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Close window to return to IVIS Proceeding of the NAVC North American Veterinary Conference Jan. 8-12, 2005, Orlando, Florida Reprinted in the IVIS website with the permission of the NAVC http://www.ivis.org/ Published in IVIS with the permission of the NAVC Small Animal - Immunology IMMUNOLOGIC CONCEPTS - OVERVIEW OF PHAGOCYTIC, CELL MEDIATED & HUMORAL IMMUNITY Leah A. Cohn, DVM, PhD, DACVIM College of Veterinary Medicine University of Missouri, Columbia, MO INTRODUCTION Because the immune system must ward off or kill a wide variety of pathogens, and yet manage to recognize and avoid attacking the host’s own tissues, it requires complex, redundant, and overlapping systems of effectors and regulators. Our understanding of these systems has grown exponentially in recent years. A basic understanding of these systems is important for veterinarians as they recognize and treat a myriad of infectious and immunologically mediated diseases. Protection from infection is not entirely immunologic. Crucial physical defense systems provide the initial barrier to infection. In addition to physical barriers (e.g., skin, epithelial surfaces), physical defenses include directional movement (e.g., respiratory mucociliary escalator, cough, sneeze, flushing action of urination), chemical properties (e.g., acidic gastric pH, concentrated urine, secreted antimicrobial molecules), and more. When these systems malfunction, infection follows. Immunity is integrally tied to inflammation, although the two aren’t quite the same thing. Inflammation is a cyclic, complex series of events initiated when tissue is injured (by pathogens, trauma, chemicals, or nearly anything) designed to destroy, dilute, and wall off the injurious agents. It utilizes both soluble mediators (e.g., cytokines, histamine, serotonin, eicosanoids, kinins, complement, coagulation factors) and cells (e.g., monocytes, neutrophils (PMN), mast cells, platelets, basophils, eosinophils) to accomplish these goals. Many of these same mediators and cells are integrally involved in immune responsiveness. Inflammation presents the injurious agent to the immune system, which attempts to eliminate the agent. If successful, inflammation resolves. Immunity itself is often categorized as innate and adaptive. Innate immunity is “ready to go”, and requires no previous exposure to a pathogen. Adaptive immunity “learns” from prior exposure. After initial exposure to a pathogen, memory forms of that specific pathogen allowing a more rapid, precise, and effective immune response on subsequent exposure. Both forms of immunity are necessary for health. An alternative way to classify immunity is into three systems described as phagocytic immunity (PI), cell mediated immunity (CMI), and humoral immunity (HI). PHAGOCYTIC IMMUNITY Phagocytic immunity is fundamental to innate immunity, and is carried out by effector cells that literally devour pathogens or other foreign material. Animals with defective PI are particularly prone to bacterial and fungal infections. The two major cell types involved in PI are the PMN and the monocyte, which develops into a mature macrophage (MØ). The PMN and MØ share many similarities, but there are key differences as well. Both cells are derived from myeloid precursors in the marrow, then released into peripheral circulation. Both leave circulation to enter tissues under the influence of chemotaxins, which are chemical signals that attract phagocytes much the way a hound follows the scent of its prey. Both use cell surface receptors and ligands, 451 Close window to return to IVIS www.ivis.org including integrins and cell adhesion molecules, to receive signals and then to carry out actions. Both PMN and MØ are capable of engulfing many types of particulates (including pathogens) without prior exposure, but they do so much more avidly when the target has been opsonized by antibodies or complement (c’). Both cell types are equipped with a large arsenal of weapons such as preformed chemical poisons and newly synthesized oxygen radicals to kill ingested microbes. There are crucial differences between PMN and M∅ too. The PMN is a single purpose cell that engulfs the pathogen, kills it, then itself dies. The M∅ assumes multiple functions including killing pathogens, but also including roles in tissue remodeling and repair, inflammation, clean up of debris, and regulation of immunity. The M∅ does not die after completing phagocytosis, but assumes a vital role which ties innate to acquired immunity. Both the M∅ and closely related dendritic cells can digest a pathogen into many individual antigens (recognizable small bits), and then present those antigens to T-lymphocytes