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Value of the Immune System

Value of the Immune System

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Value of the Immune System

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  1. Value of the Immune System • Protection from infectious diseases (Immune responses against infectious diseases) • The “threats” - Bacterial pathogens, toxins and viral pathogens • Innate immunity – phagocytes, NK cells and complement • When innate immunity is not good enough • Adaptive immunity – lymphocytes & antibodies • Systemic and mucosal immune “systems” • Destruction of cancer cells (Cancer immunology ) • Normal (self) -> cancer (non-self markers) • Clinical applications (Clinical applications of immunology) • Diagnostic • Therapeutic • Some problems caused by the immune system • Allergic reactions (allergens are non-self; IgE antibodies and mast cells) • Autoimmunity (loss of self/non-self discrimination) • Transplant rejection (another person is not self to me) • Survival of fetus • Bone marrow transplants • Graft-vs-host disease

  2. Value of the Immune System • Immune responses against infectious diseases • Bacterial pathogens, bacterial exotoxins and viral pathogens

  3. Bacterial Pathogens

  4. Bacterial Exotoxins

  5. Viral Pathogens

  6. Value of the Immune System • Immune responses against infectious diseases • Bacterial pathogens, toxins and viral pathogens • Innate immunity – what does that mean? • Cells (phagocytes and NK cells) and molecules present all the time • Cells are ready to respond immediately • Response does not improve with use • Not uniquely specific (cells can bind to a wide variety of pathogens) • Generally effective against bacterial pathogens (and not viruses or exotoxins)

  7. Innate Immunity • Cells and molecules present all the time • Cells are ready to respond immediately • Does not improve with use

  8. Innate Immunity • Not uniquely specific (cells can bind to a wide variety of pathogens) • Generally effective against bacterial pathogens (and not viruses or exotoxins) A B A

  9. Value of the Immune System • Components of the innate immune system • Cells • Phagocytes • PMNs & macrophages

  10. Value of the Immune System • Components of the innate immune system • Cells • Phagocytes • PMNs & macrophages • Macrophages & toll-like receptors (TLR)

  11. Value of the Immune System Macrophages & toll-like receptors (TLRs) 10-12 different TLRs can (collectively) bind a wide range of pathogens Each macrophage has all of the set of TLRs

  12. Innate Immune Responses • Phagocytosis animation (select “Normal phagocytosis by a macrophage”) • Initiated by attachment of phagocyte surface receptor to molecule(s) on pathogen • e.g., TLRs bind to PAMPS (pathogen-associated molecular patterns) • Shared by many different bacteria • Large number of TLRs that can bind large number of PAMPS • Bacterial cell is ingested • Phagosome forms around the intact bacterial cell • Phagosome fuses with lysosome -> phagolysosomeanimation • Lysosome contains variety of degradative enzymes and toxic forms of oxygen • Bacterial cell is degraded in the phagolysosome • Degraded contents are expelled from phagocyte (not shown) • Phagocyte can continue to phagocytize indefinitely • No improvement in the rate or success of phagocytosis

  13. TWO Clicker questions at the start of class • 1. Toll-like receptors (TLRs) participate in which one of the following important steps in an innate immune response? • A bacterial capsule interferes with macrophage-mediated phagocytosis in which one of the following ways? • HANDOUT of two recently changed ppt slides on ends of classroom tables

  14. Toll-like receptors (TLRs) participate in which one of the following important steps in an innate immune response? • A. degradation of a bacterial cell in a phagolysosome • B. activation of complement • C. attachment by macrophages to molecules (e.g., PAMPs) on the surfaces of bacterial cells • D. development of a lymphoid cell into a fully functional blood monocyte

  15. A bacterial capsule interferes with macrophage-mediated phagocytosis in which one of the following ways? • A. kills the macrophage • B. prevents the attachment of receptors on the macrophage surface (e.g.,, TLRs) with molecules on the bacterial cell surface (e.g., PAMPs) • animation • C. downregulates the production of all of the toxic forms of oxygen that can kill bacterial cells in a phagolysosome • D. interferes with somatic recombination; renders the macrophage not specific for any bacterial PAMP

  16. START of December 15 discussion

  17. Value of the Immune System • Components of the innate immune system • Molecules • Complement (often abbreviated with a capital C) • A set of >30 different proteins (most are enzymes) • Acting in a collaborative fashion with several outcomes • Attract phagocytes to an area of bacterial infection • Increase phagocytic activity of phagocytes • Assist phagocytes to attach to bacteria • Directly kill bacteria (destroy bacterial cell membrane)

