The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research

The Lancet Neurology

Volumn 15, Issue 3, 2016, Pages 317-331

  Hohlfeld, Reinhard ^a,b   Dornmair, Klaus ^a   Meinl, Edgar ^a   Wekerle, Hartmut ^c  

^a UNIVERSITY OF MUNICH   (Germany)

^b Technische Universität München Munich Cluster for Systems Neurology   (Germany)

^c MAX PLANCK INSTITUTE OF NEUROBIOLOGY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIGEN; ANTIINFECTIVE AGENT; DRUG ANTIBODY; IMMUNOGLOBULIN G ANTIBODY; IMMUNOGLOBULIN M ANTIBODY; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; PROTEIN ANTIBODY; RECOMBINANT ANTIBODY; T LYMPHOCYTE RECEPTOR; AUTOANTIBODY; AUTOANTIGEN;

ACUTE DISSEMINATED ENCEPHALOMYELITIS; AUTOIMMUNITY; B LYMPHOCYTE; BRAIN DAMAGE; CD8+ T LYMPHOCYTE; CELL EXPANSION; CELL MIGRATION; CEREBROSPINAL FLUID CYTOLOGY; ENCEPHALOMYELITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; IMMUNOPATHOGENESIS; MUCOSAL-ASSOCIATED INVARIANT T CELL; MULTIPLE SCLEROSIS; NONHUMAN; PEDIGREE; PRIORITY JOURNAL; PROTEIN MICROARRAY; PROTEIN TARGETING; REVIEW; SOMATIC HYPERMUTATION; TRANSLATIONAL RESEARCH; IMMUNOLOGY;

AUTOANTIBODIES; AUTOANTIGENS; B-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; HUMANS; MULTIPLE SCLEROSIS; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84981244317     PISSN: 14744422     EISSN: 14744465     Source Type: Journal    
DOI: 10.1016/S1474-4422(15)00313-0     Document Type: Review

References (178)

1. 1 Hohlfeld, R, Dornmair, K, Meinl, E, Wekerle, H, The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol, 2015 published online Dec 23. http://dx.doi.org/S1474-4422(15)00334-8.
2. 2 Goverman, J, Perchellet, A, Huseby, ES, The role of CD8(+) T cells in multiple sclerosis and its animal models. Curr Drug Targets Inflamm Allergy 4 (2005), 239–245.
3. 3 Friese, MA, Fugger, L, Pathogenic CD8(+) T cells in multiple sclerosis. Ann Neurol 66 (2009), 132–141.
4. 4 Saxena, A, Martin-Blondel, G, Mars, LT, Liblau, RS, Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett 585 (2011), 3758–3763.
5. 5 Stritesky, GL, Jameson, SC, Hogquist, KA, Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30 (2012), 95–114.
6. 6 Zang, YC, Li, S, Rivera, VM, et al. Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis. J Immunol 172 (2004), 5120–5127.
7. 7 Biddison, WE, Taub, DD, Cruikshank, WW, Center, DM, Connor, EW, Honma, K, Chemokine and matrix metalloproteinase secretion by myelin proteolipid protein-specific CD8+ T cells: potential roles in inflammation. J Immunol 158 (1997), 3046–3053.
8. 8 Tsuchida, T, Parker, KC, Turner, RV, McFarland, HF, Coligan, JE, Biddison, WE, Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides. Proc Natl Acad Sci USA 91 (1994), 10859–10863.
9. 9 Honma, K, Parker, KC, Becker, KG, McFarland, HF, Coligan, JE, Biddison, WE, Identification of an epitope derived from human proteolipid protein that can induce autoreactive CD8+ cytotoxic T lymphocytes restricted by HLA-A3: evidence for cross-reactivity with an environmental microorganism. J Neuroimmunol 73 (1997), 7–14.
10. 10 Niland, B, Banki, K, Biddison, WE, Perl, A, CD8+ T cell-mediated HLA-A*0201-restricted cytotoxicity to transaldolase peptide 168–176 in patients with multiple sclerosis. J Immunol 175 (2005), 8365–8378.
11. 11 Lassmann, H, Niedobitek, G, Aloisi, F, Middeldorp, JM, for the NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134 (2011), 2772–2786.
