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Innate immunity, while critical to the defense of the body, is insufficient to guarantee protection. It lacks the flexibility to respond optimally to a diversity of microorganisms. By its very nature it may result in significant tissue damage. A third layer of defense is required that can act automatically in response to microbial invasion, generate resistance proportional to the threat, and improve with experience. These are the key features of the acquired immune system. Acquired immune responses are of 2 major types, antibody (humoral) immunity directed against extracellular invaders and cell-mediated immunity directed against intra-cellular invaders.
Acquired immune responses are complex and must be very carefully regulated. The immune defenses of the body are a potent system whose use must be carefully controlled in order to minimize damage to normal tissues. As a result, a major portion of the immune system is devoted to the production of regulatory cells whose function is to ensure that acquired immune responses only occur under appropriate circumstances. If these regulatory pathways fail, disease or death may result.
The acquired immune system functions through a series of steps that must occur sequentially for either an antibody-mediated or cell-mediated immune response to occur. The first step involves the capture and processing of antigens. Once processed, these antigens are located on the cell surface where they are available for recognition by lymphocytes carrying receptors for specific antigens. Each antigen receptor is highly specific, and each lymphocyte expresses only a single form of antigen receptor. Thus millions of cells have the potential to recognize millions of antigens. In order to ensure that only foreign antigens trigger acquired immunity, cells with receptors that bind and respond to normal body antigens are selectively killed early in their development. The surviving cells are located within lymphoid organs at sites where they can most effectively encounter antigens on microbial invaders, triggering them to respond by mounting immune responses. There are 3 major populations of lymphocytes: B cells that are responsible for antibody responses, effector T cells that are responsible for cell-mediated immune responses, and regulatory T cells that control these responses and minimize inappropriate responses.
Antibody Responses (Humoral Immunity)
Antibodies are B cell antigen receptors synthesized in large quantities and secreted by the cell into the bloodstream where they circulate as immunoglobulins. They are produced by B cells and from B cell-derived plasma cells. Antibodies bind to foreign molecules and mark them for destruction by phagocytic cells or complement-mediated lysis. Plasma cells are differentiated B cells optimized to synthesize and secrete enormous quantities of antibodies. Antibodies are critical to host defense against extracellular invaders such as most bacteria, some blood parasites, and viruses traveling between cells.
B cells originate in the bone marrow and reside in lymphoid tissues such as lymph nodes, bone marrow, Peyer's patches, and the spleen. Each B cell is covered by several thousand identical antigen receptors and can bind and respond to only a single antigenic molecule. When a microbe enters the body, it will inevitably encounter B cells that can bind to some of its surface antigens. As a result of antigen binding, and under suitable circumstances, these B cells divide repeatedly and differentiate into 2 subpopulations. One subpopulation, antibody-producing plasma cells, are capable of enormously increased immunoglobulin synthesis and are the major sources of antibodies. The other B cell subpopulation becomes memory B cells that persist in lymphoid tissues for months or years. When an animal encounters an antigen for a second time, these memory B cells respond rapidly, producing large numbers of plasma cells (and more memory cells). As a result, the animal mounts a vastly improved antibody response and the invader is rapidly eliminated. Subsequent exposure to a microbe leads in turn to the accumulation of more memory cells resulting in better protection, virtually guaranteeing that the organism will never be able to cause disease in that individual. This response is the basis of all vaccination programs.
Although simple in concept, B cell responses and antibody production are made more complex by the need to ensure their careful regulation. Thus a B cell is not usually able to respond to a bound foreign antigen unless it also receives “permission” in the form of a second signal from cells called helper T cells (T cells). These T cells in turn can only be activated if they are presented with antigen under carefully controlled circumstances.
Antibodies
Mammals use 5 different classes of antibodies: immunoglobulin G (IgG), IgM, IgA, IgE, and IgD. The class of immunoglobulin secreted by B cells and plasma cells depends primarily on their location. Cells located in lymphoid organs within the body secrete IgM and IgG, whereas cells located on body surfaces secrete IgM, IgA, and IgE.
