1. Defense Lec Study 2 For Bio 260 Compiled and adapted from Marieb A&P 8 th Edition

2. Antibodies Immunoglobulins—gamma globulin portion of blood Proteins secreted by plasma cells Capable of binding specifically with antigen detected by B cells

3. Basic Antibody Structure T-or Y-shaped monomer of four looping linked polypeptide chains Two identical heavy (H) chains and two identical light (L) chains Variable (V) regions of each arm combine to form two identical antigen-binding sites

4. Basic Antibody Structure Constant (C) region of stem determines – The antibody class (IgM, IgA, IgD, IgG, or IgE) – The cells and chemicals that the antibody can bind to – How the antibody class functions in antigen elimination

5. Figure 21.14a Antigen-binding site Stem region Hinge region Light chain constant region Disulfide bond Light chain variable region Heavy chain constant region Heavy chain variable region (a)

6. Classes of Antibodies IgM – A pentamer; first antibody released – Potent agglutinating agent – Readily fixes and activates complement IgA (secretory IgA) – Monomer or dimer; in mucus and other secretions – Helps prevent entry of pathogens

7. Table 21.3

8. Classes of Antibodies IgD – Monomer attached to the surface of B cells – Functions as a B cell receptor IgG – Monomer; 75–85% of antibodies in plasma – From secondary and late primary responses – Crosses the placental barrier

9. Classes of Antibodies IgE – Monomer active in some allergies and parasitic infections – Causes mast cells and basophils to release histamine

10. Table 21.3

11. Generating Antibody Diversity Billions of antibodies result from somatic recombination of gene segments Hypervariable regions of some genes increase antibody variation through somatic mutations Each plasma cell can switch the type of H chain produced, making an antibody of a different class

12. Antibody Targets Antibodies inactivate and tag antigens – Form antigen-antibody (immune) complexes Defensive mechanisms used by antibodies – Neutralization and agglutination (the two most important) – Precipitation and complement fixation

13. Neutralization Simplest mechanism Antibodies block specific sites on viruses or bacterial exotoxins Prevent these antigens from binding to receptors on tissue cells Antigen-antibody complexes undergo phagocytosis

14. Agglutination Antibodies bind the same determinant on more than one cell-bound antigen Cross-linked antigen-antibody complexes agglutinate – Example: clumping of mismatched blood cells

15. Precipitation Soluble molecules are cross-linked Complexes precipitate and are subject to phagocytosis

16. Complement Fixation and Activation Main antibody defense against cellular antigens Several antibodies bind close together on a cellular antigen Their complement-binding sites trigger complement fixation into the cell’s surface Complement triggers cell lysis

17. Complement Fixation and Activation Activated complement functions – Amplifies the inflammatory response – Opsonization – Enlists more and more defensive elements

18. Figure 21.15 Inactivates by AntigenAntibody Fixes and activates Enhances Leads to Phagocytosis Chemotaxis Histamine release Inflammation Cell lysis Agglutination (cell-bound antigens) Precipitation (soluble antigens) Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Complement Antigen-antibody complex Adaptive defensesHumoral immunity

19. Monoclonal Antibodies Commercially prepared pure antibody Produced by hybridomas – Cell hybrids: fusion of a tumor cell and a B cell Proliferate indefinitely and have the ability to produce a single type of antibody Used in research, clinical testing, and cancer treatment

20. Cell-Mediated Immune Response T cells provide defense against intracellular antigens – Two types of surface receptors of T cells T cell antigen receptors Cell differentiation glycoproteins – CD4 or CD8 – Play a role in T cell interactions with other cells

21. Cell-Mediated Immune Response Major types of T cells – CD4 cells become helper T cells (TH) when activated – CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens Other types of T cells – Regulatory T cells (TREG) – Memory T cells

22. Figure 21.16 Maturation CD4 cell T cell receptor T cell receptor CD4 Helper T cells (or regulatory T cells) Cytotoxic T cells APC (dendritic cell) APC (dendritic cell) Activation Memory cells CD8 cell CD8 Lymphoid tissues and organs Blood plasma Thymus Class I MHC protein Class II MHC protein Effector cells Adaptive defensesCellular immunity Immature lymphocyte Red bone marrow

23. Comparison of Humoral and Cell- Mediated Response Antibodies of the humoral response – The simplest ammunition of the immune response Targets – Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph)

