中科院细胞与分子免疫学课程chapter10ppt课件

B细胞激活所需第二信号： C3d, CR2-CD19-C81 T依赖抗原是怎样使B细胞产生各种各样抗体的： 1. T、B细胞被抗原激活 2. 激活的T、B细胞相互迁移，发生接触。 3. B细胞作为抗原递承细胞呈递抗原给T细胞。 4. T细胞表面表达的CD40L，B细胞表面表达CD40。 CD40L与CD40相互作用。 5. T细胞分泌的细胞因子刺激B细胞 B细胞分化为可产生抗体的细胞： 上堂课回顾： 1.发生在mRNA水平上的编辑：抗体膜型向分泌型 转化 2.发生在DNA水平上的重组：发生重链的转换，受 不同细胞因子的刺激产生不同的抗体，IL-4：IgE ； IFN-g：IgG 晚期事件： 1.亲和力发生改变 2.产生记忆性细胞 不依赖T细胞抗原产生抗体 早期事件： Chapter 10 Immunologic Tolerance What is immunologic tolerance? Unresponsiveness to an antigen that is induced by previous exposure to that antigen. 1. 1945, Owen reported one immunologically tolerance phemomenon: How the immunologically specific phenomenon -tolerance has been discovered? 2. 1950，Peter Medawar establish one tolerance experiment: General features of Immunologic Tolerance 1. Tolerance is specific immunological response. 2. Self tolerance can be divided into two types: Central tolerance: Site: in generative lymphoid organs Immune response: immature self-reactive lymphocytes recognizing self antigens. Peripheral tolerance: Site: in peripheral sites Immune response: mature self-reactive lymphocytes encountering self antigens under particular conditions. Self tolerance can be divided into two types: Eliminate many of the potentially most dangerous lymphocytes Unresponsiveness to self antigens that are expressed in peripheral tissues The principal mechanisms of lymphocyte tolerance are: 1. Apoptotic cell death: deletion 2. Functional inactivation without cell death, called anergy 3. Supression of lymphocyte activation and effector functions by regulatory lymphocytes. T lymphocyte Tolerance 1Central Tolerance in T cell 1.Two main factors that determine whether a particular self antigen will initiate the central tolerance of T cells: I.The concentration of that antigen in the thymus II.The affinity of the thymocyte TCR 2.In additional: AIRE gene: autoimmune regulator gene, is to stimulate expression of some peripheral antigens in thymic epithelial cells. For example: APS, autoimmune polyendocrine syndrom. 3.Not known: I.What signal triggers the cell to die in response to high affinity of the antigen? 2Peripheral T cell Tolerance Three mechanisms in inducing the peripheral T cell tolerance 1. Without adequate costimulators or with inhibitory signals 1) Role of B7 costimulators in T cell activation and anergy Several experimental systems illustrated the anergy related with costimulator. 2) Administrate foreign antigens in different ways that result in immunogenic or tolerogenic. 3) Aberrant expression of costimulators may trigger autoimmune reactions. Use the inhibitory receptor for B7 molecules, CTLA-4 1) Knockout mice lacking CTLA-4 develop uncontrolled lymphocyte activation with massively enlarged lymph nodes and spleen and multiorgan lymphocytic infiltrates. 2) Blocking CTLA-4 with antibodies also enhances autoimmune disease in animal models. 3) T cells lacking CTLA-4 are resistant to the induction of anergy. Hypothesis: The nature of tissue APCs is an important determinant of whether self-tolerance or autoimmunity develops. 2 Deletion of T Cells by Apoptotic Cell Death T lymphocytes will die by apoptosis if: 1) T lymphocytes that recognize self antigens without inflammation 2) T lymphocytes are repeatedly stimulated by persistent antigens Two reasons to explain the apoptosis: 1) Repeated stimulation of T cells results in the coexpression of death receptors and their ligand. In CD4+ T cells, death receptor: Fas, the ligand:FasL. FasL is expressed on T cell surface when T cells are repeatedly activated. T cells that recognize self antigens activate a pro-apoptotic protein called Bim, resulting in apoptosis by the mitochondrial pathway. 3. Tolerance Induced by Regulatory T Lymphocytes 1) Regulatory T cells: Can inhibit some immune responses . 2) Regulatory T cells are CD4+ and express high levels of the IL-2 receptor a chain(CD25). 3) The development and function of regulatory T cells are dependent on the Foxp3 transcription factor. 4) Regulatory T cells inhibit immune responses by secreting immunosuppressive cytokines such as IL-10 and TGF-b. 3.1 Mechanisms of action of regulatory T cells Factor Factors that favor stimulation of immune responses Factors that favor tolerance AmountOptimal doses that vary for different antigens High doses PersistenceShort-lived (eliminated by immune response) Prolonged (repeated T cell stimulation induces apoptosis) Portal of entry; location Subcutaneous, intradermal; absence from generative organs Intravenous, oral; presence in generative organs Presence of adjuvants Antigens with adjuvants: stimulate helper T cells Antigens without adjuvants: nonimmunogenic or tolerogenic Properties of antigen presenting cells High levels of costimulatorsLow levels of costimulators and cytokines 4 Factors that Determine the Tolerogenicity of Self Antigens B lymphocyte Tolerance 1Central Tolerance in B Cells 1. In the F1 offspring, immature B cells specific for HEL are exposed to HEL in the absence of HEL-specific helper T cells. 2. the immature B cells may be deleted or change the specificity. 2 Peripheral B Cell Tolerance 1. Self recognizing B cells is long-lived functional anergy, resulting in an inability to respond to antigen. 2. If anergic B cells do encounter any antigen- specific helper T cells, the B cells may be killed by FasL on the T cells. 3. Lose capacity to migrate into lymphoid follicles. FeatureT lymphocytesB lymphocytes Principal sites of tolerance induction Thymus (cortex); peripheryBone marrow; periphery Tolerance- sensitive stage of maturation CD4+CD8+ (double-positive) thymocyteImmature (IgM+IgD-) B lymphocyte Stimuli for tolerance induction Central: high-avidity recognition of antigen in thymus Central: high-avidity recognition of multivalent antigen in bone marrow Peripheral: antigen presentation by APCs lacking costimulators; repeated stimulation by self antigen Peripheral: antigen recognition without T cell help Principal mechanisms of tolerance Central tolerance: clonal deletion (apoptosis) Central tolerance: clonal deletion (apoptosis), receptor editing Peripheral tolerance: anergy, apoptotic cell death, suppression Peripheral tolerance: block in signal transduction (anergy); failure to enter lymphoid follicles Difference Between Tolerance of T And B cells Tolerance Induced by Foreign Protein Antigens 1. Without adjuvants 2. Activate regulatory T cells 3. Produce some cytok