WHY IS THIS IMPORTANT?

Transcription

1 CHAPTER 16 THE ADAPTIVE IMMUNE RESPONSE Photo courtesy of Ann Dvorak WHY IS THIS IMPORTANT? The adaptive immune system protects us from many infections. The adaptive immune system has memory so we are not infected by the same pathogen a second time. This is why vaccinations work. OVERVIEW

2 INTRODUCTION The adaptive immune response is the second level of immunity. It involves lymphocytes. It is a response to specific antigens. It is extraordinarily specific. It can adapt to any infection. It has memory. This confers life-long immunity. INTRODUCTION: Types of Response The innate response is a prerequisite for the adaptive immune response. The adaptive immune response has two types of response: Humoral production of antibodies Cellular killing and regulation of infected cells INTRODUCTION: Antigens There are two types of antigens: Self Nonself Self antigens are part of the immunological memory and cause tolerance. Nonself antigens are any molecules that are not self.

3 INTRODUCTION: Lymphatic System The adaptive response is associated with the lymphatic system. It covers the entire body. It involves lymphocytes and lymphoid structures. INTRODUCTION: Lymphatic System COMPONENTS OF THE ADAPTIVE RESPONSE Cells involved in the adaptive response arise in the bone marrow. They differentiate from stem cells. Dendritic cells are the most important cells in the adaptive immune response. This is because: They have enormous surface areas. They take up and process antigens. They present antigens to T cells.

4 COMPONENTS OF THE ADAPTIVE RESPONSE David Scharf / Science Photo Library COMPONENTS OF THE ADAPTIVE RESPONSE Immature dendritic cells migrate from bone marrow into blood and tissues. They use phagocytosis and micropinocytosis to capture both self and nonself antigens. They eventually migrate to regional lymph nodes where they are responsible for: Presentation of antigens to lymphocytes. Triggering of adaptive response. COMPONENTS OF THE ADAPTIVE RESPONSE Dr Olivier Schwartz, Institute Pasteur / Science Photo Library

5 COMPONENTS OF THE ADAPTIVE RESPONSE Presentation of self antigens maintains tolerance. Presentation of nonself antigens sends signals to T cells. The adaptive response begins. DIFFERENTIATION AND MATURATION OF LYMPHOCYTES Common lymphoid precursor gives rise to: T cells B cells B cells can differentiate into plasma cells. Natural Killer cells DIFFERENTIATION AND MATURATION OF LYMPHOCYTES There are two types of T cell: Cytotoxic (Tc) Helper T cells

6 DIFFERENTIATION AND MATURATION OF LYMPHOCYTES There are two types of helper T cells: Th1 Th2 These activate the B cells and macrophages. T cells are naive until they encounter antigens. Co-stimulatory signals must also be present. DIFFERENTIATION AND MATURATION OF LYMPHOCYTES When B cells and T cells mature, they acquire specific antigen receptors. The B cell receptor is an immunoglobulin molecule. It has two antigen binding sites. The T cell receptor is similar to Ig. It has only one antigen binding site. DIFFERENTIATION AND MATURATION OF LYMPHOCYTES

7 DIFFERENTIATION AND MATURATION OF LYMPHOCYTES T cells mature in the thymus gland. B cells mature in the bone marrow. When mature, both circulate through the blood and tissues looking for antigens. STRATEGIC LYMPHOID STRUCTURES Strategic lymphoid structures are found in places where pathogens enter. GALT gut associated lymphoid tissue Examples include the tonsils, adenoids, appendix, and Peyer s patches. STRATEGIC LYMPHOID STRUCTURES Strategic lymphoid structures are found in places where pathogens enter. BALT bronchial associated lymphoid tissue Associated with the respiratory portal of entry Most available portal of entry

8 STRATEGIC LYMPHOID STRUCTURES Strategic lymphoid structures are found in places where pathogens enter. MALT mucosal associated lymphoid tissue Associated with mucous membranes An important portal of entry STRATEGIC LYMPHOID STRUCTURES Peyer s patches are the most important part of GALT. They contain M cells. M cells are antigen collecting cells. Under M cells are germinal centers. Filled with B cells Surrounded by T cells RELATIONSHIP BETWEEN INNATE AND ADAPTIVE IMMUNE RESPONSES The innate immune response deals with infection first. It must hold off infection until the adaptive response begins. It helps regulate the adaptive response via chemokines and cytokines. Innate response cells present antigens to the adaptive response.