  18. Value of the Immune System • Complement must first be activated to function • Three different ways complement can be activated • Outcome is the same in all three (diagram is of alternative pathway)

  19. Value of the Immune System • Immune responses against infectious diseases • When the innate immune system is not good enough • Phagocytes can not attach to pathogens • bacterial pathogens • no bacterial surface molecules to which phagocyte can bind • e.g., no PAMPS to which TLRs can bind • bacterial surface molecules covered by a capsule – animation • viruses • Usually nothing on virus to which phagocyte can attach

  20. Value of the Immune System • When the innate immune system is not good enough • Phagocytosis is not completely successful (several animations below) • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome • bacterium preventing the phagosome from fusing with the lysosome • bacterium preventing the lysosome from moving to the phagosome • bacterium preventing acidification of the phagosome following ingestion (tuberculosis) • bacterium killing a phagocyte

  21. Bonus Clicker question – If a phagocygte (e.g., macrophage) is able to attach to a bacterial cell and ingest it, but is not able to carry out the remaining steps of phagocytosis to destroy the ingested cell, what might be a way for this phagocyte to get some assistance (“help”)? • A. activated complement • B. natural killer (NK) cell activity • C. T-cytotoxic cell • D. TH1-helper cell

  22. Value of the Immune System • When the innate immune system is not good enough • Phagocytosis is not completely successful (several animations below) • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome • bacterium preventing the phagosome from fusing with the lysosome • bacterium preventing the lysosome from moving to the phagosome • bacterium preventing acidification of the phagosome following ingestion (tuberculosis) • bacterium killing a phagocyte • Complement is not activated or not successful • Bacteria block complement activation • Capsule prevents complement activation • Bacteria alter the membrane – prevents the final stage of C-mediated killing Elongation of O-Polysaccharide Preventing the Insertion of MAC* into the Cell Wall of Gram-Negative Bacteria *MAC = complement membrane attack complex

  23. Value of the Immune System • Immune responses against infectious diseases • Adaptive immunity – what does that mean? (essentially a review) • Cells (lymphocytes) are present, but few in number and not ready to respond immediately (must “wait” until it binds to the antigen for which it is specific) • Each lymphocyte is uniquely specific (each one can bind to only one antigen) • Response doesimprove with use (the lymphocyte population expands as an “adaption” to the first exposure to the antigen -> “memory” cells) • Generally effective against bacterial pathogens, extracellularviruses, virus-infected cells and exotoxins • Antibodies are the molecular component of the adaptive immune system • Adaptive response can also assist the innate immune system • Can help macrophages (TH1-helper lymphocytes) • Can activate complement (antibody when it binds to antigen)

  24. Value of the Immune System • Adaptive immunity • Antibodies • Antigen-specific proteins secreted by plasma cells and (almost) identical to the original antigen-specific receptor on the surface of the originalB-lymphocyte

  25. Value of the Immune System • Adaptive immunity • Antibodies Antibody isotypes and related properties Associated with the constant portion of the heavy chain

  26. Value of the Immune System • Adaptive immunity • Antibodies Antibody isotypes and related properties Associated with the constant portion of the heavy chain Five different isotypes, depending on which one of the constant portion genes is chosen when making a complete heavy chain after variable portion has been created Called Immunoglobulins (Ig) when referring to isotype IgM isotype – has selected the mu gene IgD isotype – has selected the delta gene IgG isotype – has selected one of the four gamma genes IgA isotype – has selected one of the two alpha genes IgE isotype – has selected the epsilon gene Selection of constant portion of heavy chain appears to be under the influence of the TH2-helper cell

  27. Value of the Immune System Antibody isotypes and related properties Associated with the constant portion of the heavy chain

  28. Value of the Immune System Antibodies can 1. Prevent attachment of exotoxins, bacteria, viruses (IgG and IgA are best) antibody only needs to bind to the antigen to prevent attachment – neutralization Animation for toxin neutralization http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/neutexo/toxin_neut.html

  29. Antibodies can 2. Assist macrophages to attach to pathogens (IgG only) – opsonization (Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/opsonization/opson_IgG.html) Macrophages have a receptor that binds to portion of the IgG isotype

  30. Antibodies can 3. Assist NK cells to attach to virus-infected cells and tumor cells (IgG only) NK cell “sensitization for killing” also called antibody-dependent cellular cytotoxicity (ADCC) Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/intro/nk/adcc.html NK cells also have a receptor for the IgG isotype antibody Receptors for Ig molecules are called Fc receptors NK cell

