title: Stage-specific immune dysregulation in multiple sclerosis.
abstract: A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4(+) T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to disease-modifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.
authors.affiliation: Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan , Ann Arbor, Michigan.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Segal
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015551:Autoimmunity; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy; D012008:Recurrence; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D054316:Biomarkers, Pharmacological
references.citation: J Neuroimmunol. 1999 Sep 1;99(1):36-43
references.pmid: 10496175
references.citation: Ann Neurol. 2009 Sep;66(3):390-402
references.pmid: 19810097
references.citation: J Neuroimmunol. 1989 Apr;22(2):93-105
references.pmid: 2466872
references.citation: J Neuroimmunol. 2003 Apr;137(1-2):197-209
references.pmid: 12667664
references.citation: Neurology. 2009 Dec 8;73(23):2003-10
references.pmid: 19996075
references.citation: J Immunol. 2000 Nov 1;165(9):5322-31
references.pmid: 11046067
references.citation: Ann Neurol. 2013 Mar;73(3):341-54
references.pmid: 23463494
references.citation: Science. 1979 Mar 16;203(4385):1123-5
references.pmid: 424741
references.citation: AJR Am J Roentgenol. 2007 Mar;188(3):697-702
references.pmid: 17312056
references.citation: Immun Ageing. 2013 Jan 10;10(1):1
references.pmid: 23305498
references.citation: Nat Immunol. 2011 Mar;12(3):255-63
references.pmid: 21278737
references.citation: Immunology. 2008 Oct;125(2):161-9
references.pmid: 18397264
references.citation: Nat Med. 2000 Oct;6(10):1167-75
references.pmid: 11017150
references.citation: J Immunol. 2004 Mar 15;172(6):3893-904
references.pmid: 15004197
references.citation: J Immunol. 1986 Sep 1;137(5):1527-31
references.pmid: 3489035
references.citation: Neurology. 1998 May;50(5):1294-300
references.pmid: 9595977
references.citation: Ann Neurol. 1999 Feb;45(2):247-50
references.pmid: 9989628
references.citation: Brain. 2007 Apr;130(Pt 4):1089-104
references.pmid: 17438020
references.citation: Am J Pathol. 2008 Jan;172(1):146-55
references.pmid: 18156204
references.citation: Mult Scler. 2009 Nov;15(11):1271-9
references.pmid: 19805441
references.citation: Neurology. 2004 Nov 23;63(10):1788-95
references.pmid: 15557491
references.citation: Mult Scler. 2013 Aug;19(9):1204-8
references.pmid: 23322500
references.citation: Brain Pathol. 2004 Apr;14(2):164-74
references.pmid: 15193029
references.citation: J Exp Med. 2005 Jan 17;201(2):233-40
references.pmid: 15657292
references.citation: Mult Scler. 2011 Mar;17(3):335-43
references.pmid: 21135023
references.citation: Neurology. 2011 Apr 5;76(14):1214-21
references.pmid: 21464424
references.citation: J Neurol Sci. 1989 Sep;92(2-3):291-306
references.pmid: 2809622
references.citation: Immunity. 2000 Nov;13(5):715-25
references.pmid: 11114383
references.citation: J Neuroimmunol. 2002 Apr;125(1-2):134-40
references.pmid: 11960649
references.citation: J Int Med Res. 2011;39(5):1625-35
references.pmid: 22117963
references.citation: Immunity. 2011 Dec 23;35(6):986-96
references.pmid: 22177922
references.citation: N Engl J Med. 2010 Feb 4;362(5):402-15
references.pmid: 20089954
references.citation: AJNR Am J Neuroradiol. 1997 Sep;18(8):1549-56
references.pmid: 9296198
references.citation: J Neurol Sci. 2008 Nov 15;274(1-2):39-41
references.pmid: 18474372
references.citation: Lancet. 2013 Jun 22;381(9884):2167-75
references.pmid: 23562009
references.citation: PLoS One. 2012;7(11):e48370
references.pmid: 23226202
references.citation: Mult Scler. 2005 Jun;11(3):251-60
references.pmid: 15957503
references.citation: Nature. 2011 Aug 10;476(7359):214-9
references.pmid: 21833088
references.citation: Brain. 2009 May;132(Pt 5):1175-89
references.pmid: 19339255
references.citation: N Engl J Med. 2006 Mar 2;354(9):899-910
references.pmid: 16510744
references.citation: J Immunol. 2006 Sep 15;177(6):4196-202
references.pmid: 16951385
references.citation: J Neurol. 2008 Mar;255 Suppl 1:3-11
references.pmid: 18317671
references.citation: Mult Scler. 2011 Jul;17(7):819-29
references.pmid: 21372118
references.citation: Lancet. 2012 Nov 24;380(9856):1829-39
references.pmid: 23122650
references.citation: Arch Neurol. 2010 Jun;67(6):707-14
references.pmid: 20558389
references.citation: J Autoimmun. 1998 Aug;11(4):287-99
references.pmid: 9776706
references.citation: J Exp Med. 2008 Jul 7;205(7):1535-41
references.pmid: 18573909
references.citation: Exp Neurol. 2010 Sep;225(1):2-8
references.pmid: 19840788
references.citation: Immunity. 2011 Feb 25;34(2):149-62
references.pmid: 21349428
references.citation: Mult Scler. 2013 Jun;19(7):877-84
references.pmid: 23178691
references.citation: Brain. 2005 Nov;128(Pt 11):2705-12
references.pmid: 16230320
references.citation: J Neuroimmunol. 2013 Jan 15;254(1-2):131-40
references.pmid: 22999187
references.citation: Annu Rev Neurosci. 2008;31:247-69
references.pmid: 18558855
references.citation: Neurology. 1999 Sep 11;53(4):751-7
references.pmid: 10489036
references.citation: Ann Neurol. 2006 Jul;60(1):12-21
references.pmid: 16802293
references.citation: J Immunol. 1995 Mar 15;154(6):2959-68
references.pmid: 7533188
references.citation: J Neurosci Res. 1996 Aug 15;45(4):322-33
references.pmid: 8872892
references.citation: J Neuroimmunol. 2001 Jan 1;112(1-2):139-45
references.pmid: 11108942
references.citation: PLoS One. 2013;8(3):e57820
references.pmid: 23469245
references.citation: Hum Genet. 2010 Mar;127(5):525-35
references.pmid: 20112030
references.citation: J Neurosci Res. 2001 Feb 1;63(3):290-302
references.pmid: 11170179
references.citation: Clin Immunol. 2013 May;147(2):105-19
references.pmid: 23578552
references.citation: Immunity. 2008 Apr;28(4):454-67
references.pmid: 18400188
references.citation: Clin Immunol. 2003 Feb;106(2):127-38
references.pmid: 12672403
references.citation: Brain. 2006 Jan;129(Pt 1):200-11
references.pmid: 16280350
references.citation: Autoimmun Rev. 2009 Jul;8(8):650-3
references.pmid: 19393199
references.citation: Neurology. 1990 Jun;40(6):971-5
references.pmid: 2189084
references.citation: J Neurol Sci. 2013 Feb 15;325(1-2):79-85
references.pmid: 23273903
references.citation: J Neuroimmunol. 2002 May;126(1-2):143-60
references.pmid: 12020966
references.citation: Eur Radiol. 2012 Jan;22(1):221-31
references.pmid: 21874361
references.citation: J Neuroimmunol. 1998 May 15;85(2):212-9
references.pmid: 9630170
references.citation: J Neuroimmunol. 2003 Aug;141(1-2):132-40
references.pmid: 12965264