Chapter 22: The Lymphatic System and Immunity Introduction Immune system the body s defenses against pathogens that produce disease 2 types of immunity Nonspecific immune mechanisms (Innate immunity) Provide general protection against invasion by a wide range of pathogens Innate present at birth Specific immune mechanisms (Adaptive immunity) Specific lymphocytes combat particular pathogens Overview of the body s defenses Innate immunity Adaptive immunity Summary of Nonspecific Defenses First line of defense: external barriers Skin Mucous membranes Secretions - inhibit growth of microbes Lysozyme, gastric acid, sebum Three cooperative lines of defense protect us from pathogens When external barriers fail The body s second line of defense Inflammation: a second-line defense When tissue is damaged, the body responds with a coordinated set of nonspecific defenses called the inflammatory response Neutrophils and macrophages surround and kill the pathogens (phagocytosis) Inflammation is usually recognized by its four hallmark symptoms Redness, heat, swelling, pain
Specific Defenses The immune system Consists of a large collection of cells that work together to respond to infection. Attacks specific kinds of invading microbes and cancer cells Bacteria, toxins, viruses, foreign tissues Outcome: the body is able to defend itself against specific invading agents Specific defenses Two properties distinguish specific from nonspecific defenses Specificity for particular foreign molecules () Memory for previously encountered So that a 2nd exposure prompts a rapid and strong response Vocabulary Antigens (Ag) Are foreign substances that elicit an immune response. Antibodies (Ab) Are proteins found in blood plasma that recognize a particular and help counter its effects. Specific defenses: lecture outline The basics: B and T cells Maturation of T cells and B cells T cell and B cell receptors Antigen recognition Clonal selection Antibody-mediated immunity Specific defenses: the basics Major players in the immune system Depend on the action of B and T cells Basic concepts: Immunologic memory - here? Lymphocytes White blood cells that produce the immune response Specific immunity depends on the action of B cells and T cells B cells Secrete antibodies Directed against extracellular pathogens (bacteria and viruses) T cells Differentiate into helper T cells or cytotoxic T cells Directed against Copyright intracellular 2009, John Wiley pathogens, & some cancer cells and tissue transplants
Maturation of T cells and B cells Both develop from stem cells in bone marrow B cells complete their development in bone marrow T cells develop from pre-t cells that migrate to the thymus B cells and T cells are named based on where they mature Maturation of B cells and T cells During maturation, T cells and B cells become immunocompetent and acquire distinctive surface proteins Some function as receptors, proteins that recognize specific Others are specific cell surface proteins (markers) Helper T cells (CD4 protein) Cytotoxic T cells (CD8 protein) Types of Specific Immunity Recognizing the invader Destruction of by T cells Particularly effective against intracellular pathogens, some cancer cells and foreign tissue transplants CMI always involves cells attacking cells Antibody-mediated immunity Destruction of by antibodies B cells make antibodies (Abs) Antibodies recognize extracellular pathogens, primarily viruses, bacteria or fungi 2 types of immunity work together Helper T cells aid in both types of immunity Antigen receptors on the surface of a lymphocyte can bind to only one specific type of Mature B and T cells can recognize a specific and mount an immune response to it One cell may recognize an on the mumps virus, another an on an E. coli bacterium Specificity of receptors Antigens foreign substances Many B and T cells with different receptors develop in each person, but only a tiny fraction will ever be used. Antigens have 2 characteristics Immunogenic able to provoke immune response Reactive able to react specifically with antibodies it provoked Antigens are large, complex molecules Entire microbes may act as Typically, small parts of molecules (or epitopes) trigger immune responses Pathogen Recognition in a Macrophage Cell http://www.youtube.com/watch?v=cl9ky_eczfo&feature=related
Responding to the invader In most cases, when a pathogen enters the body there is only a small group of B and T cells with the correct receptors to respond But there are many copies of the pathogen Lymphocytes proliferate and differentiate form a population of identical cells, called a clone, that recognize a specific Process is called clonal selection Clonal selection Process by which immune cells proliferate and differentiate in response to a specific Clone population of identical cells that recognize the same Clonal selection thousands of lymphocytes that respond to the Clonal selection When an gets past the non-specific defenses Two types of cells result from clonal selection: Effector cells do the work to destroy the Include helper T cells, cytotoxic T cells, plasma cells die after immune response Memory cells respond to 2 nd invasion by proliferating and differentiating into effector cells long life spans Pathogens take 3 routes into lymphatic tissue If they enter the blood stream, they re trapped as they flow through the spleen If they penetrate the skin, they enter lymphatic vessels and lodge in lymph nodes If they penetrate mucous membranes, they re trapped by mucosa-associated lymphatic tissue (MALT) Diversity of receptors Human immune system is able to recognize and bind to at least a billion different epitopes Due to equally large diversity of receptors Results from genetic recombination shuffling and rearranging a few hundred versions of several small gene segments Major Histocompatibility Complex (MHC) Self- located in the plasma membrane of body cells unique to each person Function: to help T cells recognize foreign or self all body cells except RBCs display MHC Class I Some cells also display MHC Class II
