自身免疫性疾病--英五班課件

1、自身免疫性疾病-英五班Autoimmunity and Autoimmune DiseasesGuangjie Chen Dept. of Immunology and Microbiology2015自身免疫性疾病-英五班Autoimmunity is defined as an acquired immune reactivity against self antigensThe normal physiological activityessence-autoimmune responseLow affinity IgM-CD5+B1- “natural” Ab spectrum自身免疫

2、性疾病-英五班Autoimmune diseases occur when autoimmune responses lead to tissue damage The pathological activityessence-autoimmune responseImmunological tolerance fails to eliminate or control pathogenic self-reactive lymphocytes 自身免疫性疾病-英五班 Breaking of self-tolerance自身免疫性疾病-英五班I. The features and classif

3、ication of AID1. Features 自身免疫性疾病-英五班2. Classification Organ specific Nonorgan specific自身免疫性疾病-英五班II. The pathological mechanism of AID1. autoantibody binding to cell membrane 2. autoantibody binding to membrane receptor3. autoantibody binding to extracellular components4. The effect of immune compl

4、ex deposition5. The effect of autoreactive T cell自身免疫性疾病-英五班Type II hypersensitivity（autoantibody)The effect of autoantibody binding to cell membrane （IgM、IgG） Autoimmune hemolytic anemia thrombocytopenic purpura 1. Hemolytic disease of the newborn induced by Rhesus incompatibility自身免疫性疾病-英五班自身免疫性疾病

5、-英五班自身免疫性疾病-英五班The effect of autoantibody to membrane receptor Myasthenia gravis Graves disease自身免疫性疾病-英五班自身免疫性疾病-英五班Thyroid epithelial cellTSH-RTSHT3、T4Anti-TSH-R Ab自身免疫性疾病-英五班Figure 13-29 part 1 of 2自身免疫性疾病-英五班3. The effect of autoantibody to extracellular components Goodpastures syndrome * anti b

6、asement membrane（kidney, lung）type IV collagen Ab自身免疫性疾病-英五班4. The effect of immune complex deposition * Type III hypersensitivity自身免疫性疾病-英五班(1) SLE自身免疫性疾病-英五班（2）RA(2) RA自身免疫性疾病-英五班5. The effect of autoreactive T cell * Type IV hypersensitivityMultiple sclerosis(MS）Th1、Tc、MBPType I diabetes mellitus

7、 Tc cell自身免疫性疾病-英五班AutoimmuneMechanismsin MS自身免疫性疾病-英五班自身免疫性疾病-英五班自身免疫性疾病-英五班III. Pathogenic factors related to AID Antigen-related factors Releasing of sequestered antigen自身免疫性疾病-英五班 Alteration of self antigen properties Molecular mimicrycommon antigencross reactionstreptococcuskidney, heart Epitop

8、e spreading自身免疫性疾病-英五班自身免疫性疾病-英五班2. Abnormalities of immune regulation Failure of self-toleranceAbul K. abbas et al. Cellular and Molecular Immunology, 7th edition, Elsevier Saunders自身免疫性疾病-英五班 Broken central and peripheral toleranceAbul K. abbas et al. Cellular and Molecular Immunology, 7th edition

9、, Elsevier Saunders自身免疫性疾病-英五班AutoantigensAutoantigen induced T cell expansionAutoimmune lymphoproliferative syndrome , ALPS Abnormal expression of Fas/FasL自身免疫性疾病-英五班 Polyclonal activation of T and B cells自身免疫性疾病-英五班Abul K. abbas et al. Cellular and Molecular Immunology, 7th edition, Elsevier Saund

10、ers Dysfunction of Treg Abnormal expression of MHC-II自身免疫性疾病-英五班3. Genetic factors Association of HLA with autoimmune disease自身免疫性疾病-英五班自身免疫性疾病-英五班 Other genes C1q, C4 gene deficiency：SLE DNase deficiency ：SLE mutant CTLA-4：Diabetes4. Other factors Gender Age Environment factor自身免疫性疾病-英五班IV. Immunol

11、ogical control strategies Deletion factors which induce abnormal self-tolerance Inhibition of immune response to autoAg Rebuilding self-toleranceControl of infectionAdministration of immunosuppressive drugAntibodiesautoAg自身免疫性疾病-英五班自身免疫性疾病-英五班AutoreactiveT cellSynovial fibroblastMIFN-, IL-17IL-1, IL

12、-15IL-1, TNF-ChondrocyteOsteoclastMMPs, IL-6, IL-8, GM-CSFCartilage and bone destructionTNF inhibitorsIL-1 inhibitorIL-6 inhibitorOral toleranceT cell vaccineMMPsT cell costimulatory blockers Archivum Immunologiae et Therapiae Experimentalis (AITE), 2010, 58：27-36自身免疫性疾病-英五班TargetName of therapeutic

13、Product of descriptionStage of developmentCurrentTNF-EtanerceptSoluble p75 TNFRhuman IgG1Fc fusion proteinLisencedInfliximabChimeric mAb specific for TNF-LisencedAdalimumabHumanized mAb specific for TNF-LisencedIL-1AnakinraIL-1raLisencedIL-6TocilizumabHumanized mAb specific for IL-6RPhase III clinical trialsIn perspectiveIL-1AMG 108Humanized mAb specific for IL-1Phase II clinical trialsIL-15HuMaxIL-15 (AMG 714)HuMax IL-15 (AMG 714)Phase II clinical trialsIL-17Lubberts E (2008)IL-21Andersson AK et al (20