Human Body Immunity PDF

The human body is constantly exposed to potentially deleterious micro-organisms and foreign substances. Therefore, it has evolved a complete system composed of complementary and inter-related mechanisms to defend against invasion by bacteria, viruses, parasites, and other foreign substances. Through...

The human body is constantly exposed to potentially deleterious micro-organisms and foreign substances. Therefore, it has evolved a complete system composed of complementary and inter-related mechanisms to defend against invasion by bacteria, viruses, parasites, and other foreign substances. Through recognition of molecular patterns, the body's immune system is able to distinguish itself from these foreign substances and discriminate potentially harmful from non-harmful agents. In addition, it can defend against abnormal cells and molecules that periodically develop. The skin and its epithelial layers, in conjunction with the body's normal inflammatory processes, make up the first line of the body's defense and confer innate or natural immunity to the host. After these protective barriers have been crossed, the body relies on a second line of defense known as the adaptive immune response to eradicate infection by invading organisms. The adaptive immune response evolves slowly over time but results in the development of antibodies capable of targeting specific micro-organisms and foreign substances should a second exposure occur [1,2]. This course will cover immunity and the immune system, including a discussion of innate and adaptive immunity. Concepts related to key cellular functions, recognition systems, and effector responses integral to the immune system are also presented. In addition, developmental aspects of the immune system are discussed. OVERVIEW OF IMMUNITY Immunity can be defined as the body's ability to defend against specific pathogens and/or foreign substances in the initiation of disease processes. The multidimensional response initiated by the body's various defense systems is known as the immune response. Some of these responses become active almost immediately, while others develop slowly over time. It is the coordinated interaction of these mechanisms that allows the body to maintain normal internal homeostasis. However, when these mechanisms are either depressed or overactive, they become responsible for many of the pathophysiologic processes encountered in health care [1,2]. In order for a host organism to remain healthy, the immune system must function properly. A weakened immune response may lead to immunodeficiency, but an inappropriate or excessive response can cause allergic/hypersensitivity reactions or autoimmune diseases. Therefore, the immune system must be capable of regulating itself. The process by which this regulation occurs is poorly understood but involves all aspects of the innate and adaptive immune responses. Intact innate immune mechanisms are essential for the initiation of the adaptive immune response, and therefore, a successful immune response depends upon cooperation between the two systems. Dendritic cells are an essential component of both innate and adaptive responses and act through the release of dendritic cell-derived substances, such as cytokines and chemokines. Innate immune cells are capable of communicating important information regarding key characteristics of the invading micro- organism or foreign substance to the B and T lymphocytes involved in adaptive immunity. The adaptive immune response is also capable of increasing its efficiency by recruitment and activation of additional phagocytes and molecules of the innate immune system. Each system is thus essential for an effective immune response and occurs in concert in the fight against infection [1,2]. Each exposure to an antigen elicits a predictable response from the immune system. After activation, the response is amplified until it peaks and eventually subsides. This occurs because the body's normal immune responses are self-limiting. After the antigen is destroyed and the action of chemical mediators terminated, the immune response ceases. It is believed that anti-inflammatory cytokines and regulatory T lymphocytes play a role in this process. Tolerance, or the ability of the immune system to react to foreign antigens but remain nonreactive to self-antigens, also plays a role in the self-regulation of the immune response. Tolerance to self-antigens protects the body from harmful autoimmune responses. This is exquisitely important in vital organs such as the brain, testes, ovaries, and eyes, where immunologic damage could be lethal. ACTIVE VERSUS PASSIVE IMMUNITY The goal of the immune system is to protect the host against invasion by potentially dangerous pathogens, foreign substances, and other sources of harmful antigens. Adaptive immune responses accomplish this goal though the activation of cell-mediated and humoral responses. This type of protection can be induced in one of two ways : After exposure to the offending substance and activation of B and T lymphocytes (active immunity) Through the transfer of antibodies against an antigen directly to the host (passive immunity) Active immunity is acquired when the host mounts an immune response to an antigen, either through the process of vaccination or from environmental exposure. It is called active immunity because it requires the host's own immune system to develop an immunologic