VIEWS: 5 PAGES: 11 POSTED ON: 10/11/2011
Immunology Historical Perspective: As far back as the 5th century B.C., Greek physicians noted that people who had recovered from the plague would never get it again and understood that somehow they acquired immunity. 1796 witnessed the first vaccine, Jenner using cowpox for immunity to smallpox. In 1880, Pasteur introduced the concept of attenuated vaccines. He used a vaccine against rabies using attenuated form of the organism. In 1883 Metchnikoff discovers leukocytes, starting the controversy of cellular versus antibody-mediated immunity. In 1898, Ehrlich tries to harmonize the two components of the immune system by suggesting that immune cells bind antigens leading to formation of antibodies that kill the intruder. He also suggested a direct role for these cells. The years between 1943 and 1970 witnessed an appreciation for the role of cells in the immune system, isolation of B and T cells and a better understanding of how the immune system works. The immune system is a complex network of specialized cells and organs that defends the body against attacks by foreign invaders. When functioning properly it fights off cancerous cells and infections by agents such as bacteria, viruses, fungi and parasites. When it malfunctions it can unleash a torrent of diseases, from allergy to arthritis or allow spread of other diseases such as cancer and AIDS. The immune system equals in complexity the intricacies of the brain and nervous system and displays several remarkable characteristics. It can distinguish between "self" and "non-self" agents and cells. It is able to remember previous experiences and react accordingly; thus, once you have had chickenpox, your immune system will prevent you from getting it again. The immune system displays both enormous diversity and extraordinary specificity; not only is it able to recognize many millions of distinctive foreign molecules, it can produce molecules and cells to match up with and counteract each one of them. The success of this system in defending the body relies on an incredibly elaborate and dynamic regulatory and communication network. Types of Immunity: Passive immunity refers to receiving immunoglobulins directly. It typically lasts only a short time. Examples include infants acquiring immunity from their mothers through the placenta; nursed children receive other immunoglobulins from breast milk and travelers may receive antibody- containing serum to an infectious agent such as hepatitis. Active immunity is when the immune system mounts an immune response to specific agent, usually triggered by an infection or a vaccination. Innate or Natural Immunity does not require previous exposure to a pathogen. It is provided by circulating proteins and enzymes such as Lyzozymes, soluble CD proteins and complement proteins. Acquired Immunity is absent or weak prior to exposure and increases with subsequent exposure to the same pathogen. Types of Immune Systems: Cellular Immunity is provided by a group of specialized cells, T cells, Humoral Immunity is provided by immunoglobulins produced by B cells. The two arms of the immune response are closely intertwined where almost all antigens evoke both a humoral and a cellular response and most B cell responses require T cell help. In practice, however, one arm is usually more effective than the other and regulatory mechanisms end up skewing the response toward either the cellular or the humoral side. Major Histocompatibility Complex (MHC): They are molecules that mark a cell as being "self". MHC genes and the molecules they encode vary widely in their structure from one individual to another (a diversity known as polymorphism), which is why transplants are likely to be identified as foreign and rejected by the immune system. MHCs also: Help immune cells' communication. Alert T cells to the presence of body cells that have been infected with a virus or transformed by cancer. Combine with foreign antigens in a way that showcases the antigen and captures the attention of the immune cells. Immune System Organs: Lymphoid organs are stationed throughout the body and are concerned with the growth, development, and deployment of lymphocytes, the white cells that are the key operatives of the immune system. Lymphoid organs include the bone marrow, thymus, lymph nodes, spleen and tonsils. Cells destined to become immune cells, are produced in the bone marrow and develop to be either lymphocytes or phagocytes. In a process referred to as lymphocytes education, they travel to the thymus to learn to distinguish self-cells from non-self cells; cells that would react against self-antigens are eliminated. The life span of cells is short unless pathogens or foreign substances are present, when they are activated and start dividing. Some of these cells stay behind after the infection is destroyed go to a resting stage and become memory lymphocytes. Cellular Immunity: The immune system stockpiles a tremendous arsenal of cells. Some cells are important for general defenses, while others are trained on highly specific targets. To work effectively, however, most immune cells require the active cooperation of their fellow cells. They communicate through direct physical contact, or by releasing versatile chemical messengers. In order to have room for enough cells to match millions of possible foreign invaders, the immune system stores just a few of each. When an antigen appears, those few specifically matched cells are stimulated to multiply into a full-scale army. A powerful suppressor mechanism prevents this army from expanding wildly after the infection is gone. The main components of the cellular immunity are T cells. T cells contribute to the immune defenses in two major ways: Regulatory T cells are vital