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Lymphatic & Immune Systems Lymphatic System Reabsorbs about 15% of fluid filtered by blood capillaries & returns it to blood Provides immunity & protection from foreign cells & matter in the body Absorbs dietary lipids in small intestine & transports them to blood p 809 Lymph = fluid in lymphatic vessels • Usually clear, colorless fluid • Originates in lymphatic capillaries p 810 Lymphatic Vessels Histology similar to veins •Thinner walls •More valves Flow of Lymph Like venous; low pressure & speed Primary driving force is rhythmic contractions of vessels Assisted by Milking & “Thoracic pump” p 811 p 813 p 813 Lymph Nodes In-line filters that cleanse the lymph as it passes through Reticular fibers act as a filter and delay microbes & debris Macrophages & reticular cells remove about 99% of impurities from lymph p 817 p 817 Lymphatic Cells Natural killer (NK) = lymphocytes that attack & destroy bacteria, transplanted cells, & host cells that are cancerous or viral-infected Provide immune surveillance T lymphocytes = mature in thymus & provide cell-mediated immunity B lymphocytes = mature in bone marrow & provide antibody-mediated immunity Lymphatic Cells Macrophages = develop from monocytes into large highly phagocytic cells that destroy foreign matter and dead tissues & cells Act as antigen-presenting cells (APCs) by breaking down foreign matter & displaying parts of it on their cell membrane Lymphatic Cells Dendritic cells = APCs that engulf foreign matter by endocytosis Located in epidermis (Langerhans cells), mucous membranes, & lymphatic organs Reticular cells = act as APCs in thymus Form blood-thymus barrier that isolates lymphocytes from blood-borne antigens Produce hormones that promote development & actions of T cells Lymphatic Tissues Lymphatic Nodules = dense masses of lymphocytes & macrophages Some appear temporarily to fight infections Permanent nodules are found in; • Lymph nodes • Tonsils • Appendix • Ileum of Sm. Intestine (Peyer’s Patches) Red Bone Marrow Source of all blood cells which enter the blood through sinusoids Site where B lymphocytes mature p 814 Thymus •Site where T lymphocytes mature •Shrinks to small size in adults •Secretes hormones that stimulate development and activities of T lymphocytes p 815 Tonsils. Patches of lymphatic tissue that guard entrances to the pharynx Surface has deep pits called crypts that help trap foreign materials p 819 Spleen: Largest lymphatic organ Acts as in-line filter for blood, with reticular fibers as filter and macrophages to ingest microbes & foreign material “Erythrocyte graveyard” where worn out RBCs are phagocytized by macrophages p 819 Nonspecific Defenses Protection against a wide range of pathogens Pathogens = anything capable of causing disease • Bacteria • Viruses • Toxic chemicals • Radiation Nonspecific Defenses • • • • • • • External Barriers Leukocytes & Macrophages Immunological Surveillance Interferons Complement System Inflammatory Response Fever External Barriers Skin Mucous Membranes Secretions; Tears, saliva, urine, vaginal secretions, perspiration Lysozymes = antibacterial enzymes that breakdown cell walls Stomach acid Leukocytes & Macrophages Neutrophils Phagocytosis, plus Lysozymes release enzymes that trigger the respiratory burst, which produces; Superoxide (O2-) Hydrogen peroxide (H2O2) Hypochlorite (HClO) All highly toxic, so form a killing zone, that kills many bacteria & neutrophils Eosinophils Phagocytosis Release toxic chemicals Particularly effective against allergens & parasites Basophils Secrete histamine (vasodilator) Secrete heparin (anticoagulant) Stimulated by Eosinophils Monocytes Leave blood and become macrophages • Wandering (Free) macrophages • Fixed macrophages Includes; • Dendritic cells • Microglia • Alveolar macrophages • Hepatic macrophages (Kuppfer’s cells) Interferons Small proteins Released from viral-infected cells & bind to receptors on surface of nearby cells causing them to make antiviral proteins that prevent viral replication, thereby protecting those cells Act as cell to cell signals to stimulate activities of macrophages and NK cells Complement System Group of 30 or more proteins Important role in both Specific and Nonspecific defenses p 823 Membrane Attack Complex p 824 Immune Surveillance Natural Killer (NK) Cells patrol body looking to find & destroy bacteria, transplanted cells, viral-infected cells, & cancer cells. p 824 Inflammation Inflammation is a local defensive response to injury, like trauma or infection Purposes; 1. Limit spread of pathogens & eventually destroy them 2. Remove debris of damaged tissue 3. Start