LESSON 3: LYMPHATIC SYSTEM AND BODY DEFENSES 3rd QUARTER | ANATOMY AND PHYSIOLOGY 2 OUTLINE I. Lymphatic System II. Body Defenses III. Developmental Aspect of Lymphatic System and Body Defenses IV. Interrelation among other organ systems • Figure 11.1 shows the one way system of lymphatic vessels where lymph flows only towards the heart (see pink arrow) LYMPHATIC SYSTEM • • Consists of two semi-independent parts: 1. Lymphatic Vessels 2. Lymphoid Tissues and Organs Lymphatic System Functions § Transports escaped fluids from the cardiovascular system back to the blood § Plays essential roles in body defense and resistance to disease • LYMPHATIC VESSELS • • • Lymph consists of excess tissue fluid and plasma proteins carried by lymphatic vessels If fluids are not picked up, edema occurs as fluid accumulates in tissues Lymphatic vessels (lymphatics) pick up excess fluid (lymph) and return it to the blood Figure 11.1 shows the relationship between the blood vessels and lymphatic vessels. As pointed by the pink arrow, the tissue fluid that goes out of the capillaries will become lymph and will enter the lymph capillaries Figure 11.2 shows how edema looks like which is a consequence of failure to pick up fluids that accumulates in tissues. Edema can also be a consequence of high blood pressure A.G. RODRIGUEZ & D. TAN Lymphatic Vessels (lymphatics) § Form a one-way system § Lymph flows only toward the heart. Lymphatic Capillaries § Weave between tissue cells and blood capillaries § Walls overlap to form flaplike minivalves § Fluid leaks into lymph capillaries § Capillaries are anchored to connective tissue by filaments § Higher pressure on the inside closes minivalves § Fluid is forced along the vessel Figure 11.3a shows how the lymphatic capillaries (green vessels in the photo above) weaves itself to the blood capillaries. Figure 11.3b shows the flaplike minivalve of the lymphatic capillary as well as the filaments that it uses to anchor to connective tissues. • Lymphatic collecting vessels § Collect lymph from lymph capillaries § Carry lymph to and away from lymph nodes § Return fluid to circulatory veins near the heart o Right lymphatic duct drains the lymph from the right arm and the right side of the head and thorax o Thoracic duct drains lymph from rest of body. PAGE 1 OF 10 LYMPHATIC NODES • • Figure 11.1 highlights the location of the lymphatic collecting vessels. • • • • Lymph nodes filter lymph before it is returned to the blood Harmful materials that are filtered: § Bacteria § Viruses § Cancer cells § Cell debris Defense cells within lymph nodes § Macrophages – engulf and destroy bacteria, viruses, and other foreign substances in lymph § Lymphocytes – respond to foreign substances in lymph Most lymph nodes are kidney-shaped, less than 1 inch long, and buried in connective tissue § Surrounded by a capsule § Divided into compartments by trabeculae Cortex (outer part) § Contains follicles - collections of lymphocytes § Germinal centers enlarge when antibodies are released by plasma cells Medulla (inner part) § Contains phagocytic macrophages Figure 11.4 highlights the different regions of the body that is drained by the right lymphatic and thoracic duct. LYMPHATIC VESSELS (continuation) • • Lymphatic vessels are similar to veins of the cardiovascular system § Thin-walled § Larger vessels have valves § Low-pressure, pumpless system Lymph transport is aided by: § Milking action of skeletal muscles (similar to how skeletal muscles can open valves of veins when it is “squeezed” by the muscles) § Pressure changes in thorax during breathing § Smooth muscle in walls of lymphatics Figure 11.5 shows the parts of the lymphatic nodes. Highlighted are the cortex and the follicle cells and germinal center in it and the medulla. • Flow of lymph through nodes 1. Lymph enters the convex side through afferent lymphatic vessels. 