自身免疫研究生课件

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1、自身免疫研究生考试时间：考试时间：12月月2日日 1：30-3：30地点：第地点：第28教室教室通知通知自身免疫研究生Self tolerance and Autoimmunity自身免疫研究生Part I Celluar and genetic mechanisms of self tolerance and autoimmunity自身免疫研究生GOAL OF THE IMMUNE SYSTEMSeparate self from non-selfStay in harmony with self antigens and tissues of the host自身免疫研究生V(D)J r

2、ecombination assembles unique BCR and TCR genes 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 ti

3、ssues(such as the spleen,lymph nodes and tonsils).自身免疫研究生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.自身免疫研究生Tolerance:the failure to mount an immune response

4、to self antigens(endogenous antigens)-Note:failure=/=passivity;tolerance is active自身免疫研究生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

5、 mature cells can lead to tolerancePrimarily a function of T cells;however B cells can be tolerizedT cell tolerance:long lived,requires less Ag stimulationB cell tolerance:shorter lived,requires more antigenCHARACTERISTICS of TOLERANCE自身免疫研究生自身免疫研究生自身免疫研究生BCR tolerance mechanisms in central lymphoid

6、 organs:Arrest of immature B-cell maturation;If the strength of receptor crosslinking 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 n

7、ot expressed.Such receptors are needed for B cells to enter the lymph nodes.b.receptors 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

8、recombination,continue to be expressed.自身免疫研究生(2)BCR light chain editing by V(D)J recombination;(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 a

9、rriving in the spleen.a.The process of clonal deletion may result partly from growth-factor 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).自身免疫研究生自

10、身免疫研究生TCR tolerance mechanisms in central lymphoid organs:(4)TCR a a-chain editing by V(D)J recombination;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 expr

11、ession(thereby closing off the option of editing),increase TCR cell-surface expression and induce the 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 downre

12、gulated,RAG expression continues and the offending TCR a a-chain is replaced or diluted with a second a a-chain that is less self reactive.自身免疫研究生(5)Death and deletion of semi-mature T cells.TCRs that bind strongly to self-peptideMHC combinations trigger the death(negative selection)of thymocytes.au

13、toimmune regulator(AIRE)geneZAP70(-chain-associated protein kinase of 70 kDa)GRB2(growth-factor-receptor-bound protein 2)MINK(misshapen-Nck-interacting kinase(NIK)related kinase)prolonged p38 and JNK(Jun kinase)activationBIMNur77 family of orphan nuclear receptorsThe combination of strong stimulator

14、y signals through TCR and CD28 is,paradoxically,a potent trigger of nuclear factor-B(NF-k kB)activation.自身免疫研究生自身免疫研究生Intrinsic 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

15、 endocytosis and blocked transport of new BCRs out of the endoplasmic reticulum.Self-reactive BCRs activate tyrosine kinase signalling poorly,limiting cell survival because of weak NF-k kB1 activation.a.Constitutively or changed express some proteins through which increase the threshold for B-cell a

16、ctivation regardless of BCR specificity.Such as SHP1(SH2-domain-containing protein tyrosine phosphatase 1),SHIP(SH2-domain-containing inositol-5-phosphatase),CD5.自身免疫研究生(7)TCR tuning/anergy.CD5 levels increase,downregulating the response of TCRs to self peptides to avoid T-cell activation or deletio

17、n;Cytotoxic T-lymphocyte antigen 4(CTLA4)inhibits T-cell activation by competing with CD28 for ligation with B7 molecules and by transmitting inhibitory signals;c.Tagged ubiquitin liagases interfere TCR,CD28 and cytokine receptor signaling through triggering endocytosis,altering intracellular traffi

18、cking of TCRs,promoting proteolytic degradation of receptors or signaling subunits,or allosterically interfering with signaling.自身免疫研究生Extrinsic regulation of self-reactive receptors by competitive mechanisms:(8)Follicular exclusion of B cells;Self-reactive BCRs induce subtle differences in B-cell r

19、esponsiveness to the opposing chemokine gradients between follicles and extrafollicular zones,excluding them from follicles and thus minimizing their participation in germinal-centre responses.(9)B-cell competition for BAFF;The self-reactive cells fail to receive enough BAFF and are competitively de

20、leted.(10)T-cell competition for IL-7.Keeping T cells alive requires TCR signalling through contact with ubiquitous MHC ligands as well as exposure 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

21、 these cells into extralymphoid sites,thereby risking the development of autoimmune disease at these sites.自身免疫研究生Extrinsic regulation of self-reactive receptors by limiting immunogenic co-stimuli:(11)Controls on availability of extrafollicular T-cell help;(12)Control of TLR ligands and signalling;(

22、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 molecules;(16)T-cell death induced by FASL;(17)T-cell suppression by TR cells.自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生Regulation of self-reactive receptors in follicle

23、s:(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-induced death of germinal-centre B cells;Less than 4 hours(20)Germinal-centre B-cell death from competition for follicular

24、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 自身免疫研究生Tolerance of self-reactive receptors at the final effector phase:(21)Control of autoantibody accumulation and inflammation in tissues.自身免疫研究生Part II

25、Initiation of autoimmunity自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生Mutations that interfere with the apoptotic death of mature lymphocytes may result in autoimmune diseasesDefective T cell-mediated suppressio

26、n may contribute to autoimmunityOther mechanisms of autoimmunity自身免疫研究生自身免疫研究生Part IIIClinical aspects of autoimmune diseases自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生Representative autoimmune diseasesInsulin-dependent diabetes mellitus,IDDMSystemic lupus erythematosus,SLERheumatoid arthritis,RAMultiple sclerosis,MSAnkylosing spondylitis,AS自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生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 自身免疫研究生自身免疫研究生自身免疫研究生自身免疫研究生You should know:Possible mechanisms of tolerance induction to self.1.Possible etiology and mechanisms of autoimmune diseases.