title: Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-γ, and GM-CSF and Diminished IL-10 Production.
abstract: Myasthenia gravis (MG) is a prototypical autoimmune disease that is among the few for which the target Ag and the pathogenic autoantibodies are clearly defined. The pathology of the disease is affected by autoantibodies directed toward the acetylcholine receptor (AChR). Mature, Ag-experienced B cells rely on the action of Th cells to produce these pathogenic Abs. The phenotype of the MG Ag-reactive T cell compartment is not well defined; thus, we sought to determine whether such cells exhibit both a proinflammatory and a pathogenic phenotype. A novel T cell library assay that affords multiparameter interrogation of rare Ag-reactive CD4(+) T cells was applied. Proliferation and cytokine production in response to both AChR and control Ags were measured from 3120 T cell libraries derived from 11 MG patients and paired healthy control subjects. The frequency of CCR6(+) memory T cells from MG patients proliferating in response to AChR-derived peptides was significantly higher than that of healthy control subjects. Production of both IFN-γ and IL-17, in response to AChR, was also restricted to the CCR6(+) memory T cell compartment in the MG cohort, indicating a proinflammatory phenotype. These T cells also included an elevated expression of GM-CSF and absence of IL-10 expression, indicating a proinflammatory and pathogenic phenotype. This component of the autoimmune response in MG is of particular importance when considering the durability of MG treatment strategies that eliminate B cells, because the autoreactive T cells could renew autoimmunity in the reconstituted B cell compartment with ensuing clinical manifestations.
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511; kevin.oconnor@yale.edu yonghao.cao@yale.edu.
authors.forename: Yonghao
authors.identifier: http://orcid.org/0000-0002-1350-7316
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Amezquita
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511; Department of Pathology, Yale School of Medicine, New Haven, CT 06511; and Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511;
authors.forename: Panos
authors.initials: P
authors.lastname: Stathopoulos
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Nowak
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511; kevin.oconnor@yale.edu yonghao.cao@yale.edu.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: J Immunol. 2005 Jan 1;174(1):164-73
references.pmid: 15611238
references.citation: Clin Exp Immunol. 2010 Oct;162(1):1-11
references.pmid: 20682002
references.citation: J Immunol. 2011 Jul 15;187(2):1039-46
references.pmid: 21653833
references.citation: Mol Immunol. 1995 Nov;32(16):1215-23
references.pmid: 8559146
references.citation: J Autoimmun. 2014 Aug;52:90-100
references.pmid: 24389034
references.citation: J Neuroimmunol. 2005 Feb;159(1-2):137-45
references.pmid: 15652413
references.citation: J Immunol. 2010 Nov 1;185(9):5656-67
references.pmid: 20881192
references.citation: Neurology. 1981 Mar;31(3):282-7
references.pmid: 6259556
references.citation: Eur J Biochem. 1993 Jul 15;215(2):229-38
references.pmid: 7688301
references.citation: JAMA Neurol. 2015 Jun;72(6):642-9
references.pmid: 25894002
references.citation: Eur J Biochem. 2000 Dec;267(23):6717-28
references.pmid: 11082182
references.citation: J Exp Med. 2004 Jul 5;200(1):79-87
references.pmid: 15238607
references.citation: J Autoimmun. 2014 Aug;52:53-63
references.pmid: 24405842
references.citation: Nature. 1984 Jul 19-25;310(5974):244-6
references.pmid: 6611507
references.citation: Blood. 2005 Jan 15;105(2):735-41
references.pmid: 15454488
references.citation: Clin Immunol. 2012 Dec;145(3):209-23
references.pmid: 23110942
references.citation: Proc Natl Acad Sci U S A. 1982 Jan;79(1):188-92
references.pmid: 6948300
references.citation: J Neuroimmunol. 1998 Nov 2;91(1-2):33-42