12. 12 Owens, GP, Bennett, JL, Trigger, pathogen, or bystander: the complex nexus linking Epstein-Barr virus and multiple sclerosis. Mult Scler 18 (2012), 1204–1208.
13. 13 Huseby, ES, Liggitt, D, Brabb, T, Schnabel, B, Ohlín, C, Goverman, J, A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 194 (2001), 669–676.
14. 14 Sasaki, K, Bean, A, Shah, S, et al. Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J Immunol 192 (2014), 3029–3042.
15. 15 Sun, D, Whitaker, JN, Huang, Z, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 166 (2001), 7579–7587.
16. 16 Anderson, AC, Chandwaskar, R, Lee, DH, et al. A transgenic model of central nervous system autoimmunity mediated by CD4+ and CD8+ T and B cells. J Immunol 188 (2012), 2084–2092.
17. 17 Saxena, A, Bauer, J, Scheikl, T, et al. Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol 181 (2008), 1617–1621.
18. 18 Na, SY, Cao, Y, Toben, C, et al. Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system. Brain 131 (2008), 2353–2365.
19. 19 Friese, MA, Jakobsen, KB, Friis, L, et al. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nat Med 14 (2008), 1227–1235.
20. 20 Sun, D, Qin, Y, Chluba, J, Epplen, JT, Wekerle, H, Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T–T cell interactions. Nature 332 (1988), 843–845.
21. 21 Koh, DR, Fung-Leung, WP, Ho, A, Gray, D, Acha-Orbea, H, Mak, TW, Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science 256 (1992), 1210–1213.
22. 22 Lu, L, Kim, HJ, Werneck, MB, Cantor, H, Regulation of CD8+ regulatory T cells: interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc Natl Acad Sci USA 105 (2008), 19420–19425.
23. 23 Kumar, V, Coulsell, E, Ober, B, Hubbard, G, Sercarz, E, Ward, ES, Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis: dose effects and involvement of both CD4 and CD8 T cells. J Immunol 159 (1997), 5150–5156.
24. 24 Jiang, H, Curran, S, Ruiz-Vazquez, E, Liang, B, Winchester, R, Chess, L, Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 100 (2003), 8378–8383.
25. 25 Sinha, S, Itani, FR, Karandikar, NJ, Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res 59 (2014), 254–265.
26. 26 DeKosky, BJ, Kojima, T, Rodin, A, et al. In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat Med 21 (2015), 86–91.
27. 27 Leipold, MD, Newell, EW, Maecker, HT, Multiparameter phenotyping of human PBMCs using mass cytometry. Methods Mol Biol 1343 (2015), 81–95.
28. 28 Vogl, BA, Fagin, U, Nerbas, L, Schlenke, P, Lamprecht, P, Jabs, WJ, Longitudinal analysis of frequency and reactivity of Epstein-Barr virus-specific T lymphocytes and their association with intermittent viral reactivation. J Med Virol 84 (2012), 119–131.
29. 29 Farber, DL, Yudanin, NA, Restifo, NP, Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 14 (2014), 24–35.
30. 30 Sospedra, M, Pinilla, C, Martin, R, Use of combinatorial peptide libraries for T-cell epitope mapping. Methods 29 (2003), 236–247.
31. 31 Siewert, K, Malotka, J, Kawakami, N, Wekerle, H, Hohlfeld, R, Dornmair, K, Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides. Nat Med 18 (2012), 824–828.
32. 32 Crawford, F, Jordan, KR, Stadinski, B, et al. Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands. Immunol Rev 210 (2006), 156–170.
33. 33 Dornmair, K, Goebels, N, Weltzien, HU, Wekerle, H, Hohlfeld, R, T-cell-mediated autoimmunity: novel techniques to characterize autoreactive T-cell receptors. Am J Pathol 163 (2003), 1215–1226.
34. 34 Howie, B, Sherwood, AM, Berkebile, AD, et al. High-throughput pairing of T cell receptor alpha and beta sequences. Sci Transl Med, 7, 2015, 301ra131.
35. 35 Planas, R, Metz, I, Ortiz, Y, et al. Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions. Ann Clin Transl Neurol 2 (2015), 875–893.
36. 36 Bruder, J, Siewert, K, Obermeier, B, et al. Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. J Biol Chem 287 (2012), 20986–20995.
37. 37 Hohlfeld, R, Engel, AG, Ii, K, Harper, MC, Polymyositis mediated by T lymphocytes that express the gamma/delta receptor. N Engl J Med 324 (1991), 877–881.