9 DEVELOPMENT OF LYMPHOCYTE POPULATIONS Both B and T cells are formed in bone marrow. B cells mature there. There is always a supply of new B cells. T cells mature in the thymus. The thymus atrophies at puberty. T cells are long lived. Maturation requires specific signals. CLONAL SELECTION OF LYMPHOCYTES Clonal selection is the process by which some lymphocytes are destroyed and others are maintained. It takes place in the bone marrow for B cells and in the thymus for T cells. CLONAL SELECTION OF LYMPHOCYTES Precursor cells produce lymphocytes. Each lymphocyte is specific for a different antigen. Specificity is generated through genetic rearrangement. Clonal deletion is part of selection. Lymphocytes that react with self are deleted. The mechanism is not understood.

10 CLONAL SELECTION OF LYMPHOCYTES Lymphocytes that remain after clonal deletion mature. Each is specific for a nonself antigen. If an antigen is encountered, the lymphocyte is activated. It begins to divide and proliferate. It forms a clone of cells specific for one antigen. Lymphocytes that never encounter antigen eventually die. CLONAL SELECTION OF LYMPHOCYTES Three important points about clonal selection: It generates a vast number of different antigen receptors. Each receptor is specific for a different antigen. All progeny of that lymphocyte will have the exact same receptor. CLONAL SELECTION OF LYMPHOCYTES

11 SURVIVAL OF LYMPHOCYTE POPULATIONS: B Cells Millions of B cells are produced each day. Their survival depends on signals from peripheral tissues. These signals cause activation and proliferation or death. B cells that never get stimulated undergo apoptosis. SURVIVAL OF LYMPHOCYTE POPULATIONS: T Cells T cells get survival signals from two places: Specialized epithelial cells in the thymus These occur during development. Dendritic cells in peripheral lymphoid tissue SURVIVAL OF LYMPHOCYTE POPULATIONS: T Cells Once signaled, T cells stop migrating and become activated. They become larger and multiply. They multiply fourfold every 24 hours for 3-5 days. Each one can differentiate into an armed effector T cell. They can migrate into tissue or stay in the node.

12 SURVIVAL OF LYMPHOCYTE POPULATIONS: T Cells Some activated effector T cells eventually die. This is a safety precaution. Some will become memory cells. These respond very fast the second time an antigen is encountered. RESPONSES TO ANTIGEN FOR T OR B CELLS This requires a second co-stimulatory signal. This comes from innate response cells. No second signal causes lymphocyte inactivation anergy. RESPONSES TO ANTIGEN FOR T OR B CELLS After inactivation, lymphocytes cannot be reactivated. This is another safety measure. This is all part of tolerance.

13 LYMPHOID TISSUES Lymphocytes move through blood to the lymphoid tissues. T and B cells are found in specific locations. B cells are found in follicles. These are in the outer cortex. T cells surround follicles in paracortical areas. LYMPHOID TISSUES Lymphocytes circulate continuously through the lymphoid tissue. They either find their specific antigen or die. LYMPHOID TISSUES: B Cells B cells are constantly produced in the bone marrow. Most of them die when they reach the peripheral tissue. They are constantly replaced and therefore the number remains constant.

14 LYMPHOID TISSUES: T Cells T cells leave the thymus fully mature. They are produced in smaller numbers than B cells. T cells have a long life span. They are thought to be self-renewing in peripheral tissue. ANTIGEN PRESENTATION: MHC For presentation to occur, the antigen must be bound to the major histocompatibility complex (MHC). The MHC is found on antigen presenting cells. There are two types of MHC: Class I is found on all cells except immune cells. Class II is found only on immune cells. ANTIGEN PRESENTATION: T Cells T cell receptors must recognize both the antigen and the MHC. This is referred to as the antigen-mhc complex. There are two types of T cells: Helper T cells have CD 4 antigens. Cytotoxic T cells have CD 8 antigens.

