B cells and autoantibodies in multiple sclerosis

International Journal of Molecular Sciences

Volumn 16, Issue 7, 2015, Pages 16576-16592

  Pröbstel, Anne Katrin ^a,b   Sanderson, Nicholas S R ^a,b   Derfuss, Tobias ^a,b  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

^b UNIVERSITY OF BASEL   (Switzerland)

Author keywords

Autoantibodies; Autoantigen; B cells; Multiple sclerosis; Neuromyelitis optica; Pathogenesis; Therapy

Indexed keywords

ALEMTUZUMAB; AQUAPORIN 4; ATACICEPT; AUTOANTIBODY; AXONIN 1; B CELL ACTIVATING FACTOR; CD1 ANTIGEN; CHEMOKINE RECEPTOR CXCR4; CXCL13 CHEMOKINE; GLYCOPROTEIN; IMMUNOGLOBULIN; INTERLEUKIN 6; INWARDLY RECTIFYING POTASSIUM CHANNEL; INWARDLY RECTIFYING POTASSIUM CHANNEL SUBUNIT KIR4.1; LYMPHOTOXIN; MACROPHAGE INFLAMMATORY PROTEIN 3BETA; MEDI 551; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; NATALIZUMAB; NEUROFASCIN; OCRELIZUMAB; OFATUMUMAB; OLIGOCLONAL BAND; RITUXIMAB; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; VAY736;

ANTIBODY PRODUCTION; B LYMPHOCYTE; CEREBROSPINAL FLUID; COMPLEMENT DEPOSITION; DEMYELINATING DISEASE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; INFLAMMATION; MAJOR HISTOCOMPATIBILITY COMPLEX; MULTIPLE SCLEROSIS; MYELOOPTIC NEUROPATHY; NONHUMAN; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; T LYMPHOCYTE; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; PERSONALIZED MEDICINE; PROCEDURES;

ANIMALIA;

ANIMALS; AUTOANTIBODIES; B-LYMPHOCYTES; HUMANS; IMMUNOTHERAPY; MULTIPLE SCLEROSIS; PRECISION MEDICINE;

EID: 84937951194     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms160716576     Document Type: Review

References (121)

1. Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502-1517.
2. Hauser, S.L.; Oksenberg, J.R. The neurobiology of multiple sclerosis: Genes, inflammation, and neurodegeneration. Neuron 2006, 52, 61-76.
3. Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann. Neurol. 2007, 61, 288-299.
4. Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann. Neurol. 2007, 61, 504-513.
5. International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 2007, 357, 851-862.
6. Patsopoulos, N.A.; Bayer Pharma MS Genetics Working Group; Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist; ANZgene Consortium; GeneMSA; International Multiple Sclerosis Genetics Consortium; de Bakker, P.I.W. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann. Neurol. 2011, 70, 897-912.
7. Lünemann, J.D.; Jelcić, I.; Roberts, S.; Lutterotti, A.; Tackenberg, B.; Martin, R.; Münz, C. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J. Exp. Med. 2008, 205, 1763-1773.
8. Sospedra, M.; Zhao, Y.; zur Hausen, H.; Muraro, P.A.; Hamashin, C.; de Villiers, E.M.; Pinilla, C.; Martin, R. Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity. PLoS Pathog. 2005, 1, e41.
9. Krumbholz, M.; Derfuss, T.; Hohlfeld, R.; Meinl, E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 2012, 8, 613-623.
10. Mayer, M.C.; Hohlfeld, R.; Meinl, E. Viability of autoantibody-targets: How to tackle pathogenetic heterogeneity as an obstacle for treatment of multiple sclerosis. J. Neurol. Sci. 2012, 319, 2-7.
11. 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.
12. Abraira, V.; Alvarez-Cermeño, J.C.; Arroyo, R.; Cámara, C.; Casanova, B.; Cubillo, S.; de Andrés, C.; Espejo, C.; Fernández, O.; Ferrer, J.; et al. Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice. J. Immunol. Methods 2011, 371, 170-173.