38. 38 Babbe, H, Roers, A, Waisman, 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 192 (2000), 393–404.
39. 39 Skulina, C, Schmidt, S, Dornmair, K, et al. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci USA 101 (2004), 2428–2433.
40. 40 Jacobsen, M, Cepok, S, Quak, E, et al. Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 125 (2002), 538–550.
41. 41 Junker, A, Ivanidze, J, Malotka, J, et al. Multiple sclerosis: T-cell receptor expression in distinct brain regions. Brain 130 (2007), 2789–2799.
42. 42 Oksenberg, JR, Stuart, S, Begovich, AB, et al. Limited heterogeneity of rearranged T-cell receptor V alpha transcripts in brains of multiple sclerosis patients. Nature 345 (1990), 344–346.
43. 43 Seitz, S, Schneider, CK, Malotka, J, et al. Reconstitution of paired T cell receptor alpha- and beta-chains from microdissected single cells of human inflammatory tissues. Proc Natl Acad Sci USA 103 (2006), 12057–12062.
44. 44 Held, K, Bhonsle-Deeng, L, Siewert, K, et al. αβ T-cell receptors from multiple sclerosis brain lesions show MAIT cell-related features. Neurol Neuroimmunol Neuroinflamm, 2, 2015, e107.
45. 45 Godfrey, DI, Uldrich, AP, McCluskey, J, et al. The burgeoning family of unconventional T cells. Nat Immunol 16 (2015), 1114–1123.
46. 46 Kjer-Nielsen, L, Patel, O, Corbett, AJ, et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491 (2012), 717–723.
47. 47 Patel, O, Kjer-Nielsen, L, Le Nours, J, et al. Recognition of vitamin B metabolites by mucosal-associated invariant T cells. Nat Commun, 4, 2013, 2142.
48. 48 Schrijver, IA, van Meurs, M, Melief, MJ, et al. Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis. Brain 124 (2001), 1544–1554.
49. 49 Miyazaki, Y, Miyake, S, Chiba, A, Lantz, O, Yamamura, T, Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis. Int Immunol 23 (2011), 529–535.
50. 50 Illís, Z, Shimamura, M, Newcombe, J, Oka, N, Yamamura, T, Accumulation of Valpha7.2-Jalpha33 invariant T cells in human autoimmune inflammatory lesions in the nervous system. Int Immunol 16 (2004), 223–230.
51. 51 Willing, A, Leach, OA, Ufer, F, et al. CD8+ MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis. Eur J Immunol 44 (2014), 3119–3128.
52. 52 Illís, Z, Kondo, T, Newcombe, J, Oka, N, Tabira, T, Yamamura, T, Differential expression of NK T cell V alpha 24J alpha Q invariant TCR chain in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J Immunol 164 (2000), 4375–4381.
53. 53 Yamamura, T, Sakuishi, K, Illís, Z, Miyake, S, Understanding the behavior of invariant NKT cells in autoimmune diseases. J Neuroimmunol 191 (2007), 8–15.
54. 54 Paul, S, Shilpi, Lal, G, Role of gamma-delta (γδ) T cells in autoimmunity. J Leukoc Biol 97 (2015), 259–271.
55. 55 Wucherpfennig, KW, Newcombe, J, Li, H, Keddy, C, Cuzner, ML, Hafler, DA, Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc Natl Acad Sci USA 89 (1992), 4588–4592.
56. 56 Battistini, L, Selmaj, K, Kowal, C, et al. Multiple sclerosis: limited diversity of the V delta 2-J delta 3 T-cell receptor in chronic active lesions. Ann Neurol 37 (1995), 198–203.
57. 57 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 59 (2006), 880–892.
58. 58 von Büdingen, HC, Bar-Or, A, Zamvil, SS, B cells in multiple sclerosis: connecting the dots. Curr Opin Immunol 23 (2011), 713–720.
59. 59 Hauser, SL, The Charcot Lecture | beating MS: a story of B cells, with twists and turns. Mult Scler 21 (2015), 8–21.
60. 60 Krumbholz, M, Derfuss, T, Hohlfeld, R, Meinl, E, B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8 (2012), 613–623.
61. 61 Schirmer, L, Srivastava, R, Hemmer, B, To look for a needle in a haystack: the search for autoantibodies in multiple sclerosis. Mult Scler 20 (2014), 271–279.
