Saladin Ch. 21 Lymphatic & Immune Systems Lymphatic System General Lymphatic System - composed of lymph, lymphatic vessels, and lymphatic tissue Functions of Lymphatic system functions Draining of interstitial fluid Transporting dietary lipids/lipid soluble vitamins from GI to blood. Facilitating the Immune Response - by B and T lymphocytes. Lymph & Lymphatic Vessels Lymph Usually clear, colorless, derived from blood plasma but with less protein Lacteals - specialized capillaries along the small intestine - pick up lipids - gives fluid white, opaque look = chyle Contains large numbers of lymphocytes, etc. Lymph & Lymphatic Vessels Lymphatic capillaries Closed ends; One way flow - wall cells overlap; fluid pushes in & can separate the cells. Anchoring filaments - hold capillaries in place & help open gaps when interstitial fluid builds up. Location - not in cartilage, epidermis, CNS, parts of spleen or red marrow. Lymph & Lymphatic Vessels Lymph trunk and ducts In embryo form from buds from veins - similar structure. Flow - capillaries into vessels into nodes. After passing through a string of nodes - goes into "trunks Lymph & Lymphatic Vessels [Trunks: Lumbar, intestinal, subclavian bronchomediastinal, & juglar] From trunks, lymph flows into either the thoracic duct or the right lymphatic duct From the ducts, flow is into venous blood Lymph & Lymphatic Vessels Right lymphatic duct Drains from upper R side Drains into R. subclavian vein Trunk feeders - R juglar from R head and neck, R subclavian from R upper limb, R bronchmediastinal from R thorax. Lymph & Lymphatic Vessels Thoracic Duct - begins as cisterna chyli - anterior to L2 vertebra Receives from left of head & neck, chest, left upper limb, & all of the body below the ribs. Drains into the left subclavian vein Feeder trunks - lower body -R & L lumbar, intestinal Lymph & Lymphatic Vessels Lumbars drain from lower limbs, pelvis, kidneys, adrenals & abdominal wall. Intestinal drains from intestines, pancreas, spleen & liver From the neck, the thoracic duct gets lymph from the l. juglar, l. subclavian, l. bronchomediastinal trunks Lymphatic Cells Lymphocytes - stem cells divide to produce B & T cells Produced in red marrow B cells may become plasma cells that produce antibody Pluripotent cells in red marrow pre-T cells thymus to mature. Lymphatic Cells Macrophages [Phago. & APC's] Dendritic Cells [activate T cells - APC's] Reticular cells fibroblasts that produce reticular fibers for tissue stroma Lymphatic Tissue Aggregations of lymphocytes in connective tissues of mucus membranes MALT, Galt, nodules, Peyer's patches Malt Peyers Patches Lymphoid Organs Include marrow, thymus, lymph nodes, spleen, tonsils Red Bone Marrow --> lymphocytes [review blood chapter] Lymphoid Organs Thymus Gland Functions in T cell maturation Reticular epithelial cells produce thymic hormones that aid in maturation of T cells Below sternum - large in infants, shrinks with age from puberty on. 2 lobes have capsule with trabeculae Lymphoid Organs Lobules - 2 regions - cortex and medulla Cortex - deep staining - lymphocytes & reticular epithelial cells Medulla - paler - mostly reticular epithelium - fewer lymphocytes -Has thymic corpuscles [Hassall's] - concentric whorls of flattened reticular epithelium Thymus Lymphoid Organs Lymph Nodes - about 600 bean-shaped organs Concentrated in axillae, groin & near mammaries. Function: Trap material on reticular fibers, Clear out foreign & damaged materials through phagocytosis, Immune processes Lymphoid Organs Structure - stroma & parenchyma Stroma - capsule - dense connective tissue covering - has trabeculae.Supports & holds vessels. Also has network of reticular fibers & fibroblasts. Lymphoid Organs Parenchyma - 2 regions - cortex and medulla Cortex - outer and inner Outer - lymphatic nodules of B cells. Germinal centers - where B cells proliferate into plasma cells. Dendritic cells - APC's - initiate immune response. Also have macrophages. Inner - T-cells Lymph Node Lymphoid Organs Medulla B & T cells, plasma cells tightly packed in "medullary cords Lymph nodes have unidirectional flow - enters through afferent vessels sinuses efferent lymphatic vessels. [Hilus - place where efferent vessels emerge.] Lymph flows through a series of nodes --> quite clean at the end. Lymphoid Organs Metastasis - spread of cancer. Sites for metastasis are predictable based on lymphatic flow patterns. Conversely, when a secondary tumor is found, the primary can usually be located by going in reverse back the flow paths. Lymphoid Organs Tonsils Pharyngeal = adenoid, palatine =at base of palatine bones, lingual = base of tongue, tubal = around auditory tube openings No capsule crypts that trap bacteria & particulate material Tonsils Lymphoid Organs Spleen - largest lymphatic structure - between stomach & diaphragm. Function: Immunologic precipitate, kill antigens Clean up old rbcs, Store platelets, Stabilize blood volume Lymphoid Organs Parenchyma White pulp - Lymphocytes & macrophages Red pulp venous sinuses filled with blood & Billroths [splenic] cords [rbcs, macrophages, lymphocytes, B cells, granulocytes pressed together] Lymphoid Organs Stroma Capsule with trabeculae covered, with serous visceral peritoneum. Interior reticular tissue. Non-specific Disease Resistance Non-specific Resistance to Disease > immediate protection against a wide variety of pathogens & foreign substances NO memory always the same Pathogen = a disease-causing agent Non-specific Disease Resistance Lines of Defense: 1 - external barriers - non-specific 2 - non-specific internal responses 3 - immune system - specific Non-specific Disease Resistance External Barriers Skin & Mucous Membranes Mechanical factors physical barriers intact skin, tight junctions Mucous membranes physical barriers also mucous catches dirt, etc.; hairs filter out material, cilia sweeps out invaders Non-specific Disease Resistance Chemical Factors: Defensins pH of skin [3-5] antimicrobial Sweat flushes, contains lactic acid = acid mantle Non-specific Disease Resistance Tears dilute agents. Also some lysozyme - antibiotic properties Saliva same Urine / vaginal secretions Dermal hyaluronic acid - viscous - hard to traverse Some organisms have hyaluronidase to dissolve it. Non-specific Disease Resistance Internal Defenses - Leukocytes & Macrophages Phagocytes eat foreign matter Neutrophils in most body tissues. In addition to phagocytosis, use respiratory burst - series of reactions/agents that create H 2 O 2, HClO & superoxide ions that destroy bacteria Non-specific Disease Resistance Eosinophils can attack parasitic worms, promote basophil action, reduce inflammatory response Basophils - secrete histamine - vasodilator and Heparin - anticoagulant [both also released by mast cells]. Non-specific Disease Resistance Lymphocytes - 3 classes [specific and non] 80% T, 15% B, 5% NK Monocytes Special "macrophages" - dendritic cells, microglia, alveolar, hepatic Non-specific Disease Resistance Internal Defenses - Antimicrobial Proteins Interferons produced by virally infected lymphocytes, macrophages, & fibroblasts Attach to uninfected cells & induce synthesis of proteins that interfere with viral replication Protects these cells from infection Also activate NK cells Non-specific Disease Resistance Complement a group of 30+ proteins that are synthesized by the liver & in the blood normally inactivated When activated enhance all parts of the immune response as well as allergic responses Activated 3 ways - complement fixation [Ab], alternative path [ spontaneous - no Ab], Lectin path - attach to sugars on microbes Non-specific Disease Resistance 4 methods. Inflammation - C3a stimulates mast and basophils to release histamine and initiate the IR, activates & attracts neutrophils Immune Clearance - C3b - binds Ab-Ag complexes to rbc's - collected by macrophages in liver & spleen Non-specific Disease Resistance Phagocytosis - opsonization by C3b Cytolysis - C3b initiated.--> cascade -->makes a hole in membrane of target cell Non-specific Disease Resistance Immune Surveillance NK cells patrol for foreign agents and diseased host cells - destroy them Use perforins + granzymes Non-specific Disease Resistance Inflammation tumor, rubror, calor and pain 3 stages mobilization = vasodilation and increased permeability, emigration, containments & destruction, tissue repair [see table 21.1 for cells and chemicals] Non-specific Disease Resistance Sequence of inflammation events Vasodilation Causes normal or damaged cells release histamine & other vasoactive chemicals --> Dilation & increased permeability --> redness, heat & swelling Non-specific Disease Resistance Emigration - Neutrophils, then macrophages come into clean up - Attracted by cytokines Margination neutrophils in vessels adhere to walls of vessel near injury due to selectins Diapedesis neutrophils leave vessels Non-specific Disease Resistance Chemotaxis neutrophils outside vessels attracted to site of injury Pain is produced from damaged sensors or irritation by toxic substances & bradykinin. Prostaglandins also increase pain Non-specific Disease Resistance Containment Blood clotting factors reach site and form clot walls off injured area Anticoagulants prevent clot at immediate entry area - enhances clearance by leukocytes Chemotaxis brings neutrophils, then and other macrophages --> rapid increase in neutrophils Non-specific Disease Resistance Tissue Cleanup & Repair Monocytes do phagocytosis & are Ag- presenting cells Pus forms [dead material] Ulcer open edge, abscess all enclosed Platelet-derived growth factor stimulates fibroblasts --> collagen --> scaffold for new cells Non-specific Disease Resistance Fever increase in body temperature produced by the hypothalamus In response to pyrogens secreted by leukocytes and macrophages Accompanies infection and inflammation Promotes interferon production, inhibits bacterial growth, speeds up metabolism --> faster repair Non-specific Disease Resistance Reye Syndrome Children less than 15yo - with acute viral infection - brain swelling, etc. Can be triggered by use of aspirin. Specific Immunity General Aspects of Specific Immunity Immunity is systemic body-wide Immunity is specific - ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses & alien tissues. Specific Immunity Requires initial exposure before can develop "memory" of the agent remains after infection--> continued defense. Antigens [Ag] are substances that provoke such an immune response [usually foreign] Specific Immunity Forms of Immunity 2 classes of response: Cell-mediated cells [lymphocytes] attack other cells. Intracellular agents Humoral Response antibody-mediated. Ab usually in body fluids. Extracellular agents & molecular pathogens Specific Immunity Active versus Passive Immunity Active make our own Ab/T cells Natural infection/exposure to fully active Ag B and T cell memory Artificial vaccination [mostly B cell responses not T] Specific Immunity Passive get Ab from elsewhere Natural maternal placenta & milk Artificial pooled gamma globulin Specific Immunity Ags - trigger immune responses Immunogenicity ability to provoke either a T or B cell response Reactivity ability of Ag to react with Ab or cells provoked If an Ag does both it is complete Ag Specific Immunity Ags include whole or parts of microbes, bacterial toxins, pollen, egg white, blood cells, tissues Large molecules made of small repeating units usually evoke no response Hapten a substance that cannot evoke a response by itself, but can if bound to something else [e.g., a cell receptor]. Specific Immunity Antigenic Determinants = epitopes specific regions of Ag molecules that trigger a response Many / Ag thus for a given invader get a variety of Abs per Ag Specific Immunity Lymphocytes - Cells of the Immune System Develop from pluripotent red marrow cells 3 populations of lymphocytes NK, Bs and Ts Ts cells leave marrow and go to the thymus for final processing by thymic hormones Specific Immunity Becoming immunocompetent means being able to recognize a foreign antigen & not responding to self-antigens.Tested for self-recognition 1) must be able to bind MHC molecules bearing Ag presented for recognition, & 2) must NOT react with self Ag. If they do, they are eliminated. Those that pass --> clones Specific Immunity Bs mature into immunocompetent cells in the marrow throughout life humoral responses [Develop receptors for 1 AG receptors are ABs.] B cells that recognize self-antigens are either inactivated in the marrow, or killed Each individual B or T cell is genetically programmed to recognize only one antigenic determinant Specific Immunity Antigen-Presenting Cells - Pathway of Ag processing for response T cells usually need help recognizing Ag, they require APC's - B cells, or macrophages, or reticular cells, or dendritic cells. Specific Immunity Self-Ags - Major Histocompatibility Complex = MHC On membrane surfaces glycoproteins Also called HLA Ags first found on wbcs Unique - usually recognize them before birth & don't attack Specific Immunity APCs engulf foreign particles & then present fragments on their own cell surfaces, signal flags. Strategically located so as to ensure coverage of all body parts & tissues Secrete proteins interleukins that activate T cells & stimulate killer cells T-cells circulate [enhances chances of encountering the AG] Specific Immunity Cell-Mediated Immunity Targets body cells infected with viruses or bacteria, abnormal or cancerous cells, & foreign transplants T cells classed by type of cell differentiation glycoprotein on their surfaces CD4 - helper T cells CD8 - cytotoxic T cells Specific Immunity Recognition: T cells only recognize processed fragments of protein Ags displayed on cell surfaces Antigen Recognition and MHC Restriction 2 types of MHCs are important to T cell activation MHCI are found on all self cells except red blood cells Specific Immunity Pick up endogenous materials on way to surface - display them. If Ag is foreign material from inside