13. Thompson, E.J.; Kaufmann, P.; Rudge, P. Sequential changes in oligoclonal patterns during the course of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 1983, 46, 547-550.
14. Walsh, M.J.; Tourtellotte, W.W. Temporal invariance and clonal uniformity of brain and cerebrospinal IgG, IgA, and IgM in multiple sclerosis. J. Exp. Med. 1986, 163, 41-53.
15. Mancuso, R.; Franciotta, D.; Rovaris, M.; Caputo, D.; Sala, A.; Hernis, A.; Agostini, S.; Calvo, M.; Clerici, M. Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: A longitudinal study. Mult. Scler. 2014, 20, 1900-1903.
16. Owens, G.P.; Bennett, J.L.; Lassmann, H.; O'Connor, K.C.; Ritchie, A.M.; Shearer, A.; Lam, C.; Yu, X.; Birlea, M.; DuPree, C.; et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann. Neurol. 2009, 65, 639-649.
17. Obermeier, B.; Mentele, R.; Malotka, J.; Kellermann, J.; Kümpfel, T.; Wekerle, H.; Lottspeich, F.; Hohlfeld, R.; Dornmair, K. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat. Med. 2008, 14, 688-693.
18. Obermeier, B.; Lovato, L.; Mentele, R.; Brück, W.; Forne, I.; Imhof, A.; Lottspeich, F.; Turk, K.W.; Willis, S.N.; Wekerle, H.; et al. Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. J. Neuroimmunol. 2011, 233, 245-248.
19. Beltrán, E.; Obermeier, B.; Moser, M.; Coret, F.; Simó-Castelló, M.; Boscá, I.; Pérez-Miralles, F.; Villar, L.M.; Senel, M.; Tumani, H.; et al. Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain 2014, 137, 2703-2714.
20. 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. Investig. 1998, 102, 1045-1050.
21. Owens, G.P.; 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.
22. Bankoti, J.; Apeltsin, L.; Hauser, S.L.; Allen, S.; Albertolle, M.E.; Witkowska, H.E.; von Büdingen, H.C. In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses. Ann. Neurol. 2014, 75, 266-276.
23. Von Büdingen, H.C.; Kuo, T.C.; Sirota, M.; van Belle, C.J.; Apeltsin, L.; Glanville, J.; Cree, B.A.; Gourraud, P.A.; Schwartzburg, A.; Huerta, G.; et al. B cell exchange across the blood-brain barrier in multiple sclerosis. J. Clin. Investig. 2012, 122, 4533-4543.
24. Palanichamy, A.; Apeltsin, L.; Kuo, T.C.; Sirota, M.; Wang, S.; Pitts, S.J.; Sundar, P.D.; Telman, D.; Zhao, L.Z.; Derstine, M.; et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci. Transl. Med. 2014, 6, 248ra106.
25. Stern, J.N.H.; Yaari, G.; Vander Heiden, J.A.; Church, G.; Donahue, W.F.; Hintzen, R.Q.; Huttner, A.J.; Laman, J.D.; Nagra, R.M.; Nylander, A.; et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci. Transl. Med. 2014, 6, 248ra107.
26. Storch, M.K.; Piddlesden, S.; Haltia, M.; Iivanainen, M.; Morgan, P.; Lassmann, H. Multiple sclerosis: In situ evidence for antibody- and complement-mediated demyelination. Ann. Neurol. 1998, 43, 465-471.
27. 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. 2000, 47, 707-717.
28. Serafini, B.; Rosicarelli, B.; Magliozzi, R.; Stigliano, E.; Aloisi, F. 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.
29. Magliozzi, R.; Howell, O.; Vora, A.; Serafini, B.; Nicholas, R.; Puopolo, M.; Reynolds, R.; Aloisi, F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007, 130, 1089-1104.
