CHAPTER 16 SPECIFIC HOST DEFENSE MECHANISMS: AN INTRODUCTION TO IMMUNOLOGY IMMUNOLOGY is the scientific study of the immune system and

immune responses There are 2 major arms of the immune system: HUMORAL IMMUNITY AND CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY- special glycoproteins called antibodies are produced by lymphocytes to recognize, bind with, inactivate and destroy specific microorganisms. It is also called antibody mediated immunity. CELL-MEDIATED IMMUNITY- involves a variety of cell types, but antibodies play only a minor role, if any. ORIGINS OF IMMUNOLOGY Edward Jenner- first administered smallpox vaccine in 1796 Louis Pasteur- developed vaccine against cholera, anthrax and rabies in the late 1800s 1890- Emil Behring and Kitasato Shibasaburo- discovered antibodies while developing dipththeria toxin. At about the same time, Elie Metchnikoff discovered phagocytes and introduced the cellular theory of immunity By 1910, the main elements of clinical immunology (allergy, autoimmunity and transplantation immunity) had been described. Major advances in immunology began to take shape in the late 1950s, when the focus shifted from serology (investigating antigens and antibodies) to cells. Defining the role of lymphocytes signaled the start of the new era. The emphasis on immune cells and the emergence of the concepts and tools of molecular biology were the two most powerful influences on immunology since its inception. IMMUNITY- is a condition of being resistant to a particular infectious disease Acquired Immunity-immunity that results from the active ones lifetime Types of Immunity 1. Natural active acquired immunity- immunity that is acquired in response to the entry of a live pathogen into the body 2. Artificial active acquired immunity- immunity that is acquired in response to vaccines 3. Natural passive acquired immunity- immunity that is acquired by a fetus when it receives maternal antibodies in utero or by an infant when it receives maternal antibodies contained in colostrums 4. Artificial passive acquired immunity- immunity that is acquired when a person receives antibodies contained in anti-sera or gamma globulin Vaccine is a material that can artificially induce immunity to an infectious disease. A person is deliberately exposed to a harmless version of the pathogen or toxin, which will stimulate the persons immune system to produce protective antibodies and memory cells, but will not cause disease in that person. Ideal Vaccine a. Contains enough antigen to protect against infection by the pathogen b. Contains antigens from all strains of the pathogen that cause that disease c. Has few (preferably no) side effects d. Does not cause disease in the vaccinated person Types of Vaccines production or receipt of antibodies during

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Attenuated Vaccine- the organism (live) that is used is a mutant strain of a pathogen that is rendered avirulent by growing them for many generations under various conditions or exposing them to mutagenic chemicals or radiation. This should not be given to immunosuppressed individuals because even weakened pathogens could cause disease in these persons. Ex. Adenovirus, varicella (chicken pox), measles (rubeola), mumps, German measles (Rubella), polio, rotavirus, smallpox (variola), yellow fever; BCG, cholera, tularemia, typhoid fever(oral vaccine)

2. Inactivated vaccines- vaccines made from pathogens that have been killed by heat or chemicals. Easier and faster to produce but less effective and produce a shorter immunity. Ex. Hepatitis A, influenza, Japanese encephalitis, polio, rabies; anthrax, typhoid fever (subcutaneous vaccine), Q fever 3. Subunit vaccines- acellular vaccine- uses antigenic (antibody stimulating) portion of the pathogen rather than the whole pathogen. Ex. Hepatitis B, Lyme disease, whooping cough 4. Conjugate vaccines- made by conjugating bacterial capsular antigens (themselves not very antigenic) to molecules that stimulate the immune system to produce antibodies against the less antigenic capsular antigens. Ex. Haemophilus influenza type b, meningococcal meningitis, pneumococcal pneumonia 5. Toxoid vaccines- a toxoid is an exotoxin that has been inactivated by heat or chemicals. the antibodies that neutralize toxins are called antitoxins, and the serum containing such antitoxins are called antiserum. Ex. Diphtheria, tetanus, botulism 6. DNA vaccines- gene vaccines- experimental 7. Autogenous vaccines- one that has been prepared from bacteria isolated from the localized infection, such as staphylococcal boil. The pathogens are killed and injected into the same person to stimulated production of more antibodies

