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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 15 Lecture Outline
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T Cells 15-43
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Killer or Cytotoxic T Cells Carry CD8 cell surface marker Destroy body cells that possess foreign antigens Usually from a pathogen, but can be from malignancy or self cells never seen by immune system Kill by cell-mediated destruction That is, must be in contact with victim cell Kill by secreting perforins which create a pore in victim's membrane and cause lysis Also secrete granzymes which cause destruction of victim's DNA 15-44
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Helper and Suppressor T Cells Helper T-cells carry CD4 surface marker Indirectly participate by enhancing responses of both killer T-cells and B- cells Regulatory T-cells decrease responses of killer T-cells and B cells Carry CD25 surface marker (and CD4) Help protect against autoimmune responses 15-45
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Lymphokines Are cytokines secreted by lymphocytes Usually called interleukin-1, 2, 3... or IL- 1, IL-2... 15-46
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T Cell Receptor Proteins Only protein antigens are recognized by most T cells T cell receptors cannot bind to free antigens T cells respond to foreign antigens when they are presented on surface of antigen-presenting cells Chief antigen presenting cells are macrophages and dendritic cells 15-47
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Originate in marrow, then migrate to most tissues Prominent where pathogens might enter body Engulf protein antigens, partially digest them, and display polypeptide fragments on surface for T cells to "see" Dendritic Cells 15-48
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Dendritic Cells continued Fragments are associated on surface with histocompatibility antigens which are necessary to activate T-cells To increase chance of interacting with correct T-cells, dendritic cells migrate to secondary lymphoid organs Where secrete chemokines to attract T-cells 15-49
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Histocompatibility Antigens 15-50
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Histocompatibility Antigens Are on surface of all body's cells except mature RBCs Also called human leukocyte antigens (HLAs) Are coded for by group of 4 genes on chromosome 6 called the major histocompatibility complex (MHC) The 4 genes have multiple alleles creating many possible MHC types 15-51
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MHC genes produce 2 types of cell surface molecules: class-1 and class-2 Class-1s are made by all cells except RBCs Class-2s are made only by antigen-presenting cells and B-cells These present class-2s, together with foreign antigens, to helper T-cells This is the only way to activate helper T-cells so they can promote B-cell activity MHC 15-52
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In order for killer and helper T-cells to function they require co-presentation of antigen with a specific MHC marker Killer T-cells are activated to kill victim cell only by co- presentation of antigen and class-1 marker Helper T-cells require antigen and class-2 marker MHC continued 15-53
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Co-presentation requirement comes from presence of different coreceptors on killer and helper T cells Killer T coreceptor CD8 interacts only with class-1s Helper T coreceptor CD4 interacts only with class-2s MHC continued 15-54
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Interactions Between Antigen Presenting Cells and Lymphocytes 15-55
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T Cell Response to a Virus When virus infects body it is phagocytized by macrophage or dendritic cell Its partially-digested polypeptide fragments are antigens that are displayed on surface Form a complex with class-2 MHC molecules that macrophages present to helper T-cells Helper T-cells bind and are activated Can now promote B-cell activity 15-56
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15-57 The interaction of an antigen-presenting cell (a macrophage in this example), T- cells, and B-cells: Contact between a macrophage and a T-cell requires helper T-cell interact with antigen and Class 2-MHC molecule. The helper T-cell is now activated and able to interact with B-cell
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When macrophages and T cells form a complex, macros secrete IL-1 and Tumor Necrosis Factor (which is good at killing cancer cells) IL-1 stimulates cell division and proliferation of helper T-cells Activated helpers secrete M-CSF and gamma- interferon and IL-2 Promotes activity of macrophages Activated helpers activate B cells Macrophage-T cell Interaction 15-58
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Killer T cell Activity Killer Ts destroy infected cells if class-1 markers are present 15-59
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Helper T cell-B cell Interactions Activated helper Ts promote humoral response of B cells by binding to their surface antigens and MHC class 2s This stimulates proliferation of Bs, their conversion to plasma cells, and their secretion of antibodies 15-60
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Destruction of T cells Activated Ts must be destroyed after infection is over Occurs because Ts produce a surface receptor called FAS FAS production increases during infection After a few days, Ts begin to produce FAS ligand Binding of FAS to FAS ligand triggers apoptosis (cell suicide) 15-61
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Active Immunity 15-62
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Primary and Secondary Responses On 1st exposure to pathogen, there is latency of 5-10 days before specific antibodies are made (= primary response) Antibody levels plateau after few days and decline after a few weeks Subsequent exposure to same antigen causes secondary response Antibody production is much more rapid and sustained 15-63