15 ANTIGEN PRESENTATION: T Cell & MHC Interaction Cytotoxic T cells bind Class I MHC molecules. Helper T cells bind Class II MHC molecules. The MHC is a co-receptor. ANTIGEN PRESENTATION: Delivery Antigens are delivered by the MHC in different ways: Class I molecules associate with cytoplasmic antigens. They present to cytotoxic T cells. Class II molecules associate with antigens from phagocytic cell vesicles. They present to helper T cells. T CELL RESPONSE TO SUPERANTIGENS T cells can respond to superantigens. These are distinct classes of antigens produced by many pathogens. They provoke a response beneficial to the pathogen.

16 T CELL RESPONSE TO SUPERANTIGENS Superantigens do not need to be bound to the MHC to be recognized. They can bind to the outside of MHC molecules. They cause massive overproduction of cytokines. They cause systemic toxicity and suppression of the adaptive response. THE HUMORAL (B CELL) RESPONSE The humoral response is carried out by B lymphocytes. It involves the production of the antibody. In most cases, activation of B cells requires help from T cells. THE HUMORAL RESPONSE: Activation After activation: Some B cells proliferate and differentiate into plasma cells. Plasma cells produce massive amounts of antibody. Some B cells become memory cells.

17 THE HUMORAL RESPONSE: Antibodies Antibodies are found in the blood and in extracellular spaces. They contribute to the adaptive response in three ways: Neutralization Neutralizes toxins and viruses Prevents bacterial attachment (staying in) Opsonization Facilitates uptake of pathogens by phagocytic cells Complement Activates the classical pathway THE HUMORAL RESPONSE: Antibodies THE IMMUNOGLOBULIN MOLECULE Antigen receptors on B cells are called immunoglobulins (Ig). All Ig molecules have a Y shape. They are composed of 4 polypeptide chains. Two light chains Two heavy chains The 4 amino terminal ends make up the antigenbinding site. Remainders of the heavy chains make up the constant region.

18 THE IMMUNOGLOBULIN MOLECULE THE IMMUNOGLOBULIN MOLECULE: Binding Antibodies bind antigens. Binding: Is based on contacts between the antigen and binding site. Depends on the size and shape of the antigen. Binding is along the side of large antigens. THE IMMUNOGLOBULIN MOLECULE: Binding Antibodies are generally made against epitopes. Epitopes are small surface regions of antigens. Antibody binding involves hydrophobic and electrostatic forces. Hydrogen bonds are also involved.

19 IMMUNOGLOBULIN ISOTYPES There are 5 isotypes: IgG IgM IgA IgD IgE IMMUNOGLOBULIN ISOTYPES IMMUNOGLOBULIN ISOTYPES The constant region of any immunoglobulin has three main functions: Recognition by specialized receptors on phagocytic cells Forming antigen-antibody complexes that initiate classical complement pathway Delivering antibody to tissues and secretions

20 DISTRIBUTION AND FUNCTION OF IMMUNOGLOBULINS Most antibodies are distributed by diffusion. Some are distributed by specialized transport mechanisms. These are used to bring the antibody to the epithelial surfaces including: Digestive tract Lungs DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: IgM IgM is the first antibody to be produced. IgM can be in a pentamer structure. This has ten binding sites and great binding strength. It is usually found in blood. It is an excellent activator of the complement system. It is the primary response to bloodborne pathogens. It is also found in pleural spaces. This protects against environmental pathogens. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: IgG IgG, IgA, and IgE are all smaller than IgM. They can easily diffuse out of the blood. The principle isotype of IgG is found in the blood and extracellular fluid. It is very effective for opsonization and complement activation.

