Zusammenfassung
Die Multiple Sklerose (MS) ist eine entzündlich-demyelinisierende Autoimmunerkrankung des Zentralnervensystems und eine Hauptursache bleibender Behinderung im jüngeren Erwachsenenalter. In den letzten Jahren konnte unser Verständnis der Immunpathogenese dieser Erkrankung wesentlich vertieft werden. Zunehmend anerkannt ist, dass B-Zellen eine wesentliche Rolle hierbei spielen. Sie sind dabei nicht nur Vorstufen antikörperproduzierender Plasmazellen, sondern können als effiziente antigenpräsentierende Zellen oder durch Sezernierung zahlreicher proinflammatorischer Zytokine eine autoreaktive Entzündung unterhalten. Mit diesem Wissen sind mehrere klinische Studien zur Wirksamkeit von Rituximab bei MS durchgeführt worden. Rituximab ist ein chimärischer B-Zell-depletierender monoklonaler Antikörper, der an das auf frühen, naiven und Gedächtnis-B-Zellen, nicht aber Stammzellen oder Plasmazellen exprimierte CD20-Oberflächenantigen bindet. Neben zahlreichen kleineren Studien ist bislang eine doppelblinde, placebokontrollierte klinische Phase-II-Studie durchgeführt worden, die eine beeindruckende klinische Wirksamkeit und eine Wirksamkeit auf den Surrogatmarker MRT nachweisen konnte.
In diesem Übersichtsartikel werden die Rolle autoreaktiver B-Zellen, die Ergebnisse der B-Zell-depletierenden Studien sowie zukünftige B-Zell-gerichtete Therapiestrategien vorgestellt und im Kontext der MS zusammengefasst.
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the CNS and a leading cause of lasting neurological disability in younger adults. In the last decade our knowledge of its immunopathogenesis expanded vastly. It is now widely appreciated that B cells are key players in the autoreactive immune network. They exert far more functions than merely being the precursors of antibody-producing plasma cells. B cells act as efficient antigen-presenting cells and may stimulate an autoreactive immune response through secretion of proinflammatory cytokines. It is thus only logical to test therapeutic strategies targeting B cells in MS. Rituximab is a depleting chimeric monoclonal antibody directed against CD20 and expressed on developing, naïve, and memory B cells but not stem or plasma cells. Several smaller studies have been conducted that led to a placebo controlled, double blind phase II study on efficacy which was reported recently. The results are very promising, meeting not only the primary endpoint of reduction of the surrogate MRI marker of contrast-enhancing lesions but also showing a reduction in clinical relapse rate of patients treated with rituximab. This review discusses the role of autoreactive B cells in the context of MS, analyzes the B-cell-depleting treatment studies reported, and provides information on planned and future B-cell-directed therapeutic strategies in MS.
Literatur
Rituxan warning (2007) FDA Consum. 41:3
Allen CD, Ansel KM, Low C et al (2004) Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 5:943–952
Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6:205–217
Archelos JJ, Hartung HP (2000) Pathogenetic role of autoantibodies in neurological diseases. Trends Neurosci 23:317–327
Archelos JJ, Storch MK, Hartung HP (2000) The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol 47:694–706
Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61:288–299
Baker KP, Edwards BM, Main SH et al (2003) Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum 48:3253–3265
Bar-Or A, Calabresi PA, Arnlod D et al (2008) Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 63:395–400
Baranzini SE, Jeong MC, Butunoi C et al (1999) B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 163:5133–5144
Binder M, Otto F, Mertelsmann R et al (2006) The epitope recognized by rituximab. Blood 108:1975–1978
Browning JL (2006) B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5:564–576
Cepok S, Jacobsen M, Schock S et al (2001) Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 124:2169–2176
Cepok S, Rosche B, Grummel V et al (2005) Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128:1667–1676
Cohen IR (2007) Biomarkers, self-antigens and the immunological homunculus. J Autoimmun 29:246–249
Cohen SB, Emery P, Greenwald MW et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793–2806
Corcione A, Casazza S, Ferretti E et al (2004) Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci U S A 101:11064–11069
Cree BA, Lamb S, Morgan K et al (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64:1270–1272
Cross AH, Stark JL, Lauber J et al (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180:63–70
Cross AH, Trotter JL, Lyons J (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 112:1–14
Dalakas MC (2006) B cells in the pathophysiology of autoimmune neurological disorders: a credible therapeutic target. Pharmacol Ther 112:57–70
Di Gaetano N, Cittera E, Nota R et al (2003) Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 171:1581–1587
Dillon SR, Gross JA, Ansell SM, Novak AJ (2006) An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 5:235–246
Dorner T, Burmester GR (2008) New approaches of B-cell-directed therapy: beyond rituximab. Curr Opin Rheumatol 20:263–268
Duddy M, Bar-Or A (2006) B-cells in multiple sclerosis. Int MS J 13:84–90
Duddy M, Niino M, Adatia F et al (2007) Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol 178:6092–6099
Fillatreau S, Sweenie CH, McGeachy MJ et al (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–950
Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170–175
Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis reserach. Brain 129:1953–1971
Goldberg SL, Pecora AL, Alter RS et al (2002) Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab. Blood 99:1486–1488
Gommerman JL, Browning JL (2003) Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3:642–655
Gross JA, Dillon SR, Mudri S et al (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302
Hafler DA, Compston A, Sawcer S et al (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862
