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

51. Figure 15.16

52. Figure 15.17

53. Other Types of Killer Cells
Natural killer (NK) cells
Related to T cells
Lack specificity for antigens
Circulate through the spleen, blood, and lungs
Probably the first killer cells to attack cancer cells and virus-infected cells

54. 15.7 A Practical Scheme for Classifying Specific Immunities
Active Immunity
Passive Immunity
Natural Immunity
Artificial Immunity

55. Figure 15.18

56. 15.8 Immunization: Methods of Manipulating Immunity for Therapeutic Purposes
Passive Immunization
Immune serum globulin
Specific immune globulin
Antisera and antitoxins of animal origin
Artificial Active Immunity: Vaccination

57. Immune Serum Globulin (ISG), aka Gamma Globulin
Contains immunoglobulin extracted from the pooled blood of at least 1,000 human donors
Processing concentrates the antibodies to increase potency and eliminates potential pathogens
Method of choice for preventing measles and hepatitis A and in replacing antibodies in immunodeficient patients
Injected intramuscularly
Protection lasts 2-3 months

58. Specific Immune Globulin (ISG)
Derived from a more defined group of donors
Serum is obtained from patients who are in a hyperimmune state after infections (ex. pertussis, tetanus, chickenpox, hepatitis B)
Contain higher titers of specific antibodies from a smaller pool of patients than ISG

59. Antisera and Antitoxins of Animal Origin
Can be used when a human immune globulin is not available
Example: sera produced in horses for diphtheria, botulism, and spider and snake bites

60. Artificial Active Immunity: Vaccination
Vaccination: exposing a person to material that is antigenic but not pathogenic
Stimulate a primary and secondary anamnestic response to prime the immune system for future exposure to a virulent pathogen

61. Principles of Vaccine Preparation

62. Figure 15.19

64. Development of New Vaccines
Difficult to design vaccines for latent or persistent viral infections
Host’s natural immunity can’t clear the infection
Artificial immunity must then outperform the host’s response to a natural infection
Difficult to choose vaccine antigens that are safe and that properly stimulate immunity
Research focused on newer strategies for vaccine preparation using antigen synthesis, recombinant DNA, and gene cloning technology

65. Genetically Engineered Vaccines
Recombinant DNA technology
Trojan horse vaccine
Genetic material from an infectious agent is inserted into a live carrier microbe that is nonpathogenic
The recombinant microbe multiplies and expresses the foreign genes
The vaccine recipient will be immunized against the microbial antigens
DNA vaccines

66. Figure 15.20

67. Route of Administration and Side Effects of Vaccines
Most vaccines are injected by subcutaneous, intramuscular, or intradermal routes
Only a few oral vaccines available, even though they have advantages
Some vaccines required the addition of an adjuvant
Common side effects
Local reactions at the injection site
Fever
Allergies
Some patients experience reactions to the medium rather than the antigens

68. To Vaccinate: Why, Whom, and When?
Not only confers protection to the individual receiving the vaccine, but it also protects public heath
Herd immunity
Collective immunity through mass immunization confers indirect protection on the nonimmune members
Important force in preventing epidemics