2. Lymph flows through a number of sinuses inside the node 3. Lymph exits through efferent lymphatic vessels. Because there are fewer efferent than afferent vessels, flow is slowed. Figure 11.1 shows the relationship of the lymph nodes to the lymphatic vessels in terms of location. Figure 11.5 shows the flow of lymph from the afferent lymphatic vessels to the efferent lymphatic vessels. A.G. RODRIGUEZ & D. TAN PAGE 2 OF 10 OTHER LYMPHOID ORGANS • Several other lymphoid organs contribute to lymphatic function (in addition to the lymph nodes) § Spleen § Thymus § Tonsils § Peyer’s patches § Appendix BODY DEFENSES Innate (nonspecific) defense system • Mechanisms protect against a variety of invaders • Responds immediately to protect body from foreign materials Adaptive (specific) defense system • Fights invaders that get past the innate system • Specific defense is required for each type of invader • The highly specific resistance to disease is immunity INNATE (NONSPECIFIC) BODY DEFENSES • Figure 11.6 shows the location of other lymphoid organs in the body. • Innate body defenses are mechanical barriers to pathogens (harmful or disease-causing microorganisms) and include: § Body surface coverings o Intact skin o Mucous membranes § Specialized human cells § Chemicals produced by the body Table 12.1 provides a more detailed summary Spleen • Located on the left side of the abdomen • Filters and cleans blood of bacteria, viruses, debris • Provides a site for lymphocyte proliferation and immune surveillance • Destroys worn-out blood cells • Forms blood cells in the fetus (this function will later on be passed to the bone marrow) • Acts as a blood reservoir. Thymus • Found overlying the heart • Functions at peak levels only during youth • Produces T-lymphocytes Tonsils • Small masses of lymphoid tissue deep to the mucosa surrounding the pharynx (throat) • Trap and remove bacteria and other foreign pathogens • Tonsillitis results when the tonsils become congested with bacteria Peyer’s Patches • Found in the wall of the small intestine • Similar lymphoid follicles are found in the appendix • Macrophages capture and destroy bacteria in the intestine Mucosa-associated lymphoid tissue (MALT) • Includes: § Peyer’s patches § Tonsils § Appendix • Acts as a sentinel (indicator of the presence of a disease) to protect respiratory and digestive tracts A.G. RODRIGUEZ & D. TAN PAGE 3 OF 10 1st Surface membrane barriers • Surface membrane barriers, such as the skin and mucous membranes, provide the first line of defense against the invasion of microorganisms. o Protective secretions produced by these membranes. § Acidic skin secretions inhibit bacterial growth § Sebum is toxic to bacteria § Mucus traps microorganisms § Gastric juices are acidic and kill pathogens § Saliva and tears contain lysozyme (enzyme that destroys bacteria). Cells and chemicals: Internal defenses 2nd • Cells and chemicals provide a second line of defense. § Natural killer cells and phagocytes § Inflammatory response § Chemicals that kill pathogens § Fever Natural Killers (NK) Cells • Lyse (burst) and kill cancer cells, virus-infected cells • Release chemicals called perforin and granzymes to degrade target cell contents Inflammatory Response • Triggered when body tissues are injured • Four most common indicators (cardinal signs) of acute inflammation. 1. Redness 2. Heat 3. Pain 4. Swelling (edema) • Damaged cells release inflammatory chemicals § Histamine § Kinin • These chemicals cause: § Blood vessels to dilate § Capillaries to become leaky § Phagocytes and white blood cells to move into the area (called positive chemotaxis) • Process of the inflammatory response 1. Neutrophils migrate to the area of inflammation by rolling along the vessel wall (following the scent of chemicals from inflammation) 2. Neutrophils squeeze through the capillary walls by diapedesis (passage of blood vessels through the intact walls of the capillaries) to sites of inflammation 3. Neutrophils gather in the precise site of tissue injury (positive chemotaxis) and consume any foreign material present Figure 11.8 shows the process of inflammatory response through phagocytes such as neutrophils Phagocytes • Cells such as neutrophils and macrophages engulf foreign material by phagocytosis • The phagocytic vesicle is fused with a lysosome, and enzymes digest the cell’s contents Figure 11.9 shows a scanning electron micrograph of phagocytosis by a macrophage as it ingests a bacillus-shaped bacteria (encircled) Figure 11.7 is a flowchart that shows the cascade of inflammatory events after an injury. Release