HUMORAL IMMUNOLOGY We are surrounded by a sea of microorganisms that threaten to overwhelm us. This threat is made dramatically clear by the condition of AIDS, where the immune system is crippled by a slowly progressive infection extending over a period of years. In an AIDS patient, opportunistic infectious agents, including bacteria, viruses, and fungi, take advantage of the weakened immune system to invade and multiply unhindered. These are not exotic infectious agents rarely encountered in our environment, but rather widely distributed disease-causing agents that a healthy, functional immune system is able to control under normal circumstances. How does the immune system manage this control? It does so in two ways, as detailed below: via humoral and cellular immunity. Humoral immunity depends on the immune system’s ability to produce antibody molecules which bind and inactivate infectious agents. Cellular immunity involves the development of immune cells that are able to recognize, bind, and kill other cells that have previously been infected by foreign infectious agents. THE HUMORAL IMMUNE SYSTEM The word humoral refers to fluids (Latin - humors) that pass through the body. In this case, the fluids - both blood plasma (the non-cellular fluid portion of blood) and lymph (the plasma-like clear fluid that fills the space between cells and drains via lymph ducts to the lymph glands and eventually into the venous circulation) carry specific molecules, which are termed variously antibodies or immunoglobulins. These are the mediators of the humoral immune response. They recognize foreign infectious agents and help the immune system to eliminate them. They are the eyes and the ears of the immune system. The nature of antigens and antibodies Antibody molecules are complex proteins which have the ability to recognize and bind to the surface of a foreign infectious agent, like a virus or bacterium, and then neutralize it. This binding is specific, in that a given antibody molecule will only bind to one type of virus and not to all others. Moreover, in the case of a virus particle, the antibody will not bind to all parts of a virus, but only to specific chemical groups displayed by the virus which are termed antigens, or more precisely, antigenic determinants. What is the chemical nature of the antigens that are displayed on the surface of a virus particle and recognized by antibody molecules? Almost all antigens are proteins or parts of proteins. An antigen might be composed chemically of an unusual, unique sidechain of sugars that is attached covalently to the coat protein of one virus but not other viruses. In reality, however, actual antigens are almost always oligopeptides - short stretches or loops of amino acid sequence - which are exposed on the outer surface of viral protein molecules. The specific sequence of amino acids that constitute this oligopeptide antigen may be present uniquely on one particular type of virus and not present in any other protein found in a normal, uninfected cell or tissue. If this oligopeptide is indeed unique, then the antigen that it creates will provide a unique signature of the presence of the virus that distinguishes this virus from all other viruses and all other normal components of the uninfected cell or organism. Because virus particles are assembled from multiple copies (from sixty up to many hundred) of certain viral proteins, a given oligopeptide antigen may be displayed dozens or even hundreds of times on the surface of a virus particle. All proteins are constructed as amino acid chains far longer than the short amino acid sequence forming an oligopeptide antigen. This means that a single protein molecule will be large enough to encompass a number of distinct oligopeptide subdomains, each one of which can serve as an antigen. Moreover, a Humoral Immunology 1 MIT Biology Department7.012: Introductory Biology - Fall 2004Instructors: Professor Eric Lander, Professor Robert A. Weinberg, Dr. Claudette Gardelvirus particle may be assembled from several distinct proteins, each of which has its set of oliogopeptide antigens. Imagine, therefore, that a virus is covered with a number of distinct antigenic determinants, A, B, C, D, etc. Each of these determinants is composed of a distinct oligopeptide sequence, and each determinant, as mentioned above, may be displayed multiple times on the surface of a virus particle. The immune system can produce a number distinct antibodies, each of which is able to specifically recognize one of these antigens. For example, antibody a may bind specifically to any one of the many copies of the antigen A on the surface of the virus particle; antibody b may bind to any one of the many copies of antigen B on the surface of the virus particle, and so forth. Hence, each antibody molecule recognizes and binds tightly to a specific, complementary antigen displayed on the surface of the virus particle. This very directed and targeted binding of an antibody to its complementary antigen represents its binding specificity. Some antibody molecules may be less specific, in that they may recognize and bind to an oligopeptide antigen that happens coincidentally to be shared by a number of otherwise unrelated proteins. (Since the uniqueness of an oligopeptide antigen is dictated by its sequence of amino acids, you can imagine that the same amino acid sequence may be present in a number of otherwise unrelated proteins). At any time, there will be many identical copies of antibody molecule a floating around in the circulation. Any one of these may recognize and bind to the A antigens present on the surface of the virus particle, in effect coating the virus particle, and functionally inactivating it- the process of virus neutralization. This coating of antibody molecules may prevent the virus particle from adsorbing to the surface of target cells that it might otherwise infect, thereby blocking its infectivity. In addition, the antibody-coated virus particle is fair game for certain specialized cells of the immune system (such as macrophages) which can recognize antibody-coated virus particles, gobble them up, and degrade them (phagocytize them). Tolerance The complexity of foreign antigens that the immune system may experience suggests another difficult problem that it must solve. Our own bodies manufacture tens of thousands of distinct normal cell proteins, each of which
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