30. Howell, O.W.; Reeves, C.A.; Nicholas, R.; Carassiti, D.; Radotra, B.; Gentleman, S.M.; Serafini, B.; Aloisi, F.; Roncaroli, F.; Magliozzi, R.; et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011, 134, 2755-2771.
31. Haugen, M.; Frederiksen, J.L.; Degn, M. B cell follicle-like structures in multiple sclerosis-with focus on the role of B cell activating factor. J. Neuroimmunol. 2014, 273, 1-7.
32. Lovato, L.; Willis, S.N.; Rodig, S.J.; Caron, T.; Almendinger, S.E.; Howell, O.W.; Reynolds, R.; O'Connor, K.C.; Hafler, D.A. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 2011, 134, 534-541.
33. Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015, 523, 337-341.
34. Hatterer, E.; Davoust, N.; Didier-Bazes, M.; Vuaillat, C.; Malcus, C.; Belin, M.F.; Nataf, S. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 2006, 107, 806-812.
35. Krumbholz, M.; Theil, D.; Derfuss, T.; Rosenwald, A.; Schrader, F.; Monoranu, C.M.; Kalled, S.L.; Hess, D.M.; Serafini, B.; Aloisi, F.; 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.
36. Krumbholz, M.; Theil, D.; Cepok, S.; Hemmer, B.; Kivisäkk, P.; Ransohoff, R.M.; Hofbauer, M.; Farina, C.; Derfuss, T.; Hartle, C.; et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 2006, 129, 200-211.
37. Krumbholz, M.; Theil, D.; Steinmeyer, F.; Cepok, S.; Hemmer, B.; Hofbauer, M.; Farina, C.; Derfuss, T.; Junker, A.; Arzberger, T.; 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.
38. Magliozzi, R.; Columba-Cabezas, S.; Serafini, B.; Aloisi, F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2004, 148, 11-23.
39. Khademi, M.; Kockum, I.; Andersson, M.L.; Iacobaeus, E.; Brundin, L.; Sellebjerg, F.; Hillert, J.; Piehl, F.; Olsson, T. Cerebrospinal fluid CXCL13 in multiple sclerosis: A suggestive prognostic marker for the disease course. Mult. Scler. 2011, 17, 335-343.
40. Molnarfi, N.; Schulze-Topphoff, U.; Weber, M.S.; Patarroyo, J.C.; Prod'homme, T.; Varrin-Doyer, M.; Shetty, A.; Linington, C.; Slavin, A.J.; Hidalgo, J.; et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 2013, 210, 2921-2937.
41. Pierson, E.R.; Stromnes, I.M.; Goverman, J.M. B cells promote induction of experimental autoimmune encephalomyelitis by facilitating reactivation of T cells in the central nervous system. J. Immunol. 2014, 192, 929-939.
42. Barr, T.A.; Shen, P.; Brown, S.; Lampropoulou, V.; Roch, T.; Lawrie, S.; Fan, B.; O'Connor, R.A.; Anderton, S.M.; Bar-Or, A.; et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med. 2012, 209, 1001-1010.
43. Shen, P.; Fillatreau, S. Antibody-independent functions of B cells: A focus on cytokines. Nat. Rev. Immunol. 2015, 15, 441-451.
44. Fillatreau, S.; Sweenie, C.H.; McGeachy, M.J.; Gray, D.; Anderton, S.M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 2002, 3, 944-950.
45. Shen, P.; Roch, T.; Lampropoulou, V.; O'Connor, R.A.; Stervbo, U.; Hilgenberg, E.; Ries, S.; Dang, V. D.; Jaimes, Y.; Daridon, C.; et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 2014, 507, 366-370.
46. Ries, S.; Hilgenberg, E.; Lampropoulou, V.; Shen, P.; Dang, V.D.; Wilantri, S.; Sakwa, I.; Fillatreau, S. B-type suppression: A role played by "regulatory B cells" or "regulatory plasma cells"? Eur. J. Immunol. 2014, 44, 1251-1257.
