Microbiology: A Systems Approach, 2 nd ed.

1. Microbiology: A Systems Approach, 2nd ed. Chapter 15: Host Defenses II- Specific Immunity and Immunization

2. 15.1 Specific Immunity: The Third and Final Line of Defense • Not innate, but adaptive • Acquired only after an immunizing event such as an infection • Immunocompetence: the ability of the body to react with myriad foreign substances • Development of B and T lymphocytes • The lymphocytes become specialized for reacting only to one specific antigen or immunogen • Antigens stimulate a response by T and B cells • Two characterizing features of the third line of defense • Specificity • Memory

3. 5 Main Stages of Immunologic Development and Interaction • Lymphocyte development and differentiation • The presentation of antigens • The challenge of B and T lymphocytes by antigens • B lymphocytes and the production and activities of antibodies • T lymphocyte responses

4. Figure 15.1

5. 15.2 An Overview of Specific Immune Responses • Development of the Dual Lymphocyte System • All lymphocytes arise from the same basic stem cell type • Final maturation of B cells occurs in specialized bone marrow sites • Maturation of T cells occurs in the thymus • Both cell types then migrate to separate areas in the lymphoid organs

6. Entrance and Presentation of Antigens and Clonal Selection • Foreign cells cross the first line of defense and enter the tissue • Phagocytes migrate to the site • Macrophages ingest the pathogen and induce an inflammatory response if appropriate • Dendritic cells ingest the antigen and migrate to the nearest lymphoid organ • Process and present antigen to T lymphocytes • Pieces of antigen drain into lymph nodes • Activate B cells

7. Activation of Lymphocytes and Clonal Expansion • When challenged by antigen, B and T cells proliferate and differentiate • This creates a clone (group of genetically identical cells) • Some become memory cells

8. Products of B Lymphocytes: Antibody Structure and Functions • Progeny of dividing B-cell clone are called plasma cells • Programmed to synthesize and secrete antibodies into tissue fluid and blood • When antibodies attach to antigen, the antigen is marked for destruction or neutralization • Humoral immunity

9. How T Cells Respond to Antigen: Cell-Mediated Immunity (CMI) • When activated by antigen, T cell gives rise to one of three different types of progeny • TH1 cells- activate macrophages and help activate TC cells • TH2 cells- assist B-cell processes • TC cells- lead to the destruction of infected host cells and other “foreign” cells

10. Receptors on Cell Surfaces Involved in Recognition of Self and Nonself • Major functions of immune system receptors: • Attachment to nonself or foreign antigens • Binding to cell surface receptors that indicate self, such as MHC molecules • Receiving and transmitting chemical messages to coordinate the response • Aiding in cellular development

11. Major Histocompatibility Complex • Set of genes that codes for human cell receptors • Gives rise to a series of glycoproteins (MHC molecules) found on all cells except red blood cells • Also known as human leukocyte antigen (HLA) system • Three classes of MHC genes identified: • Class I genes- code for markers that display unique characteristics of self • Class II genes- code for immune regulatory receptors found on macrophages, dendritic cells, and B cells; and are involved in presenting antigens to T cells during cooperative immune reactions • Class III genes- encode proteins involved with the complement system

12. Figure 15.2

13. Lymphocyte Receptors and Specificity to Antigen • B cells have receptors that bind antigens • T cells have receptors that bind processed antigens plus MHC molecules on the cells that present antigens to them

14. The Origin of Diversity and Specificity of the Immune Response • The Clonal Selection Theory and Lymphocyte Development • Early undifferentiated lymphocytes in the embryo, fetus, and adult bone marrow undergo a continuous series of divisions and genetic changes • Generates hundreds of millions of different types of B and T cells

15. Figure 15.3

16. Summary of the Mechanism • Stem cells in bone marrow can become granulocytes, monocytes, or lymphocytes • Lymphocytic cells become either T cells or B cells • Cells destined to become B cells stay in bone marrow • T cells migrate to the thymus where they build their unique antigen receptor • B and T cells then migrate to secondary lymphoid tissues

17. Figure 15.4

18. Proliferative Stage of Development • Does not require the actual presence of foreign antigens • By the time T and B cells reach the lymphoid tissues, each one is equipped to respond to a single unique antigen • This diversity is generated by rearrangements of the gene segments that code for the proteinaceous antigen receptors on the T and B cells • Each genetically unique line of lymphocytes arising from these recombinations

19. Clonal Selection and Expansion • Second stage of development • Requires stimulation by an antigen • Antigen contact with a lymphocyte stimulates the clone to undergo mitotic divisions

20. Two Important Generalities From the Clonal Selection Theory • Lymphocyte specificity is preprogrammed, existing in the genetic makeup before an antigen has ever entered the tissues • Each genetically distinct lymphocyte expresses only a single specificity and can react to only one type of antigen

21. Preventing Reactions to Self • Any clones that react to self are destroyed during development through clonal deletion • Autoimmune diseases are thought to be caused by the loss of immune tolerance to self

22. The Specific B-Cell Receptor: An Immunoglobulin Molecule • The receptor genes that undergo recombination are those governing immunoglobulin (Ig) synthesis • Igs: large glycoprotein molecules that serve as the antigen receptors of B cells and as antibodies when secreted • Y-shaped arrangement • Ends of forks contain pockets called the antigen binding sites • Can be highly variable in shape to fit a wide range of antigens • Variable regions (V)