  31. Start of December 17 discussion

  32. TWO Clicker questions at the start of class • 1. The isotype of an antibody molecule is determined by which one of the following? • 2. TWO of the five antibody isotypes are involved in providing protection to a fetus or nursing infant. These two isotypes are indicated by which one of the following set? (select oneletter as your answer) • Handout with an added ppt slide and a modified ppt slide are on the ends of the classroom tables

  33. The isotype of an antibody molecule is determined by which one of the following? • A. randomly selected V,D,J and V,J gene fragments • B. the constant portion of the light chain (either kappa or lambda) • C. the amino acids that actually bind to the antigen • D. the constant portion of the heavy chain

  34. TWO of the five antibody isotypes are involved in providing protection to a fetus or nursing infant. These two isotypes are indicated by which one of the following set? (select oneletter as your answer) • A. IgM and IgE • B. IgG and IgE • C. IgG and IgA • D. IgM and IgD

  35. Hold your iClicker in one hand and hold both hands up as high as you can reach. When the time starts, keep both hands raised up high and then simply select one of the answers below. • A. I am in class and am using only my own iClicker • B. I am not in class and someone is using my iClicker for me so I can get credit even if I don’t come to class

  36. Antibodies can 4. Activate complement (IgM and IgG) Antibody must first bind to antigen before C is activated Animation of classical (antibody-initiated) pathway http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/c1act_flash.html

  37. Immunoglobulin isotypes Secreted version of IgM (pentamer with “J” chain)

  38. Antibodies can 5. Cross the intestinal cell lining (epithelium) and continue to function in the gi tract only dimeric form of IgA has this property has a secretory component (not shown in dimeric IgA diagram) Dimeric IgA is also called “secretory” IgA (sIgA) sIgA Monomeric IgA in blood

  39. Fetal/infant protection Antibodies can 6. Cross the human placenta from mother to fetus (IgG only) 7. Dimeric IgA also found in breast milk -> gi tract of a nursing infant

  40. Antibodies can 8. Move from the blood stream into surrounding tissue areas -“diffuse” across blood vessel endothelial cell layer (IgG only)

  41. Antibodies can 9. “Sensitize” mast cell -> allergic reaction (IgE only) Mast cell has a receptor for the IgE isotype Animation - http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120110/micro38.swf::IgE%20Mediated%20Hypersensitivity

  42. Value of the Immune System Antibody isotypes and related properties Associated with the constant portion of the heavy chain

  43. Value of the Immune System • Lymphocytes • Roles of T-helper (CD4) cells • Phagocytosis is not completely successful (several animations below) • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome • bacterium preventing the phagosome from fusing with the lysosome • bacterium preventing the lysosome from moving to the phagosome • bacterium preventing acidification of the phagosome following ingestion (tuberculosis) • bacterium killing a phagocyte • TH1helpmacrophages • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/cellular/cmidefense/macronk/th1macro.html

  44. Lymphocytes • Roles of T-helper (CD4) cells • TH2help B-lymphocytes • Influence/control • Cellreplication • Differentiation into plasma cells • (Some daughter cells retained as memory cells) • Antibody secretion • Isotype of secreted antibody (IgM, IgD, IgG, IgA, IgE)

  45. Lymphocytes • Role of T-cytotoxic (CD8) cells • Destruction of virus-infected cells and tumor cells • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/intro/apc/apoctl.html • Perforins & granzymes (the “granules” in the image to the left) • Fas-Fas ligand (FasL) T-cytotoxic cell expresses Fas ligand “target” cell expresses Fas

  46. Value of the Immune System • Destruction of cancer cells Normal (self) -> cancer (non-self markers) T-cytotoxic cells respond to non-self (tumor) peptides presented by MHC Class I Mechanisms are the same as for virus-infected cell (see previous ppt slide)

  47. Destruction of cancer cells • Natural Killer (NK) cells by themselves • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/nkapop.html • ADCC (antibody-dependent cellular cytotoxicity) • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/adcc/adccanim.html Same mechanism for tumor cell

  48. The challenges of cancer immunology • Why do tumor cells still survive if immune responses exist and are active? • What can we do to assist the immune system to more effectively kill tumor cells?

  49. Value of the Immune System • Clinical applications of immunology • Using Monoclonal antibodies – pure preparation of one specificity of antibody using cell culture • (Hybridoma Techniques 1001-315, offered in Spring quarters) • Animation – http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120110/micro43.swf::Monoclonal%20Antibody%20Production

  50. Value of the Immune System • Clinical applications of immunology Diagnostic • Detection of colon cancer using radiolabeled monoclonal antibodies