62. 62 Fraussen, J, Claes, N, de Bock, L, Somers, V, Targets of the humoral autoimmune response in multiple sclerosis. Autoimmun Rev 13 (2014), 1126–1137.
63. 63 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 129 (2006), 1953–1971.
64. 64 Ben-Nun, A, Kaushansky, N, Kawakami, N, et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J Autoimmun 54 (2014), 33–50.
65. 65 Palanichamy, A, Jahn, S, Nickles, D, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol 193 (2014), 580–586.
66. 66 Mayer, MC, Meinl, E, Glycoproteins as targets of autoantibodies in CNS inflammation: MOG and more. Ther Adv Neurol Disord 5 (2012), 147–159.
67. 67 Lebar, R, Lubetzki, C, Vincent, C, Lombrail, P, Boutry, JM, The M2 autoantigen of central nervous system myelin, a glycoprotein present in oligodendrocyte membrane. Clin Exp Immunol 66 (1986), 423–434.
68. 68 Schluesener, HJ, Sobel, RA, Linington, C, Weiner, HL, A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 139 (1987), 4016–4021.
69. 69 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 130 (1988), 443–454.
70. 70 Derfuss, T, Parikh, K, Velhin, S, 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 USA 106 (2009), 8302–8307.
71. 71 Pöllinger, B, Krishnamoorthy, G, Berer, K, et al. Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med 206 (2009), 1303–1316.
72. 72 Berer, K, Mues, M, Koutrolos, M, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479 (2011), 538–541.
73. 73 Reindl, M, Di Pauli, F, Rostásy, K, Berger, T, The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol 9 (2013), 455–461.
74. 74 Haase, CG, Guggenmos, J, Brehm, U, et al. The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls. J Neuroimmunol 114 (2001), 220–225.
75. 75 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 349 (2003), 139–145.
76. 76 Kuhle, J, Pohl, C, Mehling, M, et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 356 (2007), 371–378.
77. 77 Pelayo, R, Tintorí, M, Montalban, X, et al. Antimyelin antibodies with no progression to multiple sclerosis. N Engl J Med 356 (2007), 426–428.
78. 78 O'Connor, KC, McLaughlin, KA, De Jager, PL, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 13 (2007), 211–217.
79. 79 Brilot, F, Dale, RC, Selter, RC, et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol 66 (2009), 833–842.
80. 80 Di Pauli, F, Mader, S, Rostasy, K, et al. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin Immunol 138 (2011), 247–254.
81. 81 Lalive, PH, Häusler, MG, Maurey, H, et al. Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children. Mult Scler 17 (2011), 297–302.
82. 82 McLaughlin, KA, Chitnis, T, Newcombe, J, et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol 183 (2009), 4067–4076.
83. 83 Pröbstel, AK, Dornmair, K, Bittner, R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 77 (2011), 580–588.
84. 84 Rostasy, K, Mader, S, Schanda, K, et al. Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis. Arch Neurol 69 (2012), 752–756.
85. 85 Ketelslegers, IA, Van Pelt, DE, Bryde, S, et al. Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort. Mult Scler 21 (2015), 1513–1520.
86. 86 Mayer, MC, Breithaupt, C, Reindl, M, et al. Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol 191 (2013), 3594–3604.
87. 87 Mader, S, Gredler, V, Schanda, K, et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation, 8, 2011, 184.
88. 88 Kitley, J, Woodhall, M, Waters, P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 79 (2012), 1273–1277.
89. 89 Sato, DK, Callegaro, D, Lana-Peixoto, MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 82 (2014), 474–481.
90. 90 Waters, P, Woodhall, M, O'Connor, KC, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm, 2, 2015, e89.
91. 91 Pröbstel, AK, Rudolf, G, Dornmair, K, et al. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J Neuroinflammation, 12, 2015, 46.
92. 92 Zamvil, SS, Slavin, AJ, Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder?. Neurol Neuroimmunol Neuroinflamm, 2, 2015, e62.
93. 93 Spadaro, M, Gerdes, LA, Mayer, MC, et al. Histopathology and clinical course of MOG-antibody-associated encephalomyelitis. Ann Clin Transl Neurol 2 (2015), 295–301.
