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Chapter 10 Immunologic Tolerance. General Features and Mechanisms T Lymphocyte Tolerance B Lymphocyte Tolerance Tolerance induced by Foreign Protein Antigens Homeostasis in the Immune System. What is Immunologic Tolerance?.
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Chapter 10Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System
What is Immunologic Tolerance? Immunologic Tolerance—— an antigen induced specific unresponsiveness Tolerogens Immunogens Self-tolerance Autoimmunity Tolerance induced by foreign antigens Failure
General Features and Mechanisms • Immunologically specific • A result of antigen recognition by specific lymphocytes
Studies of graft rejection in inbred mice Strain A Strain A Strain A Neonate Adult _ Skin graft rejection + + During lymphocyte maturation in the generative lymphoid organs, all lymphocytes pass through a stage in which encounter with Ag leads to tolerance • Immunologically specific • a result of the recognition of antigens by specific lymphocytes
General Features and Mechanisms • Immunologically specific • Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens
General Features and Mechanisms • Immunologically specific • Central tolerance: generative lymphoid organs immature self-reactive lymphocyte • Peripheral tolerance: peripheral sites mature self-reactive lymphocytes The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens Important for maitaining unresponsiveness to self antigens that are not expressed in the generative lymphoid organs.
Peripheral tolerance is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.
The principal mechanisms of lymphocyte tolerance • Deletion: apoptotic cell death • Anergy: functional inactivation without cell death • Treg Central tolerance Peripheral tolerance
Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System
T Lymphocyte Tolerance • Central T Cell Tolerance • Peripheral T cell Tolerance
High affinity High concentration Negative selection: Development of central tolerance
Self antigens expressed in the thymus • ubiquitous self-antigen: widely expressed in the body • tissue-specific antigenautoimmune regulator gene, AIRE
T Lymphocyte Tolerance • Central T Cell Tolerance • Peripheral T cell Tolerance
Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • Activation induced cell death (AICD) • Regulatory T Lymphocytes • Factors that determine the tolerogenicity of self antigens
Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Treg • Factors that determine the tolerogenicity of self antigens
Two Signal model Sig2 (co-stimulation) 1975 Lafferty & Cunningham T helper cells die when they see antigen unless rescued by co-stimulation(signal two) from APCs.
Figure 8-20 Gowth factor: IL-2
Anergy is induced when mature lymphocytes recognize antigens without adequate levels of the costimulators.
Figure 8-12 CTLA-4/B7 initiate the inhibitory signal
Anergy may be induced if T cells use CTLA-4 to recognize costimulators on APCs
? ? ? ? ? ? ? Question Factors T cells T cells T cells recognize B7 molecules with CD28 (active receptor) ? Recognize the same B7 with CTLA-4 (inhibitory receptor) Immune response Tolerance
Making and breaking tolerance The nature of tissue APCs is an important determinant of whether self-tolerance or autoimmunity develops.
Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Treg • Factors that determine the tolerogenicity of self antigens
Activation induced cell death Repeated stimulation of T cells by persistent antigen results in death of the activated cells by a process of apoptosis
Fas-mediated activation-induced cell death AICD is a form of apoptosis induced by signals from membrane death receptors
activation activation The net effect is that the population of mature lymphocytes is depleted of antigen specific lymphocytes by repeated stimulation.
Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Regulatory T Lymphocytes (Treg) • Factors that determine the tolerogenicity of self antigens
Treg cell development Immunity 2009; 30: p626
Peripheral T cell Tolerance • Antigen recognition without adequate costimulation • Use CTLA-4 to recognize costimulators on APCs • AICD • Regulatory T Lymphocytes (Treg) • Factors that determine the tolerogenicity of self antigens
Factors That Determine the Immunogenicity and Tolerogenicity of Protein
Immunologic Tolerance • General Features and Mechanisms • T Lymphocyte Tolerance • B Lymphocyte Tolerance • Tolerance induced by Foreign Protein Antigens • Homeostasis in the Immune System
B Lymphocyte Tolerance • Central B Cell Tolerance • Peripheral B cell Tolerance Checkpoints during B cell maturation and activation at which encounter self Ags may abort these process
Central tolerance in B cells • Immature B cells that recognize self antigens in the bone marrow with high affinity are deleted or change their specificity. • multivalent self antigens: cell membrane molecules、polymeric molecules
HEL transgenic What is the result of self antigen recognition in generative lymphoid organ? • Down-regulation of antigen receptor expression • Change in receptor specificity (receptor editing)
B Lymphocyte Tolerance • Central B Cell Tolerance • Peripheral B cell Tolerance
CD28 B7 T-B Collaboration
Peripheral tolerance in B cells • Mature B cells that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive. If anergic B cells do encounter any antigen-specific helper T cells, what happened? The B cells maybe killed by FasL on the T cells engaging Fas on the B cells.