Advertisement

Viability of autoantibody-targets: How to tackle pathogenetic heterogeneity as an obstacle for treatment of multiple sclerosis

      Abstract

      The growing complexity number of multiple sclerosis (MS) therapy emphasizes the need for an individualized approach, tailoring therapy to the needs of the individual patient. There is evidence supporting the immunopathological heterogeneity of MS, based on the analysis of biopsy and autopsy tissues. In clinical practice it is impossible to differentiate between the pathological subtypes of MS, because blood or CSF markers of pathological heterogeneity are lacking. Identification of such markers would be important, because “tailored therapy” and “biomarkers for patient stratification” may be considered as two sides of the same coin. In this article, we discuss the emerging role of autoantibodies as potential biomarkers, focusing on myelin oligodendrocyte glycoprotein (MOG) as one of the best characterized autoantigens in MS. In addition, we discuss several strategies for the identification of novel candidate autoantigens.

      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

        • Davis J.C.
        • Furstenthal L.
        • Desai A.A.
        • Norris T.
        • Sutaria S.
        • Fleming E.
        • et al.
        The microeconomics of personalized medicine: today's challenge and tomorrow's promise.
        Nat Rev Drug Discov. Apr 2009; 8: 279-286
        • Lassmann H.
        • Bruck W.
        • Lucchinetti C.
        Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy.
        Trends Mol Med. Mar 2001; 7: 115-121
        • Hohlfeld R.
        'Gimme five': future challenges in multiple sclerosis. ECTRIMS Lecture 2009.
        Mult Scler. Jan 2010; 16: 3-14
        • Brunner C.
        • Lassmann H.
        • Waehneldt T.V.
        • Matthieu J.M.
        • Linington C.
        Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the CNS of adult rats.
        J Neurochem. Jan 1989; 52: 296-304
        • Breithaupt C.
        • Schubart A.
        • Zander H.
        • Skerra A.
        • Huber R.
        • Linington C.
        • et al.
        Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein.
        Proc Natl Acad Sci U S A. Aug 5 2003; 100: 9446-9451
        • Clements C.S.
        • Reid H.H.
        • Beddoe T.
        • Tynan F.E.
        • Perugini M.A.
        • Johns T.G.
        • et al.
        The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis.
        Proc Natl Acad Sci U S A. Sep 16 2003; 100: 11059-11064
        • Breithaupt C.
        • Schafer B.
        • Pellkofer H.
        • Huber R.
        • Linington C.
        • Jacob U.
        Demyelinating myelin oligodendrocyte glycoprotein-specific autoantibody response is focused on one dominant conformational epitope region in rodents.
        J Immunol. Jul 15 2008; 181: 1255-1263
        • Johns T.G.
        • Bernard C.C.
        Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation.
        Mol Immunol. Jan 1997; 34: 33-38
        • Cong H.
        • Jiang Y.
        • Tien P.
        Identification of the myelin oligodendrocyte glycoprotein as a cellular receptor for rubella virus.
        J Virol. Nov 2011; 85: 11038-11047
        • Delarasse C.
        • Daubas P.
        • Mars L.T.
        • Vizler C.
        • Litzenburger T.
        • Iglesias A.
        • et al.
        Myelin/oligodendrocyte glycoprotein-deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice.
        J Clin Invest. Aug 2003; 112: 544-553
        • Xiao B.G.
        • Linington C.
        • Link H.
        Antibodies to myelin-oligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls.
        J Neuroimmunol. Feb 1991; 31: 91-96
        • Reindl M.
        • Linington C.
        • Brehm U.
        • Egg R.
        • Dilitz E.
        • Deisenhammer F.
        • et al.
        Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study.
        Brain. Nov 1999; 122: 2047-2056
        • Gaertner S.
        • de Graaf K.L.
        • Greve B.
        • Weissert R.
        Antibodies against glycosylated native MOG are elevated in patients with multiple sclerosis.
        Neurology. Dec 28 2004; 63: 2381-2383
        • Wang H.
        • Munger K.L.
        • Reindl M.
        • O'Reilly E.J.
        • Levin L.I.
        • Berger T.
        • et al.
        Myelin oligodendrocyte glycoprotein antibodies and multiple sclerosis in healthy young adults.
        Neurology. Oct 7 2008; 71: 1142-1146
        • Klawiter E.C.
        • Piccio L.
        • Lyons J.A.
        • Mikesell R.
        • O'Connor K.C.
        • Cross A.H.
        Elevated intrathecal myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis.
        Arch Neurol. Sep 2010; 67: 1102-1108
        • Haase C.G.
        • Guggenmos J.
        • Brehm U.
        • Andersson M.