94. 94 Lucchinetti, C, Brück, W, Parisi, J, Scheithauer, B, Rodriguez, M, Lassmann, H, Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47 (2000), 707–717.
95. 95 Di Pauli, F, Höftberger, R, Reindl, M, et al. Fulminant demyelinating encephalomyelitis: insights from antibody studies and neuropathology. Neurol Neuroimmunol Neuroinflamm, 2015 published online Nov 4. DOI: http://dx.doi.org/10.1212/NXI.0000000000000175.
96. 96 Ramanathan, S, Reddel, SW, Henderson, A, et al. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm, 1, 2014, e40.
97. 97 Titulaer, MJ, Höftberger, R, Iizuka, T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 75 (2014), 411–428.
98. 98 Spadaro, M, Gerdes, LA, Ertl-Wagner, B, et al. Autoantibodies to myelin-oligodendrocyte glycoprotein in a small proportion of adult multiple sclerosis patients. Mult Scler 21:suppl 11 (2015), 347–348.
99. 99 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 USA 103 (2006), 19057–19062.
100. 100 Lalive, PH, 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 USA 103 (2006), 2280–2285.
101. 101 Dale, RC, Tantsis, EM, Merheb, V, et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol Neuroimmunol Neuroinflamm, 1, 2014, e12.
102. 102 Hoftberger, R, Sepulveda, M, Armangue, T, et al. Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler 21 (2015), 866–874.
103. 103 Dalmau, J, Lancaster, E, Martinez-Hernandez, E, Rosenfeld, MR, Balice-Gordon, R, Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10 (2011), 63–74.
104. 104 Saadoun, S, Waters, P, Owens, GP, Bennett, JL, Vincent, A, Papadopoulos, MC, Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun, 2, 2014, 35.
105. 105 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 143 (1993), 555–564.
106. 106 Linington, C, Morgan, BP, Scolding, NJ, Wilkins, P, Piddlesden, S, Compston, DA, The role of complement in the pathogenesis of experimental allergic encephalomyelitis. Brain 112 (1989), 895–911.
107. 107 Keegan, M, König, F, McClelland, R, et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366 (2005), 579–582.
108. 108 Elliott, C, Lindner, M, Arthur, A, et al. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 135 (2012), 1819–1833.
109. 109 Mathey, EK, Derfuss, T, Storch, MK, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204 (2007), 2363–2372.
110. 110 Srivastava, R, Aslam, M, Kalluri, SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 367 (2012), 115–123.
111. 111 Quintana, FJ, Farez, MF, Izquierdo, G, Lucas, M, Cohen, IR, Weiner, HL, Antigen microarrays identify CNS-produced autoantibodies in RRMS. Neurology 78 (2012), 532–539.
112. 112 Kanter, JL, Narayana, S, Ho, PP, et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 12 (2006), 138–143.
113. 113 Querol, L, Clark, PL, Bailey, MA, et al. Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 81 (2013), 956–963.
114. 114 Stathopoulos, P, Alexopoulos, H, Dalakas, MC, Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders. Nat Rev Neurol 11 (2015), 143–156.
115. 115 Ng, JK, Malotka, J, Kawakami, N, et al. Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 79 (2012), 2241–2248.
116. 116 Querol, L, Nogales-Gadea, G, Rojas-Garcia, R, et al. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 82 (2014), 879–886.
117. 117 Kawamura, N, Yamasaki, R, Yonekawa, T, et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 81 (2013), 714–722.
118. 118 Schirmer, L, Srivastava, R, Kalluri, SR, et al. Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions. Ann Neurol 75 (2014), 810–828.
119. 119 Brickshawana, A, Hinson, SR, Romero, MF, et al. Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol 13 (2014), 795–806.
120. 120 Ayoglu B, Mitsios N, Khademi M, et al. Anoctamin 2, a novel autoimmune target in multiple sclerosis. Joint ACTRIMS-ECTRIMS meeting; Boston, MA, USA; Sept 10–13, 2014. PS7.5.
121. 121 Qin, Y, Duquette, P, Zhang, Y, Talbot, P, Poole, R, Antel, J, Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102 (1998), 1045–1050.
122. 122 Lovato, L, Willis, SN, Rodig, SJ, et al. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 134 (2011), 534–541.
123. 123 Obermeier, B, Lovato, L, Mentele, R, et al. Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. J Neuroimmunol 233 (2011), 245–248.