response, including the development of memory. Active immunity is usually long-lasting but requires a few days to weeks after first exposure to sufficiently develop an appropriate immunologic response that culminates in the destruction of the presenting antigen. With subsequent exposures, the immune system rapidly becomes fully activated because of the presence of memory B and T lymphocytes and circulating antibodies. The process by which active immunity is acquired through the administration of a vaccine is termed immunization. An acquired immune response can improve on repeated exposures to an injected antigen (booster vaccines) or natural infections. Passive immunity is immunity transferred from another source. The most common form is immunity conferred from mother to fetus. During fetal development, maternal immunoglobulin G (IgG) antibodies are transferred to the fetus via the placenta. After birth, the neonate also receives IgG antibodies from the mother in breast milk or colostrum. Therefore, infants are provided with some degree of protection from infection for approximately three to six months, giving their own immune system time to mature. Some protection against infectious diseases can also be provided by the administration of immunoglobulins pooled from human or animal sources. Passive immunity produces only short-term protection that lasts weeks to months. CYTOKINES AND THEIR ROLE IN IMMUNITY The ability of the cells of both the innate and adaptive immune systems to communicate critical information with each other and initiate end effector responses is dependent upon the secretion of short-acting, biologically active, soluble molecules called cytokines. Cytokines are an essential component of host defense mechanisms and the primary means by which cells of innate and adaptive immunity interact. Chemokines are a subset of cytokines that consist of small-protein molecules involved in both immune and inflammatory responses. They are responsible for directing leukocyte migration to areas of injury and to locations where primary immune responses are initiated, such as lymph nodes, the spleen, Peyer patches, and the tonsils. General Properties of Cytokines Cytokines are low-molecular-weight, regulatory, pro- or anti-inflammatory proteins that are produced by cells of the innate and adaptive immune systems and that mediate many of the actions of these cells. The majority of the functionally important cytokines are interleukins, interferons, and tumor necrosis factor-alpha (TNF-α). Cytokines generate their responses by binding to specific receptors on their target cells and activating G-protein-coupled receptors [6,7]. Interleukins are produced by macrophages and lymphocytes in response to the presence of an invading micro-organism or activation of the inflammatory process. Their primary function is to enhance the acquired immune response through alteration of molecular expression, induction of leukocyte maturation, enhanced leukocyte chemotaxis, and general suppression or enhancement of the inflammatory process [1,6,7]. Interferons are cytokines that primarily protect the host against viral infections and play a role in the modulation of the inflammatory response. Interferons are cell-type specific, with IFN-α and IFN-β produced primarily by macrophages and IFN-γ produced primarily by T lymphocytes. TNF-α, a cytokine in a class by itself, is one of the most important mediators of the inflammatory response and is produced by macrophages when surface toll-like receptors recognize pathogen- associated molecular patterns (PAMPs) on the surface of micro-organisms. TNF-α acts as an endogenous pyrogen (i.e., fever producer) and induces synthesis of preinflammatory substances in the liver. With prolonged exposure, it has the ability to cause intravascular coagulation and subsequent thrombosis production [1,6,7]. Despite the diverse functions of the cytokines, they all share certain important properties. All cytokines are secreted in a brief, self-limited manner. They are rarely stored as preformed molecules but rather are synthesized through transcription as a result of cellular activation. The actions of cytokines are often pleiotropic, meaning that a single cytokine has the ability to act on a variety of different cell types. For example, the interleukin IL-17 is produced by T-helper 17 (T17H) cells and acts on several cell types, including leukocytes, epithelial cells, mesothelial cells, vascular endothelial cells, and fibroblasts. As a result, T17H cells play a critical role in host defense against pathogens that infiltrate the mucosal barrier. Although pleiotropic action allows cytokines to mediate diverse effects, it greatly limits their use for therapeutic purposes. Because of this redundancy, antagonists against a single cytokine may not have functional consequences; other cytokines may compensate. Redundancy refers to the ability of different cytokines to stimulate the same or overlapping biologic functions [1,6,7]. In addition to being pleiotropic and redundant, cytokines can have broad activity. Several different cell types are capable of producing a single cytokine. For example, IL-1 is a preinflammatory cytokine that is primarily produced by macrophages but can be produced by virtually all leukocytes, endothelial cells, and fibroblasts. Cytokines also function to initiate cascade functions, with one cytokine influencing the synthesis and actions of other