47. Yoshizaki, A.; Miyagaki, T.; DiLillo, D.J.; Matsushita, T.; Horikawa, M.; Kountikov, E.I.; Spolski, R.; Poe, J.C.; Leonard, W.J.; Tedder, T.F. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 2012, 491, 264-268.
48. Metz, I.; Weigand, S.D.; Popescu, B.F.G.; Frischer, J.M.; Parisi, J.E.; Guo, Y.; Lassmann, H.; Brück, W.; Lucchinetti, C.F. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann. Neurol. 2014, 75, 728-738.
49. Keegan, M.; König, F.; McClelland, R.; Brück, W.; Morales, Y.; Bitsch, A.; Panitch, H.; Lassmann, H.; Weinshenker, B.; Rodriguez, M.; et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 2005, 366, 579-582.
50. Elliott, C.; Lindner, M.; Arthur, A.; Brennan, K.; Jarius, S.; Hussey, J.; Chan, A.; Stroet, A.; Olsson, T.; Willison, H.; et al. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 2012, 135, 1819-1833.
51. Schirmer, L.; Srivastava, R.; Hemmer, B. To look for a needle in a haystack: The search for autoantibodies in multiple sclerosis. Mult. Scler. 2014, 20, 271-279.
52. Derfuss, T.; Meinl, E. Identifying autoantigens in demyelinating diseases: Valuable clues to diagnosis and treatment? Curr. Opin. Neurol. 2012, 25, 231-238.
53. Von Büdingen, H.C.; Harrer, M.D.; Kuenzle, S.; Meier, M.; Goebels, N. Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur. J. Immunol. 2008, 38, 2014-2023.
54. O'Connor, K.C.; Appel, H.; Bregoli, L.; Call, M.E.; Catz, I.; Chan, J.A.; Moore, N.H.; Warren, K.G.; Wong, S.J.; Hafler, D.A.; et al. Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein. J. Immunol. 2005, 175, 1974-1982.
55. Berger, T.; Rubner, P.; Schautzer, F.; Egg, R.; Ulmer, H.; Mayringer, I.; Dilitz, E.; Deisenhammer, F.; Reindl, M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N. Engl. J. Med. 2003, 349, 139-145.
56. Kuhle, J.; Pohl, C.; Mehling, M.; Edan, G.; Freedman, M.S.; Hartung, H.P.; Polman, C.H.; Miller, D.H.; Montalban, X.; Barkhof, F.; et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N. Engl. J. Med. 2007, 356, 371-378.
57. O'Connor, K.C.; McLaughlin, K.A.; de Jager, P.L.; Chitnis, T.; Bettelli, E.; Xu, C.; Robinson, W.H.; Cherry, S.V.; Bar-Or, A.; Banwell, B.; et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 2007, 13, 211-217.
58. McLaughlin, K.A.; Chitnis, T.; Newcombe, J.; Franz, B.; Kennedy, J.; McArdel, S.; Kuhle, J.; Kappos, L.; Rostásy, K.; Pohl, D.; et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J. Immunol. 2009, 183, 4067-4076.
59. Brilot, F.; Dale, R.C.; Selter, R.C.; Grummel, V.; Kalluri, S.R.; Aslam, M.; Busch, V.; Zhou, D.; Cepok, S.; Hemmer, B. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann. Neurol. 2009, 66, 833-842.
60. Rostásy, K.; Mader, S.; Schanda, K.; Huppke, P.; Gärtner, J.; Kraus, V.; Karenfort, M.; Tibussek, D.; Blaschek, A.; Bajer-Kornek, B.; et al. Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis. Arch. Neurol. 2012, 69, 752-756.
61. Baumann, M.; Sahin, K.; Lechner, C.; Hennes, E.M.; Schanda, K.; Mader, S.; Karenfort, M.; Selch, C.; Häusler, M.; Eisenkölbl, A.; et al. Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J. Neurol. Neurosurg. Psychiatry 2015, 86, 265-272.