        • Olsson T.
        • Reindl M.
        • et al.
        The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls.
        J Neuroimmunol. Mar 1 2001; 114: 220-225
        • Gori F.
        • Mulinacci B.
        • Massai L.
        • Avolio C.
        • Caragnano M.
        • Peroni E.
        • et al.
        IgG and IgM antibodies to the refolded MOG(1–125) extracellular domain in humans.
        J Neuroimmunol. Apr 2011; 233: 216-220
        • Menge T.
        • von Budingen H.C.
        • Lalive P.H.
        • Genain C.P.
        Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA.
        Eur J Immunol. Nov 2007; 37: 3229-3239
        • O'Connor K.C.
        • Appel H.
        • Bregoli L.
        • Call M.E.
        • Catz I.
        • Chan J.A.
        • et al.
        Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein.
        J Immunol. Aug 1 2005; 175: 1974-1982
        • Genain C.P.
        • Cannella B.
        • Hauser S.L.
        • Raine C.S.
        Identification of autoantibodies associated with myelin damage in multiple sclerosis.
        Nat Med. Feb 1999; 5: 170-175
        • Lindert R.B.
        • Haase C.G.
        • Brehm U.
        • Linington C.
        • Wekerle H.
        • Hohlfeld R.
        Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein.
        Brain. Nov 1999; 122: 2089-2100
        • Berger T.
        • Rubner P.
        • Schautzer F.
        • Egg R.
        • Ulmer H.
        • Mayringer I.
        • et al.
        Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.
        N Engl J Med. Jul 10 2003; 349: 139-145
        • Kuhle J.
        • Pohl C.
        • Mehling M.
        • Edan G.
        • Freedman M.S.
        • Hartung H.P.
        • et al.
        Lack of association between antimyelin antibodies and progression to multiple sclerosis.
        N Engl J Med. Jan 25 2007; 356: 371-378
        • Pelayo R.
        • Tintore M.
        • Montalban X.
        • Rovira A.
        • Espejo C.
        • Reindl M.
        • et al.
        Antimyelin antibodies with no progression to multiple sclerosis.
        N Engl J Med. Jan 25 2007; 356: 426-428
        • Zhou D.
        • Srivastava R.
        • Nessler S.
        • Grummel V.
        • Sommer N.
        • Bruck W.
        • et al.
        Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis.
        Proc Natl Acad Sci U S A. Dec 12 2006; 103: 19057-19062
        • O'Connor K.C.
        • McLaughlin K.A.
        • De Jager P.L.
        • Chitnis T.
        • Bettelli E.
        • Xu C.
        • et al.
        Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.
        Nat Med. Feb 2007; 13: 211-217
        • Brilot F.
        • Dale R.C.
        • Selter R.C.
        • Grummel V.
        • Kalluri S.R.
        • Aslam M.
        • et al.
        Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease.
        Ann Neurol. Dec 2009; 66: 833-842
        • Di Pauli F.
        • Mader S.
        • Rostasy K.
        • Schanda K.
        • Bajer-Kornek B.
        • Ehling R.
        • et al.
        Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases.
        Clin Immunol. Mar 2011; 138: 247-254
        • Lalive P.H.
        • Menge T.
        • Delarasse C.
        • Della G.B.
        • Pham-Dinh D.
        • Villoslada P.
        • et al.
        Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis.
        Proc Natl Acad Sci U S A. Feb 14 2006; 103: 2280-2285
        • Lalive P.H.
        • Hausler M.G.
        • Maurey H.
        • Mikaeloff Y.
        • Tardieu M.
        • Wiendl H.
        • et al.
        Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children.
        Mult Scler. Mar 2011; 17: 297-302
        • McLaughlin K.A.
        • Chitnis T.
        • Newcombe J.
        • Franz B.
        • Kennedy J.
        • McArdel S.
        • et al.
        Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis.
        J Immunol. Sep 15 2009; 183: 4067-4076
        • Probstel A.K.
        • Dornmair K.
        • Bittner R.
        • Sperl P.
        • Jenne D.
        • Magalhaes S.
        • et al.
        Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.
        Neurology. Aug 9 2011; 77: 580-588
        • Tenembaum S.
        • Chamoles N.
        • Fejerman N.
        Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients.
        Neurology. Oct 22 2002; 59: 1224-1231
        • Selter R.C.
        • Brilot F.
        • Grummel V.
        • Kraus V.
        • Cepok S.
        • Dale R.C.
        • et al.
        Antibody responses to EBV and native MOG in pediatric inflammatory demyelinating CNS diseases.
        Neurology. May 25 2010; 74: 1711-1715
        • Rostasy K.
        • Mader S.
        • Schanda K.
        • Huppke P.
        • Gartner J.
        • Kraus V.
        • et al.
        Anti-MOG antibodies in children with optic neuritis.