cytokines. Often, the second and third cytokines will mediate the biologic effects of the first cytokine. These effects may be localized, acting on a single cell or group of cells in the area surrounding the effector cell, or systematic, with the cytokines secreted into the bloodstream and transported to their site of action. TNF-α is an example of a cytokine with wide-reaching systemic effects. Cytokines may also serve as antagonists to inhibit the action of another cytokine and as a result act as anti-inflammatory cytokines. For example, IL-10 is an anti-inflammatory cytokine that down-regulates the inflammatory and adaptive immune response [1,6,7]. Chemokines As noted, chemokines are small-protein molecules (consisting of 70 to 130 amino acids) that are involved in immune and inflammatory cellular responses and function to control the migration of leukocytes to their primary site of action in the immune response. There are four distinct classes of chemokines (C, CC, CXC, and CX3C), each named for the number and location of cysteine residing on the terminal amino acid of the protein. Currently, 47 distinct chemokine molecules have been identified within the four different classes. The vast majority of these are classified as either CC or CXC chemokines. The CC chemokines have the first two cysteine molecules adjacent to each other, while these molecules are separated by an amino acid in the CXC chemokines. The CC chemokines attract monocytes, lymphocytes, and eosinophils to sites of chronic inflammation. The CXC chemokines attract neutrophils to sites of acute inflammation [8,9]. Functionally, chemokines may be categorized as either homeostatic or inflammatory. Homeostatic chemokines are produced in relatively constant amounts (constitutively) regardless of cellular environmental conditions, while inflammatory chemokines are produced in response to proinflammatory stimuli. However, there is some overlap in the actions of specific chemokines. Colony-Stimulating Factors Colony-stimulating factors (CSFs) are a subset of cytokines that participate in hematopoiesis by stimulating bone marrow pluripotent stem cells and progenitor or precursor cells to produce large numbers of mature platelets, erythrocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and dendritic cells. The CSFs are named according to the type of target cell on which they act. Macrophages, endothelial cells, and fibroblasts produce granulocyte colony-stimulating factor (G-CSF) during times of stress or inflammation, and this factor promotes growth and maturation of neutrophils. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the mononuclear phagocyte progenitor. While CSFs are necessary for normal blood cell production and maturation, excess production has been implicated in several disease processes and in the development of corticosteroid-resistant chronic obstructive pulmonary disease (COPD). Impaired macrophage function and subsequent impairment of G-CSF activity have been associated with the development of neutrophilia in animal studies. In clinical practice, recombinant CSF is being used to increase the success rates of bone marrow transplantation and to treat chemotherapy-induced neutropenia and myelosuppression. The availability of recombinant CSFs and other cytokines offers the possibility of clinical therapy in which stimulation or inhibition of the immune response or cell production is desirable [8,9]. PATHOGEN RECOGNITION The innate immune response plays a crucial role in the proinflammatory response to infection and relies on the ability of host defenses to differentiate self from non-self, so only invading organisms are targeted. The leukocytes involved in this response recognize certain evolutionarily retained patterns present on the surface of pathogens and in response bind to the membrane and destroy the invading organism through the process of phagocytosis. Invading pathogens contain conserved structures in their cell membranes termed PAMPs, which are recognized by the cells of the innate immune system because they possess a limited number of germline-encoded pattern-recognition receptors (PRRs). Upon PAMP recognition, PRRs come in contact with the cell surface and/or send intracellular signals to the host that trigger proinflammatory and antimicrobial responses, including the synthesis and release of cytokines, chemokines, and cell-adhesion molecules. The PAMPs recognized by host PRRs are made up of a combination of sugars, lipid molecules, proteins, and/or patterns of modified nucleic acids. Because PAMPs are essential for the functioning and infectivity of the micro-organism, mutation cannot help it avoid immune recognition. The human complement of PRRs is extensive (approximately 1,000), so the classes of pathogens recognized are diverse. Pathogens of very different biochemical composition are recognized by relatively similar mechanisms by host PRRs, and no single class of pathogens is sensed by only one type of PRR; the host genetic code allows for the unique receptors involved in both innate and adaptive immunity to recognize fine details of molecular structure. The ability of the innate immune response to limit microbes early in the infectious process results from the binding of pathogens to the PRRs on leukocytes, which in turn initiates the signaling events that lead to complement activation, phagocytosis, and autophagy. Once initiated, white blood cells, neutrophils, and monocytes