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Clonal Selection Theory Is mechanism by which secondary immune responses are produced Each B cell produces only 1 kind of antibody and related antigen receptor (on its surface) Exposure to its antigen stimulates a B cell to divide until a large population of genetically identical cells (clones) is produced Some of these become plasma cells and secrete antibodies Some become memory cells that can be stimulated to produce antibodies in the secondary response 15-64
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15-65 The clonal selection theory as applied to B- lymphocytes
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Germinal Centers Develop in lymph nodes and spleen from a cloned and activated B-cell Which proliferate and undergo hypermutation Generating and secreting diverse antibodies for the secondary immune response 15-67
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Active Immunity Development of a secondary response provides active immunity Immunizations induce primary responses by inoculating people with pathogens whose virulence has been attenuated or destroyed (vaccinations) Cause development of B-cell clones that can provide secondary response 15-68
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Immunological Tolerance Ability to produce antibodies against non-self antigens while tolerating self-antigens (immunological competence) occurs during 1 st month of life Tolerance requires continuous exposure to an antigen Some self-antigens, such as lens protein in eye, are normally hidden from blood Exposure to such self-antigens results in production of autoantibodies Killer T-cells that attack self-antigens are called autoreactive T-cells 15-69
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Immunological Tolerance continued 2 possible mechanisms for tolerance: Clonal deletion : tolerance occurs because T cells that recognize self-antigens are destroyed Clonal anergy: lymphocytes directed against self- antigens are present throughout life but don't attack self-antigens Central tolerance: mechanisms that occur in thymus or bone marrow (T-cells by apoptosis; B- cells by clonal deletion and anergy Peripheral tolerance: involves complex mech. that produce anergy 15-70
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Passive Immunity 15-71
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Passive Immunity Is immune protection produced by transfer of antibodies to a recipient from a donor Donor was actively immunized Person who receives these ready-made antibodies is passively immunized Used to treat snakebite, rabies, tetanus, hepatitis 15-72
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Passive Immunity continued Occurs naturally before and after birth Some antibodies from mother pass placenta to fetus during pregnancy and provide passive immunity During 1st 2-3 days of nursing, mother produces colostrum which is rich in her antibodies and gives her immunity to infant Immunological competence (ability to mount a specific immune response) does not develop until 1 month after birth 15-73
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15-74
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Monoclonal Antibodies In a variation of passive immunity, animals (mice, sheep, rabbits) are injected with antigens and used to obtain monoclonal antibodies which are prod. by an isolated pure clone of cells A single B-cell is fused with a cancerous myeloma cell to form a hybrid cell capable of dividing indefinitely Result is a clone of cells that secretes monoclonal antibodies specific for single antigenic determ. site Use for diagnosis, lab tests, and medical treatment of some cancers 15-75
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15-76 The Production of Monoclonal Antibodies
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Immune System and Cancer 15-77
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Tumor Immunology Believed that tumor cells arise often but are normally recognized and killed by immune system When cancer develops, the immunological surveillance system of T-cells and natural killer cells has failed Tumor biology is similar to and interrelated with functions of immune system Most tumors are clones of single cells whose mitosis is not controlled by normal inhibitory mechanisms 15-78
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Tumor Immunology continued Tumor cells dedifferentiate (become less specialized like cells of an embryo) As dedifferentiate, produce surface antigens that are normally recognized by immunological surveillance and destroyed Because were absent at the time immunological competence was established Body treats these antigens as foreign Presence of these antigens provides basis of laboratory diagnostic tests for some cancers 15-79
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Natural Killer (NK) Cells Are lymphocytes related to T-cells Provide first line of cell-mediated defense Considered to be part of the innate immune system Possess an array of surface receptors that allow them to fight viruses, bacteria, parasites and malignant cells NK cells destroy tumors in a non-specific fashion; backed up by specific response of killer T-cells NKs are stimulated by interferon from T-cells NKs attack cells that lack class-1 MHC antigens Kill with perforins and granzymes 15-80
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Immunotherapy for Cancer Monoclonal antibodies have been used About 20-25% of breast cancer patients have HERZ receptors on plasma membrane of tumor cells Monoclonal antibodies for these receptors is commercially available as Hereceptin, which blocks these receptors. Human interferons obtained from genetically engineered bacteria are now available Have been used for treatment of some types of lymphomas, renal carcinoma, and melanoma 15-81
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Effects of Aging and Stress Little is known about why susceptibility to cancer is so variable Cancer risk increases with age One factor may be that aging lymphocytes accumulate genetic errors that decrease effectiveness Thymus function declines with age Tumors grow faster in stressed animals Stress hormones (corticosteroids) cause decreased immune function 15-82
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