references.pmid: 9846817
references.citation: Acta Neurol Scand. 1998 Dec;98(6):422-6
references.pmid: 9875621
references.citation: Nature. 2010 Oct 21;467(7318):967-71
references.pmid: 20962846
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7000-4
references.pmid: 7688469
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14292-7
references.pmid: 20660725
references.citation: Nat Immunol. 2012 Oct;13(10):991-9
references.pmid: 22961052
references.citation: Sci Transl Med. 2015 May 13;7(287):287ra74
references.pmid: 25972006
references.citation: Neurology. 2012 Jan 17;78(3):189-93
references.pmid: 22218276
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Ann Neurol. 2012 Jul;72(1):53-64
references.pmid: 22807325
references.citation: Diabetes. 2010 Feb;59(2):433-9
references.pmid: 19934002
references.citation: Tissue Antigens. 1999 May;53(5):486-97
references.pmid: 10372544
references.citation: J Neurol. 1991 Aug;238(5):256-61
references.pmid: 1919609
references.citation: J Exp Med. 2009 Jul 6;206(7):1525-34
references.pmid: 19564353
references.citation: Tissue Antigens. 1992 May;39(5):225-35
references.pmid: 1357775
references.citation: Autoimmun Rev. 2005 Jul;4(6):351-63
references.pmid: 16081026
references.citation: J Clin Invest. 1988 Dec;82(6):1894-900
references.pmid: 2461962
references.citation: J Neuroimmunol. 2010 Aug 25;225(1-2):123-31
references.pmid: 20472307
references.citation: J Intern Med. 2014 Jan;275(1):12-26
references.pmid: 24215230
references.citation: Clin Exp Immunol. 1987 Jan;67(1):82-8
references.pmid: 3621677
references.citation: Cell Res. 2014 Dec;24(12):1387-402
references.pmid: 25412660
references.citation: J Exp Med. 1976 Sep 1;144(3):739-53
references.pmid: 182897
references.citation: JAMA Neurol. 2015 Apr;72(4):396-404
references.pmid: 25643325
references.citation: Nat Immunol. 2011 Jun;12(6):568-75
references.pmid: 21516111
references.citation: Nat Immunol. 2011 Jun;12(6):560-7
references.pmid: 21516112
references.citation: J Clin Invest. 1993 Aug;92(2):1055-67
references.pmid: 7688757
references.citation: Arch Neurol. 1999 Jan;56(1):25-7
references.pmid: 9923757
references.citation: J Neuroimmunol. 2000 Aug 1;108(1-2):29-39
references.pmid: 10900334
references.citation: J Immunol. 2012 Mar 15;188(6):2477-82
references.pmid: 22389204
references.citation: J Clin Invest. 2006 Dec;116(12):3252-7
references.pmid: 17099776
references.citation: Eur J Immunol. 2010 Jun;40(6):1577-89
references.pmid: 20352624
references.citation: Ther Adv Neurol Disord. 2011 Sep;4(5):259-66
references.pmid: 22010039
references.citation: Muscle Nerve. 1986 May;9(4):306-12
references.pmid: 2423869
references.citation: Neurology. 1999 Feb;52(3):484-97
references.pmid: 10025776
references.citation: Neurology. 1997 Jun;48(6):1638-42
references.pmid: 9191780
references.citation: Int Immunol. 1997 Sep;9(9):1311-8
references.pmid: 9310834
references.citation: Neurology. 1998 Apr;50(4):1045-54
references.pmid: 9566393
references.citation: Diabetes. 2005 Jan;54(1):92-9
references.pmid: 15616015
references.citation: Nature. 2012 Apr 26;484(7395):514-8
references.pmid: 22466287
references.citation: J Clin Invest. 1994 Mar;93(3):1020-8
references.pmid: 7510715
references.citation: J Clin Neurophysiol. 1993 Apr;10(2):167-80
references.pmid: 8389381
references.citation: J Neuroimmunol. 2011 Dec 15;240-241:65-73
references.pmid: 22099723
references.citation: PLoS One. 2015;10(4):e0123546
references.pmid: 25893403
references.citation: Curr Opin Neurol. 2013 Oct;26(5):459-65
references.pmid: 23945282
references.citation: Eur J Immunol. 2015 May;45(5):1339-47
references.pmid: 25676041
references.citation: J Exp Med. 2004 Apr 5;199(7):971-9
references.pmid: 15067033
references.citation: J Clin Invest. 1999 Dec;104(12):R63-7
references.pmid: 10606632
references.citation: Immunity. 2008 Apr;28(4):454-67
references.pmid: 18400188
references.citation: Exp Neurol. 2012 Apr;234(2):506-12
references.pmid: 22326541