Specific Host Defenses: Adaptive Immunity ACQUIRED or SPECIFIC IMMUNITY

Two major kinds of defense Innate immunity Acquired immunity

The Immune System is the Third Line of Defense Against Infection Immune Response: Third line of defense. Involves production of antibodies and generation of specialized lymphocytes against specific antigens. Immune Response: Third line of defense. Involves production of antibodies and generation of specialized lymphocytes against specific antigens.

Innate or Natural or Non specific Immunity : Immunity an organism is born with. Immunity an organism is born with. Genetically determined. Effective from birth. Genetically determined. Effective from birth. Present before exposure to pathogens Present before exposure to pathogens Nonspecific responses to pathogens Nonspecific responses to pathogens Acquired or Specific Immunity : Immunity that an organism develops during lifetime. Immunity that an organism develops during lifetime. Not genetically determined. Not genetically determined. Develops after exposure to antigens (microbes, toxins, or other foreign substances) Develops after exposure to antigens (microbes, toxins, or other foreign substances) Very specific response to pathogens Very specific response to pathogens May be acquired naturally or artificially. May be acquired naturally or artificially.

Types of Acquired Immunity Acquired Immunity

Types of acquired immunity (1). Natural Acquired Active immunity (2). Natural Acquired Passively, (3) Artificially Acquired Active Immunity, & (4) Artificially Acquired Passive Immunity (1). Natural Acquired Active immunity (2). Natural Acquired Passively, (3) Artificially Acquired Active Immunity, & (4) Artificially Acquired Passive Immunity

Serum: Fluid that remains after blood has clotted and cells have been removed. Serum: Fluid that remains after blood has clotted and cells have been removed. Antiserum: Serum containing antibodies to a specific antigen(s). Obtained from injecting an animal (horse, rabbit, goat) with antigen (snake venom, botulism or diphtheria toxin). Antiserum: Serum containing antibodies to a specific antigen(s). Obtained from injecting an animal (horse, rabbit, goat) with antigen (snake venom, botulism or diphtheria toxin). Serology: The study of reactions between antibodies and antigens. Serology: The study of reactions between antibodies and antigens. Gamma Globulins: Fraction of serum that contains most of the antibodies. Gamma Globulins: Fraction of serum that contains most of the antibodies. Serum Sickness: Disease caused by multiple injections of antiserum. Immune response to foreign proteins. May cause fever, kidney problems, and joint pain. Rare today. Serum Sickness: Disease caused by multiple injections of antiserum. Immune response to foreign proteins. May cause fever, kidney problems, and joint pain. Rare today.

Types of Acquired Immunity 1. Naturally Acquired Immunity: - Obtained in the course of daily life. - Obtained in the course of daily life. 1A. Naturally Acquired Active Immunity: Antigens or pathogens enter body naturally. Antigens or pathogens enter body naturally. Person contracts disease; generates specific immune response to the antigen. Person contracts disease; generates specific immune response to the antigen. Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections). Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections). 1B. Naturally Acquired Passive Immunity: Antibodies pass from mother to fetus via placenta or breast feeding (colostrum). No immune response to antigens. Antibodies pass from mother to fetus via placenta or breast feeding (colostrum). No immune response to antigens. Develops immediately immunity & is usually short-lived (weeks to months). Develops immediately immunity & is usually short-lived (weeks to months). Affects all antigens to which the mother has immunity. Affects all antigens to which the mother has immunity. Protection until child’s immune system develops. Protection until child’s immune system develops.

2. Artificially Acquired Immunity : Obtained by receiving a vaccine or immune serum. Obtained by receiving a vaccine or immune serum. 2A. Artificially Acquired Active Immunity: Involves production of Antibody following exposure of specially prepared Antigen Involves production of Antibody following exposure of specially prepared Antigen Antigens are introduced as vaccines (immunization). Antigens are introduced as vaccines (immunization). Body generates an immune response slowly and is specific to the antigen for which the immunization was given. Body generates an immune response slowly and is specific to the antigen for which the immunization was given. Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid & Diphtheria toxoid). Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid & Diphtheria toxoid). 2B. Artificially Acquired Passive Immunity: Transfer of immunity from the immunised person to a non- immunized person by trnsfering Abs or sensitised cells. Transfer of immunity from the immunised person to a non- immunized person by trnsfering Abs or sensitised cells. Eg. Snake antivenom injection from horses or rabbits Eg. Snake antivenom injection from horses or rabbits Used in the ttt. Of Tetanus, Diphtheria &Mumps Used in the ttt. Of Tetanus, Diphtheria &Mumps Immunity is immediate, but short lived (half life 3 weeks). Immunity is immediate, but short lived (half life 3 weeks). Affects all antigens to which the donor has the immunity. Affects all antigens to which the donor has the immunity. Host immune system does not respond to antigens. Host immune system does not respond to antigens.

