1. PowerPoint ® Lecture Slides prepared by Janice Meeking, Mount Royal College C H A P T E R Copyright © 2010 Pearson Education, Inc. 21 The Immune System: Innate and Adaptive Body Defenses: Part B

2. Copyright © 2010 Pearson Education, Inc. Properties of specific immunity Specificity – activated by and responds to a specific antigen Versatility – is ready to confront any antigen at any time Memory – “remembers” any antigen it has encountered Tolerance – responds to foreign substances but ignores normal tissues

3. Copyright © 2010 Pearson Education, Inc. Complete Antigens Substances that can mobilize the immune system and provoke an immune response mostly large, complex molecules not normally found in the body (nonself) Important properties of antigene: Immunogenicity – ability to stimulate proliferation of specific lymphocytes and antibody production Reactivity – ability to react with products of activated lymphocytes and the antibodies released in response to them Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides

4. Copyright © 2010 Pearson Education, Inc. Haptens (Incomplete Antigens) Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy) Haptens are found in poison ivy, dander, some detergents, and cosmetics

5. Copyright © 2010 Pearson Education, Inc. Cells of the Adaptive Immune System Two types of lymphocytes B lymphocytes – oversee humoral immunity T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity Antigen-presenting cells (APCs): Do not respond to specific antigens

6. Copyright © 2010 Pearson Education, Inc. Lymphocytes Immature lymphocytes released from bone marrow are identical During their development the lymphocyte: Must become able to recognize its one specific antigen – become immunocompetent Must be relatively unresponsive to self so it will not attack the body’s own cells – self tolerance Location of becoming immunocompetent is the key for a lymphocyte to become B cell or a T cell B cells mature in the bone marrow T cells mature in the thymus

7. Copyright © 2010 Pearson Education, Inc. Immunocompetent B or T cells It is genes, not antigens, that determine which foreign substances our immune system will recognize and resist Become immunocompetent before they encounter antigens they may later attack Immunocompetence - displaying a unique type of receptor that responds to a specific antigen Each cell develops numerous plasma membrane proteins that serve as antigen receptors and become immunocompetent.

8. Copyright © 2010 Pearson Education, Inc. Immunocompetent B or T cells An immunocompetent cell divides rapidly to form a clone of cells with identical receptors. All clones yet to encounter an antigen are called the virgin/naive lymphocyte pool. Are exported to secondary lymphoid tissue where encounters with antigens occur Mature into fully functional antigen-activated cells upon binding with their recognized antigen Clonal selection of B or T cells occurs when antigens bind to their receptors, causing them to proliferate.

9. Copyright © 2010 Pearson Education, Inc. T Cells T cells mature in the thymus under negative and positive selection pressures Positive selection Selects T cells capable of binding to self-MHC proteins (MHC restriction) Negative selection Prompts apoptosis of T cells that bind to self- antigens displayed by self-MHC Ensures self-tolerance

10. Copyright © 2010 Pearson Education, Inc. B Cells B cells mature in red bone marrow Self-reactive B cells Are eliminated by apoptosis (clonal deletion) or Undergo receptor editing – rearrangement of their receptors Are inactivated (anergy) if they escape from the bone marrow

11. Copyright © 2010 Pearson Education, Inc. Antigen-Presenting Cells (APCs) Major rolls in immunity are: To engulf foreign particles To present fragments of antigens on their own surfaces, to be recognized by T cells Major APCs are Dendritic cells (DCs), Dendritic cells (DC) are bone marrow-derived cells that are specialized to take up, process and present antigen Dendritic cells are present in small quantities in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells) and the inner lining of the nose, lungs, stomach and the intestines. Macrophages that are found all over the body Activated B cells

12. Copyright © 2010 Pearson Education, Inc. Importance of Cellular and humoral Responses Importance of Humoral Response (Soluble antibodies) The simplest ammunition of the immune response Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph Importance of Cellular Response (T-cells) T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells are best suited for cell-to-cell interactions, and target: Cells infected with viruses, bacteria, or intracellular parasites Abnormal or cancerous cells Cells of infused or transplanted foreign tissue

13. Copyright © 2010 Pearson Education, Inc. Humoral Immunity Response

14. Copyright © 2010 Pearson Education, Inc. Humoral Immunity Response Antigen challenge – first encounter between an antigen and a naive immunocompetent cell Takes place usually in the spleen or lymph node If the lymphocyte is a B cell: The challenging antigen provokes a humoral immune response Antibodies are produced against the challenger Clonal Selection - A naive, immunocompetent B cell is activated when antigens bind to its surface receptors

