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B cells in MS and NMO: pathogenesis and therapy

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Abstract

B linage cells are versatile players in multiple sclerosis (MS) and neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO). New potential targets of autoantibodies have been described recently. Pathogenic mechanisms extend further to antigen presentation and cytokine production, which are increasingly recognized as therapeutic targets. In addition to pro-inflammatory effects of B cells, they may act also as anti-inflammatory via production of interleukin (IL)-10, IL-35, and other mechanisms. Definition of regulatory B cell subsets is an ongoing issue. Recent studies have provided evidence for a loss of B cell self-tolerance in MS. An immunogenetic approach demonstrated exchange of B cell clones between CSF and blood. The central nervous system (CNS) of MS patients fosters B cell survival, at least partly via BAFF and APRIL. The unexpected increase of relapses in a trial with a soluble BAFF/APRIL receptor (atacicept) suggests that this system is involved in MS, but with features that are not yet understood. In this review, we further discuss evidence for B cell and Ig contribution to human MS and NMO pathogenesis, pro-inflammatory and regulatory B cell effector functions, impaired B cell immune tolerance, the B cell-fostering microenvironment in the CNS, and B cell-targeted therapeutic interventions for MS and NMO, including CD20 depletion (rituximab, ocrelizumab, and ofatumumab), anti-IL6-R (tocilizumab), complement-blocking (eculizumab), inhibitors of AQP4-Ig binding (aquaporumab, small molecular compounds), and BAFF/BAFF-R-targeting agents.

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Abbreviations

MS:

Multiple sclerosis

PP-MS:

Primary progressive MS

RR-MS:

Relapsing-remitting MS

SP-MS:

Secondary progressive MS

NMO:

Neuromyelitis optica/neuromyelitis optica spectrum disorder

RA:

Rheumatoid arthritis

CNS:

Central nervous system

IL:

Interleukin

TNF:

Tumor necrosis factor

TGF-β:

Transforming growth factor β

LTα:

Lymphotoxin α

EAE:

Experimental autoimmune encephalomyelitis

AQP4:

Aquaporin 4

MOG:

Myelin oligodendrocyte glycoprotein

mAb:

Monoclonal antibody

References

  1. Hauser S, Waubant E, Arnold D, Vollmer T, Antel J, et al. (2007). A phase II randomized, placebo-controlled, multicenter trial of rituximab in adults with relapsing remitting multiple sclerosis (RRMS) Neurology 68 (12): Suppl. 1: A99-A100

  2. Pellkofer HL, Krumbholz M, Berthele A, Hemmer B, Gerdes LA et al (2011) Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 76:1310–1315

    CAS  PubMed  Google Scholar 

  3. Koziolek M, Tampe D, Bahr M, Dihazi H, Jung K et al (2012) Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis. J Neuroinflammation 9:80–89

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Keegan M, Konig F, McClelland R, Bruck W, Morales Y et al (2005) Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366:579–582

    PubMed  Google Scholar 

  5. Heigl F, Hettich R, Arendt R, Durner J, Koehler J et al (2013) Immunoadsorption in steroid-refractory multiple sclerosis: clinical experience in 60 patients. Atheroscler Suppl 14:167–173

    CAS  PubMed  Google Scholar 

  6. Trebst C, Jarius S, Berthele A, Paul F, Schippling S et al (2013) Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. doi:10.1007/s00415-013-7169-7

    PubMed Central  PubMed  Google Scholar 

  7. Elliott C, Lindner M, Arthur A, Brennan K, Jarius S et al (2012) Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 135:1819–1833

    PubMed Central  PubMed  Google Scholar 

  8. Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb S et al (2012) Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol 246:85–95

    CAS  PubMed  Google Scholar 

  9. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Bradl M, Misu T, Takahashi T, Watanabe M, Mader S et al (2009) Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 66:630–643

    CAS  PubMed  Google Scholar 

  11. Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K et al (2009) Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 66:617–629

