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J Clin Invest. May 1, 1998; 101(9): 1923–1931.
PMCID: PMC508779

Dual implication of 2',3'-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis.


Multiple sclerosis (MS) is characterized by intra-blood-brain barrier immunoglobulin synthesis that persists lifelong. Subcellular fractionation and two-dimensional electrophoresis were used in conjunction with immune precipitation and immunoblotting to identify antigenic determinants for this immunoglobulin. We report that 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein associated with oligodendrocyte/myelin membranes, also present in lymphocytes and retina, is one major target for the humoral response. Antibodies to CNP are detected in sera of 74% of MS patients. The antibodies are IgM and are present in serum in high titer as well as in cerebrospinal fluid. The antibody response is temporally persistent, consistent with systemic immune activation and persistent antigenic stimulation. Moreover, CNP is isolated as an immune complex from MS brain. CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-amino acid extension at the amino terminus of CNPII; however, the antibody response is exclusively restricted to CNPI. In contrast, both isoforms bind the C3 complement, providing a plausible mechanism in MS central nervous system (CNS) for opsonization of myelin membrane CNP, mediated via the C3 receptor, and phagocytosis of CNP-Ig immune complexes, mediated by membrane Ig Fc receptors of macrophages and CNS microglia.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Martin R, McFarland HF, McFarlin DE. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–187. [PubMed]
  • Bansil S, Cook SD, Rohowsky-Kochan C. Multiple sclerosis: immune mechanism and update on current therapies. Ann Neurol. 1995 May;37 (Suppl 1):S87–101. [PubMed]
  • Walsh MJ, Tourtellotte WW, Roman J, Dreyer W. Immunoglobulin G, A, and M--clonal restriction in multiple sclerosis cerebrospinal fluid and serum--analysis by two-dimensional electrophoresis. Clin Immunol Immunopathol. 1985 Jun;35(3):313–327. [PubMed]
  • Walsh MJ, Tourtellotte WW. Temporal invariance and clonal uniformity of brain and cerebrospinal IgG, IgA, and IgM in multiple sclerosis. J Exp Med. 1986 Jan 1;163(1):41–53. [PMC free article] [PubMed]
  • Colombo E, Banki K, Tatum AH, Daucher J, Ferrante P, Murray RS, Phillips PE, Perl A. Comparative analysis of antibody and cell-mediated autoimmunity to transaldolase and myelin basic protein in patients with multiple sclerosis. J Clin Invest. 1997 Mar 15;99(6):1238–1250. [PMC free article] [PubMed]
  • Miller DH, Albert PS, Barkhof F, Francis G, Frank JA, Hodgkinson S, Lublin FD, Paty DW, Reingold SC, Simon J. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. Ann Neurol. 1996 Jan;39(1):6–16. [PubMed]
  • Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. [PubMed]
  • Pozzilli P. Prevention of insulin-dependent diabetes: where are we now? Diabetes Metab Rev. 1996 Jul;12(2):127–135. [PubMed]
  • Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, Schultz ER, Bennett JL, Garber RL, Chang M, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7440–7444. [PMC free article] [PubMed]
  • Sanders VJ, Waddell AE, Felisan SL, Li X, Conrad AJ, Tourtellotte WW. Herpes simplex virus in postmortem multiple sclerosis brain tissue. Arch Neurol. 1996 Feb;53(2):125–133. [PubMed]
  • Sprinkle TJ. 2',3'-cyclic nucleotide 3'-phosphodiesterase, an oligodendrocyte-Schwann cell and myelin-associated enzyme of the nervous system. Crit Rev Neurobiol. 1989;4(3):235–301. [PubMed]
  • Thompson RJ. 2',3'-cyclic nucleotide-3'-phosphohydrolase and signal transduction in central nervous system myelin. Biochem Soc Trans. 1992 Aug;20(3):621–626. [PubMed]
  • Bernier L, Alvarez F, Norgard EM, Raible DW, Mentaberry A, Schembri JG, Sabatini DD, Colman DR. Molecular cloning of a 2',3'-cyclic nucleotide 3'-phosphodiesterase: mRNAs with different 5' ends encode the same set of proteins in nervous and lymphoid tissues. J Neurosci. 1987 Sep;7(9):2703–2710. [PubMed]
