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Transcript
Chapter 15 Lecture Outline Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 15 Outline Defense Mechansims Functions of B Lymphocytes Functions of T Lymphocytes Active and Passive Immunity Tumor Immunology Diseases Caused By Immune System 15-2 Defense Mechanisms Against pathogens constitute the immune system Can be grouped into 2 categories: Innate (nonspecific) immunity is inherited as part of structure of each organism Adaptive (specific) immunity is a function of lymphocytes and changes with exposure 15-3 Innate (Nonspecific) Immunity 15-4 Innate Immunity Distinguishes between “self” and “non-self” by recognizing molecules called PAMPs=pathogenassociated molecular patterns Is 1st line of defense against invading pathogens Includes epithelial barriers, high acidity of gastric juice, phagocytosis, interferons, and fever 15-5 Activation of Innate Immunity Is triggered in response to pathogen-associated molecular patterns (PAMPs) produced only by microorganisms Best known are lipopolysaccharide (LPS) from gram neg. bacteria and peptidoglycan from gram pos. bacteria Some immune cells have receptors for PAMPs displayed on their surfaces Receptors called Toll receptors Ten different Toll receptors identified in humans 15-6 Phagocytosis continued Is performed by 3 classes of phagocytic cells: Neutrophils - 1st to arrive at infection sites Mononuclear phagocytes - macrophages and monocytes Organ-specific phagocytes in liver, spleen, lymph nodes, lungs, and brain Fixed phagocytes line sinusoids of liver, spleen, and lymph nodes and remove pathogens 15-7 Phagocytosis continued Connective tissue and blood contain mobile leukocytes (WBCs) These are attracted to infection (chemotaxis) by chemokines WBCs from blood exit capillaries by extravasation (diapedesis) and ingest pathogens 15-8 Phagocytosis continued Pseudopods from phagocyte surround pathogen Forming a vacuole Vacuole fuses with lysosomes which digest pathogen 15-9 Fever Appears to be component of innate immunity Occurs when hypothalamic thermostat is reset upwards by interleukin-1 and other cytokines (endogenous pyrogens) Pyrogens are released by WBCs in response to endotoxin from gram negative bacteria Cytokines also increase sleepiness and a fall in the plasma Fe concentration, which functions in inhibiting bacterial activity 15-10 Interferons Are polypeptides produced by cells infected with virus that provide short-acting, non-specific resistance to viral infection in nearby cells 3 types: alpha, beta, and gamma interferon 15-11 The Life Cycle of HIV: HIV contains RNA. Once inside the host, viral RNA is transcribed by reverse transcriptase into cDNA. The genes in cDNA direct synthesis of new viral particles 15-12 15-13 Adaptive (Specific) Immunity 15-14 Adaptive Immunity Is acquired ability to defend against specific pathogens by prior exposure to those pathogens Is mediated by production of specific antibodies by lymphocytes 15-15 Antigens Are molecules that elicit production of antibodies that specifically bind those antigens Are usually large molecules that are foreign to the body Immune system can distinguish “self” molecules from non-self antigens Normally makes antibodies only against non-self antigens Large, complex molecules can have a number of antigenic determinant sites (different sites that stimulate production of, and bind to, different antibodies) 15-16 Haptens Are small non-antigenic molecules that become antigens when bound to proteins (form an antigenic determinant site) Useful for creating antibodies for research and diagnosis 15-17 Immunoassays Are tests that use specific antibodies to identify a particular antigen The binding of antibody to antigen causes clumping (agglutination) which can be visualized 15-18 Lymphocytes Are derived from stem cells in bone marrow Which replace selves by cell division so are not depleted Lymphocytes produced by this process seed thymus, spleen, and lymph nodes with self-replacing colonies 15-19 T Lymphocytes (T cells) Develop from lymphocytes that seed thymus Do not secrete antibodies Attack infected host cells, cancer cells, and foreign cells Thus they provide cell-mediated immunity Supply 65 – 85% of lymphocytes for blood and most of lymphocytes in germinal centers of lymph nodes and spleen 15-20 B Lymphocytes (B cells) Fight bacterial infections by secreting antibodies into blood and lymph Thus provide humoral immunity 15-21 Thymus Is located below the thyroid gland Grows during childhood, gradually regresses after puberty Contains T cells that supply other tissues T cells can be depleted, e.g. by AIDs or chemotherapy These can only be replenished up to late childhood After that, repopulation is accomplished by production in secondary lymphoid organs 15-22 Secondary Lymphoid Organs Consist of lymph nodes, spleen, tonsils, and Peyer’s patches Located in areas where antigens could gain entry to blood or lymph Lymphocytes migrate constantly through blood and lymph from one lymphoid organ to another Enhances chance that antibody will encounter its antigen Spleen filters blood; other lymphoid organs filter lymph 15-23 Local Inflammation Occurs when bacteria enter a break in the skin Inflammatory reaction is initiated by nonspecific mechanisms of phagocytosis and complement activation Complement activation attracts phagocytes to area 15-24 Local