21 DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: IgA IgA is the principle antibody in secretions. It is found in the respiratory and digestive tracts. It is not very effective in activating the complement system. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: IgE IgE is found in low levels in the blood and extracellular fluids. It binds tightly to mast cells just below the skin and mucosa. It is also found along the blood vessels in connective tissue. After antigen binding, powerful chemical mediators are released. They cause coughing, sneezing and vomiting. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: IgD IgD is found in very small amounts in the blood. It is found on the surface of B cells. It is involved as an early antigen receptor.

22 DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Transcytosis Immunoglobulins can move across epithelial barriers transcytosis. It occurs most frequently with IgA. IgA is secreted as a dimer. It is held together by a J chain and a secretory piece. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Transcytosis DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Newborns IgA is found in colostrum. It is transferred from mother to child. It protects against newly encountered bacteria. Newborns also get maternal IgG for further protection. IgG can cross the placenta.

23 DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Bacterial Toxins IgG and IgA can neutralize bacterial toxins. They bind the toxin molecule and prevent it entering the cell. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Blocking Attachment IgG and IgA can block viral and bacterial attachment. IgA acts at the mucosal surfaces. IgG acts in tissues. DISTRIBUTION & FUNCTION OF IMMUNOGLOBULINS: Cell Activation Antibody can also activate the following cells: NK cells Basophils Mast cells Activation triggers the release of mediators. It is important in parasitic infections.

24 ACTIVATION OF BASOPHILS AND MAST CELLS BY IgE A substantial amount of IgE is bound to mast cells and basophils. When bound to antigen, antibody causes the release of histamine. This occurs in seconds. It causes an increase in blood flow vascular dilation. It promotes the movement of blood proteins and fluids in tissue. There is a following influx of neutrophils, macrophages, and lymphocytes. ACTIVATION OF BASOPHILS AND MAST CELLS BY IgE Photo courtesy of Ann Dvorak B CELL ACTIVATION BY T CELLS B cells have an antigen receptor that is a surface immunoglobulin molecule. The bound antigen is endocytosed and degraded. It is then combined with MHC class II and sent to the surface. The complex is recognized by helper T cells. The B cell is activated and differentiates into a plasma cell. It produces antibody against the antigen.

25 B CELL ACTIVATION BY T CELLS: Primary Response Naive B cells express both IgM and IgD on their surface. After activation, IgD disappears. IgM is the first isotype of antibody produced. This is the primary response. B CELL ACTIVATION BY T CELLS: Secondary Response Isotype switching occurs in the secondary response. IgM gives way to IgG. The secondary response occurs when the antigen is seen again. It is faster and more powerful than the primary response. Helper T cells regulate the production and isotype of antibody. B CELL ACTIVATION BY T CELLS: Primary and Secondary Response

26 T AND B CELL INTERACTION For the humoral response to work, each B cell must find a helper T cell. This is accomplished by trapping. Trapping occurs in the peripheral lymphoid tissue. T AND B CELL INTERACTION: Trapping Antigens are captured and processed by antigen-presenting cells (APCs). APCs migrate to lymph nodes and lodge in the paracortical areas. Naive T cells move through the node. If a T cell is presented with its antigen it is activated and remains trapped in the lymph node. T AND B CELL INTERACTION: Trapping B cells also pass through the paracortical areas. B cells are trapped if there is an activated T cell present. T and B cells cooperate in the paracortical area. B cells then move to follicular areas and differentiate into plasma cells.

27 PLASMA CELLS Plasma cells have a variety of life spans Some live for only a few days. Others live for significantly longer periods They receive survival signals from bone marrow stromal cells. THE CELLULAR (T CELL) RESPONSE The cellular immune response is generated by T cells. Cytotoxic T cells Helper T cells T cells that have not seen antigen are considered to be naive. After encountering antigen, both types become armed effector T cells. CYTOTOXIC T CELLS: Antigen Encounter Some antigens are degraded in the cytoplasm of infected cells. They are carried to the cell surface by class 1 MHC molecules. They are then presented to cytotoxic (CD8) T cells. Cytotoxic T cells proliferate and look for any cells also expressing that antigen. They will kill those cells.

