Pathophysiology JP Advis DVM, Ph.D. Bartlett Hall, Animal Sciences, Cook, 932-9240, advis@aesop.rutgers.edu 03 Course website: rci.rutgers.edu/~advis Lectures, tests, grades, office hours, textbook, Material to be covered: About lecture slides: Lectures 1-2: Introduction to Pathophysiology (2) Lectures 3-4: Mechanisms of Self-Defense and Stress (2) Lectures 5-8: Endocrine and Nervous System Dysfunctions (4) Lecture 9: Alterations of Skeletal Muscle Function (1) REVIEW AND TEST #1 Lectures 12-18: Cardiovascular, Respiratory and Renal Dysfunctions (7) REVIEW AND TEST #2 Lectures 21-24: Alterations of Digestive Function and Intermediary Metabolism (4) Lectures 25-26: Alterations of the Reproductive System (2) REVIEW AND TEST #3 There are not intended to be the sole source for studying the course material!!!!!!!!!!!!!!!! Slides are good to review the course material after you have study your course textbook Slides are a good indicator of the relative importance of lecture topics (see slide # per topic Group slides by titles when using them to review course material. Match lectures and text. LINES OF DEFENSE MECHANISM: There are 2 types, innate resistance (barriers, inflammation) and the adaptive (acquired) immune system. Physical /mechanical barriers prevent damage to individual and pathogen invasion. Include skin & mucous membranes. Antibacterial peptides in mucous secretions, perspiration, saliva, tears, and other secretions are., a rapid /non-specific response in vascularized tissues, has as its macroscopic hallmarks redness, swelling, heat, pain, and loss of function of the site. Its microscopic hallmark is accumulation of fluid and cells at the site. is a line of defense that is slower to start than innate resistance but it is specific and has a memory that makes it have a long life. It is acquired after birth, is mediated by T and B-lymphocytes, and is initiated by innate defense signals. is active or passive depen-ding on its immune components origin, host or donor. Page 1
Defense Mechanisms CHARACTERISTIC Defense level INNATE IMMUNITY BARRIERS First line of defense against infection and tissue injury INNATE IMMUNITY INFLAMMATION Second line of defense (occurs as a response to tissue injury or infection) Timing of defense Constant Immediate response Specificity Cells Broadly specific Epithelial cell make barrier (eg. Skin) Broadly specific Mast cell, granulocyte, monocyte, macrophage, NKC, platelet, endothelial ADAPTIVE (ACQUIRED) IMMUNITY Third line of defense; becomes active when innate immune system signal cells of adaptive immunity Delay in exposure to antigen & max. response Very specific T lymphocytes, B-lymphocytes Macrophages Dendritic cells Memory No memory No memory Specific by T & B lymphocytes Protein factors Cytokines and chemokines Toxins from epithelial cells, lysozymes, bacterial toxins Complements, clotting factors, kinins Few Many Many Antibodies, complement CHARACTERISTIC INNATE IMMUNITY BARRIERS INNATE IMMUNITY INFLAMMATION ADAPTIVE (ACQUIRED) IMMUNITY Defense level First line of defense against infection and tissue injury Second line of defense (occurs as a response to tissue injury or infection) Third line of defense; becomes active when innate immune system signal cells of adaptive immunity Timing of defense Constant Immediate response Delay in exposure to antigen & max. response Specificity Cells Broadly specific Epithelial cell make barrier (eg. Skin) Broadly specific Mast cell, granulocyte, monocyte, macrophage, NKC, platelet, endothelial Very specific T lymphocytes, B-lymphocytes Macrophages Dendritic cells Memory No memory No memory Specific by T & B lymphocytes Protein factors Toxins from epithelial cells, lysozymes, bacterial toxins Complements, clotting factors, kinins Antibodies, complement Cytokines and chemokines Few Many Many Page 2
- general INFLAMMATION: A rapid / non-specific response in vascularized tissues. Its hallmarks are redness, swelling, heat, pain, loss of function of the site, and accumulation of fluid and cells at the site. Mast cells activates inflammation by releasing biochemical mediators (histamine, chemotactic factors) from preformed cytoplasmic granules and by synthetizing others (PG, leukotriens) in response to a stimulus. Three are involved in inflammation: the complement, the clotting and the kinin systems. Different cell types are involved in inflammation including neutrophils, monocytes and macrophages, eosinophils, natural killer cells and platelets. Cells involved in inflammation stimulate other cells through the release of cytokines, which include interleukins, interferons, and other molecules. - general Sequence of events in the process of inflammation: 1- vasodilation; 2- vascular permeability; 3- WBC adherence Page 3
