title: Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges.
abstract: Recent years have substantially broadened our view on the pathogenesis of multiple sclerosis (MS). While earlier concepts focused predominantly on T lymphocytes as the key cell type to mediate inflammatory damage within central nervous system (CNS) lesions, emerging evidence suggests that B lymphocytes may play a comparably important role both as precursors of antibody-secreting plasma cells and as antigen-presenting cells (APCs) for the activation of T cells. With greater appreciation of this pathogenic B-cell function in MS, B-cell-directed therapies, and in particular B-cell-depleting monoclonal antibodies targeting the CD20 molecule, have gained enormous interest over recent years. Clinical trials demonstrated that anti-CD20 treatment, which depletes immature and mature B cells but spares CD20 negative plasma cells, rapidly reduces formation of new inflammatory CNS lesions. While these findings clearly corroborate a pathogenic contribution of B cells, recent experimental but also clinical findings indicate that not all B cells contribute in an equally pathogenic manner and that certain subsets may in contrast mediate anti-inflammatory effects. In this review, we summarize current findings in support of pathogenic B-cell function in MS, including the encouraging clinical data which derived from anti-CD20 MS trials. Further, we review novel findings suggestive of regulatory properties of B-cell subsets which may be collaterally abolished by pan-CD20 depletion. In conclusion, we aim to provide an outlook on how this currently differentiating concept of pro- and anti-inflammatory B-cell function could be harnessed to further improve safety and effectiveness of B-cell-directed therapeutic approaches in MS.
authors: Department of Neurology, Technische Universität München, Munich, Germany.
authors: Klaus
authors: K
authors: Lehmann-Horn
authors: Helena C
authors: HC
authors: Kronsbein
authors: Martin S
authors: MS
authors: Weber
keywords: B cell; Multiple sclerosis; anti-CD20; antibody; cellular subsets; experimental autoimmune encephalomyelitis; immune phenotyping; intrathecal; therapy
references: Ann Neurol. 2010 Sep;68(3):369-83
references: 20641064
references: J Immunol. 1999 Nov 1;163(9):5133-44
references: 10528220
references: Nat Med. 2008 Jun;14(6):688-93
references: 18488038
references: J Clin Invest. 1942 Sep;21(5):571-7
references: 16694947
references: Nature. 2012 Nov 8;491(7423):264-8
references: 23064231
references: Nature. 1985 Apr 11-17;314(6011):537-9
references: 3157869
references: J Neuroimmunol. 2006 Nov;180(1-2):63-70
references: 16904756
references: Int Immunol. 2001 Dec;13(12):1583-93
references: 11717199
references: Arch Neurol. 2007 Oct;64(10):1531-3
references: 17923639
references: Mod Rheumatol. 2013 Jul;23(4):827-31
references: 22782533
references: J Clin Oncol. 2007 Apr 10;25(11):1350-6
references: 17312328
references: Ann Rheum Dis. 2011 Aug;70(8):1507-10
references: 21551509
references: Ann Neurol. 2010 Apr;67(4):452-61
references: 20437580
references: J Exp Med. 2000 Aug 21;192(4):475-82
references: 10952717
references: Neurology. 1980 Oct;30(10):1023-8
references: 6448360
references: Arthritis Rheum. 2011 Jul;63(7):1793-803
references: 21452293
references: J Neurooncol. 2007 Jan;81(2):197-9
references: 16937012
references: J Exp Med. 1996 Dec 1;184(6):2271-8
references: 8976182
references: Brain. 2007 Apr;130(Pt 4):1089-104
references: 17438020
references: Blood. 2009 May 14;113(20):4834-40
references: 19264918
references: J Immunol. 1995 May 15;154(10):4915-23
references: 7730604
references: Nature. 1984 Jan 19-25;307(5948):273-6
references: 6198590
references: Eur J Immunol. 2004 Dec;34(12):3346-58
references: 15495164
references: Muscle Nerve. 2003 May;27(5):611-5
references: 12707982