15. Copyright © 2010 Pearson Education, Inc. Fate of the Clones Most clone cells become antibody-secreting plasma cells Plasma cells secrete specific antibody at the rate of 2000 molecules per second Secreted antibodies: Bind to free antigens Mark the antigens for destruction by specific or nonspecific mechanisms Clones that do not become plasma cells become memory cells that can mount an immediate response to subsequent exposures of the same antigen

16. Copyright © 2010 Pearson Education, Inc. Antibodies Also called immunoglobulins Plasma cells make over a billion types of antibodies makes the gamma globulin portion of blood proteins Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen Are capable of binding specifically with that antigen There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction

17. Copyright © 2010 Pearson Education, Inc. Basic Antibody Structure Consists of four polypeptide chains linked together with disulfide bonds Two identical heavy (H) chains and two identical light (L) chains The four chains bound together form an antibody monomer Each chain has a variable (V) region at one end and a constant (C) region at the other Variable regions of the heavy and light chains combine to form the antigen-binding site Constant region Determine the class of the antibody (one of the 5 groups)

18. Copyright © 2010 Pearson Education, Inc. Classes of Antibodies IgD – monomer attached to the surface of B cells, important in B cell activation IgM – pentamer released by plasma cells during the primary immune response IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces IgE – monomer that binds to mast cells and basophils, causing histamine release when activated

19. Copyright © 2010 Pearson Education, Inc. Antibodies functions

20. Copyright © 2010 Pearson Education, Inc. http://www.as.wvu.edu/~rbrundage/chapter12b/sld012.htm Neutralization – by binding to specific sites on the antigen, the antibody prevents its binding to cells

21. Copyright © 2010 Pearson Education, Inc. Actions of antibodies – agglutination and precipitation Ab molecules have at least 2 binding sites Ag have many antigenic determinant sites When Ag are far apart Ab will bind with 2 binding sites to the same antigen If Ag are close, Ab can bind to antigenic determinant sites of different Ag. As a consequence, the Ab “tie” Ag molecules together. Such a complex is called immune complex When the complexes are too big to be soluble they “sink” in a process called precipitation When the target Ag are on the surface of the cell or virus the formation of the large complex is called agglutination (example: clumping of RBCs in incompatible blood transfusion)

22. Copyright © 2010 Pearson Education, Inc. http://www.as.wvu.edu/~rbrundage/chapter12b/sld012.htm

23. Copyright © 2010 Pearson Education, Inc. Complement Fixation and Activation Complement fixation: Main mechanism used against cellular antigens Antibodies bound to cells change shape and expose complement binding sites This triggers complement fixation and cell lysis Complement activation: Enhances the inflammatory response Uses a positive feedback cycle to promote phagocytosis Enlists more and more defensive elements

24. Copyright © 2010 Pearson Education, Inc. http://www.as.wvu.edu/~rbrundage/chapter12b/sld012.htm Activation of complement (nonspecific reaction) – when antibody bind to antigen, the Ab shape changes and that allows the binding of the complement proteins (which pathway?)

25. Copyright © 2010 Pearson Education, Inc. The prevention of bacterial and viral adhesion Covered by Ab, pathogens have reduced ability to attach to body surfaces and penetrate. Fig. 1: Bacterial Adherence Via Pili Fig. 1A: Blocking Bacterial Adherence with Antibody Molecules http://www.cat.cc.md.us/courses/bio141/lecguide/unit3/humoral/abydefense/opsonization/opsonization.html

26. Copyright © 2010 Pearson Education, Inc. http://www.as.wvu.edu/~rbrundage/chapter12b/sld012.htm Phagocytes membrane carry receptors that can bind to the complex of the complement proteins and antibodies. The binding results in much more efficient phagocytosis. The antibodies in such a complex are called opsonins and the effect is called opsonization (enhanced attachment )

27. Copyright © 2010 Pearson Education, Inc. Other actions of antibodies Attraction of phagocytes – the antigen-antibody complex attracts phgocytes that destroy pathogens Antibodies may promote inflammation through the stimulation of basophils and mast cells

28. Copyright © 2010 Pearson Education, Inc. Immunological Memory Primary response – the initial response to an antigen Cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen Lag period: 3 to 6 days after antigen challenge Peak levels of plasma antibody are achieved in 10 days Antibody levels then decline If the antigen is not present anymore, the antibody production decrease. This reduction happens because: Plasma cells have short life span (few days) Suppressor T cells suppress plasma cells production IgM molecules are the first to appear during primary response. IgM provide the immediate defense. This defense is limited because no memory cells are being produced IgG – rise slow. Memory cells are formed

29. Copyright © 2010 Pearson Education, Inc. Secondary immune response – re-exposure to the same antigen Sensitized memory cells respond within hours Antibody levels peak in 2 to 3 days at much higher levels than in the primary response Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months Memory B cells can leave for 20 years or longer When a second exposure to antigen occur, memory B cells differentiate into plasma cells This response is immediate because memory B cells are activated by relatively low levels of antigen The antibody titer rises rapidly and to higher levels than during primary response Secondary antibody response