Inflammation continued As inflammation progresses, B cells produce antibodies against bacterial antigens Attachment of antibodies to antigens amplifies nonspecific responses because of complement activation And promotes phagocytic activity of neutrophils, macrophages, and monocytes (= opsonization) 15-25 Local Inflammation continued In inflamed area, leukocytes attach to surface of endothelial cells Move by chemotaxis to inflamed site Neutrophils arrive 1st, then monocytes, then T cells Undergo extravasation 15-26 Local Inflammation continued Mast cells secrete heparin, histamine, prostaglandins, leukotrienes, cytokines, and TNF-a These produce redness, warmth, swelling, pus, and pain Recruit more leukocytes If infection continues, endogenous pyrogens are released 15-27 B Lymphocytes (B cells) Have antibodies on surface that are receptors for antigens When bound to antigen, are stimulated to divide and secrete antibodies 15-28 B Lymphocytes (B cells) continued When B cells divide, some progeny become memory cells Others become plasma cells that produce about 2000 antibodies/sec that are specific for original antigen This provides active immunity 15-29 B Lymphocytes (B cells) continued Binding of B cells to antigen also triggers a cascade of reactions that activate complement proteins Complement proteins can kill antigen-bearing cells and promote phagocytosis 15-30 Antibodies Are proteins called immunoglobulins Part of gamma globulin class of plasma proteins Antibodies have same basic structure but their differences provide for antibody specificity 15-31 15-32 Antibody Structure Is in shape of “Y” 2 long heavy (H) chains are joined to 2 shorter light (L) chains When cleaved, stalk of Y becomes crystallizable fragment (Fc) Fc is constant among different antibodies Arms of Y contain antigenbinding fragment (Fab) Fab contains a variable region that confers antibody specifity All antibodies consists of four polypeptide chains: 2 heavy and 2 light chains, as seen in the diagram below. 15-33 Diversity of Antibodies person has about 1020 antibody molecules With a few million different specificities Likely there is an antibody specific for any antigen a person might encounter Each 15-34 Antibody Diversity continued 2 mechanisms might account for diversity If a few hundred genes code for Heavy chains and a few hundred for Light chains, different combinations could lead to millions of different antibodies Recombination of these in developing lymphocytes of marrow produces antigen-independent diversity Diversity further increases via somatic hypermutation in which there is a high rate of single base pair mutations Occurs as B cells undergo proliferation in 2o lymphoid tissues in response to foreign antigens Antigen-dependent diversification also occurs in genetic recombination—there is a switch in constant regions of heavy chains of antibodies so that IgM are converted to IgA or IgE=class switch recombination. 15-35 Complement System 15-36 The Complement System Is part of nonspecific defense system Activity is triggered by binding of antibodies to antigens (classic pathway) and by unique polysaccharide coating of bacteria (alternative pathway) Binding of antibodies to antigens does not by itself destroy antigens or pathogens Antibodies label targets for complement system attack and also stimulate opsonization (the ability of antibodies to stim. phagocytosis) 15-37 The Complement System continued Is a series of proteins whose activation forms a membrane attack complex which perforates a cell causing it to undergo lysis Complement proteins can be subdivided into 3 functional groups: C1 - recognition C4, C2, C3 - activation C5-C9 - attack (complement fixation) These form the membrane attack complex 15-38 The Complement System continued In classic pathway, antibody-antigen binding activates C1 C1 hydrolyzes C4 into C4a and C4b C4b binds to cell membrane and becomes active, splitting C2 into C2a and C2b C2a attaches to C4b and cleaves C3 into C3a and C3b Alternate pathway also cleaves C3 (and so converges with classic pathway at this step) C3b converts C5 to C5a and C5b 15-39 Fixation of Complement Proteins 15-40 Membrane Attack Complex C5b and C6 - C9 are inserted into bacterial cell membrane, forming membrane attack complex This creates large pore in membrane, causing osmotic influx of H2O, lysis, and cell death 15-41 Complement Fragments That are liberated during activation have a number of effects, including Attracting phagocytes (chemotaxis) Phagocytes have receptors for C3b which can serve as bridge to victim cell (opsonization) C3a and C5a stimulate mast cells to release histamine Which increases blood flow and capillary permeability, bringing in more phagocytes 15-42 T Cells 15-43 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 Helper and Suppressor T Cells Helper T-cells carry CD4 surface marker Indirectly participate by enhancing responses of both killer T-cells and Bcells 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 Lymphokines Are cytokines secreted by lymphocytes Usually called interleukin-1, 2, 3 . . . or IL1, IL-2 . . . 