医学免疫学课件：T细胞DNA甲基化异常与系统性红斑狼疮发病相关的研究进展

1、Aberrant DNA methylation of T cells associates with systemic lupus erythematosusContentsDNA methylation in mammalsdefinitionestablishment and maintenance of patternssignificance in gene expressionSystemic Lupus Erythematosus (SLE)briefingmanifestations and classificationEarly evidenceLatest studiesF

2、uture perspectiveAcknowledgementsDNA Methylation in MammalsDefinitionepigenetic modification of DNAmethylation of cytosine at position C5 mainly in CpG dinucleotidesDNA methyltransferases (DNMTs) and methyl-CpG binding proteins (MBDs)/publications/arcr351/images/zakhari01.pngde novo methylationDNMT3

3、a and DNMT3bde novo methylationDNMT3a and DNMT3bMaintenance methylationDNMT1T lymphocytes differentiationSignificancehttps:/www.elitenetzwerk.bayern.de/uploads/tx_templavoila/Forschungsbericht_Epicombing_Zillner_figure1.jpgSLEAutoimmune disease bodys immune system mistakenly attacks healthy tissue i

4、n many parts of the bodymassive autoantibodies in serumChronic & no cureCausesnot clearinvolving hormonal/ environmental/ genetic factorshttps:/w/index.php?curid=8805434https:/w/index.php?curid=36008045 Common symptoms Preventing flares and reducing their severity and duration when they occurTable 1

5、 An overview of features of Systemic Lupus Erythematosus, Rheumatoid Arthritis and DermatomyositisTarget TissueAge of onsetW:M*PrevalenceSystemic Lupus ErythematosusSkin, joints, heart, lungs, blood vessels, liver, kidneys, and nervous systemReproductive years9:150 per 100,000Rheumatoid ArthritisJoi

6、nts (mainly), skin, lung, kidneys, heart, blood vesselsAt any age, most frequent between 40-502-3:11 per 100DermatomyositisMuscle, skinChildren 5 15Adults 40 602:11 per 100,000*W.M: proportion women to menJavierre B M, Fernandez A F, Richter J, et al. Genome Research, 2009, 20(2):170-9.Immunologic C

7、riteriaANA level above laboratory reference rangeAnti-dsDNA antibody level above laboratory referenceAnti-Sm: presence of antibody to Sm nuclear antigenAntiphospholipid antibody positivity as determined by any of the following:Positive test result for lupus anticoagulantFalse-positive test result fo

8、r rapid plasma reaginMedium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)Positive test result for anti2-glycoprotein I (IgA, IgG, or IgM)Low complementLow C3Low C4Low CH50Direct Coombs test in the absence of hemolytic anemiaEarly EvidenceGenomes globally hypomethylated & DNMT1 lev

9、els reducedEarly EvidenceGenomes globally hypomethylated & DNMT1 levels reducedIn miceCD4+ T cells treated with Decitabine* autoreactiveadoptive transfer causes SLE-like disease*=5-aza-2-deoxycytidineEarly EvidenceGenomes globally hypomethylated & DNMT1 levels reducedIn miceCD4+ T cells treated with

10、 Decitabine* autoreactiveadoptive transfer causes SLE-like diseaseGenes relevant to SLE phenotype demethylatedCD70CD11a*=5-aza-2-deoxycytidineMarinos C Dalakas. Nature Clinical Practice Neurology(2008)4, 557-567Oelke, K. et al. Arthritis Rheum. 50, 18501860 (2004).Overexpression of CD70 and overstim

11、ulation of IgG synthesis by lupus T cells andT cells treated with DNA methylation inhibitors.Impaired ERK signallingDNMT1 levels reduced hydralazine as inhibitorSchmidt A, Oberle N, Krammer P H. Frontiers in Immunology, 2012, 3:51-51.Deng, C. et al. Arthritis Rheum. 48, 746756 (2003).Representative

12、scatterplots showing methylation profiles of twins with the three autoimmune diseases studied (SLE, RA, and DM) compared with their respective healthy twins. Biola M. Javierre et al. Genome Res. 2010;20:170-1792010 by Cold Spring Harbor Laboratory PressLatest StudiesCD4-CD8- (DN) T cellsHedrich C M,

13、 Crispn J C, Rauen T, et al. Journal of Biological Chemistry, 2014, 289(4):2361-70.PKCGorelik G, Sawalha A H, Patel D, et al. Clinical Immunology, 2015, 158(2):193-203.DNMT1CD70/CD11a/ Anti-dsDNA PKCGorelik G, Sawalha A H, Patel D, et al. Clinical Immunology, 2015, 158(2):193-203.Oxidative stressH2O

14、2 ONOO-Lupus-like disease in micePKC nitratedBefore or After ? Future PerspectiveFuture Perspective/about/how-benlysta-works.htmlBock C, Tomazou E M, Brinkman A B, et al. Nature Biotechnology, 2010, 28(10):1106-14.AcknowledgementsWolffe AP, Matzke MA. Epigenetics: regulation through repressionJ. Sci

15、ence, 1999, 286(5439):481-486.Hedrich C M, Mbert K, Rauen T, et al. DNA methylation in systemic lupus erythematosusJ. Epigenomics. 2016 Nov 25. Epub ahead of printJavierre B M, Fernandez A F, Richter J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupu

16、s erythematosusJ. Genome Research, 2009, 20(2):170-9.Petri M, Orbai A M, Alarcn G S, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.J. Arthritis & Rheumatology, 2012, 64(8):2677-86.Robertson K. DNA m

17、ethylation and human disease.J. Nature Reviews Genetics, 2005, 6(8):597-610.Acknowledgements曹学涛, 何维. 医学免疫学(供8年制及7年制临床医学等专业用)(第3版)M. 人民卫生出版社, 2015.Hedrich C M, Crispn J C, Rauen T, et al. cAMP responsive element modulator (CREM) mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells.J. Journal of Biological Chemistry, 2014, 289(4):2361-70.Gorelik G, Sawalha A H, Patel D, et al. T cell PKC kinase inac