Download Lecture Notes for Med. Tech. Class

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?
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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
FcR1,2,3
• 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
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Immune chimerism (Medawar’s mice)
Soluble antigen induced tolerance
Oral tolerance
Tolerance by clonal activation (and activation induced cell death)
Anti-coreceptor induced tolerance