124. 124 Stern, JN, Yaari, G, Vander Heiden, JA, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med, 6, 2014, 248ra107.
125. 125 von Büdingen, HC, Harrer, MD, Kuenzle, S, Meier, M, Goebels, N, Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur J Immunol 38 (2008), 2014–2023.
126. 126 Cameron, EM, Spencer, S, Lazarini, J, et al. Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J Neuroimmunol 213 (2009), 123–130.
127. 127 Palanichamy, A, Apeltsin, L, Kuo, TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med, 6, 2014, 248ra106.
128. 128 von Büdingen, HC, Kuo, TC, Sirota, M, et al. B cell exchange across the blood–brain barrier in multiple sclerosis. J Clin Invest 122 (2012), 4533–4543.
129. 129 Louveau, A, Smirnov, I, Keyes, TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523 (2015), 337–341.
130. 130 Aspelund, A, Antila, S, Proulx, ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212 (2015), 991–999.
131. 131 de Vos, AF, van Meurs, M, Brok, HP, et al. Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169 (2002), 5415–5423.
132. 132 Stangel, M, Fredrikson, S, Meinl, E, Petzold, A, Stüve, O, Tumani, H, The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol 9 (2013), 267–276.
133. 133 Laurent, SA, Hoffmann, FS, Kuhn, PH, et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun, 6, 2015, 7333.
134. 134 Hoffmann, FS, Kuhn, PH, Laurent, SA, et al. The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. J Immunol 194 (2015), 542–552.
135. 135 Villar, LM, Sádaba, MC, Roldán, E, et al. Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS. J Clin Invest 115 (2005), 187–194.
136. 136 Beltrán, E, Obermeier, B, Moser, M, et al. Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain 137 (2014), 2703–2714.
137. 137 Cepok, S, Rosche, B, Grummel, V, et al. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128 (2005), 1667–1676.
138. 138 Seifert, M, Küppers, R, Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation. J Exp Med 206 (2009), 2659–2669.
139. 139 Franciotta, D, Salvetti, M, Lolli, F, Serafini, B, Aloisi, F, B cells and multiple sclerosis. Lancet Neurol 7 (2008), 852–858.
140. 140 Baranzini, SE, Jeong, MC, Butunoi, C, Murray, RS, Bernard, CC, Oksenberg, JR, B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 163 (1999), 5133–5144.
141. 141 Obermeier, B, Mentele, R, Malotka, J, et al. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat Med 14 (2008), 688–693.
142. 142 Villar, LM, Masjuan, J, González-Porquí, P, et al. Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis. Ann Neurol 53 (2003), 222–226.
143. 143 Villar, LM, Casanova, B, Ouamara, N, et al. Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis. Ann Neurol 76 (2014), 231–240.
144. 144 Alvarez-Cermeño, JC, Gasalla, T, Villar, LM, Value of oligoclonal band study in clinically isolated syndromes and multiple sclerosis. Expert Rev Neurother 8 (2008), 1279–1280.
145. 145 Singh, V, Stoop, MP, Stingl, C, et al. Cerebrospinal-fluid-derived immunoglobulin G of different multiple sclerosis patients shares mutated sequences in complementarity determining regions. Mol Cell Proteomics 12 (2013), 3924–3934.
146. 146 Vartdal, F, Vandvik, B, Norrby, E, Viral and bacterial antibody responses in multiple sclerosis. Ann Neurol 8 (1980), 248–255.
147. 147 Felgenhauer, K, Schädlich, HJ, Nekic, M, Ackermann, R, Cerebrospinal fluid virus antibodies. A diagnostic indicator for multiple sclerosis?. J Neurol Sci 71 (1985), 291–299.
148. 148 Sindic, CJ, Monteyne, P, Laterre, EC, The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 54 (1994), 75–80.
149. 149 Reiber, H, Kruse-Sauter, H, Quentin, CD, Antibody patterns vary arbitrarily between cerebrospinal fluid and aqueous humor of the individual multiple sclerosis patient: specificity-independent pathological B cell function. J Neuroimmunol 278 (2015), 247–254.
150. 150 Derfuss, T, Gürkov, R, Then Bergh, F, et al. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response. Brain 124 (2001), 1325–1335.
151. 151 Sriram, S, Stratton, CW, Yao, S, et al. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol 46 (1999), 6–14.