28 HELPER T CELLS: Antigen Encounter Some pathogens multiply in intracellular vesicles and there are pathogens in extracellular fluid. Antigens from both are taken to the surface of the APC. They are coupled with MHC class II molecules. They are then presented to helper (CD 4) T cells. Helper T cells then differentiate into Th1 or Th2 cells. Th1 cells help with pathogens in vesicles. Th2 cells deal with extracellular pathogens. HELPER T CELLS PRODUCTION OF ARMED EFFECTOR T CELLS The arming of naive T cells can be done by: Dendritic cells Macrophages B cells

29 ARMING BY DENDRITIC CELLS Dendritic cells secrete chemokines. Chemokines attract naive T cells. Dendritic cells present viral, fungal, and bacterial antigens. They also participate in transplantation rejection and allergic reactions. ARMING BY MACROPHAGES Resting macrophages have few or no class II MHC molecules. After ingesting a microorganism, they produce more. They then degrade the microorganism and present antigen-class II MHC complex to T cells. This causes the release of co-stimulatory molecules. These allow the activation of T cells to continue. ARMING OF T CELLS BY B CELLS Surface immunoglobulin on B cells is an antigen receptor. It binds antigen and is internalized by endocytosis. Antigen is then bound to MHC class II molecules. The complex is moved back to the surface of the B cell. It is presented to T cells. This causes the release of co-stimulatory molecules.

30 ARMING OF T CELLS BY B CELLS PROPERTIES OF ARMED EFFECTOR T CELLS There are three classes of armed effector T cells: Cytotoxic Th1 helper Th2 helper Most of these move into the blood when they are activated. Cytotoxins are released by cytotoxic T cells. Cytokines are released by helper T cells. PROPERTIES OF ARMED EFFECTOR T CELLS

31 T CELL CYTOTOXICITY All viruses and some bacteria multiply in the cytoplasm of infected cells. Once inside a cell, pathogens are no longer susceptible to antibodies. Cytotoxic T cells kill infected cells by inducing apoptosis in the infected cell. They kill through cytotoxic granule release. T CELL CYTOTOXICITY Cytotoxic T cells are selective and repetitive killers of target cells. They cells also release cytokines (interferon and TNF). These are part of the innate immune response. MACROPHAGE ACTIVATION BY T CELLS Some bacteria proliferate in macrophages. They can be eliminated if the macrophage becomes activated. Th1 helper cells provide the activation signal. Activation increases the number of Class II molecules. This enhances antigen presentation and increases the adaptive response.

32 IMMUNOLOGICAL MEMORY Immunological memory is one of the most important properties of the adaptive immune response. It can be seen in both T cells and B cells and is produced after infection or vaccination. Memory is due to a persistent population of memory cells. Most are at rest but a small percentage is dividing at all times. Interleukins help to maintain the memory T cell population. MEMORY AND EFFECTOR T CELLS After activation, the number of T cells increases. As the infection subsides, the number decreases to a persistent level. This level is times higher than the initial number before activation. This increase is due to the increased number of memory cells. IMMUNITY TO INFECTION Innate and adaptive immune responses work together as fully integrated systems to defeat infection. The end result is the control and elimination of infection and protection from re-infection.

33 IMMUNITY TO INFECTION The innate response works primarily in the early stages of the infection. The adaptive immune response takes place a few days after first exposure to an antigen. Once pathogens have established an infection, it is only the adaptive response that can get rid of them. IMMUNITY TO INFECTION COURSE OF THE ADAPTIVE RESPONSE

34 MECHANISMS OF THE ADAPTIVE RESPONSE VACCINATION Vaccination is essentially an artificially derived infection. Weakened or dead pathogens are administered to a healthy individual with the intent of conferring immunity. In many case, antigen is derived from the toxin produced by the pathogen. Most vaccinations are administered in childhood. VACCINATION There can be risks with vaccinations. Some vaccines can contain adjuvants, which are chemicals designed to boost immune response. In some people, adjuvants and some preservatives in vaccines can cause adverse reactions. Vaccines composed of weakened pathogens may cause a small percentage of vaccinated individuals to become infected.