tissue repair Words ending in itis denote inflammation of that tissue (arthritis, dermatitis, etc) Signs = heat, redness, swelling, pain Inflammation Vasodilation triggered by histamine & other chemicals released from basophils, mast cells & damaged cells (flow=heat, redness) These chemicals also cause Increased Blood Vessel Permeability as intercellular clefts widen & allow increased filtration of; • Fluids (swelling) • Leukocytes • Proteins (complement, antibodies, clotting factors) Neutrophil Behavior Margination = loose adhesion to vessel wall Diapedesis = crawl thru gaps between cells Chemotaxis = move toward chemical signals from damaged cells Phagocytosis = engulf and digest foreign cells & molecules p 826 Neutrophils release signaling molecules to attract more phagocytes (neutrophils & macrophages) through chemotaxis Macrophages engulf & destroy pathogens, and casualties, like tissue cells & neutrophils Macrophages secrete colony-stimulating factors, that trigger increased production of more leukocytes (reinforcements) What remains is Pus which is the dead cells, tissue debris & fluid that are eventually absorbed Pain receptors are stimulated by; 1. Direct injury 2. Pressure from edema 3. Chemicals released by damaged cells (like prostaglandins & bradykinin) and bacterial toxins Fever Fever is an abnormal increase in body temp due to hypothalamus raising the set point for body temp. Pyrogen (fever-causing agent) = interleukin-1, that triggers hypothalamus release of prostaglandin E (PGE) which raises set point for temp p 827 Specific Immunity Specific immunity is directed at one and only one specific pathogen An initial exposure to a pathogen will create a memory When exposed again to the same pathogen the body reacts so quickly that there is no noticeable illness. Specific Immunity Cellular (cell-mediated) immunity = lymphocytes directly attack & destroy foreign cells or diseased host cells where Pathogen is inside human cells Intracellular Viruses, Bacteria, Protozoans, & Yeast Cells of Transplanted Tissue & Cancer Cells Specific Immunity Humoral (antibody-mediated) immunity = antibodies tag or mark the pathogen for destruction by other mechanisms Indirect attack by antibodies, instead of immune cells directly Extracellular Viruses, Bacteria, Protozoans, & Yeast Molecular (noncellular) pathogens like, toxins, venoms and allergens Antigens Antigen = any molecule that triggers an immune response, normally proteins, polysaccharides, glycoproteins, & glycolipids Antigenic Determinant Sites (epitopes) = portions of the exposed surface of the antigen that actually make it an antigen, (trigger an immune response) = sites where antibodies bind Immune system must distinguish between; Self vs. Nonself molecules Haptens • • • • Too small to be an antigen Bind host macromolecule = then antigenic Second exposure may not require binding Include many allergens; • Cosmetics • Detergents • Industrial chemicals • Poison ivy • Animal dander T Lymphocytes (T Cells) “Born” in bone marrow, then to thymus where they become immunocompetent, meaning they get receptors on their surface for one antigen Must pass a test to be sure they can recognize foreign antigens, but not attack self-antigens (only 2% pass) Graduation = multiple & form clones of identical T cells that recognize that one specific antigen, then leave thymus as naive T lymphocytes B Lymphocytes (B Cells) Born and become immunocompetent in bone marrow (develop receptors on surface for specific antigen) Must pass same test to be sure they will tolerate “self” cells and recognize foreign or “nonself” cells Then multiple & form clones of identical B cells that recognize that one specific antigen and leave marrow as naive B lymphcytes Major Histocompatiblity Complex (MHC) Proteins Complex = genes are on chromosome #6 Glycoproteins on surface of cells (except RBC), about 200,000 per cell Unique to each person Shaped like hotdog bun, they pick up antigens from inside the cell, migrate to the surface & hold them in their central groove Class I on all cells (except RBC) . Acting like an information relay, the MHC Class I (MHC-I) molecules retrieve bits and pieces of the proteins from inside the cell and display them on the cell surface. MHC complexes essentially give a read out of what's inside the cell Antigen-Presenting Cells (APCs) 1. Phagocytosis of antigen 2. Break down into molecular fragments 3. Display (present) the epitopes on its MHC proteins Class II MHC proteins on APCs only macrophages, B cells, reticular & dendritic cells p 831 Cellular Immunity Cytotoxic T (TC) cells = carry out direct attack on enemy cells Also known as T8, CD8, or