152. 152 Leibovitch, EC, Jacobson, S, Evidence linking HHV-6 with multiple sclerosis: an update. Curr Opin Virol 9 (2014), 127–133.
153. 153 Alenda, R, Alvarez-Lafuente, R, Costa-Frossard, L, et al. Identification of the major HHV-6 antigen recognized by cerebrospinal fluid IgG in multiple sclerosis. Eur J Neurol 21 (2014), 1096–1101.
154. 154 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 252 (2005), 968–971.
155. 155 Owens, GP, Gilden, D, Burgoon, MP, Yu, X, Bennett, JL, Viruses and multiple sclerosis. Neuroscientist 17 (2011), 659–676.
156. 156 Martin, R, Martens, U, Sticht-Groh, V, Dörries, R, Krüger, H, Persistent intrathecal secretion of oligoclonal, Borrelia burgdorferi-specific IgG in chronic meningoradiculomyelitis. J Neurol 235 (1988), 229–233.
157. 157 Burgoon, MP, Cohrs, RJ, Bennett, JL, et al. Varicella zoster virus is not a disease-relevant antigen in multiple sclerosis. Ann Neurol 65 (2009), 474–479.
158. 158 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 115 (2005), 1352–1360.
159. 159 Yao, SY, Stratton, CW, Mitchell, WM, Sriram, S, CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens. Neurology 56 (2001), 1168–1176.
160. 160 Virtanen, JO, Pietiläinen-Nicklín, J, Uotila, L, Färkkilä, M, Vaheri, A, Koskiniemi, M, Intrathecal human herpesvirus 6 antibodies in multiple sclerosis and other demyelinating diseases presenting as oligoclonal bands in cerebrospinal fluid. J Neuroimmunol 237 (2011), 93–97.
161. 161 Robinson, WH, DiGennaro, C, Hueber, W, et al. Autoantigen microarrays for multiplex characterization of autoantibody responses. Nat Med 8 (2002), 295–301.
162. 162 Owens, GP, Bennett, JL, Lassmann, H, et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 65 (2009), 639–649.
163. 163 Lambracht-Washington, D, O'Connor, KC, Cameron, EM, et al. Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS. J Neuroimmunol 186 (2007), 164–176.
164. 164 Brennan, KM, Galban-Horcajo, F, Rinaldi, S, et al. Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis. J Neuroimmunol 238 (2011), 87–95.
165. 165 Ilyas, AA, Chen, ZW, Cook, SD, Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis. J Neuroimmunol 139 (2003), 76–80.
166. 166 Vincent, A, Bien, CG, Irani, SR, Waters, P, Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 10 (2011), 759–772.
167. 167 Britten, CM, Janetzki, S, Butterfield, LH, et al. T cell assays and MIATA: the essential minimum for maximum impact. Immunity 37 (2012), 1–2.
168. 168 Fessenden, M, The cell menagerie: human immune profiling. Nature 525 (2015), 409–411.
169. 169 van Noort, JM, van Sechel, AC, Bajramovic, JJ, et al. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375 (1995), 798–801.
170. 170 Ousman, SS, Tomooka, BH, van Noort, JM, et al. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448 (2007), 474–479.
171. 171 Ransohoff, RM, Inflammatory disease: assault on the guardian. Nature 448 (2007), 421–422.
172. 172 Dalmau, J, Rosenfeld, MR, Autoimmune encephalitis update. Neuro Oncol 16 (2014), 771–778.
173. 173 Lennon, VA, Wingerchuk, DM, Kryzer, TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364 (2004), 2106–2112.
174. 174 Lennon, VA, Kryzer, TJ, Pittock, SJ, Verkman, AS, Hinson, SR, IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202 (2005), 473–477.
175. 175 Stys, PK, Zamponi, GW, van Minnen, J, Geurts, JJ, Will the real multiple sclerosis please stand up?. Nat Rev Neurosci 13 (2012), 507–514.
176. 176 Trapp, BD, Nave, KA, Multiple sclerosis: an immune or neurodegenerative disorder?. Annu Rev Neurosci 31 (2008), 247–269.
177. 177 Perron, H, Germi, R, Bernard, C, et al. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler 18 (2012), 1721–1736.
178. 178 Li, R, Rezk, A, Miyazaki, Y, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med, 7, 2015, 310ra166.