of kinins, histamines and other chemicals cause blood vessels to dilate, capillaries to become leaky and WBC’s to enter the area. Figure 11.10 shows the steps involved in phagocytosis by a microphage. Dilation of blood vessels can lead to increase blood flow, capillaries becoming leaky can lead to edema and clotting proteins in the area while WBC’s are for removal and damaged tissues and pathogens. This will all eventually cause healing. A.G. RODRIGUEZ & D. TAN PAGE 4 OF 10 Antimicrobial Proteins • Enhance innate defenses by: § Attacking microorganisms directly § Hindering reproduction of microorganisms • Most important types: § Complement proteins § Interferon • Antimicrobial proteins: complement proteins § Complement refers to a group of at least 20 plasma proteins that circulate in the plasma § Complement is activated when these plasma proteins encounter and attach to cells (known as complement fixation) § Membrane attack complexes (MACs), one result of complement fixation, produce holes or pores in cells. o Pores allow water to rush into the cell o Cell bursts (lyses) § Activated complement enhances the inflammatory response Figure 11.13 shows activated complement proteins forming a membrane attack complex after complement fixation. This causes formation of pores that allow water to rush into the cell causing cell lysis • Antimicrobial proteins: interferons § Interferons are small proteins secreted by virus-infected cells. § Interferons bind to membrane receptors on healthy cell surfaces to interfere with the ability of viruses to multiply. Fever • Abnormally high body temperature is a systemic response to invasion by microorganisms • Hypothalamus regulates body temperature at 37oC (98.6oF) • The hypothalamus thermostat can be reset higher by pyrogens (secreted by white blood cells) • High temperatures inhibit the release of iron and zinc (needed by bacteria) from the liver and spleen • Fever also increases the speed of repair processes A.G. RODRIGUEZ & D. TAN ADAPTIVE DEFENSE SYSTEM • Adaptive Body Defenses Three aspects of Adaptive Defense § Antigen specific – the adaptive defense system recognizes and acts against particular foreign substances § Systemic—immunity is not restricted to the initial infection site § Memory – the adaptive defense system recognizes and mounts a stronger attack on previously encountered pathogens o Two arms of the Adaptive Defense System § Humoral immunity = antibody-mediated immunity ² Provided by antibodies present in body fluids § Cellular immunity = cell-mediated immunity ² Targets virus-infected cells, cancer cells, and cells of foreign grafts 1. Antigen o Antigens are any substance capable of exciting the immune system and provoking an immune response for using words and different patterns of development o Examples of common nonself antigens (those that are not found in the cells of your body; “Self” antigens include the antigens A and B in our RBCs that are used to determine blood type) § Nominalization – act of transforming verbs to nouns as much as possible; instead of suggest refuse, employ, you use suggestion, arrival, employment § Foreign proteins provoke the strongest response § Nucleic acids § Large carbohydrates § Some lipids § Pollen grains § Microorganisms (bacteria, fungi, viruses) o Self-Antigens § Human cells have many protein and carbohydrate molecules § Self-antigens do not trigger an immune response in us § The presence of our cells in another person’s body can trigger an immune response because they are foreign ² Restricts donors for transplants o Haptens, or incomplete antigens, are not antigenic by themselves § Humoral immunity = antibody-mediated immunity § When they link up with our own proteins, the immune system may recognize the combination as foreign and respond with an attack § Found in poison ivy, animal dander, detergents, hair dyes, cosmetics 2. Cells of the Adaptive System o Crucial Cells of the Adaptive System § Lymphocytes – respond to specific antigens ² B lymphocytes (B cells) produce antibodies and oversee humoral immunity ² T lymphocytes (T cells) constitute the cell- PAGE 5 OF 10 mediated arm of the adaptive defenses; do not make antibodies § Antigen-presenting cells (APCs) — help the lymphocytes but do not respond to specific antigens o Lymphocytes § Arise from hemocytoblasts of bone marrow § Whether a lymphocyte matures into a B cell or T cell depends on where it becomes immunocompetent (capability to respond to a specific antigen by binding to it with antigenspecific receptors that appear on the lymphocyte’s surface) § T cells develop immunocompetence in the thymus and oversee cell-mediated immunity ² Identify foreign antigens ² Those that bind self-antigens are destroyed. Self-tolerance is important part of lymphocyte “education” § B cells develop immunocompetence in bone marrow and provide humoral immunity § Immunocompetent T and B lymphocytes migrate to the lymph nodes and spleen, where encounters with antigens occur § Differentiation from naïve cells into mature lymphocytes is complete when they bind with recognized antigens § Mature lymphocytes (especially T cells) circulate continuously throughout the body o Antigen-presenting Cells (APCs) § Lymphocytes – respond to specific antigens § Engulf antigens and then present fragments of them on their own surfaces, where they can be recognized by T cells § Major types of cells behaving as APCs ² Dendritic Cells ² Macrophages ² B lymphocytes § When they present antigens, dendritic cells and macrophages activate T cells, which release chemicals 3. Humoral (antibody-mediated) immune response o B lymphocytes with specific receptors bind to a specific antigen o The binding event sensitizes, or activates, the lymphocyte to undergo clonal selection o A large number of clones is produced (primary humoral response) o Most of the B cell clone members (descendants) become plasma cells § Produce antibodies to destroy antigens § Activity lasts for 4 or 5 days § Plasma cells begin to die o Some B cells become long-lived memory cells capable of mounting a rapid attack against the same antigen in subsequent meetings (secondary humoral response) § These cells provide immunological memory A.G. RODRIGUEZ & D. TAN o Active Immunity § Occurs when B cells encounter antigens and produce antibodies § Active immunity can be: ² Naturally acquired during bacterial and viral infections ² Artificially acquired from vaccines o Passive Immunity § Occurs when antibodies are obtained from someone else ² Naturally acquired from a mother to her fetus or in the breast milk ² Artificially acquired from immune serum or gamma globulin (donated antibodies) § Immunological memory does not occur § Protection is short-lived (2–3 weeks) § Monoclonal Antibodies ² B lymphocytes (B cells) produce antibodies and oversee humoral immunity ² Antibodies prepared for clinical testing for diagnostic services ² Produced from descendants of a single cell line ² Exhibit specificity for only one antigen ² Examples of uses for monoclonal antibodies Ä Cancer Treatment Ä Diagnosis of Pregnancy Ä Treatment after exposure to hepatitis and rabies PAGE 6 OF 10 2. IgA—found mainly in secretions, such as mucus or tears 3. IgD—important in activation of B cell 4. IgG—can cross the placental barrier and fix complement; most abundant antibody in plasma 5. IgE—involved in allergies o Antibodies (immunoglobulins, lgs) § Occurs when antibodies are obtained from someone else § Constitute gamma globulin part of blood proteins § Soluble proteins secreted by activated B cells (plasma cells) § Formed in response to a huge number of antigens o Antibody Structure § Four polypeptide chains, two heavy and two light, linked by disulfide bonds to form a T- or Yshaped molecule § Each polypeptide chain has a variable (V) region and a constant (C) region ² Variable regions form antigen-binding sites, one on each arm of the T or Y ² Constant regions determine the type of antibody formed (antibody class) o Antibody Classes § Antibodies of each class have slightly different roles and differ structurally and functionally § Five major immunoglobulin classes (MADGE) 1. IgM—can fix complement (refers to a grp of at least 20 plasma proteins that circulate in the plasma) A.G. RODRIGUEZ & D. TAN o Antibody Function § Antibodies inactivate antigens in a number of ways ² Complement fixation: chief antibody ammunition used against cellular antigens ² Neutralization: antibodies bind to specific