Harris HE (2008) Progressive multifocal leucoencephalopathy in a patient with systemic lupus erythematosus treated with rituximab. Rheumatology (Oxford) 47:224–225
Hauser SL, Waubant E, Arnold DL et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688
Hawker K (2008) B-cell-targeted treatment for multiple sclerosis: mechanism of action and clinical data. Curr Opin Neurol 21 [Suppl 1]:19–25
Hemmer B, Nessler S, Zhou D et al (2006) Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pract Neurol 2:201–211
Hohlfeld R, Wekerle H (2005) Drug insight: using monoclonal antibodies to treat multiple sclerosis. Nat Clin Pract Neurol 1:34–44
Kabat EA, Wolf A, Bezer AL (1947) The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterologous and homologous brain tissue with adjuvants. J Exp Med 85:117–129
Kalled SL (2005) The role of BAFF in immune function and implications for autoimmunity. Immunol Rev 204:43–54
Keegan M, Konig F, McClelland R et al (2005) Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366:579–582
Kleinschnitz C, Meuth SG, Kieseier BC, Wiendl H (2007) Update on pathophysiologic and immunotherapeutic approaches for the treatment of multiple sclerosis. Nervenarzt 78:883–911
Kranick SM, Mowry EM, Rosenfeld MR (2007) Progressive multifocal leukoencephalopathy after rituximab in a case of non-Hodgkin lymphoma. Neurology 69:704–706
Krumbholz M, Theil D, Cepok S et al (2006) Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 129:200–211
Krumbholz M, Theil D, Derfuss T 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
Kuenz B, Lutterotti A, Ehling R et al (2008) Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis. PLoS ONE 3:e2559
Liossis SN, Sfikakis PP (2008) Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin Immunol 127:280–285
Lucchinetti C, Bruck W, Parisi J et al (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717
Lund FE, Garvy BA, Randall TD, Harris DP (2005) Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr Dir Autoimmun 8:25–54
Lutz HU (2007) Homeostatic roles of naturally occurring antibodies: an overview. J Autoimmun 29:287–294
Lyons JA, San M, Happ MP, Cross AH (1999) B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur J Immunol 29:3432–3439
Magliozzi R, Columba-Cabezas S, Serafini B, Aloisi F (2004) 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 148:11–23
Magliozzi R, Howell O, Vora A et al (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104
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
Molina A (2008) A decade of rituximab: improving survival outcomes in non-Hodgkin’s lymphoma. Annu Rev Med 59:237–250
Monson NL, Cravens PD, Frohman EM et al (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62:258–264
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952
Onrust SV, Lamb HM, Balfour JA (1999) Rituximab. Drugs 58:79–88
Owens GP, Kraus H, Burgoon MP et al (1998) Restricted use of VH4 germline segments in an acute multiple sclerosis brain. Ann Neurol 43:236–243
Prineas JW (1979) Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 203:1123–1125
Qin Y, Duquette P, Zhang Y et al (1998) Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102:1045–1050
Raine CS, Cannella B, Hauser SL, Genain CP (1999) Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen-specific antibody mediation. Ann Neurol 46:144–160
Reff ME, Carner K, Chambers KS et al (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445
Reiber H, Ungefehr S, Jacobi C (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4:111–117
Rock KL, Benacerraf B, Abbas AK (1984) Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J Exp Med 160:1102–1113
Serafini B, Rosicarelli B, Magliozzi R et al (2006) Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 65:124–141
Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1:147–153
Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747
Stuve O, Cepok S, Elias B et al (2005) Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol 62:1620–1623
Tedder TF, Baras A, Xiu Y (2006) Fcgamma receptor-dependent effector mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity. Springer Semin Immunopathol 28:351–364
Tiller T, Tsuiji M, Yurasov S et al (2007) Autoreactivity in human IgG+ memory B cells. Immunity 26:205–213
Uccelli A, Aloisi F, Pistoia V (2005) Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol 26:254–259
von Budingen HC, Harrer MD, Kuenzle S et al (2008) Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur J Immunol 38:2014–2023
Wardemann H, Yurasov S, Schaefer A et al (2003) Predominant autoantibody production by early human B cell precursors. Science 301:1374–1377
Wingerchuk DM, Lennon VA, Lucchinetti CF et al (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815
Yurasov S, Wardemann H, Hammersen J et al (2005) Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 201:703–711
Zhou ZH, Tzioufas AG, Notkins AL (2007) Properties and function of polyreactive antibodies and polyreactive antigen-binding B cells. J Autoimmun 29:219–228
Menge T, Weber MS, Hemmer B et al (2009) Disease-modifying agents for multiple sclerosis: recent advances and future prospects. Drugs 68:2445–2468
Interessenkonflikte
Der korrespondierende Autor weist auf folgende Beziehungen hin: T.M. erhielt Honorare und Reisekostenzuschüsse von Bayer Healthcare, Biogne Idec, Merck Serono. H.-C.v.B. erhielt Vortragshonorare von Merck Serono, Schweiz. B.C.K und H.-P.H. erhielten in der Vergangenheit nach Genehmigung durch den Ärztlichen Direktor des Universitätsklinikums Düsseldorf und den Rektor der Heinrich-Heine-Universität Vortrags- bzw. Beratungshonorare der Hersteller der im Artikel erwähnten Präparate: Biogen Idec, Merck Serono sowie Genentech (H.-P.H.).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Menge, T., Büdingen, HC., Dalakas, M. et al. B-Zell-gerichtete Multiple-Sklerose-Therapie. Nervenarzt 80, 190–198 (2009). https://doi.org/10.1007/s00115-008-2664-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00115-008-2664-2