62. Hacohen, Y.; Absoud, M.; Woodhall, M.; Cummins, C.; de Goede, C.G.; Hemingway, C.; Jardine, P.E.; Kneen, R.; Pike, M.G.; Whitehouse, W.P.; et al. Autoantibody biomarkers in childhood-acquired demyelinating syndromes: Results from a national surveillance cohort. J. Neurol. Neurosurg. Psychiatry 2014, 85, 456-461.
63. Pröbstel, A.K.; Dornmair, K.; Bittner, R.; Sperl, P.; Jenne, D.; Magalhaes, S.; Villalobos, A.; Breithaupt, C.; Weissert, R.; Jacob, U.; et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 2011, 77, 580-588.
64. Dale, R.C.; Tantsis, E.M.; Merheb, V.; Kumaran, R.Y.A.; Sinmaz, N.; Pathmanandavel, K.; Ramanathan, S.; Booth, D.R.; Wienholt, L.A.; Prelog, K.; et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol.: Neuroimmunol. Neuroinflamm. 2014, 1, e12.
65. Huppke, P.; Rostásy, K.; Karenfort, M.; Huppke, B.; Seidl, R.; Leiz, S.; Reindl, M.; Gärtner, J. Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients. Mult. Scler. 2013, 19, 941-946.
66. Selter, R.C.; Brilot, F.; Grummel, V.; Kraus, V.; Cepok, S.; Dale, R.C.; Hemmer, B. Antibody responses to EBV and native MOG in pediatric inflammatory demyelinating CNS diseases. Neurology 2010, 74, 1711-1715.
67. Ketelslegers, I.A.; van Pelt, D.E.; Bryde, S. Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort. Mult. Scler. 2015, pii:1352458514566666.
68. Rostasy, K.; Mader, S.; Hennes, E.M.; Schanda, K.; Gredler, V.; Guenther, A.; Blaschek, A.; Korenke, C.; Pritsch, M.; Pohl, D.; et al. Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica. Mult. Scler. 2013, 19, 1052-1059.
69. Hacohen, Y.; Absoud, M.; Deiva, K.; Hemingway, C.; Nytrova, P.; Woodhall, M.; Palace, J.; Wassmer, E.; Tardieu, M.; Vincent, A.; et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurol.: Neuroimmunol. Neuroinflamm. 2015, 2, e81.
70. Di Pauli, F.; Mader, S.; Rostásy, K.; Schanda, K.; Bajer-Kornek, B.; Ehling, R.; Deisenhammer, F.; Reindl, M.; Berger, T. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin. Immunol. 2011, 138, 247-254.
71. Mader, S.; Gredler, V.; Schanda, K.; Rostásy, K.; Dujmovic, I.; Pfaller, K.; Lutterotti, A.; Jarius, S.; di Pauli, F.; Kuenz, B.; et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J. Neuroinflam. 2011, 8, 184.
72. Ramanathan, S.; Reddel, S.W.; Henderson, A.; Parratt, J.D.E.; Barnett, M.; Gatt, P.N.; Merheb, V.; Kumaran, R.Y.A.; Pathmanandavel, K.; Sinmaz, N.; et al. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol.: Neuroimmunol. Neuroinflamm. 2014, 1, e40.
73. Mayer, M.C.; Breithaupt, C.; Reindl, M.; Schanda, K.; Rostásy, K.; Berger, T.; Dale, R.C.; Brilot, F.; Olsson, T.; Jenne, D.; 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. 2013, 191, 3594-3604.
74. Kitley, J.; Woodhall, M.; Waters, P.; Leite, M.I.; Devenney, E.; Craig, J.; Palace, J.; Vincent, A. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012, 79, 1273-1277.
75. Kitley, J.; Waters, P.; Woodhall, M.; Leite, M.I.; Murchison, A.; George, J.; Küker, W.; Chandratre, S.; Vincent, A.; Palace, J. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: A comparative study. JAMA Neurol. 2014, 71, 276-283.