HUMORAL IMMUNITY Antigens ANTIGEN OR IMMUNOGEN can be any foreign organic substance large enough to stimulate the production of antibodies. Antigens maybe proteins of more than 10,000 daltons molecular weight, polysaccharides larger than 60,000 daltons, large molecules of DNA or RNA Antigenic determinants or Epitopes- molecules on the surface of the bacteria capable of stimulating the production of antibodies Haptens- small molecules that may act as antigens only if they are coupled with a large carrier molecule such as a protein. Ex. Penicillin Antibodies ANTIBODIES are glycoproteins produced by B lymphocytes in response to the presence of an antigen in coordination with T lymphocytes and macrophages. Usually, the antibody is specific to the antigen that stimulated its production and will bind only to that particular molecule. Occasionally, an antibody will bind to similar antigenic determinant but not identical in structure- referred to as cross-reaction. All antibodies are in a class of proteins called IMMUNOGLOBULINS- globular glycoproteins in the blood that participate in immune reactions. They are also found in the lymph, tears, saliva and colostrums STEPS IN THE RESPONSE IN ANTIBODY PRODUCTION A. LAG PHASE- the antigen is processed by macrophages, T cells and B cells or by B cells only. T dependent antigens- processing requires the presence of all three cell types. T-independent antigens- processing requires only B cells. There is delayed production of antibodies B. PRIMARY RESPONSE- in the primary response to an antigen, it takes approximately 14 days for antibodies to be produced. Ultimately, B cells develop into plasma cells that are capable of

producing antibodies by protein synthesis. When the antigen is used up, the number of antibodies in the blood declines as the plasma cells dies. C. SECONDARY RESPONSE, ANAMNESIC RESPONSE OR MEMORY RESPONSE- there is increased production of antibodies following second exposure to antigen. Other antigenstimulated B cells become memory cells which are small lymphocytes that can be stimulated rapidly (1-3 days) to produce large quantities of antibodies when later exposed to the same antigen. In addition to memory B cells. Memory T cells also contribute to immunologic memory. Ex. Clostridium tetani AGAMMAGLOBULINEMIA- absence of gamma globulin in the blood. Treatment is by bone marrow transplant involving precursor white blood cells from a closely related person. Some of these cells become lymphocytes, implanted in the lymph nodes and become immunocompetent HYPOGAMMAGLOBULINEMIA- persons who produce insufficient amount of antibodies. Resistance to infection is lower than normal and there is profoundly low circulating B cells Some patients are immunosuppressed following the administration of immunosuppressive drugs such as antilymphocytic serum given before organ transplant surgery. Patients with AIDS are infected with HIV that destroys the helper T cells that are required in the processing of T-dependent antigens, and are also involved in cell-mediated immune responses. The primary function of the immune system is to differentiate between self and non-self and destroy that which is non-self. The lymphatic is the site and source of most of the immune activity. The cells involved in the immune responses originate in the bone marrow, from which most blood cells develop. Three lines of lymphocytes- B lymphocytes, T lymphocytes and natural killer cells- are derived from lymphoid stem cells of the bone marrow. T CELLS Lymphoid stem cells that migrate to the thymus gland where they differentiate into T-lymphocytes, including helper T cells, suppressor T cells, cytotoxic T cells, and delayed hypersensitivity T cells. About 70% to 80% of lymphocytes in the peripheral blood are T cells. T cells do not actually produce humoral antibodies, but they aid in the control of antibody production and are involved in cell-mediated immune responses (tissue transplant rejection, cellular immunity to mycobacteria, fungi and viruses, etc.) B CELLS Other lymphocytic stem cells differentiate in the liver and intestinal lymphoid areas into B lymphocytes or B cells, now generally assumed to stand for bone marrow. About 10% to 15% of the lymphocytes in the peripheral blood are B cells. B cells migrate to lymphoid tissues where they produce antibodies that circulate through lymph and blood to protect the individual (humoral immunity). When stimulated by an antigen, each B cell is capable of producing hundreds of specific antibodies per second. WHERE DO IMMUNE RESPONSES OCCUR Immune responses to antigens in the blood are usually initiated in the spleen, whereas responses to microorganisms and other antigens in tissues are generated in lymph nodes located near the affected area. Ingested antigens enter specialized epithelial cells called microfold or M cells, which then transport the antigens to Peyers patches in the intestinal mucosa, where the immune responses are initiated. All the various types of cells (macrophages, B cells, T cells, etc) that collaborate to produce immune responses are present at these sites (spleen, lymph nodes, tonsils, adenoids, Peyers patches). PROCESSING OF ANTIGENS/PRODUCTION OF ANTIBODIES Humoral immunity involves the production of antibodies, as opposed to cell-mediated immunity. It is known that macrophages, T cells and B cells are often involved in a cooperative effort. The majority of antigens are referred to as T-dependent antigens because their processing is dependent on T cells. T-dependent antigens are usually complex proteins, containing large numbers of antigenic determinants with little repetition among themselves. T-dependent antigens are processed in the following manner: 1. Following invasion of the body, an antigen is ingested and digested by a macrophage