Lymphocytes mount a dual defense Lymphocytes mount a dual defense Two kinds of ( B & T) lymphocytes carry out the immune responses Two kinds of ( B & T) lymphocytes carry out the immune responses 1. Humoral immunity (Antibody mediated) involves the production of antibody by the B cells which attack Ag. 2.Cell mediated immunity - is governed by T- lymphocytes. T cells attack cells infected with pathogens Lymphocytes BONE MARROW Stem cell Immature lymphocytes Via blood Antigen receptors B cell HUMORAL IMMUNITY CELL- MEDIATED IMMUNITY T cell THYMUS Via blood OTHER PARTS OF THE LYMPHATIC SYSTEM Lymph nodes, spleen, and other lymphatic organs Final maturation of B and T cells in lymphatic organ B cell Thymus

Duality of Immune System I. Humoral (Antibody-Mediated) Immunity Involves production of antibodies by B cells against foreign antigens (bacteria, bacterial toxins, and viruses). Involves production of antibodies by B cells against foreign antigens (bacteria, bacterial toxins, and viruses). B cells develop from stem cells in the bone marrow of adults (liver of fetuses). B cells develop from stem cells in the bone marrow of adults (liver of fetuses). After maturation, B cells migrate to lymphoid organs (lymph node or Spleen). After maturation, B cells migrate to lymphoid organs (lymph node or Spleen). B cells are the main warriors of humoral immunity B cells are the main warriors of humoral immunity

Cell growth division, and differentiation in a lymph node Humoral Response to T Independent Antigens Humoral Response to T Independent Antigens Clone of many effector cells secreting antibodies ER Selection of B cells Triggering of the B cell

Humoral Response to T Dependent Antigens

Activation of B-Cells Activation of B cells involves various steps. Activation of B cells involves various steps. 1. Selection of B cells – 1 from many B-cell (Each lymphocyte bears a specific receptor to the antigen) 2. Recognition of Antigens – by B cells or Macrophage 3. Processing of Ag by Macrophages - immunogenic 4. Antigen presentation by Macrophages to B cells. T dept Ag – needs the co operation of Th cells --(BSF) activate B cells 5. Triggering of the B cell by the Ab or Th cells R-TCn-TLn 6. Clonal proliferation–Cell division & prolfn- by BSF, BCGF 7. Production of Plasma cells & Memory cells 8. Secretion of Immunoglobulin into the serum.

Humoral Immunity (Continued) Apoptosis Programmed cell death (“Falling away”). Programmed cell death (“Falling away”). Human body makes 100 million lymphocytes every day. If an equivalent number doesn’t die, will develop leukemia. Human body makes 100 million lymphocytes every day. If an equivalent number doesn’t die, will develop leukemia. B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains. B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains. Many virus infected cells will undergo apoptosis, to prevent spread of the infection. Many virus infected cells will undergo apoptosis, to prevent spread of the infection.

Clonal Selection Clonal deletion - Some self-reactive B cells are killed in the bone marrow (Not immunocompetent). Clonal deletion - Some self-reactive B cells are killed in the bone marrow (Not immunocompetent). Clonal selection- When antigen binds to antigen receptor, the “Selected” B cell undergoes proliferates into clones that will recognize one specific antigen. Clonal selection- When antigen binds to antigen receptor, the “Selected” B cell undergoes proliferates into clones that will recognize one specific antigen. Clonal selection must be a defensive forces against a specific antigen. Clonal selection must be a defensive forces against a specific antigen. Stimulated B cell growth forms clones bearing the same antigen-specific receptors Stimulated B cell growth forms clones bearing the same antigen-specific receptors ■ A naive, immunocompetent B cell is activated when antigens bind to its surface receptors. ■ These, along with T cell interactions, trigger clonal selection ■ These, along with T cell interactions, trigger clonal selection

Fate of the Clones ■ Most clone cells become antibody-secreting plasma cells ( effector cell - short-lived cells) ■ Plasma cells secrete specific antibody at a higher rate than B cells ■ 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 (long-lived) that can mount an immediate response to subsequent exposures of the same antigen

PRIMARY RESPONSE (initial encounter with antigen) Antigen Antigen receptor on a B cell Antigen binding to a B cell Memory B cell Antibody molecules Plasma cell Cell growth, division, and differentiation SECONDARY RESPONSE (can be years later) Cell growth,division, & further differentiation Larger clone of cells Plasma cell Antibody molecules Later exposure to same antigen Memory B cell Clone of cells

Immunological Memory Antibody Titer: The amount of antibody in the serum. Pattern of Antibody Levels During Infection Primary Response: After initial exposure to antigen, no antibodies are found in serum for several days. After initial exposure to antigen, no antibodies are found in serum for several days. A gradual increase in titer, first of IgM and then of IgG is observed after 3 to 6 days. A gradual increase in titer, first of IgM and then of IgG is observed after 3 to 6 days. Most B cells become plasma cells, but some B cells become long living memory cells. Most B cells become plasma cells, but some B cells become long living memory cells. Peak levels of plasma antibody are achieved in 10 days Peak levels of plasma antibody are achieved in 10 days Gradual decline of antibodies follows. Gradual decline of antibodies follows.