cells [e.g., viral protein], it is recognized T cells [Tc]kill the cell showing it MHCII on mature B, T & APCs have exogenous engulfed & digested Ag [not self] - Th respond Specific Immunity T-Cell Activation Activation [clonal selection] 2 steps Recognition & binding to presented complex by a specific T-cell receptor Co-stimulation required second signal from cytokines, & plasma membrane molecules on APCs Specific Immunity Proliferation and Differentiation After activation T cell enlarges & divides several times Forms more highly specialized T-cells in clones Activation and proliferation etc. occurs in secondary lymphatic organs & tissues tonsils, lymph nodes, etc. Specific Immunity Attack Helper = T H or T 4 essential to specific immunity. Interact with both T & B cells & macrophages. Recognize MHCII presented Ag. Activated by APCs When activated, secrete interleukins which attract neutrophils & NK's, stimulate phagocytosis, & stimulate clone formation Specific Immunity Cytotoxic = T C or T 8 = Killer T cells Recognize MHCI bound Ag [viral, tumor, transplant] T C attach to invader use Perforin pokes holes in target cells membrane => lysis, interferons, & tumor necrosis factor [kills cancer cells] Specific Immunity Memory T Cells left over after cell-mediated response is done can initiate a new response if the Ag reappears Specific Immunity Humoral Immunity Recognition B Cells - each has receptors to only one Ag B cell Ag receptors bind to Ag several pieces link together & are then endocytosed through receptor mediated process Specific Immunity The activation response is stronger if neighboring dendritic cells also process &present the Ag Ag taken in by B cell, broken down, & moved to the B cell membrane This results in co-stimulation by helper T's to proliferate & form clones Specific Immunity Activated B cells from the clone enlarge & become plasma cells secrete Ab at rate of 2000 molecules per second per cell for 4 to 5 days Some activated B cells become memory cells instead of plasma cells Specific Immunity Attack Abs match antigenic determinants that stimulate their production Also called immunoglobulins = gamma globulin fraction of blood Specific Immunity Ab structure glycoproteins = carbohydrate & protein 2 heavy chains 2 light chains Disulfide bridges hold L to H and H to H Specific Immunity 2 regions per H & L chain pair Variable Ag binding site recognizes determinant Constant same for most Ab of a given class different among classes [especially the H chains] Ab Structure Specific Immunity Ab classes 5 groups classed by their constant regions [Table 21.3]. IgG 80% - antibacterial, antiviral, opsonizing, neutralizing, complement trigger. Monomer. Can cross placenta IgA 1-15% - sweat, tears, saliva, mucus, milk, GI. Monomer & dimer Specific Immunity IgM 5-10% Activates complement, agglutinates, anti-ABO Abs in plasma. Pentamer.[Can fix complement.] IgD 0.2% Monomer. Ag receptors on B cells IgE Bound to basophils and mast cells. Allergic & hypersensitivity reaction. Protects from worms. Monomer. Specific Immunity Mechanisms of Ab Diversity Humans can produce from 10 billion to a trillion different Ab's Have about 100,000 genes to code for Ab proteins Composed of bits put together in different combinations by somatic recombination H & L chain exons on same chromosome Specific Immunity Ab Actions inactivate and tag for destruction Neutralization bind to & block antigen/toxin Agglutination/ precipitation clumping Complement Fixation Complement also stimulates inflammatory response in region, Opsonization coat & make sticky to phagocytes AgglutinationNeutralization Specific Immunity Memory Both long lasting Ab & memory cells Primary response [first exposure] takes a few days to see Ab Ab levels increase, then drop but memory cells remain Second response produces more & more effective Ab Specific Immunity Immune System Disorders Allergy hypersensitivity. One system has 4 types: Type I = immediate [acute] - hay fever, etc. Anaphylactic shock can occur. Type II - antibody-dependent cytotoxic [Ab opsonizes or complement fixation] Transfusion reactions, some drug reactions Specific Immunity Type III - Immune complex - precipitate in tissue, then activate complement, leading to tissue damage. Autoimmune SLE & Glomerulonephritis Type IV - Delayed cell-mediated. Poison ivy, graft rejection Specific Immunity Autoimmune Diseases Failures of self-tolerance 3 causes - cross-reactivity [e.g., strep], abnormal exposure to occult Ag [usually sequestered]- Hashimoto's thyroiditis], Change in self-Ag structure - [type I diabetes] Specific Immunity Immunodeficiency Diseases SCID - "boy in bubble AIDS - review on own