • Goebels N.
        • Weltzien H.U.
        • Wekerle H.
        • Hohlfeld R.
        T-cell-mediated autoimmunity — novel techniques to characterize autoreactive T-cell receptors.
        Am J Pathol. 2003; 163: 1215-1226
        • Davis M.M.
        • Bjorkman P.J.
        T-cell antigen receptor genes and T-cell recognition.
        Nature. 1988; 334: 395-402
        • Arstila T.P.
        • Casrouge A.
        • Baron V.
        • Even J.
        • Kanellopoulos J.
        • Kourilsky P.
        A direct estimate of the human ab T cell receptor diversity.
        Science. 1999; 286: 958-961
        • Oksenberg J.R.
        • Stuart S.
        • Begovich A.B.
        • Bell R.B.
        • Erlich H.A.
        • Steinman L.
        • et al.
        Limited heterogeneity of rearranged T-cell receptor Va transcripts in brains of multiple sclerosis patients.
        Nature. 1990; 345: 344-346
        • Oksenberg J.R.
        • Panzara M.A.
        • Begovich A.B.
        • Mitchell D.
        • Erlich H.A.
        • Murray R.S.
        • et al.
        Selection for T-cell receptor Vb–Db–Jb gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis.
        Nature. 1993; 362: 68-70
        • Babbe H.
        • Roers A.
        • Waisman A.
        • Lassmann H.
        • Goebels N.
        • Hohlfeld R.
        • et al.
        Clonal expansion of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions shown by micromanipulation and single cell polymerase chain reaction.
        J Exp Med. 2000; 192: 393-404
        • Skulina C.
        • Schmidt S.
        • Dornmair K.
        • Babbe H.
        • Roers A.
        • Rajewsky K.
        • et al.
        Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood.
        Proc Natl Acad Sci U S A. 2004; 101: 2428-2433
        • Steinman L.
        Myelin specific CD8 T cells in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis.
        J Exp Med. 2001; 194: F27-F30
        • 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: 14599-14606
        • Pannetier C.
        • Even J.
        • Kourilsky P.
        T-cell repertoire diversity and clonal expansions in normal and clinical samples.
        Immunol Today. 1995; 16: 176-181
        • Matsumoto Y.
        • Yoon W.K.
        • Jee Y.
        • Fujihara K.
        • Misu T.
        • Sato S.
        • et al.
        Complementarity-determining region 3 spectratype analysis of the TCR repertoire in multiple sclerosis.
        J Immunol. 2003; 170: 4846-4853
        • Muraro P.A.
        • Wandinger K.P.
        • Bielekova B.
        • Gran B.
        • Marques A.
        • Utz U.
        • et al.
        Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders.
        Brain. 2003; 126: 20-31
        • Laplaud D.A.
        • Ruiz C.
        • Wiertlewski S.
        • Brouard S.
        • Berthelot L.
        • Guillet M.
        • et al.
        Blood T-cell receptor b chain transcriptome in multiple sclerosis. Characterization of the T cells with altered CDR3 length distribution.
        Brain. 2004; 127: 981-995
        • Junker A.
        • Ivanidze J.
        • Malotka J.
        • Eiglmeier I.
        • Lassmann H.
        • Wekerle H.
        • et al.
        Multiple sclerosis: T-cell receptor expression in distinct brain regions.
        Brain. 2007; 130: 2789-2799
        • Wraith D.C.
        • McDevitt H.O.
        • Steinman L.
        • Acha-Orbea H.
        T cell recognition as the target for immune intervention in autoimmune disease.
        Cell. 1989; 57: 709-715
        • Waisman A.
        • Ruiz P.J.
        • Hirschberg D.L.
        • Gelman A.
        • Oksenberg J.R.
        • Brocke S.
        • et al.
        Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity.
        Nature Med. 1996; 2: 899-905
        • Bourdette D.N.
        • Edmonds E.
        • Smith C.
        • Bowen J.D.
        • Guttmann C.R.G.
        • Nagy Z.P.
        • et al.
        A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis.
        MS. 2005; 11: 552-561
        • Seitz S.
        • Schneider C.K.
        • Malotka J.
        • Nong X.
        • Engel A.G.
        • Wekerle H.
        • et al.