        Arch Neurol. 2012; ([2012 Feb 27 Electronic publication ahead of print])
        • Mader S.
        • Gredler V.
        • Schanda K.
        • Rostasy K.
        • Dujmovic I.
        • Pfaller K.
        • et al.
        Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders.
        J Neuroinflammation. 2011; 8: 184
        • Menge T.
        • Kieseier B.C.
        • Nessler S.
        • Hemmer B.
        • Hartung H.P.
        • Stuve O.
        Acute disseminated encephalomyelitis: an acute hit against the brain.
        Curr Opin Neurol. Jun 2007; 20: 247-254
        • Kieseier B.C.
        • Stuve O.
        A critical appraisal of treatment decisions in multiple sclerosis—old versus new.
        Nat Rev Neurol. May 2011; 7: 255-262
        • Pellkofer H.L.
        • Krumbholz M.
        • Berthele A.
        • Hemmer B.
        • Gerdes L.A.
        • Havla J.
        • et al.
        Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab.
        Neurology. Apr 12 2011; 76: 1310-1315
        • Palace J.
        • Leite M.I.
        • Nairne A.
        • Vincent A.
        Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers.
        Arch Neurol. Aug 2010; 67: 1016-1017
        • Krumbholz M.
        • Faber H.
        • Steinmeyer F.
        • Hoffmann L.A.
        • Kumpfel T.
        • Pellkofer H.
        • et al.
        Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.
        Brain. Jun 2008; 131: 1455-1463
        • Brehm U.
        • Piddlesden S.J.
        • Gardinier M.V.
        • Linington C.
        Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG).
        J Neuroimmunol. Jun 1 1999; 97: 9-15
        • Piddlesden S.J.
        • Lassmann H.
        • Zimprich F.
        • Morgan B.P.
        • Linington C.
        The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement.
        Am J Pathol. Aug 1993; 143: 555-564
        • Litzenburger T.
        • Fassler R.
        • Bauer J.
        • Lassmann H.
        • Linington C.
        • Wekerle H.
        • et al.
        B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.
        J Exp Med. Jul 6 1998; 188: 169-180
        • Poser C.M.
        • Brinar V.V.
        Disseminated encephalomyelitis and multiple sclerosis: two different diseases — a critical review.
        Acta Neurol Scand. Oct 2007; 116: 201-206
        • Waubant E.
        • Chabas D.
        • Okuda D.T.
        • Glenn O.
        • Mowry E.
        • Henry R.G.
        • et al.
        Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults.
        Arch Neurol. Aug 2009; 66: 967-971
        • Keegan M.
        • Konig F.
        • McClelland R.
        • Bruck W.
        • Morales Y.
        • Bitsch A.
        • et al.
        Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange.
        Lancet. Aug 13 2005; 366: 579-582
        • Derfuss T.
        • Parikh K.
        • Velhin S.
        • Braun M.
        • Mathey E.
        • Krumbholz M.
        • et al.
        Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals.
        Proc Natl Acad Sci U S A. May 19 2009; 106: 8302-8307
        • 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. Oct 1 2007; 204: 2363-2372
        • Derfuss T.
        • Linington C.
        • Hohlfeld R.
        • Meinl E.
        Axo-glial antigens as targets in multiple sclerosis: implications for axonal and grey matter injury.
        J Mol Med. Aug 2010; 88: 753-761
        • Lovato L.
        • Cianti R.
        • Gini B.
        • Marconi S.
        • Bianchi L.
        • Armini A.
        • et al.
        Transketolase and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase type I isoforms are specifically recognized by IgG autoantibodies in multiple sclerosis patients.
        Mol Cell Proteomics. Dec 2008; 7: 2337-2349
        • Quintana F.J.
        • Farez M.F.
        • Viglietta V.
        • Iglesias A.H.
        • Merbl Y.
        • Izquierdo G.
        • et al.
        Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis.
        Proc Natl Acad Sci U S A. Dec 2 2008; 105: 18889-18894
        • Kanter J.L.
        • Narayana S.
        • Ho P.P.
        • Catz I.
        • Warren K.G.
        • Sobel R.A.
        • et al.
        Lipid microarrays identify key mediators of autoimmune brain inflammation.
        Nat Med. Jan 2006; 12: 138-143
        • Della Gaspera B.
        • Pham-Dinh D.
        • Roussel G.
        • Nussbaum J.L.
        • Dautigny A.
        Membrane topology of the myelin/oligodendrocyte glycoprotein.
        Eur J Biochem. Dec 1 1998; 258: 478-484
        • Pham-Dinh D.
        • Mattei M.G.
        • Nussbaum J.L.
        • Roussel G.
        • Pontarotti P.
        • Roeckel N.
        • et al.
        Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex.
        Proc Natl Acad Sci U S A. Sep 1 1993; 90: 7990-7994