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Asgari N, Khorooshi R, Lillevang ST, Owens T (2013) Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. J Neuroimmunol 254:76–82

    CAS  PubMed  Google Scholar 

  13. Kitic M, Hochmeister S, Wimmer I, Bauer J, Misu T et al (2013) Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats. Acta Neuropathol Commun 1:5

    PubMed Central  PubMed  Google Scholar 

  14. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M et al (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    CAS  PubMed  Google Scholar 

  15. Breij ECW, Brink BP, Veerhuis R, van den Berg C, Vloet R et al (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63:16–25

    CAS  PubMed  Google Scholar 

  16. Barnett MH, Parratt JD, Cho ES, Prineas JW (2009) Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol 65:32–46

    PubMed  Google Scholar 

  17. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G et al (2002) A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 125:1450–1461

    PubMed  Google Scholar 

  18. Misu T, Hoftberger R, Fujihara K, Wimmer I, Takai Y et al (2013) Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica. Acta Neuropathol 125:815–827

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Lanzavecchia A (1985) Antigen-specific interaction between T and B cells. Nature 314:537–539

    CAS  PubMed  Google Scholar 

  20. Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27

    CAS  PubMed  Google Scholar 

  21. Molnarfi N, Schulze-Topphoff U, Weber MS, Patarroyo JC, Prod’homme T et al (2013) MHC class II–dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J Exp Med. doi:10.1084/jem.20130699

    PubMed Central  PubMed  Google Scholar 

  22. Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG (2008) Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9:54–62

    CAS  PubMed Central  PubMed  Google Scholar 

  23. de Vos AF, van Meurs M, Brok HP, Boven LA, Hintzen RQ et al (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169:5415–5423

    PubMed  Google Scholar 

  24. von Budingen HC, Kuo TC, Sirota M, van Belle CJ, Apeltsin L et al (2012) B cell exchange across the blood–brain barrier in multiple sclerosis. J Clin Invest 122:4533–4543

    Google Scholar 

  25. Mayer MC, Hohlfeld R, Meinl E Viability of autoantibody-targets: how to tackle pathogenetic heterogeneity as an obstacle for treatment of multiple sclerosis. J Neurol Sci. doi:10.1016/j.jns.2012.05.018

  26. Meinl E, Krumbholz M, Hohlfeld R (2006) B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59:880–892

    CAS  PubMed  Google Scholar 

  27. Barr TA, Shen P, Brown S, Lampropoulou V, Roch T et al (2012) B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6 producing B cells. J Exp Med 209:1001–1010

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Ireland SJ, Blazek M, Harp CT, Greenberg B, Frohman EM et al (2012) Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: clues to increased inflammatory and reduced regulatory B cell capacity. Autoimmunity 45:400–414

    CAS  PubMed  Google Scholar 

  29. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–950

    CAS  PubMed  Google Scholar 

  30. Shen P, Roch T, Lampropoulou V, O’Connor RA, Hilgenberg E et al (2014) IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507(7492):366–70

    CAS  PubMed  Google Scholar 

  31. Bosma A, Abdel-Gadir A, Isenberg David A, Jury Elizabeth C, Mauri C (2012) Lipid-antigen presentation by CD1d + B cells is essential for the maintenance of invariant natural killer T cells. Immunity 36:477–490

    CAS  PubMed  Google Scholar 

  32. Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114:1379–1388

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M et al (2012) Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491:264–268

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA et al (1998) IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 161:3299–3306

    CAS  PubMed  Google Scholar 

  35. Cohen SJ, Cohen IR, Nussbaum G (2010) IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88(−/−) mice. J Immunol 184:212–221

    CAS  PubMed  Google Scholar 

  36. Kessel A, Haj T, Peri R, Snir A, Melamed D et al (2012) Human CD19 + CD25high B regulatory cells suppress proliferation of CD4+ T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun Rev 11:670–677