24. Comparison of Humoral and Cell- Mediated Response T cells of the cell-mediated response – Recognize and respond only to processed fragments of antigen displayed on the surface of body cells Targets – Body cells infected by viruses or bacteria – Abnormal or cancerous cells – Cells of infused or transplanted foreign tissue

25. Antigen Recognition Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) T cells must simultaneously recognize – Nonself (the antigen) – Self (an MHC protein of a body cell)

26. MHC Proteins Two types of MHC proteins are important to T cell activation – Class I MHC proteins - displayed by all cells except RBCs – Class II MHC proteins – displayed by APCs (dendritic cells, macrophages and B cells) Both types are synthesized at the ER and bind to peptide fragments

27. Class I MHC Proteins Bind with fragment of a protein synthesized in the cell (endogenous antigen) Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens)

28. Figure 21.17a Cytoplasm of any tissue cell Transport protein (ATPase) Endogenous antigen— self-protein or foreign (viral or cancer) protein Endogenous antigen is degraded by protease. Endogenous antigen peptides enter ER via transport protein. Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Antigenic peptide Plasma membrane of a tissue cell Cisternae of endoplasmic reticulum (ER) Endogenous antigen peptide is loaded onto class I MHC protein. Loaded MHC protein migrates in vesicle to the plasma membrane, where it displays the antigenic peptide. 1 2 3 4

29. Class II MHC Proteins Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome Recognized by helper T cells

30. T Cell Activation APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells T cell activation is a two-step process 1.Antigen binding 2.Co-stimulation

31. T Cell Activation: Antigen Binding CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction) CD4 cells bind to antigen linked to class II MHC proteins of APCs CD8 cells are activated by antigen fragments linked to class I MHC of APCs

32. T Cell Activation: Antigen Binding Dendritic cells are able to obtain other cells’ endogenous antigens by – Engulfing dying virus-infected or tumor cells – Importing antigens through temporary gap junctions with infected cells Dendritic cells then display the endogenous antigens on both class I and class II MHCs

33. T Cell Activation: Antigen Binding TCR that recognizes the nonself-self complex is linked to multiple intracellular signaling pathways Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) Antigen binding stimulates the T cell, but co- stimulation is required before proliferation can occur

34. Figure 21.18 1 Dendritic cell engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein. 2 Immunocompetent CD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind to antigen-MHC complex. 3 CD4 cells are activated, proliferate (clone), and become memory and effector cells. Viral antigen Dendritic cell Class lI MHC protein displaying processed viral antigen CD4 protein Immunocom- petent CD4 T cell Activated helper T cells Helper T memory cell T cell receptor (TCR) Clone formation Adaptive defensesCellular immunity

35. T Cell Activation: Co-Stimulation Requires T cell binding to other surface receptors on an APC – Dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized – B7 binding with a CD28 receptor on a T cell is a crucial co- stimulatory signal Cytokines (interleukin 1 and 2 from APCs or T cells) trigger proliferation and differentiation of activated T cell

36. T Cell Activation: Co-Stimulation Without co-stimulation, anergy occurs – T cells Become tolerant to that antigen Are unable to divide Do not secrete cytokines

37. T Cell Activation: Co-Stimulation T cells that are activated – Enlarge, proliferate, and form clones – Differentiate and perform functions according to their T cell class

38. T Cell Activation: Co-Stimulation Primary T cell response peaks within a week T cell apoptosis occurs between days 7 and 30 Effector activity wanes as the amount of antigen declines Benefit of apoptosis: activated T cells are a hazard Memory T cells remain and mediate secondary responses

39. Cytokines Mediate cell development, differentiation, and responses in the immune system Include interleukins and interferons Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to – Release interleukin 2 (IL-2) – Synthesize more IL-2 receptors

40. Cytokines IL-2 is a key growth factor, acting on cells that release it and other T cells – Encourages activated T cells to divide rapidly – Used therapeutically to treat melanoma and kidney cancers Other cytokines amplify and regulate innate and adaptive responses

41. Roles of Helper T(T H ) Cells Play a central role in the adaptive immune response Once primed by APC presentation of antigen, they – Help activate T and B cells – Induce T and B cell proliferation – Activate macrophages and recruit other immune cells Without T H, there is no immune response

42. Helper T Cells Interact directly with B cells displaying antigen fragments bound to MHC II receptors Stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without T H cells by binding to T cell–independent antigens Most antigens require T H co-stimulation to activate B cells

