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1. 21 The Immune System: Innate and Adaptive Body Defenses: Part B

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

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

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

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. Cytoplasm of any tissue cell Cisternae ofendoplasmicreticulum (ER) Endogenous antigenpeptides enter ER viatransport protein. 2 Endogenousantigen is degradedby protease. 1 3 Endogenousantigen peptide isloaded onto classI MHC protein. Endogenous antigen—self-protein or foreign(viral or cancer) protein 4 Loaded MHC proteinmigrates in vesicle tothe plasma membrane,where it displays theantigenic peptide. Transportprotein(ATPase) Antigenic peptide Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a

29. Cytoplasm of any tissue cell Endogenousantigen is degradedby protease. 1 Endogenous antigen—self-protein or foreign(viral or cancer) protein Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a, step 1

30. Cytoplasm of any tissue cell Cisternae ofendoplasmicreticulum (ER) Endogenous antigenpeptides enter ER viatransport protein. 2 Endogenousantigen is degradedby protease. 1 Endogenous antigen—self-protein or foreign(viral or cancer) protein Transportprotein(ATPase) Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a, step 2

31. Cytoplasm of any tissue cell Cisternae ofendoplasmicreticulum (ER) Endogenous antigenpeptides enter ER viatransport protein. 2 Endogenousantigen is degradedby protease. 1 Endogenousantigen peptide isloaded onto classI MHC protein. 3 Endogenous antigen—self-protein or foreign(viral or cancer) protein Transportprotein(ATPase) Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a, step 3

32. Cytoplasm of any tissue cell Cisternae ofendoplasmicreticulum (ER) Endogenous antigenpeptides enter ER viatransport protein. 2 Endogenousantigen is degradedby protease. 1 3 Endogenousantigen peptide isloaded onto classI MHC protein. Endogenous antigen—self-protein or foreign(viral or cancer) protein 4 Loaded MHC proteinmigrates in vesicle tothe plasma membrane,where it displays theantigenic peptide. Transportprotein(ATPase) Antigenic peptide Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a, step 4

33. 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

34. Cytoplasm of APC 1a Class II MHC issynthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. Vesicle fuses withphagolysosome. Invariantchain is removed, andantigen is loaded. 3 2a Class II MHCis exportedfrom ER in avesicle. Cisternae ofendoplasmicreticulum (ER) Phagosome 1b Extracellularantigen (bacterium)is phagocytized. Vesicle withloaded MHCmigrates to theplasmamembrane. 4 2b Phagosome mergeswith lysosome, forminga phagolysosome;antigen is degraded. Lysosome Plasma membrane of APC Extracellularantigen Antigenic peptide Extracellular fluid (b) Exogenous antigens are processed and displayed on class II MHC ofantigen-presenting cells (APCs). Figure 21.17b

35. 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 • Antigen binding • Co-stimulation

36. 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

37. 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

38. 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

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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. Roles of Helper T(TH) 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 TH, there is no immune response

47. 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 TH cells by binding to T cell–independent antigens • Most antigens require TH co-stimulation to activate B cells

48. TH cell help in humoral immunity Activated helper T cell TH 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. 1 T cell receptor (TCR) Helper T cell CD4 protein MHC II protein of B cell displaying processed antigen TH cell releases interleukins as co-stimulatory signals to complete B cell activation. 2 IL- 4 and other cytokines B cell (being activated) (a) Figure 21.19a

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

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