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1、考试时间：12月2日 1：30-3：30地点：第28教室,通知,Self tolerance and Autoimmunity,Part I Celluar and genetic mechanisms of self tolerance and autoimmunity,GOAL OF THE IMMUNE SYSTEM,Separate self from non-selfStay in harmony with self antigens and tissues of the host,V(D)J recombination assembles unique BCR and TCR ge
2、nes from three separate gene segments,the variable(V),diversity(D)and joining(J)genes,during B-and T-cell differentiation.Somatic hypermutation substitutes single nucleotides of BCR genes during a late phase of the immune response in peripheral lymphoid tissues(such as the spleen,lymph nodes and ton
3、sils).,Between 20 and 50%of TCRs and BCRs generated by V(D)J recombination bind with a potentially dangerous affinity to a self antigen.Only 38%of the population develops an autoimmune disease.,Tolerance:the failure to mount an immune response to self antigens(endogenous antigens)-Note:failure=/=pas
4、sivity;tolerance is active,Immunologically specific(e.g.,specific epitopes)Learned or acquired(e.g.,active process)Immature or developing lymphocytes more susceptible to tolerance induction than mature lymphocytesInadequate stimulation of mature cells can lead to tolerancePrimarily a function of T c
5、ells;however B cells can be tolerizedT cell tolerance:long lived,requires less Ag stimulationB cell tolerance:shorter lived,requires more antigen,CHARACTERISTICS of TOLERANCE,BCR tolerance mechanisms in central lymphoid organs:Arrest of immature B-cell maturation;If the strength of receptor crosslin
6、king and intracellular signalling exceeds a certain threshold,the immature B cell rapidly internalizes the offending BCR and temporarily halts its maturation programme.a.homing receptors,such as CD62 ligand(CD62L),are not expressed.Such receptors are needed for B cells to enter the lymph nodes.b.rec
7、eptors for B-cell-activating factor(BAFF),a circulating cytokine required to sustain peripheral B-cell survival,are poorly induced.c.RAG1(recombination-activating gene 1)and RAG2,which encode the core enzymes for V(D)J recombination,continue to be expressed.,(2)BCR light chain editing by V(D)J recom
8、bination;(3)Death and deletion of immature B cells.If a B cell with a forbidden receptor fails to edit to a less self-reactive receptor,cell death occurs within 12 days,either in the bone marrow or shortly after arriving in the spleen.a.The process of clonal deletion may result partly from growth-fa
9、ctor withdrawal,owing to low expression of BAFF receptors on immature B cells.b.Deletion also involves BCR-induced cell death through increasing the levels of BIM(BCL-2-interacting mediator of cell death).,TCR tolerance mechanisms in central lymphoid organs:(4)TCR a-chain editing by V(D)J recombinat
10、ion;Composites of self peptides and MHC are displayed on the surface of cortical thymic epithelial cells,and TCRs that weakly bind these ligands trigger maturation signals that inhibit RAG gene expression(thereby closing off the option of editing),increase TCR cell-surface expression and induce the
11、expression of homing receptors for chemokines found in the thymic medulla and the peripheral lymphoid tissues.A minority of self-reactive TCRs trigger an editing process;in this case,TCRs are downregulated,RAG expression continues and the offending TCR a-chain is replaced or diluted with a second a-
12、chain that is less self reactive.,(5)Death and deletion of semi-mature T cells.TCRs that bind strongly to self-peptideMHC combinations trigger the death(negative selection)of thymocytes.autoimmune regulator(AIRE)geneZAP70(-chain-associated protein kinase of 70 kDa)GRB2(growth-factor-receptor-bound p
13、rotein 2)MINK(misshapen-Nck-interacting kinase(NIK)related kinase)prolonged p38 and JNK(Jun kinase)activationBIMNur77 family of orphan nuclear receptorsThe combination of strong stimulatory signals through TCR and CD28 is,paradoxically,a potent trigger of nuclear factor-B(NF-kB)activation.,Intrinsic
