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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 tissuesof the host,V(D)J recombination assembles unique BCR and TCR gen
2、es 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 no
3、des and tonsils).,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)-No
4、te: failure =/= passivity; 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 lymphocytes Inadequate stimulation of mature cells can lead to tolerance
5、 Primarily a function of T cells; however B cells can be tolerized T cell tolerance: long lived, requires less Ag stimulation B cell tolerance: shorter lived, requires more antigen,CHARACTERISTICS of TOLERANCE,BCR tolerance mechanisms in central lymphoid organs: Arrest of immature B-cell maturation;
6、 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 not expressed. Such receptors are needed
7、 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 recombination, continue to be
8、expressed.,(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 arriving in the spleen. a. The pr
9、ocess 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).,TCR tolerance mechanisms in centr
10、al lymphoid organs: (4) TCR 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 expression (thereby closing off the optio
11、n 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 downregulated, RAG expression continue
12、s and the offending TCR a-chain is replaced or diluted with a second a -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) gene ZAP7
13、0 ( -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) activation BIM Nur77 family of orphan nuclear receptorsThe combination of strong stimulatory signals through T
14、CR and CD28 is, paradoxically, a potent trigger of nuclear factor- B (NF-kB) activation.,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 endocytosis and blocked
15、transport of new BCRs out of the endoplasmic reticulum. Self-reactive BCRs activate tyrosine kinase signalling 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 B
16、CR specificity. Such as SHP1 (SH2-domain-containing protein tyrosine phosphatase 1), SHIP (SH2-domain-containing 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-lymphocy
17、te 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 trafficking of TCRs, promoting proteolytic degradation of receptors or signaling subunits, or allosterically interfering with signaling.,
