Immunology I IB Topic 6.3 and 11.1 The vertebrate body possesses two mechanisms which protect it from potentially dangerous viruses, bacteria, other pathogens, and abnormal cells which could develop into cancer. One of these mechanisms is nonspecific, that is, it does not distinguish between infective agents. The second mechanism is specific in that it responds in a very specific manner (production of antibodies) to the particular type of infective agent. I Nonspecific mechanisms An invading microbe must cross the external barrier formed by the skin and mucous membranes. If the external barrier is penetrated, the microbe encounters a second line of defense: interacting mechanisms of phagocytic white blood cells, antimicrobial proteins, and the inflammatory response. 6.6.3 A. The Skin and Mucous Membranes The skin and mucous membranes act as physical barriers preventing entry of pathogens Pathogen = disease causing organism; bacteria, virus, protest, fungi, animals like worms In humans, oil and sweat gland secretions acidify the skin (pH 3 – 5) which discourages microbial growth. The normal bacterial flora of the skin (adapted to the acidity) may release acids and other metabolic wastes to further inhibit pathogen growth. Saliva, tears and mucus secretions also wash away potential invading microbes in addition to containing antimicrobial proteins. An enzyme (lysozyme) in perspiration, tears, and saliva attacks the cell walls of many bacteria and destroys other microbes entering the respiratory system and eyes. In the respiratory tract, nostril hairs filter inhaled particles and mucus traps microorganisms that are then swept out of the upper respiratory tract by cilia. In digestive tract, stomach acid kills many bacteria. 6.3.4 B. Phagocytic White Cells and Natural Killer Cells Neutrophils (kamikazes) are cells that become phagocytic in infected tissue. Comprise 60% - 70% of total white cells. Attracted by chemical signals, they enter infected tissues by amoeboid movement, only live a few days as they destroy themselves when destroying pathogens. Macrophages are large amoeboid cells that use pseudopodia to phagocytize (eat) microbes. Fixed macrophages are especially numerous in the lymph nodes and spleen. This is why lymph nodes swell when you are fighting off a cold or flu virus. Nice to know Natural killer cells destroy the body’s own infected cells, especially those harboring viruses. Also assault aberrant cells that could form tumors. Are not phagocytic. 6.6.11 C. The Inflammatory Response A localized inflammatory response occurs when there is damage to a tissue due to physical injury or entry of microorganisms. Vasodilation (increase in size of blood vessel) of arterioles near the injury increases the blood supply to the area which produces the characteristic redness. The dilated (increased diameter) vessels become more permeable allowing fluids to move into surrounding tissues resulting in localized edema. Histamine is released from injured cells. Histamine causes the swelling and redness Migration of phagocytic cells into the injured area is also a result of increased blood flow and increased leakage from the capillaries. II. Specific invaders The immune system is the body’s third line of defense and is very specific in its response. Distinguished from nonspecific defenses by: specificity, diversity, self/nonself recognition, and memory. Specificity refers to this system’s ability to recognize and eliminate particular microorganisms and foreign molecules. Antigen = A foreign substance that elicits an immune response. Antibody = An antigen-binding immunoglobulin (protein), produced by B cells. Antigens may be molecules exhibited on the surface of, produced by, or released from bacteria, viruses, fungi, protozoans, parasitic worms, pollen, insect venom, f Self/nonself recognition is the ability of the immune system to distinguish between the body’s own molecules and foreign molecules (antigens), i.e. how do cell’s “see” if they c can’t “see?” 11.1.3 D. Active Versus Passive Acquired Immunity amrik is cool Active immunity is the immunity conferred by recovery from an infectious disease, May be acquired naturally from an infection to the body or artificially by vaccination. Vaccines may be inactivated bacterial toxins, killed microorganisms, or weakened living microorganisms. = In all cases the vaccine can no longer cause the disease but can provide antigens To stimulate an immune response. Passive immunity = immunity which has been transferred from one individual to another by the transfer of antibodies. Natural occurrence when antibodies cross the placenta from a pregnant woman’s system to her fetus. Passive immunity provides temporary protection to newborns whose immune systems are not fully operational at birth. Some antibodies are transferred to nursing infants through the milk. Persists for only a few weeks or months after which the infant’s own system defends its body. May also be transferred artificially from an animal or human already immune to the disease. = Rabies is treated by injecting antibodies from people vaccinated against rabies; produces an IMMEDIATE immunity important to quickly progressing infections. Is this ACTIVE OR PASSIVE IMMUNITY? 