  • Giulian D, Moore S. Identification of 2':3'-cyclic nucleotide 3'-phosphodiesterase in the vertebrate retina. J Biol Chem. 1980 Jul 10;255(13):5993–5995. [PubMed]
  • Kurihara T, Tohyama Y, Yamamoto J, Kanamatsu T, Watanabe R, Kitajima S. Origin of brain 2',3'-cyclic-nucleotide 3'-phosphodiesterase doublet. Neurosci Lett. 1992 Apr 13;138(1):49–52. [PubMed]
  • Agrawal HC, Sprinkle TJ, Agrawal D. 2',3'-cyclic nucleotide-3'-phosphodiesterase in the central nervous system is fatty-acylated by thioester linkage. J Biol Chem. 1990 Jul 15;265(20):11849–11853. [PubMed]
  • Cox ME, Gao EN, Braun PE. C-terminal CTII motif of 2',3'-cyclic nucleotide 3'-phosphodiesterase undergoes carboxylmethylation. J Neurosci Res. 1994 Dec 1;39(5):513–518. [PubMed]
  • Piddlesden SJ, Lassmann H, Zimprich F, Morgan BP, Linington C. The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol. 1993 Aug;143(2):555–564. [PMC free article] [PubMed]
  • Hafler DA, Fox DA, Manning ME, Schlossman SF, Reinherz EL, Weiner HL. In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. N Engl J Med. 1985 May 30;312(22):1405–1411. [PubMed]
  • Bongioanni P, Fioretti C, Vanacore R, Bianchi F, Lombardo F, Ambrogi F, Meucci G. Lymphocyte subsets in multiple sclerosis. A study with two-colour fluorescence analysis. J Neurol Sci. 1996 Jul;139(1):71–77. [PubMed]
  • O'Farrell PZ, Goodman HM, O'Farrell PH. High resolution two-dimensional electrophoresis of basic as well as acidic proteins. Cell. 1977 Dec;12(4):1133–1141. [PubMed]
  • Walsh MJ, McDougall J, Wittmann-Liebold B. Extended N-terminal sequencing of proteins of archaebacterial ribosomes blotted from two-dimensional gels onto glass fiber and poly(vinylidene difluoride) membrane. Biochemistry. 1988 Sep 6;27(18):6867–6876. [PubMed]
  • Norton WT. Isolation of myelin from nerve tissue. Methods Enzymol. 1974;31:435–444. [PubMed]
  • Walsh MJ, Kuruc N. The postsynaptic density: constituent and associated proteins characterized by electrophoresis, immunoblotting, and peptide sequencing. J Neurochem. 1992 Aug;59(2):667–678. [PubMed]
  • Gorga JC, Horejsí V, Johnson DR, Raghupathy R, Strominger JL. Purification and characterization of class II histocompatibility antigens from a homozygous human B cell line. J Biol Chem. 1987 Nov 25;262(33):16087–16094. [PubMed]
  • Aebersold RH, Leavitt J, Saavedra RA, Hood LE, Kent SB. Internal amino acid sequence analysis of proteins separated by one- or two-dimensional gel electrophoresis after in situ protease digestion on nitrocellulose. Proc Natl Acad Sci U S A. 1987 Oct;84(20):6970–6974. [PMC free article] [PubMed]
  • Sadegh-Nasseri S, Stern LJ, Wiley DC, Germain RN. MHC class II function preserved by low-affinity peptide interactions preceding stable binding. Nature. 1994 Aug 25;370(6491):647–650. [PubMed]
  • De Angelis DA, Braun PE. 2',3'-Cyclic nucleotide 3'-phosphodiesterase binds to actin-based cytoskeletal elements in an isoprenylation-independent manner. J Neurochem. 1996 Sep;67(3):943–951. [PubMed]
  • Forsberg P, Henriksson A, Link H, Ohman S. Reference values for CSF-IgM, CSF-IgM/S-IgM ratio and IgM index, and its application to patients with multiple sclerosis and aseptic meningoencephalitis. Scand J Clin Lab Invest. 1984 Feb;44(1):7–12. [PubMed]
  • Eisenberg R. The specificity and polyvalency of binding of a monoclonal rheumatoid factor. Immunochemistry. 1976 Apr;13(4):355–359. [PubMed]
  • Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies. Blood. 1994 Nov 1;84(9):2854–2867. [PubMed]
  • Nores GA, Dohi T, Taniguchi M, Hakomori S. Density-dependent recognition of cell surface GM3 by a certain anti-melanoma antibody, and GM3 lactone as a possible immunogen: requirements for tumor-associated antigen and immunogen. J Immunol. 1987 Nov 1;139(9):3171–3176. [PubMed]
  • Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol. 1995 May;37 (Suppl 1):S32–S42. [PubMed]
  • Nezlin R, Freywald A, Oppermann M. Proteins separated from human IgG molecules. Mol Immunol. 1993 Jul;30(10):935–940. [PubMed]
  • Newman SL, Mikus LK. Deposition of C3b and iC3b onto particulate activators of the human complement system. Quantitation with monoclonal antibodies to human C3. J Exp Med. 1985 Jun 1;161(6):1414–1431. [PMC free article] [PubMed]