arteriole capillary venule Sequence of events in inflammation 1- vasodilation; 2- vascular permeability; 3- WBC adherence - general BENEFITS OF INFLAMMATION: Limits / controls tissue damage through the influx of plasma protein systems (eg. clotting) and WBC (eg. eosinophils) that prevent inflammatory response to spread to healthy tissue. Dilute bacterial toxins, help destroy bacteria by influx /activation of plasma proteins & WBC (neutrophils, macrophages). Initiates adaptive immune response through influx of macrophages / lymphocytes & drainage of microbial Ag by lymphatic vessels to lymph node where they activate lymphocytes. Initiates healing through removal of bacterial products, dead cells, and other products of inflammation (eg. by channels in the epithelium or drainage by lymphatic vessels) and by activating repair mechanisms. can be divided into 3 phases: acute, chronic, & granulomatosus inflammation, each with different mediators. Page 4
- general Active inflammatory response: inflammation is usually initiated by cellular injury and might be complicated by infection. Mast cell degranulation, the activation of 3 plasma systems, and the release of sub- from the damaged cell occur as a consequence. These systems are interdependent so that induction of one (eg. Mast cell degranulation) can result in the induction of the other two, resulting in the hallmarks of inflammation. Mast cell degranulation Vasodilation (redness, heat) Vascular permeability (edema) Cellular injury Pathogenic invasion Activation of plasma systems Cellular infiltration (pus) Thrombosis (clots) Release of cellular products Stimulation of nerve endings (pain) Active inflammatory response: inflammation is usually initiated by cellular injury and might be complicated by infection. Mast cell degranulation, the activation of 3 plasma systems, and the release of sub- from the damaged cell occur as a consequence. These systems are interdependent so that induction of one (eg. Mast cell degranulation) can result in the induction of the other two, resulting in the hallmarks of inflammation. Page 5
mast cells Mast cells are filled with dark stained granules containing a large number of biologically active substances. Among these is histamine, an initiator of vascular changes and a variety of chemotactic factors, which is released immediately after mast cell stimulation. Other substances synthetized in response to mast cell stimulation include membrane-derived phospholipids products of PLA2 activation, such as PAF, PG, and leukotrienes. Mast cell degranulation synthesis chemotactic factors histamine vascular effects Phospholipase A2 neutrophil chemotactic factor attracts neutrophils eosinophil chemotactic factor attracts eosinophils cyclooxygenase Arachedonic acid 5-lipooxygenase Platelet activating factor vascular effects platelet activation prostaglandins vascular effects pain leukotrains vascular effects Mast cells are filled with dark stained granules containing a large number of biologically active substances. Among these is histamine, an initiator of vascular changes and a variety of chemotactic factors, which is released immediately after mast cell stimulation. Other substances synthetized in response to mast cell stimulation include membrane-derived phospholipids products of PLA2 activation, such as PAF, PG, and leukotrienes. Page 6
mast cells Effects of histamine through H1 and H2 receptors. These effects depend on (1) the density and affinity of H1 and H2 receptors on the target cell, and (2) the identity of the target cell. Smooth muscle cell Endothelial cell Neutrphil Mast cell Contraction Contraction (retraction of endothelial cell) Increased chemotaxis Prostaglandin synthesis Parietal cell of stomach mucosa Lymphocyte Eosinophil Neutrophil Mast cell Secretion of gastric acid Decreased activity Decreased activity Decreased chemotaxis Decreased degranulation Effects of histamine through H1 and H2 receptors. These effects depend on (1) the density and affinity of H1 and H2 receptors on the target cell, and (2) the identity of the target cell. Page 7
plasma proteins PLASMA PROTEIN SYSTEMS: Three are involved in inflammation: the complement system, the clotting system, and the kinin system. Their components are a series of inactive proteins that are activated sequentially. The complement system can be activated by Ag-Ab reactions (through the classical pathway) or by other products, mainly bacterial polysaccharides (through the lectin or the alternative pathway), resulting in the production of biologically active fragments and target cell lysis. Its most potent products are C3b (opsonin), C3a (anaphylatoxin), and C5a (anaphylatoxin, chemotactic factor). The clotting system stops bleeding, localizes microorganism and provides a meshwork for repair and healing. The kinin system causes vascular permeability, smooth muscle contraction, and pain. Its most important product is bradykinin. plasma proteins Page 8
Classical pathway Lectin pathway Alternative pathway Cellular injury Hageman factor XII Prokallikrein Opsonin Anaphylotoxin Pain histamine like effects Chemotactic factor anaphylatoxin Blood clot Chemotactic factor Vascular permeability Death of target cell components CELLULAR COMPONENTS OF INFLAMMATION: Different cells are involved, including neutrophils, monocytes, macrophages, eosinophils, NK cells, and platelets. Phagocytic cells (neutrophils and macrophages) engulf and destroy micro-organisms by enclosing them in vacuoles with toxic products (O2 metabolites) and lysosomal products. The early cells involved are neutrophils, they exit blood vessels by diapedesis and move to the inflammation site by chemotaxis. Macrophages are involved in the late inflammatory phase, are highly phagocytic, responsive to cytokines, and promote wound healing. Eosinophils release products that control the inflammatory response and are the main cell killing parasitic organisms. NK cells recognize and eliminate cells infected with viruses, cancer cells, and other abnormal cells. Platelets interact with clotting proteins to stop bleeding and release a number of mediators controlling inflammation. Page 9
cell components Activation of a macrophage by cytokines: some cytokines produced by lymphocytes can react with surface receptors on macrophages and greatly increase their ability to kill bacteria. (A) EM of a peripheral blood monocyte; (B) EM of an activated tissue macrophage showing increase in cytoplasmic volume, plasma membrane, and number of lysosomal granules. Additionally, activation includes increases in glucose metabolism, phagocytic activity, and bacterial killing. cell components Phagocytosis is a multiple process that involves diffusion of chemotactic factors from a site of injury. Many additional factors affect the blood vessels and increase adhesion molecules on endothelial cells and neutrophils, resulting in adherence of the neutrophils to the vessel wall (pavementing), retraction of endothelial cells (vascular permeability), and movement of the neutrophils through the opened intercellular junctions (diapedesis) and into the tissue. Cells move up-gradient to the highest concentration of chemotaxic factors (chemotaxis). Page 10
Phagocytosis is a multiple process that involves diffusion of chemotactic factors from a site of injury. Many additional factors affect the blood vessels and increase adhesion molecules on endothelial cells and neutrophils, resulting in adherence of the neutrophils to the vessel wall (pavementing), retraction of endothelial cells (vascular permeability), and movement of the neutrophils through the opened intercellular junctions (diapedesis) and into the tissue. Cells move up-gradient to the highest concentration of chemotaxic factors (chemotaxis). cell components The actual process of phagocytosis involves several steps: (1) Adherence to bacteria, which is increased by opsonins such as Ab and complement C3b (2) Engulfment of bacteria by extensions of neutrophil s membrane (pseudopods) (3) Formation of a phagosome containing the bacterium sourrounded by neutrophil s plasma membrane (4) Fusion of lysosomes with the vacuole (phagolysosome) and the production of toxic O2 molecule (H2O2, hydrogen peroxide, O?2, superoxide), and (5) Killing and breakdown of the bacterium Page 11
cell components Scanning EM of phagocytosis of RBC by a macrophage. (A) macrophage attaches to RBC; (B) a pseudopod start to enclose the RBC; (C) RBC is almost totally engulfed by the macrophage. cell products CELLULAR PRODUCTS OF INFLAMMATION: The cells involved in inflammation stimulate other cells by secreting cytokines, which include interleukins, interferons, and other molecules. Interfererons are produced by cells that are already infected by viruses. Once released from infected cells, interferons can stimulate neighboring healthy cells to produce substances that prevent viral infections. Chemokines are sythetized by a number of different cells and induce leukocytes chemotaxis. Page 12
cell products Selected cytokines that mediate inflammation and the acquired immune response. Selected cytokines that mediate inflammation and the acquired immune response. Page 13
cell products The action of interferon virus interferon molecules antiviral protein viral interferon cell infected with virus produces interferon Interferon binds to uninfected cell and induces synthesis of antiviral proteins antiviral protein blocks viral nucleic acid synthesis The action of interferon Page 14
- artery capillary venule LOCALS MANIFESTATIONS OF ACUTE INFLAMMATION: Local are the result of the vascular changes associated with the inflammatory process, including vasodilation and increased capillary permeability. The symptoms include redness, heat, swelling, and pain. The functions of vascular changes are to dilute toxin molecules produced by dying cells or contaminating microorganisms, carry plasma proteins and leukocytes to the injury site, carry debris away from the site, and induce leukocyte chemotaxis. - artery capillary venule ACUTE PHASE REACTANTS: blood proteins during inflammation FUNCTION INCREASED DECREASED Coagulation components Protease inhibitors Transport proteins Complement components Miscellaneous proteins Fibrinogen, prothrombin, factor VIII, plasminogen alpha1-anti-trypsin, alpha1 anti-chemotrypsin Haptoglobin, hemopexin, ceruloplasmin, ferritin C1s, C2, C3, C4, C5, C9, factor B, C1 inhibitor alpha1-acid glycoprotein, fibrinonectin, serum amylod A, C-reactive protein none Inter-alpha-anti-trypsin transferrin properdin Albumin, pre-albumin, alpha1-lipoprotein, beta-lipoprotein Page 15
- artery capillary venule CHRONIC INFLAMMATION: It can be a continuation of acute inflammation lasting 2 weeks or longer. It also can occur as a distinct process without much preceding inflammation. It is characterized by dense infiltration of lymphocytes & macrophages. The body may wall off and isolate the infection to protect against tissue damage by formation of a granuloma. - resolution / repair RESOLUTION AND REPAIR OF INFLAMMATION: Resolution or regeneration is the return of tissue to nearly normal structure and function. It occurs if little tissue has been lost or if injured tissue is able to regenerate. This is called healing by primary intention. Repair is healing by scar tissue formation. Tissue that sustained extensive damage or those incapable of regeneration, heal by the process of repair resulting in the formation of a scar. This is called healing by 2ndary intention. Resolution and repair occur in two separate phases, the reconstructive phase in which the wound begins the woun begins to heal, and the maturation phase in which the healed wound is remodeled. Dysfunctional wound healing can occur as a result of abnormalities in either the inflammatory response or the reconstructive phase of. Page 16
Adaptive Immunity - general GENERAL CHARACTERISTICS OF THE IMMUNE RESPONSE: is a state of protection, primarily against infection agents, that differ from inflammation by being slower to develop, being more specific, and having memory. Natural immunity is innate resistance and acquired is gain after birth. Adaptive immune response is mostly initiated by cells of the innate system, which process / present portions of invading pathogens to lymphocytes in peripheral lymphoid tissue. The B-lymphocytes are responsible for humoral immunity that is mediated by circulating Ab. T-lymphocytes are responsible for cell-mediated immunity, in which they kill targets directly or stimulate the activity of other leukocytes. can be either active or passive depending on whether immune response components originated in the host or came from a donor. Adaptive Immunity - general OVERVIEW OF THE IMMUNE RESPONSE: The immune response has two phases: generation of glonal diversity and clonal selection. In clonal diversity, bone marrow lymphoid stem cells migrate to the central lymphoid tissue (thymus, bone marrow regions) where they undergo a series of cellular divisions and differentiation stages resulting in either immunocompetent T-cells in thymus or inmunocompetent B-cells from the bone marrow. These cells have never encountered foreign antigens, they enter the circulation, and migrate to secondary lymphoid organs (spleen / lymph nodes) where they take up residence. In clonal selection, exposure to foreign Ag is processed by APC. Intercellular cooperation among APC-Th and T and B cells results in a second stage of cell proliferation and differentiation of a limited T and B cell population (those with compatible Ag receptors). The end result is an active cellular immunity or humoral immunity or both. Page 17
Adaptive Immunity - general Cellular immunity is mediated by a population of effector T-cells that can kill targets (cytotoxic T-cells) or regulate the immune response (regulatory T-cells), as well as a population of memory T-cells that respond quickly to a 2 nd challenge of the same Ag. Humoral immunity is mediated by a population of soluble Ab produced by plasma cells, and by a population of memory B-cells that can produce more Ab rapidly to a second challenge with the same Ag. Production of T and B cells with all possible receptors for antigens Selection, proliferation, and differentiation of individual T and B cells with receptors for a specific antigen Bone marrow thymus lymphoid stem cell immunocompetent T cells antigen APC CELLULAR IMMUNITY Th1 Th cell regulatory T cell cytotoxic T cell memory T cell immunocompetent B cells Th2 memory B cell plasma cell bone marrow central lymphoid organs peripheral lymphoid organs HUMORAL IMMUNITY antibody Cellular immunity is mediated by a population of effector T-cells that can kill targets (cytotoxic T-cells) or regulate the immune response (regulatory T-cells), as well as a population of memory T-cells that respond quickly to a 2 nd challenge of the same Ag. Humoral immunity is mediated by a population of soluble Ab produced by plasma cells, and by a population of memory B-cells that can produce more Ab rapidly to a second challenge with the same Ag. Page 18
Adaptive Immunity - general TOP SEM of lymphocytes and macrophages. The lymphocytes (labeled L) are small and spherical, the macrophages (M) are larger & more irregular in shape, RIGHT The lymphoid system. Immature L migrate through primary lymphoid tissues (bone marrow for B- L and the thymus for T-L). Mature L later reside in the T-L and B-L rich areas of the peripheral or secondary lymphoid tissue. Adaptive Immunity - antigens ANTIGENS AND IMMUNOGENS: Antigens (Ag) are molecules that react with components of the immune response, such as antibodies (Ab) and receptors on B and T cells. Most Ag can induce an immune response and thus the Ag are also immunogens. The antigenic determinant or epitope is the precise chemical structure with which an Ab or B/T cell receptor react. Self-antigens are antigens on an individual s own cells. The individual s immune system does not normally recognize selfantigens as immunogenics, a condition known as tolerance. Very small antigens may not normally be immunogenic (haptens) unless they are bound to a larger molecule (carrier). Page 19
Adaptive Immunity - antigens Antigenic Determinants (Epitopes): Generic examples of epitopes on protein (A) and polysacharide (B) molecules are shown. In (A) an antigenic protein may have multiple different epitopes (1 and 2) that react with different antibodies. Each sphere represent an amino acid. Individual epitopes may consist of 8 or 9 amino acids. In (B), a polysacharide is constructed with a backbone with brancged side chains. Each sphere represent an individual carbohydrate with the red ones as those forming the epitope. In this example two identical epitopes woul bind two identical antobodies. Adaptive Immunity Ag / Ab Antigen Source CLINICAL USE OF ANTIGEN OR ANTIBODY Protection to disease Protection Vaccination Diagnosis Therapy Infectious agent Cancers Environmental substances Self-antigens Neutralize or destroy pathogenic organism (eg.ab to virus) Prevent tumor growth spread (surveillance to early cancer) Prevent entry into body (IgA limits exposure to allergens) Tolerance may be altered by infection leads to aotoimmune disease Induce safe and protective immune response Prevents cancer growth or spread (vac. with cancer Ag) No clear example Some vacines alter self-ag leading tp autoimmune disease Measure blood Ag of infection or Ab (hepatitis B infection) Measure blood Ag (PSA from prostate tumor) Measure bloo Ag or Ab (IgE detection for allergy) Measure blood Ab against self- Ag for autoimmune didease) Passive, to prevent infection (hepatitis A) Immunotherapy (using Ab against cancer Ag) Immunotherapy (Ag to desensitize individual with severe allergy) Oral self-ag to low production of autoimmune disease autoab Page 20
CLINICAL USE OF ANTIGEN OR ANTIBODY Antigen Source Protection fight active disease Protection Vaccination Diagnosis Therapy Infectious agent Cancers Environmental substances Self-antigens Neutralize or destroy pathogenic organism (eg.ab to virus) Prevent tumor growth spread (surveillance to early cancer) Prevent entry into body (IgA limits exposure to allergens) Tolerance may be altered by infection leads to aotoimmune disease Induce safe and protective immune response Prevents cancer growth or spread (vac. with cancer Ag) Measure blood Ag of infection or Ab (hepatitis B infection) Measure blood Ag (PSA from prostate tumor) No clear example Measure bloo Ag or Ab (IgE detection for allergy) Some vacines alter self-ag leading tp autoimmune disease Measure blood Ab against self- Ag for autoimmune didease) Passive, to prevent infection (hepatitis A) Immunotherapy (using Ab against cancer Ag) Immunotherapy (Ag to desensitize individual with severe allergy) Oral self-ag to low production of autoimmune disease autoab Adaptive Immunity humoral THE HUMORAL IMMUNE RESPONSE: It is provided by antibodies (Ab) produced by