migrate from the blood to the tissues, along with other body fluids, causing peripheral edema. Blood monocytes mature into macrophages as they traverse the tissues and join the macrophages already present in the tissues. PRRs present on these cells become activated, which amplifies the inflammatory response through enhanced secretion of all chemical mediators, including cytokines and complements. INNATE IMMUNITY The innate immune system is comprised of two separate but inter-related lines of defense: the epithelial layer, which acts as a physical barrier to invading substances and organisms, and the inflammatory response. The innate immune response utilizes the body's natural epithelial barriers along with phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including kinins, clotting factors, and those of the complement system, to maintain internal homeostasis. The response of the innate immune system is rapid, usually within minutes to hours, and prevents the establishment of infection and deeper tissue penetration of micro-organisms. The innate immune response is effective against most pathogens. However, when the innate response is overwhelmed or ineffective, adaptive immune responses become activated as the final line of defense against invading organisms. Innate immune mechanisms are always present in the body and are rapidly activated, so the body's defenses have responded before the adaptive immune response is triggered. The innate immune system also interacts with and directs adaptive immune responses [9,10]. Under normal conditions, the innate immune response is essential to the continued health and well- being of the body. However, during times of hyper-responsiveness or hyporesponsiveness, the innate immune system plays a role in the pathogenesis of disease. One of the main functions of the innate immune system is the initiation of the inflammatory response, which involves activation of a complex cascade of events and chemical mediators. However, inflammation plays a key role in the genesis of many common pathophysiologic states, including atherosclerosis and coronary artery diseases, bronchial asthma, diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Epithelial Barriers Physical, mechanical, and biochemical barriers against microbial invasion are found in all common portals of entry into the body, including the skin and the respiratory, gastrointestinal, and urogenital tracts. The intact skin is by far the most formidable physical barrier available because of its design. It is comprised of closely packed cells that are organized in multiple layers that are continuously shed. In addition, a protective layer of protein, known as keratin, covers the skin. The skin has simple chemicals that create a nonspecific, acidic environment (acid mantle) and antibacterial proteins, such as the enzyme lysozyme, that inhibit the colonization of micro-organisms and aid in their destruction. The complexity of the skin becomes evident in cases of contact dermatitis, whereby increased susceptibility to cutaneous infection occurs as the result of abnormalities of the innate immune response, including defects in the epithelial layer itself and defects in both signaling and expressing of innate responses. Sheets of tightly packed epithelial cells also line and protect the gastrointestinal, respiratory, and urogenital tracts and physically prevent micro-organisms from entering the body. These cells destroy invading organisms by secreting antimicrobial enzymes, proteins, and peptides. Specialized cells in the lining, such as goblet cells in the gastrointestinal tract, secrete a viscous material comprised of high- molecular-weight glycoproteins known as mucins, which form mucus when hydrated. Mucins bind to pathogens, trapping them and washing away potential invaders. In the lower respiratory tract, hair-like mobile structures called cilia protrude through the epithelial cells and move microbes trapped in the mucus up the tracheobronchial tree and toward the throat. The physiologic responses of coughing and sneezing further aid in their removal from the body [3,4]. Micro-organisms that are trapped by mucus are also subjected to various chemical defenses present throughout the body. For example, lysozyme is a hydrolytic enzyme found in tears, saliva, and breast milk capable of cleaving the walls of bacterial cells by hydrolyzing the 1,4 beta-lineages between residues in peptidoglycan. In the stomach and intestines, microbes may be eliminated by the action of digestive enzymes, acid conditions, and secretions of defensins, small cationic peptides that kill both gram-positive and gram- negative micro-organisms within minutes by disrupting the microbial membrane [3,4]. When pathogens overcome the epithelial defenses, the adaptive immune response is initiated by the body's leukocytes via the recognition of common surface receptors present on the invading micro- organisms [6,11]. Cells of Innate Immunity The cells of innate immunity are capable of recognizing microbes that share common surface receptor characteristics. In response, they initiate a broad spectrum of responses that target the invading micro- organisms. The key cells of innate immunity include neutrophils, macrophages, dendritic cells, NK cells, and intraepithelial lymphocytes. Neutrophils and Macrophages The leukocytes (white blood cells) involved in the innate immune response are derived from myeloid stem cells and subdivided