Immunological Memory - Secondary Response: Subsequent exposure to the same antigen displays a faster and more intense antibody response with in an hour. Subsequent exposure to the same antigen displays a faster and more intense antibody response with in an hour. It is due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation. It is due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation. Antibody levels peak in 2 to 3 days Antibody levels peak in 2 to 3 days Antibody levels in the blood can remain high for weeks to months Antibody levels in the blood can remain high for weeks to months Unstimulated lymphocyte First exposure to antigen FIRST CLONE Memory cells Effector cells Second exposure to antigen SECOND CLONE More memory cells New effector cells

Antibody Response After Exposure to Antigen

Monoclonal antibodies are pure antibody preparations  Specific for a single antigenic determinant  Produced from descendents of a single cell  Hybridomas – cell hybrids made from a fusion of a tumor cell (easy-to-grow) and a B cell (specific for a single antigenic determinant) Monoclonal antibodies Antigen injected into mouse Tumor cells grown in culture B cells (from spleen) Tumor cells Cells fused to generate hybrid cells Single hybrid cell grown in culture Antibody Hybrid cell culture, producing monoclonal antibodies

Uses - Monoclonal Antibodies ■ Monoclonal Abs are powerful tools in the lab  Commercially prepared antibodies are used:  In research & clinical testing  To provide passive immunity  These cells are useful in medical diagnosis  They are also useful in the treatment of certain cancers. ■ Have desirable properties of both parent cells – indefinite proliferation as well as the ability to produce a single type of antibody

Acquired Immunity: Ag-Specific Responses

T Lymphocytes: Cell Mediated Immunity Figure 24-16: T lymphocytes and NK cells

T Cells and Cell Mediated Immunity Cellular Components of Immunity: T cells develop from stem cells in bone marrow and mature in the thymus gland. T cells develop from stem cells in bone marrow and mature in the thymus gland. After maturation they migrate to lymphoid organs After maturation they migrate to lymphoid organs T cells are key cellular component of immunity. T cells are key cellular component of immunity. T cells have an antigen receptor that recognizes and reacts to a specific intracellular antigen (T cell receptor). T cells have an antigen receptor that recognizes and reacts to a specific intracellular antigen (T cell receptor). T cell receptor only recognize antigens combined with major histocompatability (MHC) proteins on the surface of cells. T cell receptor only recognize antigens combined with major histocompatability (MHC) proteins on the surface of cells. MHC Class I: Found on all nucleated cells & MHC Class I: Found on all nucleated cells & MHC Class II: Found on phagocytes. MHC Class II: Found on phagocytes.

T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces

II. Cell Mediated Immunity Clonal selection increases number of effector T cells and destroy the invader. Clonal selection increases number of effector T cells and destroy the invader. T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc. T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc. Defense against: Defense against: Bacteria,Viruses, Fungi, protozoa, and helminths Bacteria,Viruses, Fungi, protozoa, and helminths Cancer cells & Transplanted tissue Cancer cells & Transplanted tissue Unlike humoral immunity, cell mediated immunity is not transferred to the fetus (no passive immunity). Unlike humoral immunity, cell mediated immunity is not transferred to the fetus (no passive immunity).

Types of T cells 1. Helper T (CD4+ T H ) Cells - have central role in immune response, these activate macrophages and help form cytotoxic T cells 2. Cytotoxic T (CD8+ CTLs) destroy target cells on contact by producing perforin that lysis an infected cells 3. Delayed hypersensitivity T (T D ) Cells: Mostly T helper and a few cytotoxic T cells that are involved in some allergic reactions (poison ivy) and rejection of transplanted tissue. 4. Suppressor T (Ts) Cells -inhibit the production of CTL cells to shut down immune response once they are unneeded, least they cause more damage than necessary. (Now called regulatory T cells).