sites on bacterial exotoxins or on viruses that can cause cell injury ² Agglutination: antibody-antigen reaction that causes clumping of cells ² Precipitation: cross-linking reaction in which antigen-antibody complex settles out of solution 4. Cellular (cell-mediated) Immune Response o Main difference between 2 arms of the adaptive response § B cells secrete antibodies § T cells fight antigens directly PAGE 7 OF 10 o Like B cells, immunocompetent T cells are activated to form a clone by binding with a recognized antigen o Unlike B cells, T cells are unable to bind to free antigens § Antigens must be presented by a macrophage, and double recognition must occur § APC (Antigen presenting cells) engulfs and presents the processed antigen in combination with a protein from the APC o Different classes of effector T cells § Helper T cells ² Recruit other cells to fight invaders ² Interact directly with B cells bound to an antigen, prodding the B cells into clone production ² Release cytokines, chemicals that act directly to rid the body of antigens § Regulatory T cells ² Release chemicals to suppress the activity of T and B cells ² Stop the immune response to prevent uncontrolled activity ² A few members of each clone are memory cells § Cytoxic (killer) T Cells ² Specialize in killing infected cells ² Insert a toxic chemical (perforin or granzyme) ² The perforin enters the foreign cell’s plasma membrane ² Pores now appear in the target cell’s membrane ² Granzymes (protein-digesting enzymes) enter and kill the foreign cell ² Cytotoxic T cell detaches and seeks other targets FUNCTION OF CELLS INVOLVED IN IMMUNITY FUNCTION IN THE IMMUNE ELEMENT RESPONSE Lymphocyte that resides in the lymph nodes, spleen, or other lymphoid tissues where it is induced B Cell to replicate by antigen-binding and helper T cell interactions; its progeny (clone members) form plasma cells and memory cells. Antibody-producing “machine” ; produces huge numbers of the Plasma Cell same antibody (immunoglobulin); specialized B cell clone descendant A T cell that binds w a specific antigen presented by an APC; it stimulates the production of other Helper T cell immune cells (cytotoxic T cells and B cells) to help fight the invader; acts both directly and indirectly by releasing cytokines Activity enhanced by Helper t Cells; its specialty is killing virus-invaded Cytotoxic T body cells, as well as body cells that Cell have become cancerous; involved in graft rejection Slows or stops the activity of B and T cells once the infection (or attack Regulatory T by foreign cells) has been Cell conquered. Thought to be important in preventing autoimmune diseases Descendant of an activated B cell or T cell; generated during both primary and secondary immune responses; may exist in the body for Memory Cell years thereafter, enabling it to respond quickly and efficiently to subsequent infections or meetings w the same antigen Any of several cell types (macrophage, dendritic cell, B cell) that engulfs and digests antigens that it encounters and presents parts of them on its plasma membrane for recognition by T cells Antigenbearing receptors for the same presenting Cell antigen; this function, antigen (APC) presentation, is essential for normal cell-mediated responses. Macrophages and dentritic cells also release chemicals (cytokines) that activate many other immune cells. o T cells must recognize nonself and self through the process of antigen presentation § Nonself—the antigen fragment presented by APC § Self—coupling with a specific glycoprotein on the APC’s surface at the same time FUNCTION OF CELLS INVOLVED IN IMMUNITY FUNCTION IN THE IMMUNE ELEMENT RESPONSE Protein produced by a B cell or its Antibody plasma-cell offspring and (immunoglobulin) released into body fluids (blood, A.G. RODRIGUEZ & D. TAN PAGE 8 OF 10 Cytokines Tumor necrosis factor (TNF) Complement Regulatory T Cell Cytotoxins lymph, saliva, mucus, etc.), where it attaches to antigens, causing neutralization, opsonization, precipitation, or agglutination, which "marks" the antigens for destruction by phagocytes or complement. Chemicals released by sensitized T cells, macrophages, and certain other cells • Migration inhibiting factor (MIF)—" inhibits" macrophage