    CAS  PubMed  Google Scholar 

  37. Mauri C, Blair PA (2010) Regulatory B cells in autoimmunity: developments and controversies. Nat Rev Rheumatol 6:636–643

    CAS  PubMed  Google Scholar 

  38. Knippenberg S, Peelen E, Smolders J, Thewissen M, Menheere P et al (2011) Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naïve/memory Breg ratio during a relapse but not in remission. J Neuroimmunol 239:80–86

    CAS  PubMed  Google Scholar 

  39. Quan C, Yu H, Qiao J, Xiao B, Zhao G et al (2013) Impaired regulatory function and enhanced intrathecal activation of B cells in neuromyelitis optica: distinct from multiple sclerosis. Mult Scler J 19:289–298

    CAS  Google Scholar 

  40. Wang HH, Dai YQ, Qiu W, Lu ZQ, Peng FH et al (2011) Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci 18:1313–1317

    CAS  PubMed  Google Scholar 

  41. Wu A, Zhong X, Wang H, Xu W, Cheng C et al (2012) Cerebrospinal fluid IL-21 levels in neuromyelitis optica and multiple sclerosis. Can J Neurol Sci 39:813–820

    PubMed  Google Scholar 

  42. Ding BB, Bi E, Chen H, Yu JJ, Ye BH (2013) IL-21 and CD40L synergistically promote plasma cell differentiation through upregulation of Blimp-1 in human B cells. J Immunol 190:1827–1836

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Korn T, Bettelli E, Gao W, Awasthi A, Jager A et al (2007) IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448:484–487

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Schwab I, Nimmerjahn F (2013) Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol 13:176–189

    CAS  PubMed  Google Scholar 

  45. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E et al (2003) Predominant autoantibody production by early human B cell precursors. Science 301:1374–1377

    CAS  PubMed  Google Scholar 

  46. Meffre E, Wardemann H (2008) B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol 20:632–638

    CAS  PubMed  Google Scholar 

  47. Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M et al (2013) Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 123:2737–2741

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A et al (2010) Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol 67:452–461

    CAS  PubMed  Google Scholar 

  49. Bennett JL, Haubold K, Ritchie AM, Edwards SJ, Burgoon M et al (2008) CSF IgG heavy-chain bias in patients at the time of a clinically isolated syndrome. J Neuroimmunol 199:126–132

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Ligocki AJ, Rounds WH, Cameron EM, Harp CT, Frohman EM et al (2013) Expansion of CD27(high) plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation. Genes and Immunity 14:291–301

    CAS  PubMed  Google Scholar 

  51. Krumbholz M, Derfuss T, Hohlfeld R, Meinl E (2012) B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8:613–623

    CAS  PubMed  Google Scholar 

  52. Hayashi T, Matsumoto I, Yasukochi T, Mamura M, Goto D et al (2007) Biased usage of synovial immunoglobulin heavy chain variable region 4 by the anti-glucose-6-phosphate isomerase antibody in patients with rheumatoid arthritis. Int J Mol Med 20:247–253

    CAS  PubMed  Google Scholar 

  53. Huang SC, Jiang R, Hufnagle WO, Furst DE, Wilske KR et al (1998) VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA). Clin Exp Immunol 112:516–527

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Dorner T, Farner NL, Lipsky PE (1999) Ig lambda and heavy chain gene usage in early untreated systemic lupus erythematosus suggests intensive B cell stimulation. J Immunol 163:1027–1036

    CAS  PubMed  Google Scholar 

  55. Fraser NL, Rowley G, Field M, Stott DI (2003) The VH gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus. Arthritis Res Ther 5:R114–R121

    PubMed Central  PubMed  Google Scholar 

  56. Cameron EM, Spencer S, Lazarini J, Harp CT, Ward ES et al (2009) Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J Neuroimmunol 213:123–130