IgG is the most abundant immunoglobulin within the bloodstream and plays the major role in binding and eliminating organisms that succeed in penetrating deep into the body. IgM serves as a “back-up” for IgG and is usually confined to the bloodstream. IgM is produced early in the antibody response, when high effectiveness compensates for its low quantity.
IgA is produced by B cells and plasma cells located on mucosal surfaces. IgA is produced and secreted in large amounts into the upper respiratory tract, the GI tract, tears, sweat, etc. It complements the physical barriers of the body and prevents microbial invasion. IgE serves as a “back-up” for IgA and is also mainly produced on body surfaces. IgE is optimized to prevent invasion by parasites such as helminths or arthropods. However, it also mediates a rapid acute inflammation in allergic states and hence may mediate life-threatening anaphylaxis. IgD is believed to be of minimal functional significance.
T Cell Help
Most antibody responses are regulated by the need to receive prior approval from T cells. The T cells in turn are activated only when they bind antigen fragments presented by specialized antigen-presenting cells called dendritic cells.
Dendritic cells are macrophage-like cells whose role is to capture and process foreign antigens. Their name derives from their many long, thin filamentous processes or dendrites that extend through tissues to form an effective antigen-trapping web. For example, a subpopulation of dendritic cells (Langerhans' cells) exists in the dermis where its web of dendrites traps micro-organisms seeking to enter the body through damaged skin. Dendritic cells capture and phagocytize invading microorganisms. However, large fragments of foreign antigens persist within the dendritic cells. These antigen fragments become attached to receptor molecules (MHC molecules) within dendritic cells. Once formed, these antigen-MHC complexes move to the cell surface where they can be recognized by T cells.
The receptors in dendritic cells that bind and present antigen fragments are specialized proteins encoded by genes clustered together in the major histocompatibility complex (MHC; originally identified as the antigens that cause graft rejection, hence their unusual name). There are many thousands of these MHC molecules expressed within an animal population but relatively few (3–6) expressed in any individual animal. Because they play a critical role in binding antigen fragments and activating T cells, MHC molecules effectively determine whether or not an individual can respond to a foreign antigen. An individual animal possesses MHC molecules that can bind many, perhaps most, foreign antigens, but not all of them. If an animal lacks MHC molecules that can bind an antigen, it will be unable to respond to that specific antigen. The set of antigens to which an individual can respond (and against which it is protected) are determined by its MHC haplotype. All domestic animal species possess their own unique MHC. The receptors coded for these genes are named after the specific species; thus BoLA is the name of these molecules in cattle, ELA in horses, SLA in swine, etc.
Like B cells, T cells possess specific antigen receptors on their surface that are generated randomly when the cells are first produced. As these T cells mature within the thymus those with receptors that can bind normal body components are killed. Surviving T cells can respond only to foreign antigens. The antigen receptors on T cells, like those on B cells, are identical on any single cell. Unlike those on B cells, however, the receptors can recognize antigen only when it is bound to an MHC molecule. Thus, when a dendritic cell presents MHC-associated antigen to T cells; only those T cells with appropriate receptors will bind to the DC. Once in contact, the cells exchange signals that confirm that the T cell is responding to a correctly processed antigen. This may take several hours. After T cells receive all the necessary signals, they begin to secrete a mixture of cytokines that permit attached B cells to respond to antigens, allowing an antibody response to proceed.
Antibodies are produced in response to, and directed against, extracellular bacteria. Cell-mediated responses, in contrast, are directed against viruses and intracellular bacteria. The decision as to the appropriate form of the immune response is made at an early stage in the immune response. Thus, there are 2 populations of dendritic cells that can trap and process antigens. One population (DC1 cells) triggers cell-mediated immunity while the other (DC2 cells) triggers antibody formation. These dendritic cell populations send different messages to T cells because they use different cytokines for signaling; DC1 cells secrete IL-12, while DC2 cells secrete IL-1. In turn, these different cytokines stimulate 2 different T cell populations: T1, which promotes cell-mediated immunity, and T2, which promotes B cell responses and antibody production. T1 cells secrete a mixture of cytokines typified by interferon-γ (IFN- γ). T 2 cells secrete a mixture of cytokines typified by IL-4. B cells will usually respond optimally to a foreign antigen only if they are stimulated by the presence of IL-4 from T2 cells.