11.1.2 C. Humoral Immunity and Cell-Mediated Immunity The body will mount either a humoral response or a cell-mediated response depending on the antigen which stimulates the system. Humoral immunity (AKA plasma-mediated immunity) produces antibodies in response to toxins, free bacteria, and viruses present in the body fluids. Cell-mediated immunity is the response to intracellular bacteria and viruses, fungi, protozoans, worms, transplanted tissues and cancer cells. D. Cells of the Immune System Early B and T cells (as well as other WBCs) develop from stem cells in the bone marrow. They only differentiate after reaching their site of maturation. B cells (B lymphocytes) are responsible for the humoral immune response. = B cells form in the bone marrow and remain there to complete their maturation. T cells (T lymphocytes) are responsible for the cell-mediated immune response. = T cells also form in the bone marrow, then migrate to the thymus gland to mature. Mature B cells and T cells are concentrated in the lymph nodes, spleen and other lymph organs. Plasma cells are the cell, which actually defend the body during an immune response. Activated B become plasma cells which secrete antibodies (humoral response) that “handcuff” the antigen and/or pathogen. Activated T cells may produce two types of cells: cytotoxic T cells which destroy infected cells and cancer cells; and helper T cells which secrete cytokines. Cytokine = Molecules secreted by one cell to activate other cells. Cytokines help regulate both B and T cells and thus are involved in both the humoral and cell-mediated responses. III. Clonal selection Each B and T cell will recognize and respond to only one antigen. When an antigen enters the body and binds to receptors on the specific B or T cell, the cells are activated and begin to divide. = The divisions produce a large number of clones, which bind to the antigen = If, for example, a B cell is activated, it will proliferate (reproduce) by mitosis to produce a large number of plasma cells that will each secrete an antibody which functions as an antigen receptor for the specific antigen that activated the original B cell. The activated B or T cells proliferate to produce a clone of millions of effector cells, which are specific for the original antigen (clonal selection). Clonal selection = Antigen-specific selection of a lymphocyte that activates it to produce clones of B or T cells dedicated to eliminating the antigen that provoked the initial immune response. IV. Memory cells The primary immune response is the increase in number of B and T cells to form clones of specific to an antigen during the body’s FIRSTt exposure to the antigen. There is a 5 to 10 day lag period between exposure and maximum production of antibodies The B or T cells selected by the antigen are differentiating into killer T cells and plasma B cells during the lag period. A secondary immune response occurs when the body is exposed to a previously encountered antigen. The response is faster (3 to 5 days) and more prolonged than a primary response. The antibodies produced are also more effective at binding the antigen. When the same antigen that caused a primary immune response again enters the body, the memory cells are activated and rapidly proliferate to form a new clone of effector cells and memory cells. These new clones of effector and memory cells are the secondary immune response. V. Self/nonself recognition Self-tolerance = The lack of a destructive immune response to the body’s own cells. Any lymphocytes with receptors for molecules present in the body are destroyed in utero; the body contains no lymphocytes with antigen receptor for its own molecules, only for foreign molecules. The major histocompatibility complex (MHC) is a group of glycoproteins embedded in the plasma membranes of cells. Important “self-makers” The probability that two individuals will have matching MHC sets is virtually zero unless they are identical twins. VI. The humoral response The humoral response occurs when an antigen binds to B cell receptors The B cells differentiate into a clone of plasma cells, which begin to secrete antibodies. These antibodies are most effective against pathogens circulating in the blood or lymph. A. The Activation of B cells Often a two- step process. One step is the binding of the antigen to a specific antigen-receptors on the surface of the B cell. The other step in B cell activation involves macrophages and helper T cells; After macrophages phagocytize pathogens, pieces of the partially digested antigen molecules are bound to the surface of the macrophage. Like in the old days when attackers had their heads cut off and put on pikes. These presented antigen molecules result in the macrophage functioning as an antigen-presenting cell.