  • Lambris JD. The multifunctional role of C3, the third component of complement. Immunol Today. 1988 Dec;9(12):387–393. [PubMed]
  • Vanguri P, Shin ML. Activation of complement by myelin: identification of C1-binding proteins of human myelin from central nervous tissue. J Neurochem. 1986 May;46(5):1535–1541. [PubMed]
  • KABAT EA, FREEDMAN DA, et al. A study of the crystalline albumin, gamma globulin and total protein in the cerebrospinal fluid of 100 cases of multiple sclerosis and in other diseases. Am J Med Sci. 1950 Jan;219(1):55–64. [PubMed]
  • Schocket AL, Weiner HL. Lymphocytotoxic antibodies in family members of patients with multiple sclerosis. Lancet. 1978 Mar 18;1(8064):571–573. [PubMed]
  • Tourtellotte WW, Parker JA. Multiple sclerosis: correlation between immunoglobulin-G in cerebrospinal fluid and brain. Science. 1966 Nov 25;154(3752):1044–1045. [PubMed]
  • Sharief MK, Thompson EJ. Intrathecal immunoglobulin M synthesis in multiple sclerosis. Relationship with clinical and cerebrospinal fluid parameters. Brain. 1991 Feb;114(Pt 1A):181–195. [PubMed]
  • Trapp BD, Bernier L, Andrews SB, Colman DR. Cellular and subcellular distribution of 2',3'-cyclic nucleotide 3'-phosphodiesterase and its mRNA in the rat central nervous system. J Neurochem. 1988 Sep;51(3):859–868. [PubMed]
  • Compston DA, Morgan BP, Campbell AK, Wilkins P, Cole G, Thomas ND, Jasani B. Immunocytochemical localization of the terminal complement complex in multiple sclerosis. Neuropathol Appl Neurobiol. 1989 Jul-Aug;15(4):307–316. [PubMed]
  • Lajtha A, Toth J, Fujimoto K, Agrawal HC. Turnover of myelin proteins in mouse brain in vivo. Biochem J. 1977 May 15;164(2):323–329. [PMC free article] [PubMed]
  • Clapshaw PA, Müller HW, Wiethölter H, Seifert W. Simultaneous measurement of 2':3' cyclic-nucleotide 3' phosphodiesterase and RNase activities in sera and spinal fluids of multiple sclerosis patients. J Neurochem. 1984 Jan;42(1):12–15. [PubMed]
  • Prineas JW, Kwon EE, Goldenberg PZ, Ilyas AA, Quarles RH, Benjamins JA, Sprinkle TJ. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest. 1989 Nov;61(5):489–503. [PubMed]
  • Sriram S, Rodriguez M. Indictment of the microglia as the villain in multiple sclerosis. Neurology. 1997 Feb;48(2):464–470. [PubMed]
  • Yuki N, Hayashi N, Ohkawa K, Hagiwara H, Oshita M, Katayama K, Sasaki Y, Kasahara A, Fusamoto H, Kamada T. The significance of immunoglobulin M antibody response to hepatitis C virus core protein in patients with chronic hepatitis C. Hepatology. 1995 Aug;22(2):402–406. [PubMed]
  • Tola MR, Granieri E, Casetta I, Monari P, Scorrano R, Mazzeo V, Paolino E, Monetti VC, Govoni V. Retinal periphlebitis in multiple sclerosis: a marker of disease activity? Eur Neurol. 1993;33(2):93–96. [PubMed]
  • Egensperger R, Maslim J, Bisti S, Holländer H, Stone J. Fate of DNA from retinal cells dying during development: uptake by microglia and macroglia (Müller cells). Brain Res Dev Brain Res. 1996 Nov 22;97(1):1–8. [PubMed]
  • Penfold PL, Provis JM, Liew SC. Human retinal microglia express phenotypic characteristics in common with dendritic antigen-presenting cells. J Neuroimmunol. 1993 Jun;45(1-2):183–191. [PubMed]
  • Simitsek PD, Campbell DG, Lanzavecchia A, Fairweather N, Watts C. Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J Exp Med. 1995 Jun 1;181(6):1957–1963. [PMC free article] [PubMed]
  • Selmaj K, Brosnan CF, Raine CS. Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6452–6456. [PMC free article] [PubMed]
  • Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature. 1995 May 11;375(6527):155–158. [PubMed]
  • Piddlesden SJ, Storch MK, Hibbs M, Freeman AM, Lassmann H, Morgan BP. Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis. J Immunol. 1994 Jun 1;152(11):5477–5484. [PubMed]
  • Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, Rudge P, McDonald WI. Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain. 1990 Oct;113(Pt 5):1477–1489. [PubMed]
  • Gay D, Esiri M. Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. Brain. 1991 Feb;114(Pt 1B):557–572. [PubMed]

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