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Immunology:

Immunology: the only science where you can still get a Nobel prize with two test-tubes and a mouse…. Immunology: the science of why you don’t get measles twice…. Defense against Disease. Non-specific and specific strategies. The Challenge.

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Immunology:

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  1. Immunology: the only science where you can still get a Nobel prize with two test-tubes and a mouse…

  2. Immunology: the science of why you don’t get measles twice…

  3. Defense against Disease Non-specific and specific strategies

  4. The Challenge • Pathogens: microorganisms that are capable of causing disease • Viruses • Bacteria • Fungi

  5. The Viruses • Modus Operandi • Dock with receptors on target cell surface • Insert viral DNA or RNA into host cell • Use host cell machinery to replicate new viruses • Lyse host cell and spread to nearby cells • Lytic vs. Lysogenic life cycles • Examples: smallpox, chickenpox, polio, HIV

  6. Bacteria • Modus operandi • Set up shop in tissues but remain EXTERNAL to cells • Reproduce rapidly • Secrete exotoxins or contain endotoxins as part of cell wall • Examples: Escherichia coli, Clostridium botulinum, Salmonella Figure from Holt Biosources

  7. Fungi • Modus Operandi • Similar to bacteria- • reproduce rapidly • Damage cells directly or indirectly • by secreting enzymes • Examples: Athletes’ Foot, • Pneumocystis carinii (fungal pneumonia) http://www.ces.ncsu.edu/depts/pp/bluemold/

  8. First line defenses: Nonspecific anatomical barriers and secretions that prevent entry, such as skin, saliva, tears (lysozyme), mucus, stomach acid, fever • Second line defenses: Inflammation A nonspecific response triggered by histamine secreted by basophils when tissue is damaged

  9. If all else fails…The Immune Response • A highly specific, long lasting response tailored to combat pathogens • Vocabulary: Antigen- a molecule (usually carried on the surface of a pathogen) that is capable of eliciting an immune response B-Lymphocytes- white blood cells that produce and secrete antibodies T-Lymphocytes- white blood cells that serve as part of the cell-mediated immune response

  10. Self- Nonself Recognition • Critical to appropriate immune system function • Tcells “learn” to distinguish self from non self as they mature in the thymus • All nucleated self cells display unique Human Leukocyte Antigens (HLA) • As T cells mature, they produce and display a variety of randomly-defined receptors • Any T cell with receptors that bind to self MHC-HLA complexes will be deleted in the thymus • Only T cells that do NOT bind to self cells with high affinity will emerge from the thymus and enter circulation

  11. Immune Response- Step by Step 1. Pathogen (carrying foreign antigens)enters and survives the inflammatory response 2. Some pathogens remain exposed in tissues where their antigens may be recognized by circulating B cells OR 3. Macrophages engulf pathogens and display their antigens on MHC (major histocompatibility complex) proteins. Macrophage has now become an Antigen Presenting Cell (APC)

  12. In a specific immune response, only those T and B cells that can bind to the antigens of the pathogen are selected to participate in the response. Proliferation of cells with receptors capable of binding epitopes of the antigen Mixture of T and B cells with different antigen specificities An antigen with 2 epitopes - red epitope, blue epitope Clonal selection of lymphocytes during the specific immune response

  13. Cell-Mediated ImmunityT cell Response • Helper T cells (a.k.a. TH or CD-4 T cells) constantly interact with macrophages • When TH cell finds a macrophage that is presenting antigen (APC) it becomes activated • Activated TH cells secrete cytokines, proteins that stimulate both T and B cells • Stimulated cytotoxic T cells (a.k.a. killer or CD-8 T cells) divide rapidly, bind directly to pathogen infected cells and secrete enzymes that lyse infected cells

  14. Central Role of Helper T Cells

  15. Humoral ImmunityB cell response • If a circulating B cell’s receptors bind to foreign antigens, the B cell becomes activated • Activated B cells divide into Memory B cells and Plasma B cells • Plasma B cells rapidly produce and secrete antibodies (immunoglobulins) • Clonal selection amplifies the production of cells that produce effective antibodies

  16. Immunity 1. specificity 2. tolerance 3. memory Paradigms: self vs non-self protection vs kill

  17. Cells of the Immune System ne baso T white blood cells MO eos B CD4 NK MAC DC MHC II CXCR4 CD8 CCR5 MHC II MHC I TCR MHC I CD3 CD3 TCR Helper T cell Cytotoxic/ “suppressor” T cell Derived from JM Austyn & KJ Wood: Principles of Cellular and Molecular Immunology 1993

  18. CD8 Th1 Th1 CD8 T T T T T T The Immune System LYMPH NODE SKIN / MUCOSAL SURFACE migration migration T cell area Cytotoxic T cells Th2 DC B B B cell area Th2 pathogen B B B Isotype switch affinity maturation Cellular immunity INFLAMMATION IgM IgG IgA IgE migration B Bone Marrow B Antibody response AFC memory

  19. Immunity Innate Immunity Adaptive Immunity Barriers (skin) Secretions (lysozyme) Complement Inflammation Granulocytes NK cells Macrophages Phagocytosis B cells-- Antibody production T cells-- Cell mediated immunity Immunoregulation

  20. Overview

  21. Generation of an adaptive immune response • During an adaptive immune response,T cells which recognize specific antigen(s) are selected for differentiation into armed effector cells which undergo clonal expansion to produce a battery of antigen-specific cells. • Clonal expansion refers to the process by which antigen-specific T cells or B cells are stimulated to reproduce clones of themselves to increase the system’s repertoire of antigen-specific effectors. • Activation of antigen-specific T cells (the initiation of the adaptive response) occurs in the secondary lymph tissues (lymph nodes and spleen). • This activation depends upon antigen presentation by a professional antigen presenting cell (APC) along with simultaneous co-stimulation. (eg., B7 on the APC, CD28 on the T cell).