migration and keeps them in the local area. • Interleukin 2—stimulates T cells and B cells to proliferate; activates NK cells. • Helper factors—enhance antibody formation by plasma cells. • Suppressor factors— suppress antibody formation or T cell-mediated immune responses (interleukin-10 transforming growth factor and others). • Chemotactic factors—attract leukocytes (neutrophils, eosinophils, and basophils) into inflamed area. • Gamma interferon— secreted by lymphocytes; helps make tissue cells resistant to viral infection; activates macrophages and NK cells; enhances maturation of cytotoxic T cells. Like perforin, causes cell killing; attracts granulocytes; activates T cells and macrophages. Group of bloodborne proteins activated after binding to antibody-covered antigens; when activated, complement causes lysis of the microorganism and enhances inflammatory response. Substance capable of provoking an immune response; typically a large, complex molecule not normally present in the body. Perforin, granzymes—cell toxins released by cytotoxic T cells and NK cells ORGAN TRANSPLANT AND REJECTIONS • Major Types of Transplants, or Grafts o Autografts—tissue transplanted from one site to another on the same person A.G. RODRIGUEZ & D. TAN o Isografts—tissue grafts from a genetically identical person (identical twin) o Allografts—tissue taken from a person other than an identical twin (most common type of graft) o Xenografts—tissue taken from a different animal species (never successful) • Blood group and tissue matching is done to ensure the best match possible o 75% match is needed to attempt a graft • Organ Transplant is followed by immunosuppressive therapy to prevent rejection DISORDERS OF IMMUNITY • The most important disorders of the immune system o Allergies § Types of Allergies ² Immediate (acute) Hypersensitivity Ä Seen in hives and anaphylaxis (allergic reaction) Ä Due to IgE antibodies and histamine Ä Anaphylactic shock is systemic, acute allergic response and is rare ² Delayed Hypersensitivity Ä Reflects activity of T cells, macrophages, and cytokines Ä Symptoms usually appear 1–3 days after contact with antigen Ä Allergic contact dermatitis (poison ivy, cosmetics) o Autoimmune diseases § Occurs when the body’s self-tolerance breaks down § The body produces auto-antibodies and sensitized T lymphocytes that attack its own tissues § Most forms of autoimmune disease result from the: ² appearance of formerly hidden self-antigens ² changes in the structure of self-antigens, and ² antibodies formed against foreign antigens PAGE 9 OF 10 that resemble self-antigens § Examples of autoimmune diseases ² Rheumatoid arthritis—destroys joints ² Myasthenia gravis—impairs communication between nerves and skeletal muscles ² Multiple sclerosis—white matter of brain and spinal cord is destroyed ² Graves’ disease—thyroid gland produces excess thyroxine ² Type I diabetes mellitus—destroys pancreatic beta cells, resulting in deficient insulin production ² Systemic lupus erythematosus (SLE)— affects kidney, heart, lung, and skin ² Glomerulonephritis—severe impairment of kidney function due to acute inflammation § Immunodeficiencies ² May be congenital or acquired Ä Severe combined immunodeficiency disease (SCID) is a congenital disease Ä AIDS (acquired immune deficiency syndrome) is caused by a virus that attacks and cripples the helper T cells ² Result from abnormalities in any immune element ² Production or function of immune cells or complement is abnormal INTERRELATION AMONG OTHER ORGAN SYSTEM DEVELOPMENTAL ASPECT OF LYMPHATIC SYSTEM AND BODY DEFENSES • Lymphatic vessels form by budding off from veins • Lymph nodes present by fifth week of development • The thymus and the spleen are the first lymphoid organs to appear in the embryo • Other lymphoid organs are poorly developed before birth • The immune response develops around the time of birth • The ability of immunocompetent cells to recognize foreign antigens is genetically determined • Stress appears to interfere with normal immune response • Efficiency of immune response wanes in old age, and infections, cancer, immunodeficiencies, and autoimmune diseases become more prevalent A.G. RODRIGUEZ & D. TAN PAGE 10 OF 10