B-cells that can be classified by chemical structure and biologic activity as IgG, IgM, IgA, IgE, or IgD. Their protective effect is direct or indirect. Direct effects result from binding of Ab directly to a harmful Ag or infectious agent. These include inhibitions of processes that are necessary for infection, such as the reaction of an infectious agent with a particular cell in the body or inactivation of harmful bacteria toxins. Indirect effects result from activation of inflammation by Ab through Fc portion of the molecule. These include opsonization to increase phagocytosis, killing the infectious agent through activation of complement, and widespread activation of inflammation through production of biologically active complements, such as C5a. IgE is a special case of Ab against parasitic infections. IgA Ab found in the secretion of mucous membranes function externally. Page 21
Adaptive Immunity humoral Structure of different immunoglobulins. Secretory IgA, IgD, IgE, IgG, and IgM. The black circle attach to each molecule represent carbohydrates residues. J chain secretory piece IgD (monomer) secretory IgA (dimer with secretory piece) IgE (monomer) IgG (monomer) IgM (pentamer) Structure of different immunoglobulins: Secretory IgA, IgD, IgE, IgG, and IgM. The black circle attach to each molecule represent carbohydrate residues. Page 22
Adaptive Immunity humoral Molecular structure of an antibody. (A) Typical Ab has 2 light and 2 heavy identical chains., linked together by intra and interchain disulfide bonds. The primary interchain between heavy chains occurs in the hinge (H) region and provides flexibility in some classes of Ab. Each chain is divided in regions of relatively constant (green) and variable (blue) amino acid sequences. Within VH & VL there are highly variable complementary determining regions (CDR1, CDR2). (B) IgG has r fragments, an FC and 2 Fab. The 2 Fab can bind Ag. (C) In this model L chains are strands of red spheres and H chains of blue spheres. H chains have sites where carbohydrates are bound. As the chains fold and interact the 6 CDRs within a Fab region are placed in close proximity to form the Ag-binding site. Molecular structure of an antibody. (A) Typical Ab has 2 light and 2 heavy identical chains., linked together by intra and inter-chain disulfide bonds. The primary interchain between heavy chains occurs in the hinge (H) region and provides flexibility in some classes of Ab. Each chain is divided in regions of relatively constant (green) and variable (blue) amino acid sequences. Within VH & VL there are highly variable complementary determining regions (CDR1, CDR2). (B) IgG has r fragments, an FC and 2 Fab. The 2 Fab can bind Ag. (C) In this model L chains are strands of red spheres and H chains of blue spheres. H chains have sites where carbohydrates are bound. As the chains fold and interact the 6 CDRs within a Fab region are placed in close proximity to form the Ag-binding site. Page 23
Adaptive Immunity humoral Antigen Antibody Binding. The specificity of an antibody binding with an antigen is determined by the shape and chemistry of the 6 complementary-determining regions (CDRs) in the combining site on the variable region of the antibody. This figure indicates two different antibodies (Fab portions of antibody 1 and 2) wich have different sets of CDRs and therefore different specificities. As indicated, the antigenic determinant that reacts well with antibody 1 is unable to react with antibody 2 because of differences in the antibody combining site Fab, Antigen binding fragment. Antigen Antibody Binding. The specificity of an antibody binding with an antigen is determined by the shape and chemistry of the 6 complementary-determining regions (CDRs) in the combining site on the variable region of the antibody. This figure indicates two different antibodies (Fab portions of antibody 1 and 2) wich have different sets of CDRs and therefore different specificities. As indicated, the antigenic determinant that reacts well with antibody 1 is unable to react with antibody 2 because of differences in the antibody combining site Fab, Antigen binding fragment. Page 24