2. Within the macrophage, antigenic determinants of the bacterial cell (antigenic peptides) attach to molecules called major histocompatibility complex (MHC) molecules 3. The combined AP-MHC molecules are displayed on the surface of the macrophage; at this point, the macrophage is referred to as an antigen presenting cell (APC). 4. A Th cell attaches to one of the AP-MHC molecules, divides and the Th cells begin to secrete chemical signals (lymphokines). 5. When the chemical signals reach a B cell that is capable of recognizing that particular signal, the activated B cell will divide to produce a clone of identical B cells. It is thought that IgD molecules on the surface of B cells enable it to recognize the chemical signal. 6. Some of the members of the newly formed clone mature into antibody-producing cell dies. Each plasma cell makes only one type of antibody; one that will bind with the antigenic determinant that activated the B cell and stimulated its production. Members of the clone that do not become plasma cells, and some of the activated T cells, remain in the body as memory cells, able to respond quickly should the antigen enter the body again at a later date. Th cells induce B cells to produce antibodies, whereas Ts cells inhibit antibody production. Acting together, they ensure that the immune response is effective but not destructive. A small percentage of antigens- called T-independent antigens- do not require antigen presenting cells or Th cells in their processing. T-independent antigens are large polymeric molecules (usually polysaccharides) containing repeating antigenic determinants; examples include lipopolysacharides (LPS) found in the cell walls of Gram negative bacteria, bacterial flagella, and bacterial capsules. Processing of T-independent antigens is initiated when an appropriate B cell makes contact with the free antigenic determinant. The activated B cell makes extensive cell division, producing a clone of identical B cells. Some of the newly formed clones mature into antibody producing plasma cells, whereas others become memory cells. ANTIGEN-ANTIBODY COMPLEXES When an antibody combines with an antigen, the antigen-antibody complex or immune complex is formed. Antigen-antibody complex is capable of activating the complement cascade resulting in the activation of leukocytes, lysis of bacterial cells, and increased phagocytosis as a result of opsonization. ANTIBODY STRUCTURE AND FUNCTION Antibodies belong to a class of glycoproteins called immunoglobulins. Antibodies are produced by plasma cells in response to stimulation of B cells by foreign antigens. The basic structure of an immunoglobulin molecule resembles the letter Y. it consists of 2 identical light polypeptide chains, 2 identical heavy polypeptide chains, 2 antigen binding sites, and an Fc region. In this basic form, the molecule is called a monomer. The light chain contains fewer amino acids than the heavy chains, are shorter and lighter in weight. The chains are connected to each other by disulfide bonds. The monomer is bivalent in that it has 2 sites for antigenic binding. The Fc region enables the molecule to bind to cells (neutrophils, macrophages, basophils, mast cells) that possess surface receptors able to recognize the Fc region. MONOCLONAL ANTIBODIES Purified antibodies that are directed against specific antigens have been produced in laboratories in which a single plasma cell that produces only one specific type of antibody is fused with a rapidly dividing tumor cell. The new long-lived, antibody producing cell is called a HYBRIDOMA. These hybridomas are capable of producing large amounts of specific antibodies called MONOCLONAL ANTIBODIES. The first monoclonal antibodies were produced in 1975. They are commonly used in immunodiagnostic procedures to diagnose diseases. Monoclonal antibodies are also being evaluated for possible use in fighting diseases, killing tumor cells, boosting immune system and preventing organ rejection. CELL- MEDIATED IMMUNITY Cell mediated immunity is an arm of the immune system capable of controlling chronic infections by intracellular pathogens (like bacteria, protozoa, fungi, viruses). It is a complex system of interactions between many types of cells and cellular secretions (cytokines). Although CMI does not involve the