23. Figure 15.5

24. T-Cell Receptors • Belongs to the same protein family as the B-cell receptor • Relatively small and never secreted

25. Figure 15.6

26. 15.3 The Lymphocyte Response System in Depth • Specific Events in B-Cell Maturation • Bone marrow sites harbor stromal cells • Stromal cells nurture the lymphocyte stem cells and provide chemical signals that initiate B-cell development • B cells circulate through the blood, “homing” to specific sites in lymph nodes, spleen, and GALT • Adhere to specific binding molecules where they come into contact with antigens

28. Specific Events in T-Cell Maturation • Directed by the thymus gland and its hormones • Mature T lymphocytes express either CD4 or CD8 coreceptors • CD4 binds to MHC class II, expressed on T helper cells • CD8 binds to MHC class I, found on cytotoxic T cells • Constantly circulate between the lymphatic and general circulatory system, migrating to specific T-cell areas of the lymph nodes and spleen

29. Entrance and Processing of Antigens and Clonal Selection • Antigen (Ag): a substance that provokes an immune response in specific lymphocytes • Antigenicity: the property of behaving as an antigen • Immonogen: another term for an antigen • Characteristics of Antigens • It is perceived as foreign • Complex molecules are more immunogenic • Categories • Proteins and polypeptides • Lipoproteins • Glycoproteins • Nucleoproteins • Polysaccharides

30. Figure 15.7

31. Effects of Molecular Shape and Size • Substance must be large enough to initiate an immune response from the surveillance cells • Lymphocyte recognizes and responds to only a portion of the antigen molecule- the epitope • Mosaic antigens- very complex with numerous component parts, each of which elicit a separate lymphocyte response • Haptens: small foreign molecules that consist of only a determinant group • Too small to elicit an immune response on their own • If linked to a larger carrier molecule, then the combination develops immunogenicity

32. Figure 15.8

33. Other Types of Antigens • Alloantigens: cell surface markers and molecules that occur in some members of the same species but not in others • Superantigens: bacterial toxins, potent stimuli for T cells • Allergens: antigens that evoke allergic reactions

34. 15.4 Cooperation in Immune Reactions to Antigens • The Role of Antigen Processing and Presentation • Antigen-presenting cells (APCs): cells that act upon and formally present antigens to lymphocytes • Macrophages • B cells • Dendritic cells • Engulf the antigen and modify it so it is more immunogenic and recognizable • After processing, the antigen is bound to the MHC receptor and moved to the surface of the APC so it is accessible to T lymphocytes

35. Figure 15.9

36. Presentation of Antigen to the Lymphocytes and Its Early Consequence • APCs activate CD4 T helper cells in the lymph nodes • This class of T cell has an antigen-specific T-cell receptor • Binds to MHC class II • Binds to a piece of the antigen • Binds to a piece of the CD4 molecule (which also binds to MHC class II) • Once identification has occurred, a molecule on the APC activates the T helper cell • TH produces interleukin-2 (IL-2) • The T helper cells can now help activate B cells

37. 15.5 B-Cell Response • Activation of B Lymphocytes: Clonal Expansion and Antibody Production • Clonal selection and binding of antigen • Antigen processing and presentation • B-cell/T-cell recognition and cooperation • B-cell activation • Clonal expansion • Antibody production and secretion

38. Figure 15.10

39. The Structure of Immunoglobulins Figure 15.11

40. Antibody-Antigen Interactions and the Function of the FAb Figure 15.12

41. Principal Activity of an Antibody Figure 15.13

42. Functions of the Fc Fragment • Fc end contains an effector protein that can bind to receptors on the membranes of cells • The effect of this binding depends upon that cell’s role

43. Classes of Immunoglobulins

44. Evidence of Antibodies in Serum Figure 15.14

45. Monitoring Antibody Production over Time: Primary and Secondary Response to Antigens Figure 15.15

46. 15.6 T-Cell Response • Cell-Mediated Immunity (CMI) • Require the direct involvement of T lymphocytes throughout the course of the reaction • T cells require some type of MHC recognition before they can be activated • T cells stimulate other T cells, B cells, and phagocytes

47. The Activation of T Cells and Their Differentiation into Subsets • Mature T cells in lymphoid organs are primed to react with antigens that have been processed and presented to them by dendritic cells and macrophages • Recognize an antigen only when it is presented in association with an MHC carrier • CD4 receptors recognize endocytosed peptides on MHC-II • CD8 receptors recognize peptides on MHC-I • T cell is sensitized when an antigen/MHC complex is bound to its receptors • The activated T cells then transform in preparation for mitotic divisions and differentiate into one of the subsets

49. T Helper (TH) Cells • Play a central role in regulating immune reactions to antigens • Also involved in activating macrophages • Directly by receptor contact • Indirectly by releasing cytokines like interferon gamma • Secrete interleukin-2 • Stimulates the primary growth and activation of many types of T cells • Some secrete interleukins-4, -5, and -6 • Stimulate various activities of B cells • When stimulated by antigen/MCH complex, differentiate into either TH1 or TH2 cells

50. Cytotoxic T (TC) Cells: Cells that Kill Other Cells • Cytotoxicity: the capacity of certain T cells to kill a specific target cell • CD8 killer T cell becomes activated when it recognizes a foreign peptide complexed with self MHC-I presented to it • After activation the TC cell severely injures the target cell • This involves the secretion of perforins and granzymes • Target cells that TC cells can destroy include: • Virally infected cells • Cancer cells • Cells from other animals and humans