30. Copyright © 2010 Pearson Education, Inc. Figure 22.22 The Primary and Secondary Immune Responses

31. Copyright © 2010 Pearson Education, Inc. Cellular response

32. Copyright © 2010 Pearson Education, Inc. Antigen Recognition and MHC Restriction Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must recognize: Nonself (the antigen) Self (a MHC protein of a body cell)

33. Copyright © 2010 Pearson Education, Inc. Self-Antigens: MHC Proteins Major histocompatibility complex - MHC proteins, mark a cell as self The two classes of MHC proteins are: Class I MHC proteins – found on virtually all body cells Class II MHC proteins – found on certain cells in the immune response Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system

34. Copyright © 2010 Pearson Education, Inc. MHC classes – class I Class I – found on all nucleated cells (“hey, I’m an abnormal cell – please kill me”) “Sign” infected, sick or abnormal cells that need to be destroyed by the T-cells When type I are forming they “pick up” peptides from the cytoplasm and carry them to the cell surface If the peptides are normal (healthy cell) the T-cells will ignore them If the cytoplasm contain abnormal peptides or viral proteins, T-cells will be activated. This activation will lead to the cell destruction

35. Copyright © 2010 Pearson Education, Inc. MHC classes – class I

36. Copyright © 2010 Pearson Education, Inc. Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells (“Hey, this antigen is dangerous – get rid of it”) Class II are found on cells that the body does not need to destroy – it is only a mean to present non-self material Phagocytes cells engulf and break down pathogens A phagosome containing pathogens (with exogenous antigens) merges with a lysosome This antigen processing creates fragments that are bound to type II MHC and inserted into the cell membrane MHC classes – class II

37. Copyright © 2010 Pearson Education, Inc. MHC classes – class II

38. Copyright © 2010 Pearson Education, Inc. Cell-Mediated Immune Response Two major populations of T cells mediate cellular immunity: CD4 cells (T4 cells) are primarily helper T cells (T H ) CD8 cells (T8 cells) are cytotoxic T cells (T C ) that destroy cells with foreign antigens MHC restriction – T H and T C bind to different classes of MHC proteins T H / CD4 cells bind to antigen linked to class II MHC proteins T C / CD8 cells are activated by antigen fragments presented by class I MHC proteins

39. Copyright © 2010 Pearson Education, Inc.

40. 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 Major Types of T Cells

41. Copyright © 2010 Pearson Education, Inc. Specific T-cells roles: Helper T Cells (T H ) Regulatory cells that play a central role in the immune response Once primed by APC presentation of antigen, they: Chemically or directly stimulate proliferation of other T cells Stimulate B cells that have already become bound to antigen Without T H, there is no immune response T H cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors T H cells stimulate B cells to divide more rapidly and begin antibody formation Most antigens require T H co-stimulation to activate B cells Cytokines released by T H amplify nonspecific defenses

42. Copyright © 2010 Pearson Education, Inc. Specific T-cells roles: Cytotoxic T Cell (T c ) T C cells, or killer T cells, are the only T cells that can directly attack and kill other cells They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Their targets include: Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells from blood transfusions or transplants

43. Copyright © 2010 Pearson Education, Inc. Mechanisms of T c Action Bind to the target cell and release perforin into its membrane In the presence of Ca 2+ perforin causes cell lysis by creating transmembrane pores Secreting lymphotoxin, which fragments the target cell’s DNA Secreting gamma interferon, which stimulates phagocytosis by macrophages

44. Copyright © 2010 Pearson Education, Inc. Figure 22.17 Antigen Recognition and the Activation of Cytotoxic T Cells

45. Copyright © 2010 Pearson Education, Inc. Other T Cells Suppressor T cells (T S ) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells

46. Copyright © 2010 Pearson Education, Inc. T Cell Activation APCs 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 It means that the T cell has to “check twice” to make sure that it is APC presenting foreign antigen The co-stimulation helps to ensure that the immune system does not attack self Co-stimulation will trigger clonal selection

47. Copyright © 2010 Pearson Education, Inc. 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 T cells that are activated Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class

48. Copyright © 2010 Pearson Education, Inc. T Cell Activation Primary T cell response peaks within a week after signal exposure T cells then undergo apoptosis between days 7 and 30 Effector activity decreases as the amount of antigen declines The disposal of activated effector cells is a protective mechanism for the body activated T-cell can be dangerous because they produce cytokins that can promote unnecessary inflammation. Memory T cells remain and mediate secondary responses to the same antigen

49. Copyright © 2010 Pearson Education, Inc. Figure 22.19 A Summary of the Pathways of T Cell Activation