76. Sato, D.K.; Callegaro, D.; Lana-Peixoto, M.A.; Waters, P.J.; Jorge, F.M.; de, H.; Takahashi, T.; Nakashima, I.; Apostolos-Pereira, S.L.; Talim, N.; et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014, 82, 474-481.
77. Höftberger, R.; Sepulveda, M.; Armangue, T.; Blanco, Y.; Rostásy, K.; Cobo Calvo, A.; Olascoaga, J.; Ramió-Torrentà, L.; Reindl, M.; Benito-León, J.; et al. Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult. Scler. 2015, 21, 866-874.
78. Pröbstel, A.-K.; Rudolf, G.; Dornmair, K.; Collongues, N.; Chanson, J.-B.; Sanderson, N.S.; Lindberg, R.L.; Kappos, L.; de Sèze, J.; Derfuss, T. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J. Neuroinflamm. 2015, 12, 46.
79. Saadoun, S.; Waters, P.; Owens, G.P.; Bennett, J.L.; Vincent, A.; Papadopoulos, M.C. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol. Commun. 2014, 2, 35.
80. Zamvil, S.S.; Slavin, A.J. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol.: Neuroimmunol. Neuroinflamm. 2015, 2, e62.
81. Lennon, V.A.; Wingerchuk, D.M.; Kryzer, T.J.; Pittock, S.J.; Lucchinetti, C.F.; Fujihara, K.; Nakashima, I.; Weinshenker, B.G. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet 2004, 364, 2106-2112.
82. Wingerchuk, D.M.; Lennon, V.A.; Pittock, S.J.; Lucchinetti, C.F.; Weinshenker, B.G. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006, 66, 1485-1489.
83. Wingerchuk, D.M.; Lennon, V.A.; Lucchinetti, C.F.; Pittock, S.J.; Weinshenker, B.G. The spectrum of neuromyelitis optica. Lancet Neurol 2007, 6, 805-815.
84. Bradl, M.; Misu, T.; Takahashi, T.; Watanabe, M.; Mader, S.; Reindl, M.; Adzemovic, M.; Bauer, J.; Berger, T.; Fujihara, K.; et al. Neuromyelitis optica: Pathogenicity of patient immunoglobulin in vivo. Ann. Neurol. 2009, 66, 630-643.
85. De Seze, J.; Stojkovic, T.; Ferriby, D.; Gauvrit, J.Y.; Montagne, C.; Mounier-Vehier, F.; Verier, A.; Pruvo, J.P.; Hache, J.C.; Vermersch, P. Devic's neuromyelitis optica: Clinical, laboratory, MRI and outcome profile. J. Neurol. Sci. 2002, 197, 57-61.
86. Bennett, J.L.; Lam, C.; Kalluri, S.R.; Saikali, P.; Bautista, K.; DuPree, C.; Glogowska, M.; Case, D.; Antel, J.P.; Owens, G.P.; et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann. Neurol. 2009, 66, 617-629.
87. 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. 2010, 88, 753-761.
88. Dhaunchak, A.S.; Becker, C.; Schulman, H.; de Faria, O.; Rajasekharan, S.; Banwell, B.; Colman, D.R.; Bar-Or, A. Canadian Pediatric Demyelinating Disease Group Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann. Neurol. 2012, 71, 601-613.
89. Howell, O.W.; Palser, A.; Polito, A.; Melrose, S.; Zonta, B.; Scheiermann, C.; Vora, A.J.; Brophy, P.J.; Reynolds, R. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 2006, 129, 3173-3185.
90. 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.
91. Mathey, E.K.; Derfuss, T.; Storch, M.K.; Williams, K.R.; Hales, K.; Woolley, D.R.; Al-Hayani, A.; Davies, S.N.; Rasband, M.N.; Olsson, T.; et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 2007, 204, 2363-2372.