into two distinct groups based on the presence or absence of specific staining granules in their cytoplasm. Leukocytes that contain granules are classified as granulocytes and include neutrophils, eosinophils, and basophils. Cells that lack granules are classified as lymphocytes or monocytes. Neutrophils, which are named for their neutral-staining granules, are the most abundant granulocytes found in the blood and make up approximately 55% of all white blood cells. They are also known as polymorphonuclear neutrophils. Neutrophils are phagocytic cells capable of amoeboid-like movement and function as early responder cells in innate immunity. They are rare in the tissues and in body cavities and lay predominantly dormant in the blood and bone marrow until they are needed in the immune response. Eosinophils have large, coarse granules and normally comprise only 1% to 4% of the total white cell count. In contrast to neutrophils, these cells ingest antigen-antibody complexes and viruses rather than cellular debris. They frequently become active in parasitic infections and allergic responses. Basophils make up less than 1% of the total white cell count and contain granules that release a multitude of substances, including histamine and proteolytic enzymes. Their function is not completely understood, but they are believed to play a role in allergy and parasitic infection as well. Monocytes are the largest in size of all the white blood cells but make up only 3% to 7% of the total leukocyte count. They are released from the bone marrow into the bloodstream, where they migrate into tissues and mature into macrophages and dendritic cells. These cells participate in the inflammatory response and phagocytize foreign substances and cellular debris. Macrophages have a long life span, reside in the tissues, and are the first phagocyte that invading organisms encounter upon entering the body. Neutrophils and macrophages work in concert with each other and are crucial to the host's defense against all intracellular and extracellular pathogens. Macrophages are essential for the clearance of bacteria that reach the epithelial barrier in the intestine and other organ systems. They also have remarkable plasticity that allows them to efficiently respond to environmental signals and change their functional characteristics. This makes them more efficient than the more abundant neutrophils. Once activated, macrophages engulf and digest microbes that attach to their cell membrane. The ability of these cells to initiate this response is dependent upon recognition of pathogenic surface structures (i.e., PAMPs or PRRs), of which the toll-like receptors have been the most extensively studied. Phagocytosis of invading micro-organisms helps to limit the spread of infection until adaptive immune responses can become fully activated [4,5]. In addition to phagocytosis, macrophages process and present antigens, acting as major initiators of the adaptive immune response. These cells secrete substances that initiate and coordinate the inflammatory response on active lymphocytes. Macrophages can also remove antigen-antibody aggregates or, under the influence of T cells, can destroy malignant host or virus-infected cells. Dendritic Cells Dendritic cells are specialized, bone marrow-derived leukocytes found in lymphoid tissue and are the bridge between the innate and adaptive immune systems. These cells take their name from the dendrites within the central nervous system (CNS), because they have surface projections that give them a similar appearance. Dendritic cells are relatively rare and are found mainly in tissues exposed to external environments, such as the respiratory and gastrointestinal systems. They are present primarily in an immature form that is available to directly sense pathogens, capture foreign agents, and transport them to secondary lymphoid tissues. Once activated, dendritic cells undergo a complex maturation process in order to function as key antigen-presenting cells capable of initiating adaptive immunity. As noted, dendritic cells are responsible for the processing and presenting of foreign antigens to the lymphocytes and, like macrophages, also release several communication molecules that direct the nature of adaptive immune responses [4,5]. Natural Killer Cells and Intraepithelial Lymphocytes NK cells and intraepithelial cells are other cell types involved in the innate immune response. NK cells are so named because of their ability to spontaneously kill target organisms. Both types of cells rely on the recognition of specific PAMPs associated with the micro-organism cell type. NK cells are a heterogeneous population of innate lymphocytes that mediate spontaneous cytotoxicity against infected cells. They resemble large granular lymphocytes and are capable of killing some types of tumor and/or infectious cells without previous exposure to surface antigens. NK cells have been shown to play an equally important role in limiting the spread of infection and assisting in the development of adaptive immune responses through the production of cytokines. NK cells assist in dendritic cell maturation and innate immune control of viral infections. These cells are capable of directly killing host cells infected with intracellular (viral) or bacterial pathogenic organisms. They comprise approximately 10% to15% of peripheral blood lymphocytes but do not bear T-cell receptors (TCRs) or cell surface