Pathways of processing In immune responses, B and T cells must recognize that a foreign is present B cells bind to in extracellular fluid T cells must be presented with processed T cells only recognize fragments of ic proteins that have been processed and presented in association with MHC self- Pathway of processing depends on whether the is outside or inside body cells Processing of found outside the cell Exogenous found in extracellular fluid Bacteria, toxins, parasitic worms, inhaled pollen Antigen-presenting cells (APCs) process and present exogenous APCs include macrophages, B cells, dendritic cells Immune responses occur primarily in the lymph nodes and spleen, which contain large numbers of APCs Exogenous APCs process and present extracellular Phagosome or endosome Antigenpresenting cell (APC) 1 Phagocytosis or endocytosis of 2 Digestion of into peptide fragments APC 5 4 3 Vesicles containing peptide fragments and MHC-II molecules fuse 6 Packaging of MHC-II molecules into a vesicle Synthesis of MHC-II molecules Antigen peptide fragments bind to MHC-II molecules Endoplasmic reticulum Key: Vesicle undergoes exocytosis and MHC-II complexes are inserted into plasma membrane APCs present exogenous in association with MHC-II molecules 7 Antigen peptide fragments MHC-II self- Presenting extracellular After processing the, the APC migrates to lymphatic tissue to present the to T cells. Triggers an immune response Processing found inside the cell Processing and presenting endogenous Endogenous e.g. viral proteins from virus-infected cells, abnormal proteins synthesized by cancer cells, toxins made by intracellular bacteria Most cells of the body can process and present endogenous Infected cells present the endogenous in association with MHC-I molecules
Presenting endogenous The display of an endogenous bound to MHC-I signals that a cell has been infected Antigen presentation APCs encounter the foreign invader and present the invader's to a group helper T cells (T H cells). APCs first engulf an invader, break it apart into its and move these to the cell surface. Each T H cell has a different receptor, allowing it to recognize a different. The APC "shows" the to T H cells until there is a match between a T H cell receptor and the. T cell activation The contact between the APC and T H cells stimulates the T H cell to divide rapidly. This is called clonal selection because only the T H cells that recognize the are selected to reproduce. Stimulated T H cells also produce chemical messengers called cytokines. Cytokines control the immune response. Cytokines Small protein hormones that help control the immune response needed for many normal cell functions Examples of cytokines (see Table 22.2 in Tortora) Interleukins (IL-1, IL-2, IL-4, IL-5) Tumor necrosis factor (TNF) Interferons Test your understanding What is the immune system? What is its function? It s a large collection of cells that presents coordinated, specific responses to infection What is an? A molecule that elicits an immune response Name some examples Proteins on the surface of bacteria and viruses Pollen Dust
What are the 2 main types of lymphocytes? B cells Secrete antibodies Fight extracellular pathogens (bacteria, viruses) T cells Differentiate into helper T cells or cytotoxic T cells Directed against intracellular pathogens, some cancer cells and tissue transplants Test your understanding How does the body produce enough B cells to fight off a major infection? The process of clonal selection causes those few B (or T) cells that are complementary to the of the pathogen to multiply. Specific defenses Antibody-mediated immunity T cells respond to pathogens that have already entered body cells T cells directly attack diseased cells and cancer cells Main types of T cells Helper T cells Cytotoxic T cells Memory T cells In a cell-mediated immune response: an is recognized specific T cells proliferate and differentiate into a clone of effector cells T H and T C cells that recognize the same and carry out an immune attack the (pathogen) is eliminated Steps in a cell-mediated immune response Activation of T cells Activation and clonal selection (proliferation) of helper T cells Activation and clonal selection of cytotoxic T cells Elimination of invaders
Activation of T cells Two signals: T-cell receptors recognize and bind to fragments associated with MHC molecules on the surface of a body cell Co-stimulation by cytokines Interaction of proteins on the surface of the T cell and APC Activated helper T cell Clonal selection and proliferation of helper T cells The cell is activated and undergoes clonal selection Proliferation and differentiation Forms clones of active helper T cells memory helper T cells Roles of activated helper T cells Proliferation Activation and clonal selection of cytotoxic T cells Cytotoxic T cells Display CD8 protein Recognize combined with MHC-I Once a cytotoxic T cell is activated, it forms clones of Active cytotoxic T cells attack infected body cells Memory cytotoxic T cells long-lived Elimination of foreign invaders by cytotoxic T cells T C cells leave lymphatic tissue to seek out and destroy infected target cells, cancer cells and transplanted cells. They recognize and attach to target cells, and deliver a lethal hit that kills the target cells Elimination of foreign invaders by cytotoxic T cells Cytotoxic T cells kill infected body cells Target cells bear the same that stimulated activation of the progenitor T cells Cytotoxic T cells have a specific receptor for particular microbe NK cells destroy a wide variety of microbe-infected cells After delivering a lethal hit, a cytotoxic T cell can attack another infected cell displaying the same The only T cells that actually kill other cells
Activity of cytotoxic T Cells Two mechanisms for killing infected target cells Perforins punch holes in target cells and trigger cytolysis Release granzymes that trigger apoptosis After killing the target cell, a cytotoxic T cell can detach and attack another infected target cell displaying the same Cytotoxic T cell vesicle perforin Perforin forms hole in target cell. Granzymes enter through the hole and cause target cell to Target cell undergo apoptosis. cytotoxic T cell granzyme target cell (virus-infected or cancer cell) How are natural killer cells different? Cytotoxic T cells kill infected target body cells much like natural killer cells do What s the difference? Cytotoxic T cells have a specific receptor for particular microbe NK cells destroy a wide variety of microbe-infected cells Nonspecific Cell mediated immunity 2:50 http://www.youtube.com/watch?v=asprpf1ny9a Immunological surveillance Immune response to cancer cells that display novel cell surface proteins called tumor If the immune system recognizes a tumor as nonself, it destroys the cell carrying the Tumor displayed on cancerous cells are targeted by cytotoxic T cells, macrophages and natural killer cells T C cells also recognize proteins in transplanted organs as foreign and mount a tissue rejection Test your understanding What are the two main types of T cells and what does each do? Helper T cells stimulate body defenses. Cytotoxic T cells destroy infected cells. Test your understanding How do cytotoxic T cells recognize and kill infected target cells? Recognize surface combined with MHC-I Kill infected cells by releasing granzymes and perforins