to orchestrating the elaborate system. Typically identifiable by the CD4 cell marker, helper T cells are essential for activating B cells and other T cells as well as natural killer cells and macrophages. Cytotoxic T cells usually carry the CD8 marker and are stimulated by a specific antigen and directly attack body cells that are infected or malignant. They also play a role in rejection of tissue and organ grafts. T cells work primarily by secreting cytokines that are diverse and potent chemical messengers such as Interferons and may activate macrophages. Natural Killer cells (NK) are yet another type of lethal lymphocytes. Like Cytotoxic T cells, they contain granules filled with potent chemicals. They are called natural killers because they do not need to recognize a specific antigen before swinging into action. They target tumor cells and protect against a wide variety of infectious microbes. Both Cytotoxic T cells and Natural Killer cells kill on contact. They bind to their target, aim their weapons, and deliver a lethal burst of chemicals that produces holes in the target cell's membrane. Fluids seep in and leak out, and the cell bursts. Phagocytes are large cells that can engulf and digest microorganisms and other antigenic particles. They often produce oxidative species and enzymes that destroy microorganisms. Important phagocytes are Monocytes and Macrophages. Granulocytes contain granules filled with potent chemicals. Examples include Neutrophil are that play a key role in acute inflammatory reactions, Eosinophils and Basophils. Mast cells are noncirculating counterpart of the Basophil and are responsible for the symptoms of allergy. Suppressor T cells act to suppress the aforementioned cells when the infection has been brought under control. Humoral Immunity: B-lymphocytes work chiefly by secreting soluble substances called antibodies. Antibodies typically interact with circulating antigens but are unable to penetrate living cells. Each B cell is programmed to make one specific antibody and when it encounters its triggering antigen, it gives rise to many daughter plasma cells that manufacture millions of identical antibody molecules. Antigens carry several characteristic shapes called epitopes, which protrude from its surface, one of which is recognized by an antibody that matches it much as a key matches a lock and marks it for destruction. Antibodies belong to a family of large molecules, immunoglobulins. They are Y-shaped molecules that have two identical heavy polypeptide chains and two identical light chains. The sections that make up the tips of the Y's arms vary greatly from one antibody to another, creating a pocket uniquely shaped to engulf a specific antigen. This is called the variable (V) region. The stem of the Y serves to link the antibody to other participants in the immune defenses. This area is identical in all antibodies of the same class, and is called the constant (C) region. Examples of Human immunoglobulins (Ig) include IgG and IgM that are very effective in killing invading forces, IgA that guards the entrances to the body and IgE that plays an important role in allergic reactions. Antibodies work in several ways, depending on the nature of the antigen: They can interlock with toxins and disable them. They may coat bacteria and makes them highly palatable to scavenger cells that destroy them. Some antibodies block viruses from entering into cells. In many cases an antigen-antibody combination unleashes a group of lethal serum enzymes known as complement. The complement system is made up of a series of about 25 proteins that work to complement the activity of antibodies in destroying bacteria, either by facilitating phagocytosis or by puncturing the bacterial cell membrane. Complement system also helps to rid the body of antigen-antibody complexes. In carrying out these tasks, it induces an inflammatory response. Once the infection is overcome antibody production wanes in response to suppressor influences by Suppressor T cells. The Big Picture: Infections remain the most common cause of human disease. Microbes attempting to enter the body must first find a chink in the body's external protection. The skin and the mucous membranes that line the body's portals not only pose a physical barrier, they are also rich in scavenger cells and IgA antibodies. Next, invaders must elude a series of nonspecific defenses, those cells and substances equipped to tackle infectious agents without regard for their antigenic peculiarities. Many potential infections are cut short when microbes are intercepted by patrolling scavenger cells or disabled by complement or other enzymes or chemicals. Virus- infected cells, for instance, secrete interferon, a chemical that rouses natural killer cells. Microbes that breach the nonspecific barriers are confronted by specific weapons tailored to fit each one. These may be cellular responses directed both by T lymphocytes and cytokines or they may be humoral responses, the work of antibodies secreted by B lymphocytes into the body's fluids. How Can the Body Produce Such an Array of Antibodies? Scientists were long puzzled by the wealth of the immune system's resources. The body apparently could recognize and mount unique responses to an endless variety of antigens-but how in the world could all that information be crammed into a limited number of genes? The answer came as a surprise. A typical gene consists of a fixed segment of DNA, which directs the manufacture of a given protein molecule (usually one gene = one protein). Antibody genes, in contrast, are assembled from bits and pieces of DNA scattered widely throughout the genetic materials. As the B cell matures, it rearranges or shuffles these gene components, picking and choosing among hundreds of