immunoglobulins. Two cell surface molecules have been identified—CD16 and CD56—and are widely used to identify NK cell activity. CD16 serves as a receptor for the IgG molecule, which provides NK cells with the ability to lyse IgG-coated target cells. NK cells can be divided into two main subsets based upon their ability to excrete proinflammatory cytokines. In addition, they differ in their expression of inhibitor versus activating receptors. Cells that express activating receptors (NKG2D) are induced in response to pathogen-infected or stressed cells, whereas the inhibitor receptors on NK cells recognize patterns (e.g., major histocompatibility complex [MHC]-1, lectins) on normal host cells and function to inhibit the action of the cells. This assures that only "foreign" cells are destroyed. In addition to their role as phagocytes, NK cells assist in T-cell polarization, dendritic cell maturation, and innate immune control of viral infection through the secretion of immune modulators and antiviral cytokines. Investigations of the potential role of these properties for the development of vaccines that can modulate and direct the immune response though enhanced cytokine activity are ongoing. Complement System The complement system is a primary effector system that functions as part of both the innate and adaptive immune responses. It is comprised of a group of proteins that are activated by three distinct but convergent pathways: the classical, the lecithin, and the alternative pathways. The primary function of the complement system is the promotion of inflammation and the destruction of microbes. The complement system is found in the blood and is essential for the activity of antibodies. It is comprised of 20 different proteins, many of which act as precursors of enzymes. An antigen-antibody complex initiates this system. Activation of the complement system increases bacteria aggregation, which renders them more susceptible to phagocytosis through activation of mast cells and basophils through the direct release of C3 and C5 from dendritic cells. ADAPTIVE IMMUNITY The adaptive immune response involves a complex series of interactions between components of the immune system and the antigens of a foreign pathogen. It is the final line of defense against infection and is activated after the innate immune response initiates the inflammatory process. In contrast to innate immunity, the adaptive immune response is capable of targeting specific cells or organisms that it recognizes as foreign to the body through activation of various lymphocytes and their products, including antibodies. The lymphocytes involved in adaptive immunity have the unique ability to remember specific pathogens and mount a heightened immune response during repeat exposures. Each exposure results in a more rapid and aggressive response. Substances present on the surface of pathogens are called antigens [10,12]. Adaptive immunity is comprised of two distinct but inter-related processes: cell-mediated and humoral immunity. Together, they respond to foreign antigens, amplify and sustain immunologic responses, distinguish self-from non-self, and confer "memory" so a heightened response can be initiated on subsequent exposures to an organism. Antigens are usually a substance foreign to the host that can stimulate an immune response. They possess specific antigenic binding sites (epitopes) for the cells of the immune system. Epitopes allow the adaptive immune system to distinguish foreign antigens from normal cellular substances whose destruction would be detrimental to the organism. Humoral immunity is mediated by B-lymphocyte activation and subsequent antibody production. It is the primary defense against extracellular microbes and toxins. In contrast, cell-mediated immunity involves the activation of specific T lymphocytes (i.e., T-helper and T-cytotoxic lymphocytes), which are responsible for the body's defense against intracellular microbes such as viruses. Antigens Antigens, or immunogens, are substances or molecules that are foreign to the body that trigger the production of antibodies by B lymphocytes, leading to the ultimate destruction of the invader. They are usually large macromolecules (>10,000 Da) such as proteins, polysaccharides, lipids, and free nucleic acids. Antigens are recognized by specific receptors present on the surface of lymphocytes and by the antibodies or immunoglobulins secreted in response to the antigen. Antigens can take the form of any foreign substance, including bacteria, fungi, viruses, protozoa, parasites, and non-microbial agents such as plant pollens, insect venom, and foreign materials (including transplanted organs). Antigens possess immunologically active sites called antigenic determinants or epitopes. These are smaller, discrete components of the antigen that have a unique molecular shape that can be recognized by and bound to a specific immunoglobulin receptor found on the surface of the lymphocyte or by an antigen-binding site of a secreted antibody. It is not unusual for a single antigen to possess several epitopes and, therefore, be capable of stimulating several different T and B lymphocytes. For example, different proteins that comprise the influenza virus may function as unique antigens (A, B, C, H, and N antigens), each of which contain several epitopes. Hundreds of epitopes are found on structures such as a bacterial cell wall. Low-molecular-weight molecules (