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Ligocki AJ, Lovato L, Xiang D, Guidry P, Scheuermann RH et al (2010) A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis. J Neuroimmunol 226:192–193

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Derfuss T, Meinl E (2012) Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment? Curr Opin Neurol 25:231–238

    CAS  PubMed  Google Scholar 

  59. Brickshawana A, Hinson SR, Fryer JP, McKeon A, Pittock SJ, et al. (2013). KIR4.1-Specific IgG Not Detected in Multiple Sclerosis Patients’ Sera (S506). Presented at Annual Meeting of the American Neurological Association, New Orleans, Louisiana, USA

  60. Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH et al (2013) Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology. doi:10.1212/WNL.0b013e3182a43b48

    PubMed Central  PubMed  Google Scholar 

  61. Reindl M, Di Pauli F, Rostasy K, Berger T (2013) The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol 9:455–461

    CAS  PubMed  Google Scholar 

  62. O’Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E et al (2007) Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 13:211–217

    PubMed Central  PubMed  Google Scholar 

  63. Rostasy K, Mader S, Schanda K, Huppke P, Gartner J, et al. (2012). Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis. Arch Neurol

  64. Pröbstel AK, Dornmair K, Bittner R, Sperl P, Jenne D et al (2011) Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 77:580–588

    PubMed  Google Scholar 

  65. Mayer MC, Breithaupt C, Reindl M, Schanda K, Rostasy K et al (2013) Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol 191:3594–3604

    CAS  PubMed  Google Scholar 

  66. Hacohen Y, Absoud M, Woodhall M, Cummins C, De Goede CG et al (2013) Autoantibody biomarkers in childhood-acquired demyelinating syndromes: results from a national surveillance cohort. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2013-306411

    PubMed Central  Google Scholar 

  67. Titulaer MJ, Hoftberger R, Iizuka T, Rosenfeld MR, Graus F, et al. (2013). Overlap of Anti-NMDAR Encephalitis with Demyelinating Disorders (S528WIP). Presented at Annual Meeting of the American Neurological Association, New Orleans, Louisiana, USA

  68. Ratelade J, Zhang H, Saadoun S, Bennett JL, Papadopoulos MC et al (2012) Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol (Berl) 123:861–872

    CAS  Google Scholar 

  69. Kitley J, Woodhall M, Waters P, Leite MI, Devenney E et al (2012) Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 79:1273–1277

    CAS  PubMed  Google Scholar 

  70. Mader S, Gredler V, Schanda K, Rostasy K, Dujmovic I, et al. (2011). Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation. 8:184.: 184

  71. Waters P, Woodhall M, Hacohen Y, O’Connor K, Absoud M, et al. (2013). Antibodies to myelin oligodendrocyte glycoprotein (MOG) in children and adults with demyelinating disorders (NMO) (S503). Presented at Annual Meeting of the American Neurological Association, New Orleans, Louisiana, USA

  72. Woodhall M, Coban A, Waters P, Ekizoglu E, Kurtuncu M et al (2013) Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci 335:221–223

    CAS  PubMed  Google Scholar 

  73. Tzartos JS, Stergiou C, Kilidireas K, Zisimopoulou P, Thomaidis T et al (2013) Anti-Aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders. PLoS One 8:e74773

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Harrer A, Tumani H, Niendorf S, Lauda F, Geis C et al (2013) Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. Mult Scler J 19:1209–1212

    CAS  Google Scholar 

  75. Krumbholz M, Meinl I, Kümpfel T, Hohlfeld R, Meinl E (2008) Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71:1350–1354

    CAS  PubMed  Google Scholar 

  76. Stangel M, Fredrikson S, Meinl E, Petzold A, Stuve O et al (2013) The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol 9:267–276

    CAS  PubMed  Google Scholar 

  77. Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F et al (2005) BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 201:195–200

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Kowarik M, Cepok S, Sellner J, Grummel V, Weber M et al (2012) CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation 9:93

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P et al (2006) Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 129:200–211

