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WSU ESRP 531 - Fundamentals of Environmental Toxicology

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ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 14 Immunotox.doc Page 1 of 11 October 12, 2005 Lecture 14 Immunotoxicity I. Overview of Immune System Structure and Function (Physiology) A. Function of the immune system in an organism’s survival 1. Resist infectious agents 2. Destroy neoplastic cells 3. Reject nonself components B. Differentiated lymphoid organs do not appear in organisms phylogenetically lower than fish; however, immunocytes (cells with immune functions) of various forms are found in all Phyla from sponges to vertebrates. C. Immunoglobulins (antibodies) are found in vertebrates only, but functionally analogous proteins called agglutinins are present in invertebrates. 1. Five immunoglobulin classes are found in mammals 2. Three in birds; 3. Two in amphibians and reptiles; 4. One immunoglobulin class is found in fish. D. The functional units of the immune system are leukocytes (a.k.a. white blood cells) that develop from pluripotent stem cells. 1. The stem cells undergo differentiation, maturation, and proliferation into morphologically and functionally distinct cell populations, including (Figure 1): a. Granulocytes 1. Neutrophils (a.k.a. polymorphonuclear leukocytes or PMNs) 2. Basophils (granulocytes found in blood) 3. Eosinophils 4. Mast cells (granulocytes found in tissue) b. Monocytes (found in blood) 1. Macrophages (designation for monocytes found in tissue) c. Lymphocytes 1. Natural killer cells (NK cells); large granular lymphocytes 2. T-lymphocytes (a.k.a. T-cells) 3. B-lymphocytes (a.k.a. B-cells) d. Plasma cells (produce antibodies; a.k.a. immunoglobulins) E. Tissues producing leukocytes 1. Primary lymphoid tissues include a. Bone marrow (Tissue from which immune cells are derived) b. Thymus (Tissue in which T-lymphocytes are differentiated) 2. Secondary lymphoid tissue a. Spleen b. Lymph nodes (scattered throughout the body) c. Tonsils & Adenoids 3. Localized lymphoid tissue aggregates found associated with bronchus, gut, and skinES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 14 Immunotox.doc Page 2 of 11 Figure 1. In mammals, pluripotent stem cells differentiate to various forms of leukocytes that form functionally distinct cell populations (from Weeks et al. 1992). The source tissue (or primary lymphoid tissue) of all the immune cells is the bone marrow. The T-lymphocytes mature and differentiate in the thymus gland (which is also a primary lymphoid tissue). Maturation, differentiation, and mobilization of immune cells are controlled by cytokines (e.g., interleukins, interferons, and chemokines), which are soluble mediators produced within immune cells and/or by cells outside the immune system (e.g., epithelial cells and nervous system cells) (Selgrade et al. 2001) F. Mediation of immunity by leukocytes occurs via two processes 1. Nonspecific immune responses that are mediated by mononuclear phagocytes (i.e., blood monocytes and tissue macrophages) and granulocytes that recognize foreign material (or cells like bacterial pathogens) a. Often called nonspecific immunity b. Includes two types of responses: 1. Phagocytosis a. Ingestion and destruction of foreign agents by specialized cells 2. Inflammation a. Infiltration of phagocytic cells into tissue at site of injury or infection 1. Characterized by activation of clotting mechanisms, increased blood flow, and increased capillary permeability. (Selgrade et al. 2001) (a) These responses facilitate mobilization of immune cells to the site of injury and result in the swelling and reddening associated with inflammation. c. Mediated mainly by polymorphonuclear leukocytes (neutrophils) and mononuclear phagocytes (macrophages)ES/RP 531 Fundamentals of Environmental Toxicology Fall 2005 ESRP531 Lect 14 Immunotox.doc Page 3 of 11 1. Neutrophils: Short lived cells specialized for ingesting and destroying microorganisms in the circulation or in tissues following infiltration of an infected site. a. Release lysozyme enzyme that is capable of lysing cell components 2. Macrophages: differentiated monocytes that “wander” within an organ or may be infiltrative into tissue. d. Phagocytic and inflammatory responses can be enhanced by products of lymphocytes, including antibodies and lymphokines. e. Mammals have natural killer cells (NK cells) that are derived from granular lymphocytes 1. Compose about 5% of the peripheral blood lymphoid cells 2. Recognize changes in cell surface markers on virus-infected cells and on some tumor cells. a. Role in preventing metastases of tumors (movement of tumor cells from the main tumor body through the circulatory system to other tissues) 3. Can be activated by lymphokines (e.g., interleukin-2 or IL-2). 2. Specific immune responses: two mechanisms a. Cell-mediated immunity (CMI) (Figure 2, left-hand side of schematic) 1. Induced by cells (known as thymus dependent lymphocytes or T-lymphocytes or T-cells) that mature in the thymus. 2. CMI responses mediate: a. Immunoregulation b. Delayed-type hypersensitivity c. Immunosurveillance d. Graft rejection e. Resistance to infection by pathogens (viruses, bacteria, protozoans, fungi) b. Humoral-mediated immunity (HMI) (Figure 2, right hand-side of schematic) 1. Mediated by lymphocytes (called B-lymphocytes or B-cells) that mature in the bursa of Fabricius in birds (tissue near the cloaca) or bursal-equivalent tissues and organs in mammals (e.g., a distal intestinal associated lymphoid tissue and/or bone marrow). a. B-lymphocytes produce antibodies (immunoglobulin) 2. In anuran amphibians and reptiles, as in higher vertebrates, a functional bone marrow produces the differentiated B-cells. 3. In fish and non-anuran amphibians that lack bone marrow, B-cells are generated in other organs. c. Both T-cells and B-cells are released into the circulation and taken up by lymphoidal organs (lymph nodes and the spleen) (Figure 2). 1. Lymph nodes filter the lymphatic fluid; spleen filters the blood. 2. Exposure to antigens in these lymphoidal organs induces the lymphocytes to assume their genetically determined functional characteristics. a. Antigens stimulate only those lymphocytes that have receptors complementary to the antigen configuration. b. The antigens can be a piece of cell membrane and associated unique proteins on a pathogen surface or it can be a small protein or other


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WSU ESRP 531 - Fundamentals of Environmental Toxicology

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