43. Figure 21.19a (a) B cell (being activated) MHC II protein of B cell displaying processed antigen IL- 4 and other cytokines Helper T cell CD4 protein T cell receptor (TCR) Activated helper T cell 1 2 T H cell binds with the self-nonself complexes of a B cell that has encountered its antigen and is displaying it on MHC II on its surface. T H cell releases interleukins as co-stimulatory signals to complete B cell activation. T H cell help in humoral immunity

44. Helper T Cells Cause dendritic cells to express co-stimulatory molecules required for CD8 cell activation

45. Figure 21.19b Class II MHC protein Class I MHC protein APC (dendritic cell) IL-2 CD4 protein CD8 T cell Helper T cell CD8 protein (b) 1 2 Previously activated T H cell binds dendritic cell. T H cell stimulates dendritic cell to express co-stimulatory molecules (not shown) needed to activate CD8 cell. 3 Dendritic cell can now activate CD8 cell with the help of interleukin 2 secreted by T H cell. T H cell help in cell-mediated immunity

46. Roles of Cytotoxic T(T C ) Cells Directly attack and kill other cells Activated T C cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize

47. Roles of Cytotoxic T(T C ) Cells Targets – Virus-infected cells – Cells with intracellular bacteria or parasites – Cancer cells – Foreign cells (transfusions or transplants)

48. Cytotoxic T Cells Bind to a self-nonself complex Can destroy all infected or abnormal cells

49. Cytotoxic T Cells Lethal hit – Tc cell releases perforins and granzymes by exocytosis – Perforins create pores through which granzymes enter the target cell – Granzymes stimulate apoptosis In some cases, TC cell binds with a Fas receptor on the target cell, and stimulates apoptosis

50. Figure 21.20a 1 T C binds tightly to the target cell when it identifies foreign antigen on MHC I proteins. 3 Perforin molecules insert into the target cell membrane, polymerize, and form transmembrane pores (cylindrical holes) similar to those produced by complement activation. 4 Granzymes enter the target cell via the pores. Once inside, these proteases degrade cellular contents, stimulating apoptosis. 5 The T C detaches and searches for another prey. (a) A mechanism of target cell killing by T C cells. 2 T C releases perforin and granzyme molecules from its granules by exocytosis. Cytotoxic T cell (T C ) Target cell Perforin T C cell membrane Target cell membrane Perforin pore Granzymes Granule Adaptive defensesCellular immunity

51. Natural Killer Cells Recognize other signs of abnormality – Lack of class I MHC – Antibody coating a target cell – Different surface marker on stressed cells Use the same key mechanisms as Tc cells for killing their target cells

52. Regulatory T (T Reg ) Cells Dampen the immune response by direct contact or by inhibitory cytokines Important in preventing autoimmune reactions

53. Figure 21.21 Ag-infected body cell engulfed by dendritic cell Becomes Activates Induce co-stimulation Free Ags may directly activate B cell Naïve CD4 T cells Activated to clone and give rise to Naïve CD8 T cells Antigen- activated B cells Activated to clone and give rise to Cytokines stimulate Activated cytotoxic T cells Memory helper T cells Activated helper T cells Memory cytotoxic T cells Together the nonspecific killers and cytotoxic T cells mount a physical attack on the Ag Nonspecific killers (macrophages and NK cells of innate immunity) Circulating lgs along with complement mount a chemical attack on the Ag Antibodies (Igs) Secrete Plasma cells (effector B cells) Memory B cells Clone and give rise to Inhibits Antigen (Ag) intruder Innate defenses Surface barriers Internal defenses Adaptive defenses Triggers Ag-presenting cell (APC) presents self-Ag complex Cell-mediated immunity Humoral immunity

54. Organ Transplants Four varieties – Autografts: from one body site to another in the same person – Isografts: between identical twins – Allografts: between individuals who are not identical twins – Xenografts: from another animal species

55. Prevention of Rejection Depends on the similarity of the tissues Patient is treated with immunosuppressive therapy – Corticosteroid drugs to suppress inflammation – Antiproliferative drugs – Immunosuppressant drugs Many of these have severe side effects

56. Immunodeficiencies Congenital and acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally

57. Severe Combined Immunodeficiency (SCID) Syndrome Genetic defect Marked deficit in B and T cells Abnormalities in interleukin receptors Defective adenosine deaminase (ADA) enzyme – Metabolites lethal to T cells accumulate SCID is fatal if untreated; treatment is with bone marrow transplants