15-46 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 Dendritic Cells 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" 15-48 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 Histocompatibility Antigens 15-50 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 MHC 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 15-52 MHC continued 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 copresentation of antigen and class-1 marker Helper T-cells require antigen and class-2 marker 15-53 MHC continued 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 15-54 Interactions Between Antigen Presenting Cells and Lymphocytes 15-55 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 The interaction of an antigen-presenting cell (a macrophage in this example), Tcells, 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 15-57 Macrophage-T cell Interaction 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 gammainterferon and IL-2 Promotes activity of macrophages Activated helpers activate B cells 15-58 Killer T cell Activity Killer Ts destroy infected cells if class-1 markers are present 15-59 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 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 Active Immunity 15-62 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 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 The clonal selection theory as applied to Blymphocytes 15-65 15-66 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 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 Immunological Tolerance Ability to produce antibodies against non-self antigens while tolerating self-antigens (immunological competence) occurs during 1st 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 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 selfantigens are present throughout life but don't attack self-antigens Central tolerance: mechanisms that occur in thymus or bone marrow (T-cells by apoptosis; Bcells by clonal deletion and anergy Peripheral tolerance: involves complex mech. that produce anergy 15-70 Passive Immunity 15-71 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 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 15-74 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 The Production of Monoclonal Antibodies 15-76 Immune System and Cancer 15-77 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 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 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 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 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 Diseases Caused By Immune System 15-83 Diseases Caused by Immune System Can be grouped into 3 categories: autoimmune diseases, immune complex diseases, and allergies All caused by abnormal functioning of immune system 15-84 Autoimmune Diseases Are produced by failure of immune system to recognize and tolerate self-antigens Autoreactive T-cells are formed and B-cells produce autoantibodies Afflicts women twice as often as men 15-85 Autoimmune Diseases continued Failure of self-tolerance may be due to: An antigen that does not normally circulate in blood being presented to immune system e.g. in Hashimoto's thyroiditis, antibodies are stimulated to attack thyroglobulin (which is normally hidden from immune surveillance) 15-86 Autoimmune Diseases continued Failure of self-tolerance may be due to: Combination of a self-antigen, that is otherwise tolerated, with a foreign hapten e.g. in thrombocytopenia (low platelet count), platelets are destroyed because they combine with victim's medications 15-87 Autoimmune Diseases continued Failure of self-tolerance may be due to: Antibodies being produced that are directed against other antibodies Happens with rheumatoid arthritis 15-88 Autoimmune Diseases continued Failure of self-tolerance may be due to: Antibodies against foreign antigens cross-reacting with self-antigens This can happen with rheumatic fever 15-89 Autoimmune Diseases continued Failure of self-tolerance may be due to: Self-antigens being presented to helper T cells together with class-2 MHC molecules This happens in Type I diabetes 15-90 Immune Complex Diseases Involve formation of immune complexes that are free and not attached to a cell These activate complement proteins and promote inflammation Can result from infections by bacteria, parasites, viruses Can result from formation of complexes between selfantigens and autoantibodies This occurs in rheumatoid arthritis and lupus 15-91 Allergy (Hypersensitivity) Is an abnormal immune response to allergens Comes in 2 forms: immediate and delayed hypersensitivity Immediate is due to abnormal B-cell response to allergen; causes effects in secs to mins Caused by foods, bee stings, pollen Delayed is abnormal T-cell response that causes symptoms 24-72 hrs after exposure 15-92 Immediate Hypersensitivity Dendritic cells stimulate a class of helper Ts to secrete interleukin-4 and -13 which cause B and plasma cells to secrete IgE antibodies IgE antibodies do not circulate in blood; are attached to mast cells and basophils When re-exposed to same allergen, antibodies on mast cells and basophils bind it and stimulate secretion of histamine, leukotrienes, and prostaglandin D Producing allergy symptoms Histamine increases capillary permeability and enhances immune response 15-93 Immediate Hypersensitivity continued 15-94 Delayed Hypersensitivity Symptoms take longer to develop (hrs to days) Is a cell-mediated T-cell response Symptoms caused by secretion of lymphokines, not histamine Antihistamines provide little benefit Examples include contact dermatitis caused by poison ivy, oak, or sumac 15-95