CD8+ cells because they have a surface glycoprotein for binding to other cells called CD8 Helper T (TH) cells = promote actions of TC cells and play a key role in humoral immunity & nonspecific defenses Also known as T4, CD4, or CD4+ cells due to CD4 glycoprotein Cellular Immunity Memory T (TM) cells = descended from cytotoxic T cells and provide memory of initial exposure to an antigen, providing for a very rapid response if exposed again Immunity as a Three Act Play Act One = Recognition Act Two = Attack Act Three = Memory OR “the three Rs of immunity” Recognize React Remember Recognition Naive T cells inspect cells MHC proteins & antigens Self antigens = okay Viral proteins, abnormal antigens made by cancer cells = Respond Like a sign that says, “I’m infected” or “I’m a cancer cell” TC cells only MHC-I TH cells only MHC-II p 833 T Cell Activation Receptor on T cell surface must match foreign antigen on MHC = binds MHC Second binding called costimulation required for activation Triggers clonal selection, repeated mitosis which produces a clone of T cells with receptors for same epitope p 833 T Cell Attack Helper T cells secrete interleukins that; 1. Attract neutrophils & natural killer cells 2. Atrract macrophages & stimulate phagocytosis 3. Stimulate T and B cell mitosis & maturation p 833 p 834 T Cell Attack Cytotoxic T cells attack & destroy cell with a release of chemicals For example, Perforin creates pores in cell membrane that kill it Recall the Membrane Attack Complex p 833 p 834 Memory Some TC and TH cells become memory cells Memory T cells are long-lived & much more numerous than naive T cells They require fewer steps, so respond to antigens much more rapidly If the body is exposed to that antigen again, the attack, called the T cell recall response is so quick that there are no symptoms Humoral Immunity Instead of directly attacking enemy cells, the B lymphocytes produce antibodies that bind to antigens and tag them for destruction by other means. Like cellular immunity, it also has 3 parts; 1. Recognition 2. Attack 3. Memory Recognition Immunocompetent B lymphocytes act as APCs 1. Receptor must bind to its specific antigen 2. Endocytosis 3. Digestion of antigen 4. Presentation of epitope in MHC-II on cell surface Now called sensitized B lymphocyte p 835 Recognition (cont’) Sensitized B lymphocytes then must bind with a helper T cell, which secretes interleukins that complete activation Activation triggers clonal selection – B cell mitosis giving rise to a battalion of identical B cells with receptors for the same antigen. p 835 Recognition (cont’) Most B cells become plasma cells that develop mainly in the germinal centers of the lymphatic nodules of the lymph nodes. Plasma cells produce antibodies at a rate of 2,000 per second over 4 to 5 days until they die. p 835 p 836 Antibodies, also called immunoglobulins (Ig) have a monomer made of four polypeptides Note the; Variable region with a specific antigenbinding site Constant region is the same for each class 5 classes include; IgA, IgD, IgE, IgG, and IgM p 837 p 837 An individual probably makes about 2 million different antibodies. The human immune system may be capable of making at least 10 billion antibodies and possibly 1 trillion antibodies. How Antibodies Render Antigens Harmless 1) Neutralization Only the part of an antigen that binds human cells is pathogenic, so antibodies bind these active regions & neutralize them. p 838 How Antibodies Render Antigens Harmless 2) Complement Fixation Antibodies IgM and IgG bind to foreign cells, particularly bacteria and mismatched RBCs, which allows complement to bind & trigger cytolysis. p 837 How Antibodies Render Antigens Harmless 3) Agglutination An antibody may have up to 10 binding sites; thus, it can bind to antigens on more than one cell at a time. This immobilizes microbes and prevents them from spreading. Effective in mismatched RBCs and more importantly against bacteria. p 838 How Antibodies Render Antigens Harmless 4) Precipitation Antibodies link antigen molecules (not whole cells) together. p 838 How Antibodies Render Antigens Harmless This creates large Ag-Ab complexes that come out of solution so they are available for complement to bind them to RBCs or be phagocytized by eosinophils . As RBCs pass through the liver & spleen, the macrophages remove and destroy the Ag-Ab complexes. This is the principle means of clearing foreign antigens from the blood. Memory During clonal selection memory B cells are also created in the germinal centers in lymph nodes. They form plasma cells within hours and mount a very quick secondary response, that prevents any symptoms. p 838