92. Derfuss, T.; Parikh, K.; Velhin, S.; Braun, M.; Mathey, E.; Krumbholz, M.; Kümpfel, T.; Moldenhauer, A.; Rader, C.; Sonderegger, P.; 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 2009, 106, 8302-8307.
93. Sherman, D.L.; Tait, S.; Melrose, S.; Johnson, R.; Zonta, B.; Court, F.A.; Macklin, W.B.; Meek, S.; Smith, A.J.H.; Cottrell, D.F.; et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 2005, 48, 737-742.
94. Feinberg, K.; Eshed-Eisenbach, Y.; Frechter, S.; Amor, V.; Salomon, D.; Sabanay, H.; Dupree, J.L.; Grumet, M.; Brophy, P.J.; Shrager, P.; et al. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 2010, 65, 490-502.
95. Kawamura, N.; Yamasaki, R.; Yonekawa, T.; Matsushita, T.; Kusunoki, S.; Nagayama, S.; Fukuda, Y.; Ogata, H.; Matsuse, D.; Murai, H.; et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 2013, 81, 714-722.
96. Seehusen, F.; Baumgärtner, W. Axonal pathology and loss precede demyelination and accompany chronic lesions in a spontaneously occurring animal model of multiple sclerosis. Brain Pathol. 2010, 20, 551-559.
97. Lucchinetti, C.F.; Popescu, B.F.G.; Bunyan, R.F.; Moll, N.M.; Roemer, S.F.; Lassmann, H.; Brück, W.; Parisi, J.E.; Scheithauer, B.W.; Giannini, C.; et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 2011, 365, 2188-2197.
98. Srivastava, R.; Aslam, M.; Kalluri, S.R.; Schirmer, L.; Buck, D.; Tackenberg, B.; Rothhammer, V.; Chan, A.; Gold, R.; Berthele, A.; et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N. Engl. J. Med. 2012, 367, 115-123.
99. Kraus, V.; Srivastava, R.; Kalluri, S.R.; Seidel, U.; Schuelke, M.; Schimmel, M.; Rostásy, K.; Leiz, S.; Hosie, S.; Grummel, V.; et al. Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease. Neurology 2014, 82, 470-473.
100. Nerrant, E.; Salsac, C.; Charif, M.; Ayrignac, X.; Carra-Dalliere, C.; Castelnovo, G.; Goulabchand, R.; Tisseyre, J.; Raoul, C.; Eliaou, J.F.; et al. Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis. Mult. Scler. 2014, 20, 1699-1703.
101. Brickshawana, A.; Hinson, S.R.; Romero, M.F.; Lucchinetti, C.F.; Guo, Y.; Buttmann, M.; Mckeon, A.; Pittock, S.J.; Chang, M.H.; Chen, A.P.; et al. Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: A comparative study. Lancet Neurol. 2014, 13, 795-806.
102. Brill, L.; Goldberg, L.; Karni, A.; Petrou, P.; Abramsky, O.; Ovadia, H.; Ben-Hur, T.; Karussis, D.; Vaknin-Dembinsky, A. Increased anti-KIR4.1 antibodies in multiple sclerosis: Could it be a marker of disease relapse? Mult. Scler. 2015, 21, 572-579.
103. Filippi, M.; Rocca, M.A.; Lassmann, H. KIR4.1: Another misleading expectation in multiple sclerosis? Lancet Neurol. 2014, 13, 753-755.
104. Hemmer, B. Antibodies to the inward rectifying potassium channel 4.1 in multiple sclerosis: Different methodologies-conflicting results? Mult. Scler. 2015, 21, 537-539.
105. Derfuss, T.; Gürkov, R.; Then Bergh, F.; Goebels, N.; Hartmann, M.; Barz, C.; Wilske, B.; Autenrieth, I.; Wick, M.; Hohlfeld, R.; et al. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response. Brain 2001, 124, 1325-1335.
106. 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.