14、 regulation of self-reactive receptors by anergy and biochemical tuning:(6)BCR tuning/anergy;Decreased display of self-reactive BCRs on the cell surface,owing to accelerated endocytosis and blocked transport of new BCRs out of the endoplasmic reticulum.Self-reactive BCRs activate tyrosine kinase sig
15、nalling poorly,limiting cell survival because of weak NF-kB1 activation.Constitutively or changed express some proteins through which increase the threshold for B-cell activation regardless of BCR specificity.Such as SHP1(SH2-domain-containing protein tyrosine phosphatase 1),SHIP(SH2-domain-containi
16、ng inositol-5-phosphatase),CD5.,(7)TCR tuning/anergy.CD5 levels increase,downregulating the response of TCRs to self peptides to avoid T-cell activation or deletion;Cytotoxic T-lymphocyte antigen 4(CTLA4)inhibits T-cell activation by competing with CD28 for ligation with B7 molecules and by transmit
17、ting inhibitory signals;c.Tagged ubiquitin liagases interfere TCR,CD28 and cytokine receptor signaling through triggering endocytosis,altering intracellular trafficking of TCRs,promoting proteolytic degradation of receptors or signaling subunits,or allosterically interfering with signaling.,Extrinsi
18、c regulation of self-reactive receptors by competitive mechanisms:(8)Follicular exclusion of B cells;Self-reactive BCRs induce subtle differences in B-cell responsiveness to the opposing chemokine gradients between follicles and extrafollicular zones,excluding them from follicles and thus minimizing
19、 their participation in germinal-centre responses.(9)B-cell competition for BAFF;The self-reactive cells fail to receive enough BAFF and are competitively deleted.(10)T-cell competition for IL-7.Keeping T cells alive requires TCR signalling through contact with ubiquitous MHC ligands as well as expo
20、sure to interleukin-7(IL-7).Naive T cells proliferation upon increase IL-7 may activate T cells reactive to tissue-specific antigens and promote migration of these cells into extralymphoid sites,thereby risking the development of autoimmune disease at these sites.,Extrinsic regulation of self-reacti
21、ve receptors by limiting immunogenic co-stimuli:(11)Controls on availability of extrafollicular T-cell help;(12)Control of TLR ligands and signalling;(13)B-cell death induced by FASL from T cells;(14)BCR inhibition of plasma-cell differentiation;(15)Control of B7 ligands and other costimulatory mole
22、cules;(16)T-cell death induced by FASL;(17)T-cell suppression by TR cells.,Regulation of self-reactive receptors in follicles:(18)Control of ICOS and follicular T helper cell differentiation,block self-reactive T cells from delivering help to germinal-centre B cells;CD40L,OX40L,SH2D1a,Roquin.(19)BCR
23、-induced death of germinal-centre B cells;Less than 4 hours(20)Germinal-centre B-cell death from competition for follicular T helper cells.by competition for BAFF,or by competition for CD40L,IL-21 and ICOS(inducible T-cell costimulator)signals from follicular T cells,Tolerance of self-reactive recep
24、tors at the final effector phase:(21)Control of autoantibody accumulation and inflammation in tissues.,Part II Initiation of autoimmunity,Mutations that interfere with the apoptotic death of mature lymphocytes may result in autoimmune diseasesDefective T cell-mediated suppression may contribute to a
25、utoimmunity,Other mechanisms of autoimmunity,Part IIIClinical aspects of autoimmune diseases,Representative autoimmune diseases,Insulin-dependent diabetes mellitus,IDDMSystemic lupus erythematosus,SLERheumatoid arthritis,RAMultiple sclerosis,MSAnkylosing spondylitis,AS,关节软骨,滑液与滑膜腔,滑膜,滑膜增厚,骨质损伤,炎性滑液,关节软骨受损变薄,(a)健康关节,(b)类风湿性关节炎,You should know:Possible mechanisms of tolerance induction to self.Possible etiology and mechanisms of autoimmune diseases.,