DNA segments, some for each of the antibody's variable (V), diversity (D), joining (J), and constant (C) regions. Intervening segments of DNA are cut out; the selected pieces are spliced together. The new gene and the antibody it encodes are virtually unique. When the B cell containing this uniquely rearranged set of gene segments proliferates, all its descendants will make this unique antibody. Then, as the cells continue to multiply, numerous mutants arise; these allow for the natural selection of antibodies that provide better and better "fits" for the target antigen. The result of this entire process is that a limited number of genetically distinct B cells can respond to a seemingly unlimited range of antigens. Problem Associated with the Immune System: Most antigens are recognized by a limited number of specific immune cells. A few antigens (superantigens) are capable of rousing large classes of T cells, setting off a massive and harmful immune response. An example is bacterial toxins that can produce Toxic Shock Syndrome. In some people, an apparently harmless substance such as ragweed pollen or cat hair (allergens) can provoke the immune system to set off a harmful response known as allergy. This is due to the formation of IgE antibodies that attach to the surfaces of mast cells or basophils and upon encountering their specific allergen causes the mast cell or basophil to unleash a group of powerful chemicals that cause the symptoms of allergy or the life- threatening anaphylactic shock. Lack of one or more components of the immune system results in immunodeficiency disorders. These can be inherited, acquired through infections or other illness, or as a side effect of certain drug treatments. In abnormal situations, the immune system can wrongly identify self as non- self and execute a misdirected immune attack by producing autoantibodies. This will result in autoimmune diseases; examples include cases of Anemia (red blood cells), Type 1 Juvenile Diabetes (pancreatic cells), Multiple Sclerosis (Nerve cells and CNS), Hashimoto's disease (thyroid gland), Rheumatoid Arthritis (attack by Rheumatoid Factors) and Lupus (autoantibodies directed to many cellular components, DNA, RNA, and proteins). The exact cause of autoimmune diseases is not known, but several factors are likely to be involved. These include viruses, environmental factors such as exposure to sunlight, chemicals, some drugs, hereditary factors and even sex hormones since most autoimmune diseases are far more common in women than in men. It is important to note that in many of these diseases the immune system is only one of the contributing factors. Immunotherapy May be defined as the use of the body's own immune system in fighting a disease. 1. In allergies, give a small dose of the allergen to desensitize the body to that allergen. 2. Immunosuppressive therapy in autoimmune diseases and organ transplants rejection. 3. The use of Monoclonal antibodies in a wide variety of application. 4. Vaccines to arouse an immune response by the immune system to an agent. 5. Cancer immunotherapy, in particular cancer vaccines. Monoclonal Antibody Production: The importance of antibodies is well documented, but any antibody that is prepared or isolated by conventional methods is a group of different antibodies that target various agents, known as polyclonal antibodies. In 1975, Köhler and Milstein were able to devise a method to isolate monoclonal antibodies that would target only one antigen. It is based on injecting an animal with the antigen, collecting the B- lymphocytes from the serum or spleen (would give rise to polyclonal antibodies). Fusing the isolated B-lymphocytes with a cancerous Melanoma cell then creates a hybridoma. This hybrid cell can be cultured and cloned. Each of these daughter clones will secrete a single specific antibody (Monoclonal Antibodies). One limitation for Mab is a the risk of an immune reaction to mouse proteins that may result in destroying the antibodies. This can be addressed by using Chimeric [using the human constant region] or humanized [using the constant plus some of the variable region] antibodies. This is achieved via splicing the mouse genes for the highly specific antigen-recognizing portion of the antibody and combining it with the human genes that encode the rest of the antibody molecule. Application of Monoclonal Antibodies: In Cancer (see below). In other disease states. Monoclonal Antibodies directed against Tumor Necrosis Factor-α (TNF-α) such as Infliximab (Remicade®) is utilized in treatment of Crohn's disease. The Monoclonal Antibody Natalizumab (Tysabri®) binds to α-4 integrin on the immune cell surface and inhibits immune cells from leaving the bloodstream into the inflamed gut tissue in Crohn's disease or the brain tissue in Multiple Sclerosis. This agent was withdrawn from the market in February 2005 due to two reported cases of Progressive Multifocal Leukoencephalopathy (PML), but was reinstated in February 2006 after undergoing further studies. Monoclonal Antibodies against receptors on surface of platelets (that play a role in converting Fibrinogen to Fibrin) are used in coronary artery diseases. An example is Abciximab (ReoPro®), a Monoclonal Antibody to the glycoprotein lIb/Ilia receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin receptor found on platelets. Palivizumab (Synagis®) is a recombinantly produced, humanized Monoclonal Antibody for the prevention of serious lower respiratory tract diseases caused by the RSV virus in pediatric patients. Omalizumab (Xolair®) is a recombinant DNA-derived humanized Monoclonal Antibody targeting Immunoglobulin- E for treatment of moderate to severe persistent asthma in adults. As Diagnostic tools To distinguish subsets of B and T cells and