Adaptive Immunity humoral Direct and indirect functions of antibody. Activities of antibodies (Ab) can be direct (through the action of Ab alone) or indirect (requiring activation of other components of inflammation, usually through Fc region). Direct means they include neutralization of viruses or bacterial toxins before they bind to receptors on the surface of the host s cells. Indirect means they include activation of the classical complement pathway through C1 resulting in formation of the membrane attack complex (MAC) or increased phagocytosis of bacteria opsonized with antibody and complement components bound to appropiate surface receptors (FcR and F3bR) or the phagocyte. Direct and indirect functions of antibody. Activities of antibodies (Ab) can be direct (through the action of Ab alone) or indirect (requiring activation of other components of inflammation, usually through Fc region).direct means they include neutralization of viruses or bacterial toxins before they bind to receptors on the surface of the host s cells. Indirect means they include activation of the classical complement pathway through C1 resulting in formation of the membrane attack complex (MAC) or increased phagocytosis of bacteria opsonized with antibody and complement components bound to appropiate surface receptors (FcR and F3bR) or the phagocyte. Page 25
Adaptive Immunity humoral Immunologyc mechanism that activate the inflammatory response. Immunologic factors may activate inflammation through 3 mechanisms: (1) IgE can bind to surface of mast cell and after binding Ag, induces cell degranulation (2) Antigen and antibody can activate the complement system, releasing anaphylatoxins and chemotactic factors, specially C5a that result in mast cell degranulation and neutrophil chemotaxis, and (3) Antigen may also react with T-lymphocytes, resulting in the production of lympho-kines that may contribute to development of either acute or chronic inflammation. mast cell degranulation antigen antigen - antibody mast cell degranulation acute inflammation complement activation antigen C5a and other lymphocytes neutrophil chemotaxis T - lymphocyte acute or lymphokines chronic inflammation activation of monocyte / macrophage Immunologic mechanism that activate the inflammatory response. Immunologic factors may activate inflammation through three mechanisms: (1) IgE can bind to surface of mast cell and after binding Ag, induces cell degranulation (2) Antigen and antibody can activate the complement system, releasing anaphylatoxins and chemotactic factors, specially C5a that result in mast cell degranulation and neutrophil chemotaxis, and (3) Antigen may also react with T-lymphocytes, resulting in the production of lympho-kines that may contribute to development of either acute or chronic inflammation. Page 26
Adaptive Immunity humoral IgE mediated Destruction of a Parasite. (1) Soluble antigens from parasitic infection causes IgE production antibody by B-cells (2) Secreted IgE binds to IgE specific receptors in the mast cell (3) Additional soluble parasite antigen cross-link the IgE on the mast cell surface (4) Leading to mast cell degranulation and release of many proinflammatory products including eosinophils chemotactic factor of anaphylaxis (ECF-A) (5) ECF-A attracts eosinophils from the circulation (6) The eosinophils attaches to the surface of the parasite and releases potent lysosomal enzymes that damage micro-organisms. endothelium eosinophil ECF - A mast cell parasite parasite antigen IgE B cell IgE mediated Destruction of a Parasite. (1) Soluble antigens from parasitic infection causes IgE production antibody by B-cells (2) Secreted IgE binds to IgE specific receptors in the mast cell (3) Additional soluble parasite antigen cross-link the IgE on the mast cell surface (4) Leading to mast cell degranulation and release of many proinflammatory products including eosinophils chemotactic factor of anaphylaxis (ECF-A) (5) ECF-A attracts eosinophils from the circulation (6) The eosinophils attaches to the surface of the parasite and releases potent lysosomal enzymes that damage microorganisms. Page 27
Adaptive Immunity cell mediated THE CELL MEDIATED IMMUNE RESPONSE: It is mediated by T-cells. There are 2 types of adult T-cells: cytotoxic (Tc), and regulatory (including T-helper or Th, T- suppression or Ts, and memory cells). T-cells have antigen specific receptors (TCR) that must see Ag presented on cell surface by special antigen presenting molecules of the major histocompatibility complex (MHC). Tc-cells bind to and kill cellular targets such as cell infected with viruses or cancer cells. NK-cells have characteristics of Tc-cells and are important for killing target cells in which viral infection of malignancy has resulted in loss of MHC molecules Development of cell mediated or humoral immune responses usually depend on populations of Th-cells. Adaptive Immunity clonal GENERATION OF CLONAL DIVERSITY VS CLONAL SELECTION Clonal diversity Clonal selection Purpose? To make large # of T & B lymphocytes with maximum Ag-R diversity Select, expand and differentiate clones of T and B cells against a specific Ag When does it occur? Primarily in the fetus Primarily after birth and throughout life Where does it occur? Central lymphoid organs: thymus for T-cells and bone marrow