(a pike with a head on it) A T cell with a receptor specific for presented antigen recognizes the antigen (head) The T cell is “activated” to form helper T cells These helper T cells secrete cytokines (chemicals) which stimulate B cells. Each plasma cell (=effector cell) then secretes antibodies specific for the antigen. Antigen-Antibody Antibodies comprise a specific class of proteins called immunoglobulins (Igs) Antibodies are Y-shaped molecules There are five types of constant regions: You don’t need to know these. IgM: circulating antibodies which appear in response to an initial exposure to an antigen. IgG: protects against bacteria, viruses, and toxins circulating in blood and lymph; triggers complement system action. IgA: prevents attachment of bacteria and viruses to epithelial surfaces IgD: probably functions as an antigen-receptor which initiates differentiation of B cells. IgE: stimulates mast cells and basophills, to release histamine and other chemicals How Antibodies Work Antibodies do not directly destroy an antigenic pathogen. The antibody binds to the antigen to form an antigen-antibody complex which gets eaten by macrophages. Monoclonal Antibody Technology Monoclonal antibodies: Defensive proteins produced by cells descended from a single cell; all antibodies produced b these cells are identical. These monoclonal antibodies: Can be used in diagnositc labs to detect pathogenic microbes in clinical samples. (ie. HIV antibodies) Form the basis for over-the-counter pregnancy tests (HCG in female urine) Are used as therapeutic agents Show promise in treating cancer Monoclonal antibodies are produced by hybridoma cells from the fusion of certain cancer cells (myelomas) with normal antibody-producing plasma cells. They will produce a single type of antibody and can be cultured indefinitely to manufacture that antibody on a larger scale. Blood Groups The human ABO blood groups provide a good example of nonself recognition Individuals of blood type A have the A antigen and make anti-B antibodies Individuals of blood type B have the B antigen and make anti-A antibodies Individuals of blood type AB have the A and B antigen and make no antibodies Individuals of blood type O have neither the A nor B antigen make anti-A and anti-B antibodies Blood group antibodies can cause blood of a different antigenic type to agglutinate, a life- threatening reaction. Type O individuals are universal donors since their blood has neither antigen. Type AB individuals are universal recipients since they produce neither antibody A or antibody B Usually IgM class antibodies do not cross the placenta, thus they present no harm to a developing fetus with a blood type different from the mother. Tissue Grafts and Organ Transplants The MHC is a biochemical fingerprint unique to each individual The MHC complicates tissue grafts and organ transplants since foreign MHC molecules are antigens and cause cytotoxic T cells to mount a cell-mediated response. Skip this part unless you want to understand allergies. Abnormal immune function leads to disease states Autoimmune disease: the immune system reacts against self Allergy: a hypersensitivity of the body’s defense system to an environmental antigen called an allergen Antibodies recognize poll as allergens The mast cell cause release of histamine and other inflammatory agents. Histamine cause dilation and increased permeability of small blood vessels which results in the common symptoms of an allergy. Anti-histamines are drugs used to treat allergies since they interfere with the action of histamine. Anaphylactic shock is a life-threatening reaction to injected or ingested antigens Death may occur in a few minutes This hypersensitivity may be associated with foods or insect venom. Epinephrine may be injected to counteract the allergic response. Immunodeficiency Immunodeficiency refers to a condition where an individual is inherently deficient in either humoral or cell-mediated immune defense. Not all cases of immunodeficiency are inborn conditions Some viral infections cause depression of the immune system (AIDS) Acquired immunodeficiency syndrome is a severe immune system disorder caused by infection with the human immunodeficiency virus (HIV) Characterized by a reduction of T cells and the appearance of characteristic secondary infections Mortality rate approaches 100% HIV probably evolved from another virus in central Africa and may have gone unrecognized for many years. The immune system is devastated by HIV since the virus targets helper T cells which play a central role in both the humoral and cell-mediated responses. The HIV may also remain as a provirus in the infected cell genome for many years before becoming active. HIV is not eliminated from the body by antibodies for several reasons: The virus is invisible to the immune system The virus undergoes rapid mutational changes in antigens during replication which eventually overwhelms the immune system The population of helper T-cells eventually declines to the point where cell-mediated immunity collapses. AIDS is the late stage of HIV infection and is defined by a reduced T cell population and the appearance of secondary infections. Takes an average of about ten years to reach this stage of infection Individuals exposed to HIV have circulating antibodies that can be detected; displaying these antibodies designates an individual as HIV-positive HIV is only transmitted through the transfer of body fluid, blood or semen, containing infected cells. Most commonly transmitted in the US and Europe through unprotected sex between male homosexuals and unsterilized needles in intravenous drug users. In Africa and Asia, transmission through unprotected heterosexual sex is increasing AIDS is currently considered an incurable disease The best way to prevent additional infections is to educate people on how the disease is transmitted and how to protect themselves.