Cell-Mediated Immunity
As described above, cell-mediated immune responses are required to combat intracellular invaders such as viruses and some intracellular bacteria. The immune system blocks virus infections by killing the cells that they infect. The cells responsible are called effector (cytotoxic) T cells. Like T cells, effector T cells undergo development and selection within the thymus so that any T cells capable of killing normal healthy cells are eliminated. The surviving T cells are released into the body where they circulate continuously through the tissues seeking out abnormal cells.
All nucleated cells produce many different proteins when functioning normally. Virus-infected cells, however, are forced by the virus to produce viral proteins. The body requires that all nucleated cells send a sample of their newly synthesized proteins to the cell surface. A small sample of newly formed protein is therefore set aside and fragmented in a complex enzyme system called a proteasome. These protein fragments are then attached to MHC molecules and carried to the cell surface where they are available for inspection by effector T cells. If the cell's receptors do not engage an antigen, nothing happens. If their antigen receptors bind to a foreign antigen in an MHC-protein complex, however, the T cell will be signaled to kill the offending cell. Like B cells, effector T cells only function if they receive permission from a T cell, specifically a T1 cell. The cytokines from T1 cells, especially IFN-γ, must be present if an effector T cell is to kill its target.
Effector T cells bind tightly to target cells and then signal them to commit suicide through apoptosis. The T cells inject their targets with enzymes called granzymes that trigger this process. As a result, effector T cells eliminate virus-infected cells but not normal, healthy cells. Most of the effector T cells die within a few days once they are no longer needed, but a few survive to become long-lived memory cells that respond rapidly should the animal encounter the virus a second time.
Effector T cells are especially effective at killing target cells producing foreign antigens. However some intracellular organisms, especially intracellular bacteria, are best destroyed by other cell-mediated mechanisms. In these cases IFN-γ from T1 cells activates macrophages. As a result, bacteria that can survive within normal macrophages are rapidly destroyed by activated macrophages.
Immunologic Memory
The effectiveness of acquired immunity is largely a result of its ability to recognize antigens encountered previously and to mount an enhanced and accelerated response against them. The more an animal encounters an antigen, the greater will be its immune response. Immunologic memory depends on the presence of persistent populations of memory cells that accumulate as an animal ages. These memory cells may be very long-lived or, more likely, turn over very slowly. As a result, animals may make small amounts of antibodies to vaccine antigens for many years after vaccination. Cell-mediated memory is also a result of the presence of very long-lived populations of memory T cells. The effectiveness of vaccines in inducing long-lasting immunity depends in large part on their ability to induce memory cell populations.
Cytokines
The cells of the acquired immune system communicate in several ways. They can come into physical contact and exchange signals through receptors within the contact area or immunologic synapse. Examples include the contact between T cells and dendritic cells or between effector T cells and their targets. Immune cells can also signal nearby cells by secreting small signaling proteins called cytokines. Several hundred different cytokines have been identified. Signaling cells secrete a mixture of cytokines that then bind to receptors on nearby cells. The target cell receives multiple signals that it must integrate in order to respond appropriately. Cytokines, acting through their specific receptors, can turn the synthesis of specific proteins on or off. They can cause the target cell to divide or differentiate, and they may trigger apoptosis. With hundreds of different cytokines acting in complex mixtures it is sometimes difficult to predict exactly how a specific target cell will respond. Major families of cytokines include the interleukins that mediate signaling between WBC, interferons that mediate interactions between cells and have significant antiviral activity, growth factors that regulate growth and differentiation of many different cell types, and tumor necrosis factors that modulate inflammatory responses.
Regulatory Cells
The acquired immune system is carefully regulated by several different cell populations. The most important are Treg cells, which secrete a mixture of cytokines that inhibit conventional immune responses. They serve to turn off an immune response once it has completed its task and the invading microorganism is eliminated. Treg cells also play a central role in preventing the development of autoimmunity. Another important population of regulatory T cells are called T 17 cells. These cells, so called because they secrete IL-17, regulate the innate immune system and the development of inflammation.
Last full review/revision July 2011 by Ian Tizard, BVMS, PhD, DACVM
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