references: Brain Pathol. 2004 Apr;14(2):164-74
references: 15193029
references: Blood. 2011 Jan 13;117(2):530-41
references: 20962324
references: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18460-5
references: 19015529
references: Eur J Immunol. 2007 Sep;37(9):2400-4
references: 17683116
references: N Engl J Med. 2008 Feb 14;358(7):676-88
references: 18272891
references: Clin Immunol. 2001 Feb;98(2):258-63
references: 11161983
references: Nat Rev Rheumatol. 2010 Nov;6(11):636-43
references: 20856268
references: J Immunol. 2007 May 15;178(10):6092-9
references: 17475834
references: J Neuroimmunol. 1992 May;38(1-2):139-46
references: 1374424
references: Haematologica. 2004 Jun;89(6):753-4
references: 15194546
references: J Exp Med. 2005 Jan 17;201(2):195-200
references: 15642740
references: Ann Neurol. 1999 Dec;46(6):878-86
references: 10589540
references: Semin Immunopathol. 2009 Nov;31(4):455-65
references: 19730864
references: Arthritis Rheum. 2008 Jan;58(1):61-72
references: 18163485
references: Ther Adv Neurol Disord. 2010 Jul;3(4):205-16
references: 21179612
references: J Neuroinflammation. 2012 Sep 03;9:209
references: 22943418
references: Blood. 2003 Jan 15;101(2):466-8
references: 12393404
references: Mult Scler. 2006 Aug;12(4):369-74
references: 16900750
references: Nat Med. 2005 Mar;11(3):328-34
references: 15735653
references: J Immunol. 1998 Dec 1;161(11):5959-66
references: 9834077
references: Eur J Immunol. 1999 Nov;29(11):3432-9
references: 10556797
references: J Exp Med. 1998 Jul 6;188(1):169-80
references: 9653093
references: Ann Neurol. 2000 Jun;47(6):707-17
references: 10852536
references: J Neuroimmunol. 2011 Dec 15;240-241:28-33
references: 21993076
references: J Neuroinflammation. 2012 May 16;9:93
references: 22591862
references: Results Probl Cell Differ. 2010;51:115-26
references: 19582406
references: Arch Neurol. 2009 Aug;66(8):1016-20
references: 19667224
references: Ann Neurol. 1998 Feb;43(2):236-43
references: 9485065
references: J Immunol. 1995 Oct 15;155(8):3734-41
references: 7561077
references: Ann Neurol. 2006 Jul;60(1):12-21
references: 16802293
references: J Immunol. 1987 Dec 15;139(12):4016-21
references: 3500978
references: Lancet. 2005 Aug 13-19;366(9485):579-82
references: 16099294
references: Clin Immunol. 2008 Sep;128(3):382-91
references: 18599355
references: Arch Neurol. 2011 Sep;68(9):1156-64
references: 21555606
references: Ann Neurol. 2008 Jan;63(1):16-25
references: 18232012
references: J Immunol. 2006 Sep 1;177(5):2749-54
references: 16920907
references: Gut. 2008 May;57(5):714-5
references: 18408106
references: Annu Rev Immunol. 2003;21:231-64
references: 12427767
references: Lancet. 2011 Nov 19;378(9805):1779-87
references: 22047971
references: J Neuroimmunol. 2010 Jan 25;218(1-2):134-9
references: 19900722
references: J Clin Apher. 1995;10(4):163-70
references: 8770707
references: Mult Scler. 2012 Jul;18(7):1045-9
references: 22086900
references: J Neuroinflammation. 2011 Oct 26;8:146
references: 22027448
references: J Clin Invest. 2012 Dec;122(12):4533-43
references: 23160197
references: Arch Neurol. 2011 Jul;68(7):870-8
references: 21403003
references: J Exp Med. 2012 May 7;209(5):1001-10
references: 22547654
references: Nat Immunol. 2002 Oct;3(10):944-50
references: 12244307
references: J Immunol. 2000 Mar 1;164(5):2782-9
references: 10679121
references: Eur J Immunol. 2002 Jul;32(7):1905-13
references: 12115610
references: Muscle Nerve. 2005 Sep;32(3):378-9
references: 15986418
references: Ann Neurol. 2009 Oct;66(4):460-71
references: 19847908
references: Biochim Biophys Acta. 2011 Feb;1812(2):239-45
references: 20600871
references: Trends Mol Med. 2001 Mar;7(3):115-21
references: 11286782
references: Yonsei Med J. 2009 Apr 30;50(2):280-3
references: 19430564
references: J Immunol. 2002 Dec 15;169(12):6720-32
references: 12471103