APC = e.g., Macrophage TCR Peptide Antigen CD4 CD4 T Cell MHC Class II

T Cells and Cell Mediated Immunity 1. T Helper (T H ) Cells: Central role in immune response. Most are CD4 + (clusters of differentiation) Most are CD4 + (clusters of differentiation) The helper T cell ’ s receptors recognize antigen on the surface of antigen presenting cells (e.g.: macrophage). The helper T cell ’ s receptors recognize antigen on the surface of antigen presenting cells (e.g.: macrophage). The interaction activates the macrophages & TH cells The interaction activates the macrophages & TH cells The helper T cell releases IL2 & other cytokines The helper T cell releases IL2 & other cytokines to activate itself, Cytotoxic T cells & the B cell Activated CTL directly attack the infected cells by Cell mediated immune response Activated CTL directly attack the infected cells by Cell mediated immune response B cells produce plasma cells which secrete antibodies – Humoral immune response. B cells produce plasma cells which secrete antibodies – Humoral immune response. T cells mount the cell-mediated defense and aid humoral immunity T cells mount the cell-mediated defense and aid humoral immunity

Central Role of Helper T Cells

Cytokines Mediators involved in cellular immunity, including hormone like glycoproteins released by activated T cells and macrophages Mediators involved in cellular immunity, including hormone like glycoproteins released by activated T cells and macrophages ■ Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to release IL 2. IL-2 is a key growth factor, which activates T cells to divide IL-2 is a key growth factor, which activates T cells to divide ■ Other cytokines amplify and regulate immune and nonspecific responses. Examples includes:  Perforin and lymphotoxin – Cell toxins  Gamma interferon – enhances the killing power of macrophages  Inflammatory factors

Cytotoxic T cells T cells that express CD8 molecule on their surface T cells that express CD8 molecule on their surface Class I MHC molecules (nucleated body cells) expose foreign proteins Class I MHC molecules (nucleated body cells) expose foreign proteins Recognize antigens on the surface of all cells: Recognize antigens on the surface of all cells: Kill host cells that are infected with viruses or bacteria. Kill host cells that are infected with viruses or bacteria. Recognize & kill - Foreign cells from blood transfusions or transplants. Recognize & kill - Foreign cells from blood transfusions or transplants. Recognize and destroy cancer cells & transplanted tissue. Recognize and destroy cancer cells & transplanted tissue. TC cell release protein called perforin and granzymes which forms a pore in target cell membrane, causing lysis of infected cells and/or Apoptosis TC cell release protein called perforin and granzymes which forms a pore in target cell membrane, causing lysis of infected cells and/or Apoptosis Cytotoxic T cell binds to infected cell Perforin makes holes in infected cell’s membrane Infected cell is destroyed

Interrelationship between cell mediated and humoral immunity Antibody production depends on macrophages and T cells (T dependent antigen) Antibody production depends on macrophages and T cells (T dependent antigen) 1. Antigen is ingested and presented by the APC 2. The helper T cells reacts with this MHC-antigen complex 3. This activates the T cell and it begins to proliferate and produce cytokines. 4. The cytokines activate macrophages, CD8 cells, and natural killer cells 5. IL-2 influences a B cell to differentiate into a plasma cell that produces antibody Sometimes antigen can stimulate B cells directly without the help of T cells. This is called T independent antigen. Sometimes antigen can stimulate B cells directly without the help of T cells. This is called T independent antigen. In this case the antigen reacts directly with the B cell receptors. This is usually weaker In this case the antigen reacts directly with the B cell receptors. This is usually weaker

The big picture…Integration of innate and adaptive immunity Courtesy: Abbas and Litchman; Basic Immunology

Summary Evolutionary need for adaptive immunity: Evolutionary need for adaptive immunity: Self/non-self discrimination, specificity, amplification, regulation, duration and memory Self/non-self discrimination, specificity, amplification, regulation, duration and memory T and B cells are mediators of adaptive immunity T and B cells are mediators of adaptive immunity T cells: cell-mediated immunity T cells: cell-mediated immunity B cells: humoral immunity B cells: humoral immunity Cells of innate immunity also participate (DCs, Macrophages) Cells of innate immunity also participate (DCs, Macrophages) Activation of T and B cells are different: Activation of T and B cells are different: T cells: specific recognition of peptide/MHC complex (signal 1) and costimulatory signals by APC (Signal 2) T cells: specific recognition of peptide/MHC complex (signal 1) and costimulatory signals by APC (Signal 2) B cells: recognize native proteins (signal 1). May/may not require signal 2 from CD4+ Th cells (TD and TI antigens) B cells: recognize native proteins (signal 1). May/may not require signal 2 from CD4+ Th cells (TD and TI antigens) Immunological memory: an important hallmark Immunological memory: an important hallmark Faster and rapid response on a second antigen encounter Faster and rapid response on a second antigen encounter Innate immune response shapes the adaptive immunity Innate immune response shapes the adaptive immunity