  22. Antigen Presentation

  23. Antigen recognition by T and B cells T and B cells exhibit fundamental differences in antigen recognition. B cells recognize antigen free in solution (native antigen). T cells recognize antigen after it has been phagocytosed, degraded and small pieces of the antigen have been bound by MHC molecules.

  24. Generic protein H N Antibody epitope - conformational shape is recognized 2 COOH T cell epitope - internal protein processed during antigen presentation HLA class II presentation of T cell epitope HLA class I presentation of T cell epitope Cell surface expression of antigen Antigens and epitopes Figure 1 Concept: C.M. Gray, PhD

  25. "B-lymphocytes have sIg molecules that recognize epitopes directly on antigens. T-lymphocytes have TCR molecules that recognize epitope only after it has been bound to MHC molecules."

  26. T cell epitopes T cell epitopes always consist of sequential amino acids

  27. Properties of T cell epitopes - linear peptide fragments of the antigen consisting of 11-20 amino acids - must be able to bind simultaneously to the T cell receptor and the MHC molecule - often amphipathic (having both hydrophobic and hydrophilic residues)

  28. The Immune system Class I Class II

  29. TCR  a a1 a2 CD8 -c a3 2-m MHC class I Antigen Presenting Cell  -N

  30. MHC structure Peptide binding cleft Peptide binding cleft 2 1 1 1 3 2-microglobulin 2 2 Class I MHC Class II MHC • MHC classes I and II have an almost identical 3-D structure. • Both classes of MHC are polygenic (each cell has many MHC genes) and polymorphic (there are many alleles for each locus), but the MHC genes do not undergo recombination. Note: Human MHC are called HLA (human leukocyte antigen).

  31. MHC / T cell interactions Class II MHC Class I MHC target cell Antigen presenting cell CD8 CD4 CD4+ T cell CD8+ T cell TCR complex TCR complex • The MCH/peptide-TCR interaction is facilitated by the CD4 or CD8 co-receptor.

  32. ANTIGEN-PRESENTING CELLS Present antigen to T cells in conjunction with MHC molecules and also provide co-stimulatory signals STIMULATION T cell receptor ANTIGEN-PRESENTING CELL T CELL MHC molecule Antigen peptide

  33. ANTIGEN-PRESENTING CELLS 1. MACROPHAGES * Distributed throughout body, versatile * Not efficient presenters of antigen until activated * When activated (e.g. by IFN-)  increase expression of MHC molecules and co-stimulatory molecules

  34. ANTIGEN-PRESENTING CELLS 2. DENDRITIC CELLS * Most effective antigen-presenters, distributed throughout body * Derived from three different sources, but all have characteristic starfish shape * Able to activate virgin T cells (unlike other antigen- presenting cells)

  35. 2. DENDRITIC CELLS In resting state, express only small amounts of MHC, but have large internal reserves of MHC molecules MHC II

  36. 2. DENDRITIC CELLS * Following encounter with antigen, dendritic cell leaves tissues  migrates to lymph node  loads foreign antigens onto the reserve MHC molecules  displays MHC+antigen peptide * Production of co-stimulatory molecules upregulated  Virgin helper T cells activated immediately Foreign antigen T cell Travel to lymph node

  37. ANTIGEN-PRESENTING CELLS 3. ACTIVATED B CELLS * B cells can present antigen to T cells - must be activated first (to increase expression of MHC II molecules) * B cells bind specific antigens (ie recognised by their BCRs)  ingest antigen  process antigen  present * Advantage of B cells over other APCs = antigen concentration - if antigen in small amounts, B cell acts like magnet to collect and concentrate it

  38. The antigen presenting cells, continued Note: this B cell is not a plasma cell -- a plasma cell is shown above. Plasma cells do not present antigen. They simply pump out antibody for a few days then die. Dendritic Cell Macrophage B cell

  39. MHCII Macrophage (APC)

  40. 1. Phagocytosis MHCII Macrophage (APC)

  41. Destruction 2. 1. Phagocytosis MHCII Macrophage (APC)

  42. Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis MHCII Macrophage (APC)

  43. Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. Phagocytosis MHCII Peptides 3. Macrophage (APC)

  44. Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. Phagocytosis MHCII Peptides 3. 4. Macrophage (APC) Antigen Presentation

  45. Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. CD4+ T cell Activation Phagocytosis MHCII TcR Peptides 3. 4. Macrophage (APC) Antigen Presentation

  46. Different MHC present different epitopes MHC TYPES HLA-A2 HLA-A3 HLA-B7

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