2) Macrophages function to engulf and present antigen to other immune cells.

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1 Immunology The immune system has specificity and memory. It specifically recognizes different antigens and has memory for these same antigens the next time they are encountered. The Cellular Components of the Immune System are: 1) Lymphocytes a) B cells function to secrete antibodies b) Cytotoxic T cells function to kill virus-infected cells and cancerous cells c) T Helper cells function to help other immune cells by secreting interleukins. Interleukins stimulate cellular proliferation and cellular differentiation 2) Macrophages function to engulf and present antigen to other immune cells. Antibodies and Antigens Substances that invade the body, be they living pathogens or inanimate chemicals, "look" different, at the molecular level, as compared to the structures of the body itself. The structures of the invader that look foreign will induce an immune response designed to eliminate the invader. These foreign structures are collectively called antigens (Ag). We can formally define an antigen as any substance that elicits an immune response against itself. Antibodies One of the most powerful defenses against foreign invaders is the activity of antibodies. Antibodies help to eliminate foreign antigens from the body. When antibodies bind to their specific antigens they mark those antigens for destruction by macrophages. Macrophages recognize, engulf and digest antigens only when bound to antibodies. This is the most potent means by which antibodies clear antigens from the body. Characteristics of antibodies they are protein molecules composed of 4 polypeptide chains ( 2 light chains, 2 heavy chains) each antibody has a constant region and a variable region all antibodies have a similar constant region, but each has a unique variable region the antigen binding site is part of the variable region each antibody has 2 antigen binding sites, it is called bivalent each antibody specifically binds to one type of antigen the specificity of antigen-antibody binding is due to shape complementarity (lock and key) once an antibody is bound to an antigen then the constant region signals macrophages to engulf and destroy the antigen. 1

2 Antibody-Mediated Immunity Antibodies are produced by B lymphocytes (B cells). Each B cell produces a uniquely shaped antibody capable of recognizing a particular antigen. Each individual has millions of unique B cells. B cells only become activated when they bind to antigen. Antigen binding occurs on B cell receptors, which are simply membrane-bound antibodies. Activated B cells produce tremendous amounts of their specific antibody and secrete the antibodies into the blood stream. Circulating antibodies bind antigen and initiate antigen clearance. Clonal Selection Theory The best explanation for the acquisition of immunity is provided by clonal selection theory. This theory, for which there is much evidence, suggests that B cells that encounter their specific antigen undergo rapid cell division to produce a large clonal population of identical cells (clonal expansion). Furthermore, this population differentiates into two distinct cell types; one type, called plasma cells, acts to immediately eradicate the antigen by secreting antibodies, and another type, called memory cells, remain quiescent (inactive) until the antigen is encountered again in the future. The Steps of Clonal Selection: 1. Activation B cell binds antigen (Ag) B cell is stimulated by growth factors (interleukins) 2. Proliferation B cells divide rapidly (clonal expansion) 3. Differentiation Half the B cell population becomes plasma cells that secrete soluble antibodies into the blood and the lymph Half become memory cells, which wait until the next encounter with the antigen to become activated 2

3 Immunologic Memory - The Primary and Secondary Responses When naive lymphocytes are exposed to specific antigens for the first time they become activated and then differentiate into effector and memory cells. This is called the primary response. The primary response is relatively weak and slow due to the fact that there are few lymphocytes capable of recognizing the antigen and it takes time for them to proliferate into a population large enough to eradicate the foreign antigen. The second time the body is exposed to the same antigen, the immune system mounts a much larger and faster response. This is called the secondary response. Memory cells are long-lived and thus represent a large population of lymphocytes capable of specifically recognizing the original antigen. If this antigen is encountered again, the secondary response is strong and rapid due to the large population of memory cells that recognize the antigen. Mechanism of Antibody Activity We have now talked about antibody specificity and the means by which antibodies are produced, but we have yet to discuss the mechanisms by which antibodies combat pathogens and other foreign invaders. Antibodies, secreted by B cells, enter the blood stream and the lymph sustem and travel throughout the body in search of the pathogen. Antibodies do not directly destroy pathogens, rather they bind to antigens on the surface of the pathogen and, in doing so, tag the pathogen for destruction by macrophages. Upon binding of antibodies to antigen the Fc region of the antibody changes it shape such that it becomes recognizable by macrophages. Macrophages have receptors on their cell membrane that bind the Fc region of antibodies attached to antigens. Macrophages "see" structures decorated with antibodies as foreign, bind to them, engulf them by phagocytosis, and destroy them with lysosomal enzymes. This mechanism, by which antibodies tag antigens for destruction by macrophages, is called opsonization. 3

4 Cell-Mediated Immunity Cytotoxic T cells (Killer T cells) recognize and destroy virus-infected cells. When a cell becomes infected with virus, some of the viral proteins are complexed (combined) with Class I MHC proteins. This antigen-mhc complex is then presented on the surface of the infected cell, bound to the plasma membrane. In this way the infected cell informs the immune system that it has been infected by virus. Cytotoxic T cells have receptors that recognize and bind to antigen-mhc complexes. A given cytotoxic T cell has only one type of receptor. However, each person has millions of unique cytotoxic T cells that differ from one another in the nature of their receptors. For any given antigen-mhc complex there will exist, in the immune system, some cytotoxic T cells capable of recognizing that particular complex. Binding of a cytotoxic T cell to an antigen-mhc complex leads to activation of the T cell. When activated, cytotoxic T cells secrete chemicals (such as perforins) that kill the virus-infected cell, thus limiting the spread of infection. Cytotoxic cells are also capable of recognizing and destroying cancerous cells. Immune surveillance of the body is thought to be an important mechanism for limiting the growth of cancers Similar to B cells, cytotoxic T cells undergo clonal expansion and differentiation when they become activated. Activation requires the binding of the cytotoxic T cell receptor to the MHC/Ag complex and further stimulation by IL-2 (secreted by T helper cells). The expanded cytotoxic T cell population differentiates into effector cells that engage and destroy virus-infected cells, and memory cells that remain quiescent until the next encounter with the antigen. 4

5 T Helper Cell Activation T Helper cells secrete IL-2 (and many other cytokines) and thus help to stimulate both antibodymediated and cell mediated immunity. Helper T cells secrete IL-2 only after being activated. Activation of T helper cells is mediated by antigen-presenting cells such as B cells and macrophages. Macrophages recognize and engulf foreign antigen (for example, a virus). Proteins from this antigen are then complexed with Class II MHC molecules. This antigen-mhc complex is then presented on the surface of the cell, bound to the plasma membrane. In this way, the macrophage informs the immune system that it has captured a foreign antigen and shows the immune system s T helper cells what the antigen looks like. Helper T cells have receptors that recognize and bind to antigen-mhc complexes. A given helper T cell has only one type of receptor. However, each person has millions of unique helper T cells that differ from one another in the nature of their receptors. For any given antigen-mhc complex there will exist, in the immune system, some helper T cells capable of recognizing that particular complex. Binding of a helper T cell to an antigen-mhc complex leads to activation of the T cell. When activated, helper T cells secrete IL-2 (and other cytokines). IL-2 helps to activate both B cells and Cytotoxic T cells. 5

6 Lymph System The lymph system plays a major role in the production and activity of immune system cells. The lymph system is divided into primary and secondary lymph organs. Primary Lymph Organs a) Bone marrow. All immune system cells originate from the bone marrow. b) Thymus. The T cells are derived from the bone marrow, but complete their maturation in the thymus. Secondary Lymph Organs a) Lymph nodes, which are packed with B cells, T cells and macrophages, screen the lymph fluid for the presence of foreign antigen. b) The spleen also contains immune system cells and functions to screen the blood for the presence of foreign antigen. c) Tonsils are packed with lymphocytes and macrophages. They are exposed to inspired air and ingested food via open channels (crypts) to the throat. They function to screen inspired air and ingested food for the presence of foreign antigen. 6

7 Vaccines Vaccines are designed to provide active immunity against virulent (disease causing) pathogens. A vaccine is typically a killed or weakened form of the pathogen itself. A vaccine provides immunity because it looks like the pathogen, but it does not cause disease because it has lost its virulence. History of Small Pox Vaccination Small Pox can be very virulent, up to 50% of infected people die depending on the strain. Survivors are scarred, but become immune to further disease. In 12 century China, risk takers would seek out mild cases and sniff powdered sores. In 17 century Europe, risk takers would soak thread in sores and poke the thread into their skin. In 1796, Edward Jenner observed that infection with cow-pox resulted in immunity to small pow. He carried out the following experiment : The French mockingly called Jenner s procedure Vaccination, which meant encowment. A small pox vaccination program was started in the 1960s by the world health organization. This program has successfully eradicated small pox virus from the planet. 7

8 Types of Vaccines 1) Killed The virus or bacterium is killed with heat or chemicals, but retains its overall conformation and immunogenicity. Advantage: can t mutate into a virulent pathogen because its dead Disadvantage: It must be injected because the stomach would destroy it. You need large amounts because it can t replicate in the body example: Salk vaccine for polio 2) Live-attenuated Live virus that does not cause disease, but looks like disease-causing strain, thus provides immunity. Advantage: Can be taken orally. Need small amount because it replicates. Disadvantage: It could mutate to become virulent example: Sabin vaccine for polio, or the new chicken pox vaccine 3) Subunit vaccine This is typically a surface protein derived from the pathogen (thus is only part of the pathogen). Advantage: It can t mutate to be virulent. It s the last resort vaccine for pathogens that can t be cultured in the lab Disadvantage: It must be injected because the stomach would destroy it. You need large amounts because it can t replicate in the body. It s a single protein so immune response is limited. example: hepatitis B vaccine 4) Recombinant vaccines This futuristic vaccine could immunize a person against as many as 10 pathogens with a single dose. It would be a live virus capable of expressing antigens from several other pathogens. 8