    PubMed  Google Scholar 

  80. Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J et al (2010) The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 5:e11986

    PubMed Central  PubMed  Google Scholar 

  81. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164–174

    PubMed  Google Scholar 

  82. Tada S, Yasui T, Nakatsuji Y, Okuno T, Koda T et al (2013) BAFF controls neural cell survival through BAFF receptor. PLoS One 8:e70924

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Zhang L, Zheng S, Wu H, Wu Y, Liu S et al (2009) Identification of BLyS (B lymphocyte stimulator), a non-myelin-associated protein, as a functional ligand for Nogo-66 receptor. J Neurosci 29:6348–6352

    CAS  PubMed  Google Scholar 

  84. Li M, Ransohoff RM (2008) Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 84:116–131

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, Nelson PA, Stroud RM et al (2012) Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol 72:53–64

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, et al. (2011). Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature advance online publication: 538–41

  87. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A et al (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378:1779–1787

    CAS  PubMed  Google Scholar 

  88. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ et al (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–1828

    CAS  PubMed  Google Scholar 

  89. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C et al (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380:1829–1839

    CAS  PubMed  Google Scholar 

  90. Hartung HP, Kieseier BC (2010) Atacicept: targeting B cells in multiple sclerosis. Ther Adv Neurol Disord 3:205–216

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR et al (2004) Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441–453

    CAS  PubMed  Google Scholar 

  92. Yang M, Sun L, Wang S, Ko KH, Xu H et al (2010) Cutting edge: novel function of B cell-activating factor in the induction of IL-10 producing regulatory B cells. J Immunol 184:3321–3325

    CAS  PubMed  Google Scholar 

  93. Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Tradtrantip L, Zhang H, Saadoun S, Phuan P-W, Lam C et al (2012) Anti–Aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol 71:314–322

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Tradtrantip L, Zhang H, Anderson MO, Saadoun S, Phuan PW et al (2012) Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J 26:2197–2208

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Yoshida M, Tamura Y, Yamada Y, Yamawaki N, Yamashita Y (1998) Immusorba TR and Immusorba PH: basics of design and features of functions. Ther Apher 2:185–192

    CAS  PubMed  Google Scholar 

  97. Elsone L, Panicker J, Mutch K, Boggild M, Appleton R et al (2013) Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler J. doi:10.1177/1352458513495938

    Google Scholar 

  98. Kuroda H, Fujihara K, Takano R, Takai Y, Takahashi T et al (2013) Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica. J Neuroimmunol 254:178–182

    CAS  PubMed  Google Scholar 

  99. Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG et al (2013) Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 12:554–562

    CAS  PubMed  Google Scholar 

  100. Benkhoucha M, Molnarfi N, Santiago-Raber ML, Weber MS, Merkler D et al (2012) IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis. J Neuroinflammation 9:209

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Maeda K, Mehta H, Drevets DA, Coggeshall KM (2010) IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production. Blood 115:4699–4706

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S et al (2011) Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci USA 108:3701–3706

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Icoz S, Tuzun E, Kurtuncu M, Durmus H, Mutlu M et al (2010) Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitis optica patients. Int J Neurosci 120:71–75

    PubMed  Google Scholar 

  104. Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, et al. (2012). Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol 1–5. doi:10.1007/s10165-012-0715-9

  105. Kieseier BC, Stüve O, Dehmel T, Goebels N, Leussink VI, et al. (2012). Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. Arch Neurol 1–4. doi:10.1001/jamaneurol.2013.668

  106. Ayzenberg I, Kleiter I, Schroder A, Hellwig K, Chan A et al (2013) Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 70:394–397

    PubMed  Google Scholar 

  107. Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S et al (2005) Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol 5:1731–1740

    CAS  PubMed  Google Scholar 

  108. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimic et Biophys Acta (BBA) - Mol Cell Res 1813:878–888