107. Brennan, K.M.; Galban-Horcajo, F.; Rinaldi, S.; O'Leary, C.P.; Goodyear, C.S.; Kalna, G.; Arthur, A.; Elliot, C.; Barnett, S.; Linington, C.; et al. Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis. J. Neuroimmunol. 2011, 238, 87-95.
108. Kanter, J.L.; Narayana, S.; Ho, P.P.; Catz, I.; Warren, K.G.; Sobel, R.A.; Steinman, L.; Robinson, W.H. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat. Med. 2006, 12, 138-143.
109. Stüve, O.; Marra, C.M.; Jerome, K.R.; Cook, L.; Cravens, P.D.; Cepok, S.; Frohman, E.M.; Phillips, J.T.; Arendt, G.; Hemmer, B.; et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann. Neurol. 2006, 59, 743-747.
110. Miyazaki, Y.; Niino, M.; Fukazawa, T.; Takahashi, E.; Nonaka, T.; Amino, I.; Tashiro, J.; Minami, N.; Fujiki, N.; Doi, S.; et al. Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations. Clin. Immunol. 2014, 151, 127-135.
111. Coles, A.J.; Twyman, C.L.; Arnold, D.L.; Cohen, J.A.; Confavreux, C.; Fox, E.J.; Hartung, H.P.; Havrdova, E.; Selmaj, K.W.; Weiner, H.L.; et al. CARE-MS II investigators Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012, 380, 1829-1839.
112. Cohen, J.A.; Coles, A.J.; Arnold, D.L.; Confavreux, C.; Fox, E.J.; Hartung, H.P.; Havrdova, E.; Selmaj, K.W.; Weiner, H.L.; Fisher, E.; et al. CARE-MS I investigators Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012, 380, 1819-1828.
113. Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S.; et al. HERMES Trial Group B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 2008, 358, 676-688.
114. Hawker, K.; O'Connor, P.; Freedman, M.S.; Calabresi, P.A.; Antel, J.; Simon, J.; Hauser, S.; Waubant, E.; Vollmer, T.; Panitch, H.; et al. OLYMPUS trial group Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 2009, 66, 460-471.
115. Kappos, L.; Li, D.; Calabresi, P.A.; O'Connor, P.; Bar-Or, A.; Barkhof, F.; Yin, M.; Leppert, D.; Glanzman, R.; Tinbergen, J.; et al. Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011, 378, 1779-1787.
116. Sorensen, P.S.; Lisby, S.; Grove, R.; Derosier, F.; Shackelford, S.; Havrdova, E.; Drulovic, J.; Filippi, M. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study. Neurology 2014, 82, 573-581.
117. Herbst, R.; Wang, Y.; Gallagher, S.; Mittereder, N.; Kuta, E.; Damschroder, M.; Woods, R.; Rowe, D.C.; Cheng, L.; Cook, K.; et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J. Pharmacol. Exp. Ther. 2010, 335, 213-222.
118. Kappos, L.; Hartung, H.P.; Freedman, M.S.; Boyko, A.; Radü, E.W.; Mikol, D.D.; Lamarine, M.; Hyvert, Y.; Freudensprung, U.; Plitz, T.; et al. ATAMS Study Group Atacicept in multiple sclerosis (ATAMS): A randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 2014, 13, 353-363.
119. Tada, S.; Yasui, T.; Nakatsuji, Y.; Okuno, T.; Koda, T.; Mochizuki, H.; Sakoda, S.; Kikutani, H. BAFF controls neural cell survival through BAFF receptor. PLoS ONE 2013, 8, e70924.
120. Yang, M.; Sun, L.; Wang, S.; Ko, K.H.; Xu, H.; Zheng, B.J.; Cao, X.; Lu, L. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J. Immunol. 2010, 184, 3321-3325.
121. Hoffmann, F.S.; Kuhn, P.H.; Laurent, S.A.; Hauck, S.M.; Berer, K.; Wendlinger, S.A.; Krumbholz, M.; Khademi, M.; Olsson, T.; Dreyling, M.; et al. The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. J. Immunol. 2015, 194, 542-552.