for B-cells Peripheral lymphoid organs, including lymph nodes, spleen, and other tissues Is foreign Ag involved? No Yes, Ag determines which cell clones will be selected What hormones / cytokines are involved? Final product? Thymic hormones, IL-7 and others Immunocompetent T and B cells that can react with Ag, but have not seen Ag, and migrate to 2 nd lymphoid organs Many cytokines produced by Th-cells and APC Plasma cells that make Ab, Th-cells, Tc-cells, Treg-cells (regulate), memory B and T cells Production of B / T lymphocytes with receptors against millions of Ag that will be possible encountered in an individual s life-time occurs in fetus in thymus and bone marrow. Immunocompetent T / B cells migrate from primary lymphoid organs in blood & secondary lymphoid organs to awaite antigens. Page 28
GENERATION OF CLONAL DIVERSITY VS CLONAL SELECTION Clonal diversity Clonal selection Purpose? To make large # of T & B lymphocytes with maximum Ag-R diversity Select, expand and differentiate clones of T and B cells against a specific Ag When does it occur? Primarily in the fetus Primarily after birth and throughout life Where does it occur? Central lymphoid organs: thymus for T-cells and bone marrow for B-cells Peripheral lymphoid organs, including lymph nodes, spleen, and other tissues Is foreign Ag involved? No Yes, Ag determines which cell clones will be selected What hormones / cytokines are involved? Final product? Thymic hormones, IL-7 and others Immunocompetent T and B cells that can react with Ag, but have not seen Ag, and migrate to 2 nd lymphoid organs Many cytokines produced by Th-cells and APC Plasma cells that make Ab, Th-cells, Tc-cells, Treg-cells (regulate), memory B and T cells Production of B / T lymphocytes with receptors against millions of Ag that will be possible encountered in an individual s life-time occurs in fetus in thymus and bone marrow. Immunocompetent T / B cells migrate from primary lymphoid organs in blood & secondary lymphoid organs to awaite antigens. Adaptive Immunity induction INDUCTION OF THE IMMUNE RESPONSE: It begins when Ag enters the individual s body and it can be divided in 2 phases: the primary and secondary responses. The primary response of humoral immunity is dominated by IgM, with lesser amount of IgG. The secondary response has a more rapid Ab production, predominantly IgG. Ag first interact with APC (macrophages) and presented on the cell surface by MHC (class 1 or class II). Tc-cells need that Ag be presented by class I-MHC and Th-cells by class II-MHC. The T-cells sees the presented Ag through the T-cell-R and accessory molecules: CD4 or CD8. CD4 is found in Th cells and react specifically with MHC class II. CD8 is found in Tc cells and reacts specifically with MHC-class I. A sub-group of Th cells (Th2) helps B-cells respond to Ag and develop into Ab-secreting plasma cells. Page 29
Your second Case Study SUMMARY: A 2-year-old colt with swollen lymph nodes. A 2-year-old colt who just returned from training has shown marked bilateral nasal discharge for at least 2 days. The colt has not been eating for the last day and appears depressed. The colt also seems to have considerable swelling under the jaw and in the throat latch area. On examination, the colt has a temperature of 39.2 C (102.7 F) but a normal heart rate of 36 beats per min and normal respiratory rate of 12 breaths per min. The horse has bilateral mucopurulent nasal discharge. The lymph nodes underneath the jaw and the throat area are both greatly swollen. No other abnormalities are present. This colt was vaccinated for Eastern and Western encephalitis as well as rhinopneumonitis, influenza, rabies tetanus and west Nile virus. However, the colt was not vaccinated against Streptococcus equi, the causative agent of strangles. TENTATIVE DIAGNOSIS: LAB TESTS: FINAL DIAGNOSIS: TREATMENT: A 2-year-old colt with swollen lymph nodes. Your second Case Study GENERAL CHARACTERISTICS OF THE IMMUNE RESPONSE: is a state of protection, primarily against infection agents, that differ from inflammation by being slower to develop, being more specific, and having memory. Natural immunity is innate resistance and acquired is gain after birth. Adaptive immune response is mostly initiated by cells of the innate system, which process / present portions of invading pathogens to lymphocytes in peripheral lymphoid tissue. The B-lymphocytes are responsible for humoral immunity that is mediated by circulating Ab. T-lymphocytes are responsible for cell-mediated immunity, in which they kill targets directly or stimulate the activity of other leukocytes. can be either active or passive depending on whether immune response components originated in the host or came from a donor. Page 30