    CAS  Google Scholar 

  109. Leibinger M, Muller A, Gobrecht P, Diekmann H, Andreadaki A et al (2013) Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation. Cell Death Dis 4:e609

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Yang P, Wen H, Ou S, Cui J, Fan D (2012) IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation. Exp Neurol 236:19–27

    CAS  PubMed  Google Scholar 

  111. Haggiag S, Zhang PL, Slutzky G, Shinder V, Kumar A et al (2001) Stimulation of myelin gene expression in vitro and of sciatic nerve remyelination by interleukin-6 receptor-interleukin-6 chimera. J Neurosci Res 64:564–574

    CAS  PubMed  Google Scholar 

  112. Valerio A, Ferrario M, Dreano M, Garotta G, Spano P et al (2002) Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells. Mol Cell Neurosci 21:602–615

    CAS  PubMed  Google Scholar 

  113. Zhang PL, Izrael M, Ainbinder E, Ben-Simchon L, Chebath J et al (2006) Increased myelinating capacity of embryonic stem cell derived oligodendrocyte precursors after treatment by interleukin-6/soluble interleukin-6 receptor fusion protein. Mol Cell Neurosci 31:387–398

    CAS  PubMed  Google Scholar 

  114. Pizzi M, Sarnico I, Boroni F, Benarese M, Dreano M et al (2004) Prevention of neuron and oligodendrocyte degeneration by interleukin-6 (IL-6) and IL-6 receptor/IL-6 fusion protein in organotypic hippocampal slices. Mol Cell Neurosci 25:301–311

    CAS  PubMed  Google Scholar 

  115. Tradtrantip L, Ratelade J, Zhang H, Verkman AS (2013) Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol 73:77–85

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Fulciniti M, Hideshima T, Vermot-Desroches C, Pozzi S, Nanjappa P et al (2009) A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res 15:7144–7152

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Jarius S, Wildemann B (2010) AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 6:383–392

    CAS  PubMed  Google Scholar 

  118. Jarius S, Probst C, Borowski K, Franciotta D, Wildemann B et al (2010) Standardized method for the detection of antibodies to aquaporin-4 based on a highly sensitive immunofluorescence assay employing recombinant target antigen. J Neurol Sci 291:52–56

    CAS  PubMed  Google Scholar 

  119. Jarius S, Franciotta D, Bergamaschi R, Rauer S, Wandinger KP et al (2008) Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 79:1134–1136

    CAS  PubMed  Google Scholar 

  120. Pedotti R, Musio S, Scabeni S, Farina C, Poliani PL et al (2013) Exacerbation of experimental autoimmune encephalomyelitis by passive transfer of IgG antibodies from a multiple sclerosis patient responsive to immunoadsorption. J Neuroimmunol 262:19–26

    CAS  PubMed  Google Scholar 

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Acknowledgments

The work of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB TR128), the Verein zur Therapieforschung für Multiple-Sklerose-Kranke, the Bundesministerium für Bildung und Forschung (“Krankheitsbezogenes Kompetenznetz Multiple Sklerose”), and the Gemeinnützige Hertie Stiftung.

Conflict of interest

E. Meinl has received compensations from TEVA and Novartis. E. Meinl and M. Krumbholz have received grant support from Novartis.

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Correspondence to Markus Krumbholz.

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Disclaimer: For all compounds mentioned (marked as asterisks): indication, approval by local regulatory authorities, combination therapy, disease, severity, contraindications, prerequisites, and individual patient characteristics have to be independently verified for each compound by the treating physician.

This article is a contribution to the special issue on B cell-mediated autoimmune diseases - Guest Editors: Thomas Winkler and Reinhard Voll

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Krumbholz, M., Meinl, E. B cells in MS and NMO: pathogenesis and therapy. Semin Immunopathol 36, 339–350 (2014). https://doi.org/10.1007/s00281-014-0424-x

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  • DOI: https://doi.org/10.1007/s00281-014-0424-x

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