58. Hodgkin’s Disease An acquired immunodeficiency Cancer of the B cells Leads to immunodeficiency by depressing lymph node cells

59. Acquired Immune Deficiency Syndrome (AIDS) Cripples the immune system by interfering with the activity of helper T cells Characterized by severe weight loss, night sweats, and swollen lymph nodes Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma

60. Acquired Immune Deficiency Syndrome (AIDS) Caused by human immunodeficiency virus (HIV) transmitted via body fluids—blood, semen, and vaginal secretions HIV enters the body via – Blood transfusions – Blood-contaminated needles – Sexual intercourse and oral sex HIV – Destroys TH cells – Depresses cell-mediated immunity

61. Acquired Immune Deficiency Syndrome (AIDS) HIV multiplies in lymph nodes throughout the asymptomatic period Symptoms appear in a few months to 10 years HIV-coated glycoprotein complex attaches to the CD4 receptor HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA The DNA copy (a provirus) directs the host cell to make viral RNA and proteins, enabling the virus to reproduce

62. Acquired Immune Deficiency Syndrome (AIDS) HIV reverse transcriptase produces frequent transcription errors; high mutation rate and resistance to drugs Treatment with antiviral drugs Reverse transcriptase inhibitors (AZT) – Protease inhibitors (saquinavir and ritonavir) – New Fusion inhibitors that block HIV’s entry to helper T cells

63. Autoimmune Diseases Immune system loses the ability to distinguish self from foreign Production of autoantibodies and sensitized TC cells that destroy body tissues Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, type I diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis

64. Mechanisms of Autoimmune Diseases 1.Foreign antigens may resemble self-antigens – Antibodies against the foreign antigen may cross-react with self-antigen 2.New self-antigens may appear, generated by – Gene mutations – Changes in self-antigens by hapten attachment or as a result of infectious damage

65. Mechanisms of Autoimmune Diseases 3.Release of novel self-antigens by trauma of a barrier (e.g., the blood-brain barrier)

66. Hypersensitivities Immune responses to a perceived (otherwise harmless) threat Causes tissue damage Different types are distinguished by – Their time course – Whether antibodies or T cells are involved Antibodies cause immediate and subacute hypersensitivities T cells cause delayed hypersensitivity

67. Immediate Hypersensitivity Acute (type I) hypersensitivities (allergies) begin in seconds after contact with allergen Initial contact is asymptomatic but sensitizes the person Reaction may be local or systemic

68. Immediate Hypersensitivity The mechanism involves IL-4 secreted by T cells IL-4 stimulates B cells to produce IgE IgE binds to mast cells and basophils, resulting in a flood of histamine release and inducing the inflammatory response

69. Anaphylactic Shock Systemic response to allergen that directly enters the blood Basophils and mast cells are enlisted throughout the body Systemic histamine releases may cause – Constriction of bronchioles – Sudden vasodilation and fluid loss from the bloodstream – Hypotensive shock and death Treatment: epinephrine

70. Subacute Hypersensitivities Caused by IgM and IgG transferred via blood plasma or serum Slow onset (1–3 hours) and long duration (10–15 hours) Cytotoxic (type II) reactions – Antibodies bind to antigens on specific body cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens – Example: mismatched blood transfusion reaction

71. Subacute Hypersensitivities Immune complex (type III) hypersensitivity – Antigens are widely distributed through the body or blood – Insoluble antigen-antibody complexes form – Complexes cannot be cleared from a particular area of the body – Intense inflammation, local cell lysis, and death may result – Example: systemic lupus erythematosus (SLE)

72. Delayed Hypersensitivities (Type IV) Slow onset (one to three days) Mechanism depends on helper T cells Cytokine-activated macrophages and cytotoxic T cells cause damage Example: allergic contact dermatitis (e.g., poison ivy)

73. Developmental Aspects Immune system stem cells develop in the liver and spleen by the ninth week Bone marrow becomes the primary source of stem cells Lymphocyte development continues in the bone marrow and thymus

74. Developmental Aspects T H 2 lymphocytes predominate in the newborn, and the T H 1 system is educated as the person encounters antigens The immune system is impaired by stress and depression With age, the immune system begins to wane, and incidence of cancer increases