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

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

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

Figure 15.1

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

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

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

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

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

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

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

Figure 15.2

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

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

Figure 15.3

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

Figure 15.4

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

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

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

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

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)

Figure 15.5

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

Figure 15.6

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

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

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

Figure 15.7

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

Figure 15.8

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

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

Figure 15.9

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

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

Figure 15.10

The Structure of Immunoglobulins Figure 15.11

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

Principal Activity of an Antibody Figure 15.13

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

Classes of Immunoglobulins

Evidence of Antibodies in Serum Figure 15.14

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

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

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

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

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

Figure 15.16

Figure 15.17

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

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

Figure 15.18

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

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

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

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

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

Principles of Vaccine Preparation

Figure 15.19

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

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

Figure 15.20

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

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