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Lecture Notes for Med. Tech. Class Immunity to Microorganisms Oct. 2000 C.K.Shieh Immunity against Microorganisms • What will happen if microbes enter your body? • • • • • From innate to acquired immunity Inflammatory cytokines Antibody and cell mediated immunity Differences in different microorganisms bacteria, fungi, viruses Immune evasion of microorganisms Epithelium: The Barrier between Inner and Outer world Immunity to Prokaryotic Microorganisms • Innate immunity: Receptors for bactericidal components (invariant structural components) • Cytokines: starting from IL-1 and TNF-. Septic shock: fatal response to super-strong stimulations • Complement, antibody and cell mediated immunity • Intra- and extra- cellular bacteria • Bacterial trategies to avoid immune attacks Immune Responses to Bacteria: How It Started: • TLRs (toll like receptors) on monocytes • Receptors for invariant bacterial components: e.g. CD14 for LPS • Association of LPS, CD14, and TLR forms a strong initiator for cytokine production and antigen presentation Septic Shock: a State of Hyper-Cytokinemia IL-1, TNF-, IL-8, IL-6, IL-12 Complement Activation: Classical and Alternative Pathways Various Mechanisms Used by Bacteria to Avoid Destruction by Complements Acquired Immunity to bacteria: The Role of Antibody in Different Steps Phagocyte Receptors for Bacteria • Lectins (glycan binding proteins) • Fc receptors FcR1,2,3 • Complement receptors CR1 (C3b receptor), CR3, CR2 (both iC3b receptor) Bactericidal Activity in Phagocytes Changes in pH for optimal enzymatic killing Production of oxygen free radicals Immune Responses to Viruses • 1.Viruses are obligate intracellular parasites. (bags of proteins and nucleic acids). Minimal machinery for nucleic acid and protein reproduction. • 2. Replication of viruses requires extracellular and intracellular stages. • 3.Viruses are great mimicker so defense against viruses requires multiple mechanisms. Again. From innate to acquired immunity. Viruses Use Immune Receptors for Invasion Direct inhibition (or killing) of immune cells. Interferons: The Anti-viral Cytokines Through modulating MHC molecules: • Increased presentation of viral antigens to reveal the intracellular infection • Increased NK activity Intracellular Effects of IFN / Final effects • Inhibition of protein synthesis • Degradation of mRNA How Do NK Cells Recognize Virus Infected Cells? • Inhibitory receptors on NK cell recognize MHC class I molecules. • Cell lacking the expression of MHC class I molecules become targets of NK killing. Specific Immunity to Viruses1.Specific Antibodies: more effective for free virus (extracellular). 2. Cytotoxic T Cells: necessary for intracellular virus. Naïve and Memory T Cells: Same TCR, Different Phenotypes Increased coreceptors, different adhesion molecules, different signal transduction. Immune Responses May Contribute to the Tissue Damages in Infections e.g. HBV, LCMV Viral Evasion of Immune Attacks 1. Attacks on immune cells 2. Suppression of immune responses 3. Mutations to avoid immune recognition Examples: hypermutations in influenza virus Drift: small changes Shift: big changes in surface structures Lecture Notes for Med. Tech. Class: Tolerance Oct. 2000 C.K. Shieh Immunological Tolerance • Tolerance is one of the central characters of the immune system (along with memory, specificity etc.). • 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: antigen expressed in sequestrated organs such as eyes and testicles 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, as well as expression levels of these receptors and other co-receptors Synthetic Peptides Were Used to Prove the Role of TCR Affinity in Thymic Selection T cell receptors with known MHC-peptide ligand recognize MHC-altered peptides with different affinity. The subsequent changes in positive and negative selection provide definite evidence for the role of TCR affinity in T cell selection. TCR Induced Cell Death in the Thymus –Fig.14.2 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) FAS on the surfaces of lymphocytes transmits a “death signal” that induces the cells to the process of programmed cell death (apoptosis). Mechanism of Peripheral Tolerance • Cell death (apoptosis) • Anergy • Ignorance (Immune deviation, inappropriate microenvironment) 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. B Cells of Different Maturation Stages Are Susceptible to Tolerization B Cells Are Susceptible to Anergy B Cells Are Susceptible to Deletion Artificially induced Tolerance • • • • • Immune chimerism (Medawar’s mice) Soluble antigen induced tolerance Oral tolerance Tolerance by clonal activation (and activation induced cell death) Anti-coreceptor induced tolerance