in a recognizable form, allowing the lymphocytes to orchestrate an adaptive immune response. Large, inert substances such as metal or ceramic implants which cannot be digested into small bits by the M∅ and dendritic cells therefore cannot elicit adaptive immunologic rejection. Using the military as an analogy for immunity, the dendritic cells and M∅ provide intelligence based on which the “brass” can make decisions regarding the optimum form of attack. Attack can only follow recognition of the enemy. CELL MEDIATED IMMUNITY Cell mediated immunity, carried out by T-lymphocytes, is quite complex. There are different types of T-lymphocytes, each with different functions. The most basic distinction is between the T helper cells (Th, a.k.a., CD4 cells) and the T-cytotoxic cells (Tc, a.k.a., CD8 cells). The term “CD” stands for cluster designation, and is simply a numerically ordered naming system for recognizable molecules on the surface of cells. The number provides no direct information on cell type or function of the molecule, and often these CD numbers also have alternative, descriptive names (e.g., CD4 is the same thing as the MHC II receptor). Continuing the military analogy, the Tc cells are soldiers that carry out CMI, while the Th cells are the commanders who stay back from the front lines and direct the military-like immune response to the pathogen. Neither the Th cells nor the Tc cells are capable of recognizing antigen unless it is presented in a specific fashion. The key to presentation of antigen is that it must be displayed to the lymphocytes in the context of a genetically encoded major histocompatibility complex molecule (MHC) on the surface of a cell. There are two major types of MHC molecules used to present antigen. Nearly every cell of the body carries MHC I molecules on its surface; these molecules can be thought of as identification badges. The “foot soldiers” of CMI, the Tc cells, examine the ID badge of the cells they encounter throughout the body. If the ID badge is recognized as belonging to the host, the cell is allowed to pass. If the ID badge has been tampered with, as when there is an intracellular infection or in transplanted tissue, the soldier kills the cell on sight. On the other hand, the commanding Th cells need more detailed information to organize an all out attack; the question of whether they should mount a cell mediated or humoral response is somewhat like deciding whether air strikes or a ground attack is more appropriate and then calling in the air www.ivis.org Published in IVIS with the permission of the NAVC The North American Veterinary Conference – 2005 Proceedings force or army. The commander Th cells only respond to information gathered by specialized intelligence units, or antigen presenting cells. These cells, including M∅, dendritic cells, and even B-lymphocytes, gather information about the pathogen and present it to the Th cells in the context of surface MHC II molecules. Once the Th cells have been presented with information from the antigen presenting cells, they consider all the circumstances and choose the most appropriate course of action. They decide if they should ignore the threat, or if they should mount an attack using CMI or HI. The type of attack is directed in large measure by the secretion of chemical cytokine signals from the Th cell. The Th cells develop into one of two mutually inhibitory types – T helper 1 or T helper 2 cells. These cell types don’t differ in structure, but rather in the type of cytokines they secrete. The Th1 cells promote CMI to defend from intracellular pathogens, activate M∅ and resist bacterial infection, and promote delayed type hypersensitivity. The Th2 cells provide antibody mediated responses including protection from parasites as well as mediation of allergic responses. The two responses are antagonistic, meaning that stimulation of Th1 inhibits Th2 response and vice versa. This means that animals with a chronic parasite burden, for instance, may be less capable of effectively dealing with viral, bacterial, or fungal infection. It also means that therapy for allergic disease might involve “tricking” the immune system into turning away from a Th2 response and towards a Th1 response. HUMORAL IMMUNITY Humoral immunity is mediated by B lymphocytes, but requires significant “help” from T-lymphocytes, and particularly from Th cells. The B cells have 2 basic jobs; to serve as an alternative type of antigen presenting cell and to cause the secretion of antibodies. Antibodies come in a variety of isotypes (IgG, IgM, IgA, IgE, IgD), each of which is particularly well suited for specific jobs in a specific environment. The jobs of the antibodies include opsonizing pathogens so