help identify different types of leukemia and lymphomas. Quantization of the number of B cells and helper T cells is useful in immune disorders such as AIDS. As Immunosuppressors for organ transplants threatened with rejection. Examples include Muromonab-CD3 (Orthoclone OKT3®), Basiliximab (Simulect®) and Daclizumab (Zenapax®) all directed against T cells. A novel approach is to fusing two hybridoma cells that produce two different antibodies. While one arm of the antibody binds to one antigen, the second arm binds to another. For example one arm may bind to a killer cell while the other locks to a tumor cell, creating a lethal bridge between the two. Monoclonal Antibodies are essential to the manufacture of genetically engineered proteins, receptors and may behave as enzymes (abzymes). Abzymes are useful for a range of applications from catalyzing chemical reactions to dissolving blood clots to destroying tumor cells to acting as DNases. Vaccines: Vaccines contain whole, particles or products of microorganisms that may have been altered and will produce an immune response but will not be able to induce full-blown disease. While killed organism will induce only the humoral arm of the immune system, live attenuated organism will induce both arms. The reason that Sabin's Polio (attenuated) vaccine is preferred over Salk's original vaccine (killed) is due to that difference. Recombinant DNA vaccines are produced from specific genes for the antigenic response, and using rDNA to produce the antigens, that can be isolated using a monoclonal antibody to that antigen. These safe vaccines are produced for Hepatitis B virus (Engerix-B®) and Malaria parasite and are being tested for Meningitis, pneumonia and AIDS vaccine. Comvax® is a vaccine of Haemophilus B conjugate and recombinant Hepatitis B for vaccination against H. Influenza, type B and Hepatitis B. Pediarix® is a mixture of Diphtheria, Tetanus, Pertussis, Hepatitis B and Polio vaccines. Cancer and the Immune System: Since 1800s, scientists have recognized that the immune system can fight cancerous cells. For example, when a cancer patient develops infections, then their tumors may regress. William Coley in 1893 deliberately infected cancer patients with bacteria and sometimes was able to actually cure the patient of all signs of cancer. The BCG vaccine (Pacis®) is now utilized using this concept when given in localized bladder cancer post surgery, which leads to complete regression of the tumor. Immune responses may actually underlie the spontaneous disappearance of some cancers. The immune system provides one of the body's main defenses against cancer. When normal cells turn into cancer cells some of the antigens on their surface change into Tumor Associated Antigens (TAA), which may be products of mutated oncogenes. These new or altered antigens flag immune defenders, including Cytotoxic T cells, Natural Killer cells, and Macrophages. According to one theory, patrolling cells of the immune system provide continuing bodywide surveillance, spying out and eliminating cells that undergo malignant transformation. Tumors develop when the surveillance system breaks down or is overwhelmed or when tumors elude the immune defenses by hiding or disguising their tumor antigens. Alternatively, tumors may survive by encouraging the production of suppressor T cells. Monoclonal Antibodies: Monoclonal Antibodies directed against oncogenic products such as Trastuzumab (Herceptin®) targeting erbB2 Growth Factor Receptor and indicated in metastatic breast cancer. Due to limited success of Monoclonal Antibodies in some cases, they may be linked to a radioactive isotope such as 131I or an immunotoxin that can target specific tumor antigens and track down and destroy hidden cancer metastases within the body. Monoclonal Antibodies against affected cells such as Rituximab (Rituxan®) that targets the CD-20 antigen and is effective against CD-20 positive non-Hodgkin's lymphomas. A newer agent, Tostitumomab (BEXXAR®) is a mixture of the same Monoclonal Antibodies and its 131I counterpart and is indicated in treatment of CD-20 positive Lymphomas refractory to Rituxan®. Immunomodulation: This approach centers on stimulating or replenishing the patient's immune responses with substances known as Cytokines such as Interferons and Interleukins. They are either injected directly into the patient or in other cases they are used in the laboratory to transform some of the patient's own lymphocytes into tumor-hungry cells known as Lymphokine-Activated Killer cells (LAK) and Tumor-Infiltrating Lymphocytes (TILS), which are then injected back into the patient. Cancer Vaccines: The problems with the preparation of these vaccines include the fact that cancer cells are masters of disguise and that it may give rise to autoimmune diseases. Researchers are using structures from the tumor cells themselves to construct custom-made anticancer vaccines or utilizing vaccines against mutated products known to be common in certain cancers. Using Immunoadjuvants, such as BCG vaccine or Cytokines, seems to improve on the effect of the vaccine. Another approach relies on unleashing chemicals and proteins from the tumor cells to cause an immune response. For example, a combination of IR absorbing dye and an immunostimulator is injected into the tumor. Expose the tumor to IR, the temperature rises in the tumor cell, leading to a photothermal destruction of the tumor. This then leads to a systemic immune response from the remaining of the cells that can attack even metastatic tumors. To listen to the lecture, click on one of the following links: mp3*: Lecture Real Player: Lecture *Download the lecture by right clicking on the mp3 link and select "save link as".
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