production of antibodies, antibodies produced during humoral immunity may play a minor role in some cell-mediated responses. 1. A macrophage engulfs and partially digests a pathogen; fragments (antigenic determinants) of the pathogen are then displayed on the surface of the macrophage. 2. A Th cell binds to one of the antigenic determinants being displayed on the macrophage surface. The Th cell produces lymphokines (cytokines produced by lymphocytes) which reach an effector cell of the immune system (Tc cell, NK cell, K cell) 3. The effector cell binds to a target cell (pathogen infected host cell displaying the same antigen determinant on its surface) 4. Vesicular contents of the effector cell are discharged. These include perforin and other enzymes/proteins, which literally punch holes in the target cell membrane. 5. Toxins produced by the effector cells enter the target cell , causing disruption of DNA and organelles. The target cell dies. Both humoral and cell-mediated immune responses play a role in the bodys defense against viral infections. Tc cells, NK cells, and K cells kill infected host cells when pathogens are established inside the cells. Thus, infected liver cells are destroyed in hepatitis infections. The AIDS virus that target Th cells is particularly destructive because it destroys the cells that would have helped in the fight against infections. The lack of Th cells impairs both humoral and cell-mediated immunity, making persons with AIDS very susceptible to many opportunistic infections and malignancies. NK AND K CELLS NK and K cells do not proliferate in response to antigen and appear not to be involved in antigen-specific recognition. They kill target cells, including foreign cells, virus infected cells, and tumor cells. Both NK and K cells have receptors on their surface for the Fc region of IgG antibody molecules, enabling them to attach to and kill antibody-coated target cells; this is called antibody-dependent cellular cytotoxicity. Once attached to an antibody coated target cell, the NK or K cell inserts molecule called perforin into the cell membrane of the target cell, creating an opening, through which cytotoxic granules called GRANZYMES are injected. IMMUNOGLOBULIN CLASSES IgA 160,000 to 385,000 daltons in weight. Exists as monomer, dimer or trimer. Approximately 10 to 20% of the Ig in the serum. It is the predominant Ig class in the saliva, tears, seminal fluid, colostrums, breast milk and mucus secretions in the lungs, nose, gastrointestinal tract. In the intestine, IgA attaches to the viruses, bacteria and protozoal parasites, preventing adhesion and invasion IgD 180,000 to 184,000 daltons. Exists as a monomer and consists of less than 1% of total serum Ig. It is found in the surface of B cells and possibly function as antigen receptors and determine which specific antigen that Bcell responds to. IgE 188,000 to 200,000 daltons. Exists as monomer and is less than 1% of total Ig in the serum. Also called P-K antibody. It is produced in response to allergens among atopic individuals. It is found on the surface of basophils and mast cells. IgG 146,000 to 170,000 daltons. Exists as a monomer and is the lightest of the Ig. It comprises 7585% of the total serum Ig. The only class of Ig that can cross the maternal placenta and help protect the newborn during the first months of life. IgG can bind to a wide variety of cellular receptors to promote phagocytosis and antibody-dependent cytotoxicity. IgG are long lived,sometimes persisting for the lifetime of the individual. IgM 900,000 to 970,000 daltons. Exists as a pentamer held together by a J chain and is the largest of the Ig. Approximates 10% of the serum level of Ig. Because a pentamer has 10 antigen-binding sites, it can bind to 10 separate viruses, preventing them from attaching to target cells. It does not cross the placenta. IgM is the first antibody formed in response to antigen and it exists in the bloodstream for only a few months. It is the most efficient complement-fixing immunoglobulin. IgG antibodies later become the most prevalent in the later part of infection. AUTOIMMUNE DISEASE

AUTOIMMUNE DISEASES results when the person develops antibodies against its own body tissues. The immune system considers its own tissue as foreign. This may occur with certain tissues that are not exposed to the immune system during fetal development, so that they are not recognized as self. They include the lens of the eye, brain, spinal cord and sperm. Subsequent exposure to this tissues during surgery or injury may allow antibodies like IgG and IgM to be formed,, which together with complement could cause destruction of these tissues. It is believed that certain drugs and viruses may alter the antigens on host cells, thus inducing the formation of autoantibodies or sensitized T cells to react against these altered tissue cells. Organ-specific autoimmune diseases are Hashimotos thyroiditis, Graves disease, primary myxedema thyrotoxicoses, pernicious anemia, and insulin dependent diabetes mellitus. Non-organ specific autoimmune diseases involve the skin, kidneys, joints and muscles. Examples include myasthenia gravis, SLE, dermatomyositis, scleroderma and rheumatoid arthritis. Autoimmune diseases result from types II, III and IV hypersensitivity reactions.