        Reconstitution of paired T cell receptor a- and b-chains from microdissected single cells of human inflammatory tissues.
        Proc Natl Acad Sci U S A. 2006; 103: 12057-12062
        • Hemmer B.
        • Archelos J.J.
        • Hartung H.P.
        New concepts in the immunopathogenesis of multiple sclerosis.
        Nature Rev Neurosci. 2002; 3: 291-301
        • Neumann H.
        • Medana I.M.
        • Bauer J.
        • Lassmann H.
        Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases.
        Trends Neurosci. 2002; 25: 313-319
        • Archelos J.J.
        • Storch M.K.
        • Hartung H.P.
        The role of B cells and autoantibodies in multiple sclerosis.
        Ann Neurol. 2000; 46: 694-706
        • Qin Y.
        • Duquette P.
        • Zhang Y.
        • Poole R.
        • Antel J.P.
        Clonal expansion and somatic hypermutation of VH genes of B cells from cerebrospinal fluid in multiple sclerosis.
        J Clin Invest. 1998; 102: 1045-1050
        • Owens G.P.
        • Kraus H.
        • Burgoon M.P.
        • Smith-Jensen T.
        • Devlin M.E.
        • Gilden D.H.
        Restricted use of VH4 germline segments in an acute multiple sclerosis brain.
        Ann Neurol. 1998; 43: 236-243
        • Baranzini S.E.
        • Jeong M.C.
        • Butunoi C.
        • Murray R.S.
        • Bernard C.C.A.
        • Oksenberg J.R.
        B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions.
        J Immunol. 1999; 163: 5133-5144
        • Colombo M.
        • Dono M.
        • Gazzola P.
        • Roncella S.
        • Valetto A.
        • Chiorazzi N.
        • et al.
        Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients.
        J Immunol. 2000; 164: 2782-2789
        • Owens G.C.
        • Ritchie A.M.
        • Burgoon M.P.
        • Williamson R.A.
        • Corboy J.R.
        • Gilden D.H.
        Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid.
        J Immunol. 2003; 171: 2725-2733
      1. Obermeier B, Mentele R, Malotka J, Kellermann J, Kumpfel T, Wekerle H, et al. Matching of oligoclonal Ig transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nature Med. in press.

        • Monson N.L.
        • Brezinschek H.P.
        • Brezinschek R.
        • Mobley A.
        • Vaughan G.K.
        • Frohman E.M.
        • et al.
        Receptor revision and atypical mutational characteristics in clonally expanded B cells from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients.
        J Neuroimmunol. 2005; 158: 170-181
        • Mathey E.K.
        • Derfuss T.
        • Storch M.K.
        • Williams K.R.
        • Hales K.
        • Woolley D.R.
        • et al.
        Neurofascin as a novel target for autoantibody-mediated axonal injury.
        J Exp Med. 2007; 204: 2363-2372
        • Meinl E.
        • Krumbholz M.
        • Hohlfeld R.
        B lineage cells in the inflammatory CNS environment: migration, maintenance, local antibody production and therapeutic modulation.
        Ann Neurol. 2006; 59: 880-892
        • Goodin D.S.
        • Frohman E.M.
        • Garmany G.P.
        • Halper J.
        • Likosky W.H.
        • Lublin F.D.
        • et al.
        Disease modifying therapies in multiple sclerosis — report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.
        Neurol. 2002; 58: 169-178
        • Polman C.H.
        • Uitdehaag B.M.J.
        New and emerging treatment options for multiple sclerosis.
        Lancet Neurology. 2003; 2: 563-566
        • Neuhaus O.
        • Archelos J.J.
        • Hartung H.P.
        Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection.
        Trends Pharmacol Sci. 2003; 24: 131-138
        • 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
        • Hohlfeld R.
        Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives.
        Brain. 1997; 120: 865-916
        • Wiendl H.
        • Hohlfeld R.
        Therapeutic approaches in multiple sclerosis — lessons from failed and interrupted treatment trials.
        BioDrugs. 2003; 16: 183-200
        • Martin R.
        • Sturzebecher C.S.
        • McFarland H.F.
        Immunotherapy of multiple sclerosis: where are we? Where should we go?.
        Nat Immunol. 2001; 2: 785-788