that they are more readily phagocytized, triggering c’ activation, promoting cytotoxic reactions to kill cells or pathogens, preventing attachment and penetration of pathogens into tissues, neutralizing some toxins, and providing maternal immunity. Each antibody is a bifunctional molecule. The aforementioned functions are triggered by the base (Fc portion) of the molecule. The opposite end of the molecule (Fab portion) provides specificity to the reactions carried out by the antibody. The ends of the Fab portion are configured in such a way that they bind to only a very limited number of structures, or antigen epitopes. Specificity is key to adaptive immunity. Both CMI and HI are restricted by very specific reaction to very specific pieces of an antigen called epitopes. Any one pathogen, even the smallest virus, can have hundreds of different epitopes. Only a very few lymphocytes (T and B) will react with any one epitope on first encounter. Once an encounter has occurred, these same few lymphocytes can be stimulated to replicate at an amazing rate. The specificity of the reaction between the lymphocytes and the epitope is conferred by receptors for the epitope on the lymphocyte. In the case of the T cells, it is the T cell receptor (TCR) that provides specificity. In the case of the B cell, it is the B cell receptor (BCR). It turns out that the BCR is an antibody molecule, but instead of a secreted antibody molecule, it is an antibody attached by its base to the surface of the B cell. Any single B cell (or T cell) has only Close window to return to IVIS www.ivis.org a single type of BCR (or TCR), but it has hundreds of them. When the BCR (or TCR) binds to the epitope that fits the receptor, and the lymphocyte receives the needed costimulatory signals, then that lucky lymphocyte is stimulated to proliferate. In the case of HI, stimulated B cells go on to develop into plasma cells and memory cells. Plasma cells produce and secrete large quantities of antibody to fight the immediate threat. Once the threat is gone, proliferation and stimulation of the lymphocytes ceases and the immune response becomes inactive. The memory cells, however, persist. These cells allow a second meeting with the same pathogen to trigger a more rapid response. This is one of the key ways in which active vaccination works. An injected epitope (either from an inactivated intact pathogen, a killed pathogen, or just a piece of a pathogen) stimulates memory cells that can then recognize the same epitope from a real infection later on, and triggers a rapid response to the pathogen. IMMUNOLOGIC TOLERANCE Immune responsiveness must be regulated in both quality and quantity to avoid damaging the host tissue. Regulation begins with immune tolerance, or the ability to tolerate or ignore given antigens. Since nearly any cell can serve as an antigen, the host must learn to ignore their own cells, and to ignore antigens that will not cause harm (e.g., food antigens, pollens, commensal bacteria). Just as there are many ways to stimulate immunity, there are many ways to induce tolerance. Central tolerance begins in utero, in the thymus for T-lymphocytes and in the marrow for B lymphocytes. Although both cell types can be made tolerant, it is more important to render T cells tolerant since they provide needed help for both CMI and HI. In the thymus, T cells are first positively selected to recognize self MHC. Those that do recognize self MHC proliferate. Next, T cells undergo negative selection. Self antigens from most of the body reach the thymic tissue in utero. Those T cells that bind to self antigens are caused to die via apoptosis (as opposed to necrosis), and they simply disappear. This “clonal deletion” means that progenitors of self-reactive T cells are simply wiped out before birth. Because not all self reactive clones will be eliminated, there are mechanisms of peripheral tolerance as well, including sequestration of antigens, deletion of self-reactive cells in the periphery, rendering selfreactive cells non-reactive through lack of co-stimulation, and deviation of the immune response. Failure of immunologic tolerance can lead to autoimmunity. Failure of immune regulation can lead to hypersensitivity related diseases, whether autoimmune in nature or not. Hay fever and atopy are examples of immune mediated but not autoimmune diseases that result from faulty immune regulation. Previously presented at the 22nd Annual ACVIM Forum, Minneapolis, MN, June 2004. REFERENCES 1. Roitt I, Brostoff J, Male D. Immunology. 6th edition. Mosby, Harcourt Publishers Lmtd. London, 2001. 2. Tizard IR, Schubot RM. Veterinary Immunology: An Introduction. WB Saunders Co, Philadelphia, 7th edition, 2004. www.ivis.org 452