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Lecture Notes for Med. Tech. Class Oct. 2006 C.K. Shieh Immunological Tolerance • Tolerance is one of the central characters of the immune system (along with memory, specificity). • Location: Central tolerance and peripheral tolerance • Cell type: T cell tolerance and B cell tolerance • Mechanisms: deletion, anergy, immune deviation (ignorance) Owen’s “Experiment of Nature”-1945 Neonatal exposure leads to life-long tolerance to the otherwise foreign cells. Medawar’s Experiment of Neonatal Tolerance Induction • Neonatal exposure of allogeneic blood cells causes tolerance to the skin grafts from the blood donor. Central and Peripheral Immunological Tolerance • Theoretically, most endogenous antigens can tolerize the immune cells during their maturation in the “central” lymphoid organs. #Exeptions? 2. Exogenous antigens usually are encountered in the peripheral tissues. e.g. food antigens, air allergens Positive and Negative Selection of Thymocytes • Negative selection is important for the central tolerization of T cells. • Avidity is determined by TCR-MHC-peptide affinity, expression levels of these receptors and other co-receptors • Aire as a promoter of organ specific genes in medullary thymic epithelial cells Synthetic Peptides Were Used to Prove the Role of TCR Affinity in Thymic Selection TCR and CD4/8 signaling for lineage determination: The ratio of Lck and TCR signals determines the T cell lineage in an “instructional model” Two kinds of T-cell death: AICD and PCD –Fig.19.12 TCR Induced Cell Death in the Thymus Cell Death (Apoptosis) for Auto-reactive Lymphocytes • Cell deletion in the thymus due to negative selection • Cell deletion in the periphery (activation induced cell death) Mechanism of Peripheral Tolerance • Cell death (apoptosis) • • • • Anergy Ignorance ? Immune deviation Regulatory T cells: CD25+CD4+ T cells, working in a cytokine dependent and cytokine independent manner. Anergy: Antigen Stimulation Without Co-stimulations • Costimulation receptor on T cells: CD28 • B7-1 and B7-2 in APC provide the necessary stimulations for CD28 • Anergy: a state of lymphocyte inactivation marked by lack of cell proliferation after proper antigen stimulation. T Cell Tolerance Prevents B cell Autoimmunity • T cell help is necessary for most B cell immune responses. • Cross reactive T epitope may break B cell tolerance. • Some B cell antigen do not require T cell help. Location and importance of mircroenvironments for B cell tolerance:Exclusion of self-reactive cells from B cell follicles Regulatory T cells • Treg are CD4+CD25+ subpopulation of T cells which mature through positive and negative selections • Treg mediate antigen-specific suppression through cell-cell contact and soluble factors • A nuclear factor, FOXP3, is very important for the development of Treg. Artificially induced Tolerance • • • • • Immune chimerism Soluble antigen induced tolerance Oral tolerance Tolerance by clonal activation Anti-coreceptor induced tolerance Thymic central tolerance induction B cell central tolerance induction Lecture Notes for Med. Tech Class Autoimmune Diseases Oct 2006 C.K.Shieh Spectrum of Autoimmune Diseases HLA Association of Autoimmune Diseases Depletion of Autoreactive T Cells in the Thymus How does autoantibody cause diseases • Direct binding to target cells thyrotoxicosis Myasthenia gravis Goodpasture’s syndrome • Immune complex deposition SLE (systemic lupus erythematosus) Rheumatoid arthritis * SLE is a disease best known for dysregulation of B cells and hence the production of autoantibodies. Different from organ specific autoimmune diseases, various autoantibodies found in other antibody-mediated autoimmune diseases may be found in SLE patients. Self-damage caused by type II and type III hypersensitivity mechanisms thus may be found in SLE patients. Cell Mediated cytotoxicity Diabetes mellitus (DM): CMI targets beta cells in the pancreas Hashimoto’s thyroiditis: CMI targets thyroid gland Experimental allergic encephalitis (EAE): CMI targets myelin in CNS, an animal model of the human disease multiple sclerosis. A spectrum of autoimmunity to thyroid gland is apparent clinically On the one end of the spectrum is the antibody mediated stimulation (non-goitrous hyperthyroidism), on the other end is the cell mediated thyroid gland destruction (Hashimoto’s (橋本) thyroiditis) Autoimmunity Is Antigen driven Anti-thyroid autoantibody disappears after thyroidectoy in OS chicken Rheumatoid factor: anti-antibody antibody found in patients with seropositive rheumatoid arthritis Breaking Self Tolerance • • Direct stimulation of autoimmune cells e.g. EBV Molecular mimickry e.g. rheumatic fever Cross-reactive microbial antigens (T Cell Antigen) Cross-reactive B cell antigen (not protected by T Cell tolerance) •Cytokine dysregulation Breaking of ignorance by changed cytokine in the tissue milieu (Immune Deviation) •Breaking of tolerance by disturbed central tolerance machinery: e.g. myasthenia gravis in patients with thymoma •Regulatory T cells play a crucial in controlling autoimmune responses: CD25+FoxP3+ CD4+T cells block the effect of autoimmune responses mediated by autoreactive T cells. This blocking may or may not require the secretion of suppressive cytokines such as TGF and IL-10. Some autoimmune diseases appear to correlate with the compromised function of regulatory T cells. Successful treatment of the autoimmune disease can restore the compromised regulatory function. How to Treat Autoimmune Reactions By trying to restore homeostasis in the immune system, various approaches have been employed to treat autoimmunity. Cytokines, anti-cytokines, and immunosuppressive agents are in use for treating patients with autoimmune diseases. 自體免疫疾病是免疫控制基轉失調的最終表現,所以經常表現出複 雜的免疫反應。在已經發生的自體免疫疾病中,找出引起疾病的元凶經 常是很困難的。學習自體免疫疾病的致病機轉,重點在於了解引發這些 自體免疫疾病的免疫控制機轉失調的原因和起始點。近十多年來基因轉 殖動物的研究對這個問題提供了全新的觀點。 本節課的另外一個重點是熟悉這些自體免疫疾病的名稱和表現。請 各位將 20.3 圖多看幾遍。