Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 3/2014

01-05-2014 | Review

B cells in MS and NMO: pathogenesis and therapy

Authors: Markus Krumbholz, Edgar Meinl

Published in: Seminars in Immunopathology | Issue 3/2014

Login to get access

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.
Literature
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 76:1310–1315PubMed
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 9:80–89PubMedCentralPubMed
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 366:579–582PubMed
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 14:167–173PubMed
6.
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 135:1819–1833PubMedCentralPubMed
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 246:85–95PubMed
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 202:473–477PubMedCentralPubMed
10.
Bradl M, Misu T, Takahashi T, Watanabe M, Mader S et al (2009) Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 66:630–643PubMed
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 66:617–629PubMedCentralPubMed
12.
Asgari N, Khorooshi R, Lillevang ST, Owens T (2013) Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. J Neuroimmunol 254:76–82PubMed
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 1:5PubMedCentralPubMed
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 47:707–717PubMed
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 63:16–25PubMed
16.
Barnett MH, Parratt JD, Cho ES, Prineas JW (2009) Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol 65:32–46PubMed
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 125:1450–1461PubMed
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 125:815–827PubMedCentralPubMed
19.
Lanzavecchia A (1985) Antigen-specific interaction between T and B cells. Nature 314:537–539PubMed
20.
Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27PubMed
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 PubMedCentralPubMed
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 9:54–62PubMedCentralPubMed
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 169:5415–5423PubMed
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
25.
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 59:880–892PubMed
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 209:1001–1010PubMedCentralPubMed
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 45:400–414PubMed
29.
Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–950PubMed
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):366–70PubMed
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 36:477–490PubMed
32.
Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114:1379–1388PubMedCentralPubMed
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 491:264–268PubMedCentralPubMed
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 161:3299–3306PubMed
35.
Cohen SJ, Cohen IR, Nussbaum G (2010) IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88(−/−) mice. J Immunol 184:212–221PubMed
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 11:670–677PubMed
37.
Mauri C, Blair PA (2010) Regulatory B cells in autoimmunity: developments and controversies. Nat Rev Rheumatol 6:636–643PubMed
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 239:80–86PubMed
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
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 18:1313–1317PubMed
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 39:813–820PubMed
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 190:1827–1836PubMedCentralPubMed
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 448:484–487PubMedCentralPubMed
44.
Schwab I, Nimmerjahn F (2013) Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol 13:176–189PubMed
45.
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E et al (2003) Predominant autoantibody production by early human B cell precursors. Science 301:1374–1377PubMed
46.
Meffre E, Wardemann H (2008) B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol 20:632–638PubMed
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 123:2737–2741PubMedCentralPubMed
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 67:452–461PubMed
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 199:126–132PubMedCentralPubMed
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 14:291–301PubMed
51.
Krumbholz M, Derfuss T, Hohlfeld R, Meinl E (2012) B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8:613–623PubMed
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 20:247–253PubMed
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 112:516–527PubMedCentralPubMed
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 163:1027–1036PubMed
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–R121PubMedCentralPubMed
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 213:123–130PubMedCentralPubMed
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 226:192–193PubMedCentralPubMed
58.
Derfuss T, Meinl E (2012) Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment? Curr Opin Neurol 25:231–238PubMed
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.
61.
Reindl M, Di Pauli F, Rostasy K, Berger T (2013) The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol 9:455–461PubMed
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 13:211–217PubMedCentralPubMed
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 77:580–588PubMed
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 191:3594–3604PubMed
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 PubMedCentral
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
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 79:1273–1277PubMed
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 335:221–223PubMed
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:e74773PubMedCentralPubMed
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
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 71:1350–1354PubMed
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 9:267–276PubMed
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 201:195–200PubMedCentralPubMed
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 9:93PubMedCentralPubMed
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 129:200–211PubMed
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:e11986PubMedCentralPubMed
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 14:164–174PubMed
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:e70924PubMedCentralPubMed
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 29:6348–6352PubMed
84.
Li M, Ransohoff RM (2008) Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 84:116–131PubMedCentralPubMed
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 72:53–64PubMedCentralPubMed
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 378:1779–1787PubMed
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 380:1819–1828PubMed
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 380:1829–1839PubMed
90.
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 20:441–453PubMed
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 184:3321–3325PubMed
93.
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 71:314–322PubMedCentralPubMed
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 26:2197–2208PubMedCentralPubMed
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 2:185–192PubMed
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​
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 254:178–182PubMed
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 12:554–562PubMed
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 9:209PubMedCentralPubMed
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 115:4699–4706PubMedCentralPubMed
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 108:3701–3706PubMedCentralPubMed
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 120:71–75PubMed
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 70:394–397PubMed
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 5:1731–1740PubMed
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
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:e609PubMedCentralPubMed
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 236:19–27PubMed
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 64:564–574PubMed
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 21:602–615PubMed
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 31:387–398PubMed
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 25:301–311PubMed
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 73:77–85PubMedCentralPubMed
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 15:7144–7152PubMedCentralPubMed
117.
Jarius S, Wildemann B (2010) AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 6:383–392PubMed
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 291:52–56PubMed
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 79:1134–1136PubMed
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 262:19–26PubMed
Metadata
Title
B cells in MS and NMO: pathogenesis and therapy
Authors
Markus Krumbholz
Edgar Meinl
Publication date
01-05-2014
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 3/2014
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-014-0424-x

Other articles of this Issue 3/2014

Seminars in Immunopathology 3/2014 Go to the issue

Review

Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases

Review

Targeting B cells and autoantibodies in the therapy of autoimmune diseases

Review

B cell-mediated pathogenesis of ANCA-mediated vasculitis

Review

The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved

Review

Plasma cells in immunopathology: concepts and therapeutic strategies

Editorial

Introduction: B cell-mediated autoimmune diseases
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits