43 The Immune System: Internal Defense Lecture Outline I. Nonspecific and specific immunity: an overview A. Overview 1. An immune response is the process of recognizing foreign macromolecules and responding to eliminate them 2. Nonspecific responses provide general protection against pathogens, parasites, some toxins and drugs, and cancer cells a) The cuticle or skin is a barrier b) Phagocytosis destroys bacteria c) Various molecules are involved as well 3. Specific immune responses are highly specific a) The immune system recognizes foreign antigens b) Antibodies are proteins that recognize and bind specific antigens c) Immunological memory is an important characteristic B. Invertebrates make mainly nonspecific immune responses 1. All invertebrates studied to date can distinguish between self and nonself 2. Nonspecific defense mechanisms include phagocytes and the inflammatory response 3. Antimicrobial peptides inactivate or kill pathogens 4. Animal cells have signaling receptors, the Toll group, which recognize molecular features of pathogens called pathogen-associated molecular patterns (PAMPs) 5. Some invertebrates have demonstrated immunological memory C. Vertebrates launch both nonspecific and specific immune responses 1. A specialized lymphatic system allows more complicated immunological responses 2. Only vertebrates have true lymphocytes II. Nonspecific defense responses involve a variety of molecules and cells A. The skin is the first defense against pathogens 1. Sweat and sebum contain antibacterial chemicals 2. Lysozyme in tears and other fluids is a defense against gram-positive bacteria 3. Enzymes and stomach acid destroy ingested pathogens 4. Nose hairs and respiratory mucous trap inhaled pathogens that are then phagocytized B. Soluble molecules destroy pathogens 1. Cytokines, regulatory proteins, act in a variety of ways a) Interferons are produced by macrophages in response to infection by intracellular parasites like viruses (1) Neighboring cells then produce proteins that interfere with viral replication (2) Recombinant interferon has been used to treat hepatitis B and C, genital warts, and other diseases b) Interleukins are secreted by macrophages and lymphocytes and are named in order of their discovery (1) IL-1 induces fever by acting on the hypothalamus c) Chemokines attract, activate, and direct the movement of various cells of the immune system d) Tumor necrosis factors (TNF) are cytokines that are important in the inflammatory response (1) TNFs also kill tumor cells, but may also be involved in some potentially harmful immune responses 2. Complement leads to the destruction of pathogens a) Complement is a set of plasma proteins that complements the action of other defense mechanisms b) Complement is typically inactive until exposed to antigens c) Complement action is a non-specific defense mechanism, and acts in a variety of ways C. Phagocytes and natural killer cells destroy pathogens 1. Inflammation leads to phagocytosis, particularly by neutrophils and macrophages, which can engulf large numbers of bacteria before being inactivated 2. Vertebrate macrophages have Toll-like receptors that recognize certain PAMPs 3. Natural killer (NK) cells account for about 15% of circulating lymphocytes a) NK cells are large, granular lymphocytes closely related to T cells b) NK cells attack a wide variety of infected cells and tumor cells c) NK cells function without prior exposure and do not require presentation of antigens d) NK cells produce cytokines, perforins, and various enzymes D. Inflammation is a protective response 1. Injured cells and basophils release histamines that dilate blood vessels 2. Increased blood flow increases the temperature of the affected area, brings increased numbers of phagocytes, and causes redness 3. Histamines make the capillaries more permeable, and phagocytes leave the blood vessels 4. The leaky blood vessels also release plasma, causing edema and accompanying pain 5. Inflammation is often simply a local response, but fever is a widespread inflammatory response a) Fever interferes with the growth of some bacteria and increases the activity of certain lymphocytes III. Specific immune responses include antibody-mediated and cell-mediated immunity E. Lymphocytes are the principal warriors in specific immune responses 1. The three types of lymphocytes are T lymphocytes (T cells), B lymphocytes (B cells), and natural killer (NK) cells 2. T cells are responsible for cell-mediated immunity 3. B cells are responsible for antibody-mediated immunity a) B cells mature into plasma cells that produce antibodies, which bind specific antigens and either neutralize them or mark them for destruction 4. All lymphocytes are produced in the bone marrow a) B cells complete their development in the bone marrow b) T cells mature in the thymus gland 5. Each B cell has a specific glycoprotein receptor a) Binding of a specific B cell with a specific antigen activates the B cell b) The activated B cell divides, forming plasma cells that produce soluble antibodies c) The antibodies bind to the antigen that originally activated the B cell d) Some B cells become long-living memory cells that continue to produce small amounts of antibodies 6. T cells are responsible for cellular immunity, originate from stem cells in the bone marrow, and become immunocompetent in the thymus gland a) Only T cells that possess particular receptors are selected to divide, hence this is an example of positive selection b) T cells that react to self-antigens undergo apoptosis, which is a form of negative selection c) They may be identified by their T cell antigen receptor (TCR) d) CD8 cells include cytotoxic T and suppressor T cells (1) Cytotoxic T cells (Tc), also called killer T cells, recognize and destroy cells with foreign antibodies (a) Their targets are virus-infected cells, tumor cells, and foreign tissue (b) Their action is via release of cytokines and various enzymes e) T helper cells are called CD4 cells because of CD4 marker molecules (1) T helper cells are regulatory cells F. Antigen-presenting cells activate T helper cells 1. Macrophages, dendritic cells, and B cells function as antigen-presenting cells (APCs) 2. Once an APC is activated, it ingests a pathogen and displays fragments of the foreign antigen on its surface 3. The APC then presents these antigens to T cells 4. Dendritic cells develop from monocytes and are specialized to process, transport, and present antigens to T cells G. The major histocompatibility complex permits recognition of self 1. The MHC is a complex of membrane proteins; in humans the MHC is called the HLA (human leukocyte antigen) group 2. A group of polymorphic genes codes for the HLA group; there may be over 40 alleles for a given gene a) Therefore, it is unlikely that any two persons, except identical twins, would ever have identical MHC proteins 3. MHC class I antigens are on most nucleated cells and aid in differentiating between self and nonself a) These antigens bind to foreign antigens, and this complex is recognized by cytotoxic T cells b) MHC class II antigens are only found on certain cells of the immune system and interact with T, B, and antigen-presenting cells c) MHC class III proteins include components of the complement system IV. Cell mediated immunity H. The T cells and APCs are responsible for cell-mediated immunity 1. When a virus infects a cell, viral antigens are displayed on class I MHC molecules 2. The binding of a specific cytotoxic T cell with this complex activates the T cell and causes it to divide into a clone 3. Cytotoxic T cells leave the lymph nodes and move to the site of infection 4. Cytotoxic T cells secrete proteins that destroy the target cell V. Antibody-mediated immunity I. B cells produce a specific antibody that can combine with a specific antigen 1. The binding activates the B cell in a complex process that involves macrophages (presenting antigens), helper T cells, or dendritic cells 2. A macrophage displaying a foreign antigen-MHC complex secretes interleukins, which activates helper T cells 3. The B cell binds with the complementary antigen and displays it with a class II MHC protein 4. The B cell grows, divides and forms a clone, known as clonal selection 5. Some of the clone mature into plasma cells, which produce an antibody specific to that antigen 6. The B cells remain in the lymph nodes, but the antibodies pass out into the lymph and ultimately the blood 7. Some activated B cells become memory cells and avoid the programmed death a) These memory cells produce small amounts of antibody, which becomes part of the gamma globulin fraction of the blood b) Memory cells can become effective plasma cells if re-exposed to the same antigen at a later time J. A typical antibody consists of four polypeptide chains 1. Antigenic determinants, or epitopes, are specific sequences of amino acids 2. Antibodies are typically Y shaped proteins 3. The portion of the antibody that binds to the antigen is the Fab section 4. The portion of the antibody that interacts with other cells of the immune system is the Fc section 5. The four polypeptide chains consist of two identical heavy chains and two identical short chains a) Each chain has a constant segment (C region) that is the same among any class of immunoglobulin b) Each chain has a junctional segment (J region) that is somewhat variable c) Each chain has a variable segment (V region) that is unique (1) The V region is like the lock for a specific antigen, as it folds 3- dimensionally K. Antibodies are grouped in five classes 1. Antibodies are immunoglobulins (IG) 2. IgG makes up about 75% of human immunoglobulins, and is part of the gamma globulin fraction of the blood a) IgG and IgM interact with macrophages and activate the complement system b) IgA is present in other body fluids, such as mucus, tears, saliva, and milk and prevents pathogens from attaching to epithelia c) IgD is present in low concentrations, and with IgM is important in the function of B cells d) IgE is important in immunity to parasitic worms and release of histamines L. Antigen-antibody binding activates other defenses 1. The antigen-antibody complex may inactivate the pathogen or its toxin 2. The antigen-antibody complex stimulates phagocytic cells to ingest the pathogen 3. Antibodies of IgG and IgM work through the complement system to more easily destroy the pathogen M. The immune system responds to millions of different antigens 1. Although each human cell has a large amount of DNA, it is not enough to provide a different gene to code for each of the possible antibodies 2.An immunoglobin has three regions (V, C, and C), each encoded by separate families of genes 3. During development of the B cell, rearrangement of these DNA segments produces an enormous number of potential combinations N. Monoclonal antibodies are highly specific 1. Monoclonal antibodies were developed in the 1970s 2. They are produced by injecting mice with an antigen followed by harvesting B cells; The B cells are fused with a culture of cancerous interest, cells, allowing the resulting hybridomas to live indefinitely 3. Monoclonal antibodies are pure and specific and have a myriad of uses in medicine and therapies VI. Long-term immunity depends on immunological memory O. A secondary immune response is more rapid than a primary response 1. The primary response results in antibodies produced within 3-14 days of exposure a) IgM is the primary antibody produced during the primary response, peaking during the logarithmic phase b) The antibody production declines after the infection is suppressed 2. The secondary response occurs after the second exposure to the same antigen, as memory cells may last throughout the entire life of a person a) The secondary response is a rapid, effective response b) Developing a second cold or flu is due to exposure to a slightly different strain of the bacterium or virus to which there are no specific memory cells or antibodies P. Active immunity can be induced with immunization 1. A vaccination causes production of the appropriate antibodies and memory cells a) Viruses may be attenuated so that they do not cause diseases after administration of a vaccine b) Some vaccines are killed pathogens or are derived from bacterial toxins c) DNA vaccines are in clinical trials Q. Passive immunity is borrowed immunity 1. Passive immunity is the acquisition of antibodies produced by the immune system of another organism 2. The effects are less long lasting, but include injections of gamma globulin and the immunity conferred to babies in the uterus (primarily IgG) or via nursing (primarily IgA) VII. Many factors compromise the immune system, leading to disease R. Cancer is a failure in immunosurveillance 1.Dendritic cells, NK cells, and cytotoxic T cells are central in defending against cancer cells 2. The immune system must make varied responses to the hundreds of types of cancer 3. Monoclonal antibodies and vaccines are promising new treatments for cancer 4. DNA microarrays are used to detect gene expression in cancer cells S. Immunodeficiency disease can be inherited or acquired 1. Absence or failure of some component of the immune system can result in immunodeficiency disease and increase susceptibility to infection 2. In DiGeorge syndrome the thymus is reduced or absent and results in a deficiency of T cells 3. Severe combined immunodeficiency syndromes (SCIDs) are sex-linked and autosomal disorders that result in multiple infections T. HIV Is the major cause of acquired immunodeficiency 1. HIV was first isolated in 1983 2. More than 38.6 million adults and 3.2 million children are infected worldwide 3. AIDS is caused by HIV 4. Immunosuppression is caused by HIV destruction of helper T cells 5. AIDS is transmitted by semen, blood, or other bodily fluids 6. AIDS begins with various unusual opportunistic diseases, and may end with AIDS dementia 7. HIV enters a helper T cell by attaching to the CD4 membrane protein 8. AZT is a drug that is used to treat AIDS, and acts by blocking reverse transcriptase, necessary for viral replication 9. Protease inhibitors are a more promising, recently developed treatment VIII. Immune responses are sometimes inconvenient or harmful U. Hypersensitivity is an exaggerated allergic reaction V. Graft rejection is an immune response against transplanted tissue 1. Tissues and organs from a donor have different MHC antigens, which provoke graft rejection by the T cells 2. Tissue typing allows close matches of MHC antigens 3. If close matching is not possible, immunosuppressive drugs are administered 4. Certain sites in the body are immunologically privileged a) The brain and cornea, for example, lack circulatory vessels and so have little or no access to lymphocytes W. Rh incompatibility can result in hypersensitivity 1. Rh incompatibility is probably the most important maternal-fetal blood type incompatibility a) If a woman is Rh-negative and the father of the fetus is Rh-positive the fetus may be Rh-positive b) The fetus's red blood cells activate the mother's white blood cells, stimulating them to produce anti-D antibodies c) This may can the disease erythroblastosis fetalis, which results in the destruction of many fetal red blood cells and death of the fetus X. Allergic reactions are directed against ordinary environmental antigens 1. Allergens are mild antigens that only trigger immune responses in some individuals 2. Allergic asthma or hay fever is seen in about 20% of the population of the United States 3. The first step is sensitization; macrophages degrade the allergen and display it to the T cells 4. T cells become activated and stimulate B cells to become plasma cells and produce IgE 5. Mast cells are activated by the allergen binding to the IgE on the mast cells a) Mast cells release histamine and seratonin that result in inflammation 6. The mast cells attract white blood cells to the inflamed area, which further damage tissue and promote the allergic response 7. Systemic anaphylaxis, which results in widespread vasodilation and may lead to death, occurs after development of an allergy 8. Allergic reactions are often treated with antihistamines, which block histamines Y. In an autoimmune disease the body attacks its own tissues 1. Autoimmune diseases are hypersensitivities to antigens of self 2. Autoimmune diseases include rheumatoid arthritis, multiple sclerosis, a form of lupus, insulin-dependent diabetes, psoriasis, and others 3. Autoimmune diseases seem to have a genetic link, and perhaps are triggered by a viral or bacterial infection Research and Discussion Topics Investigate a particular autoimmune disease. Describe the disease symptoms, treatments, and suggested causes. Subjects on which students should find sufficient research material: insulin-dependent diabetes, multiple sclerosis, lupus, psoriasis. Discuss what is known on the activity of the complement system. How do these proteins aid in suppression of pathogens? Take a look at the most recent statistics for diseases, including autoimmune disorders including AIDS. Look at the Centers for Disease Control (CDC) site, particularly their MMR information (Morbidity and Mortality Rate).