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The Lymphatic System and Immunity (Chapter 22) Lymphatic System Functions: 1. Reclaim lost fluid for return to cardiovascular system 30 L of fluid pass from the blood capillaries into interstitial fluid each day, & only 27 L pass from interstitial fluid back into the blood capillaries---------------If the extra 3 L of fluid were to remain in the interstitial fluid, edema would occur (tissue damage & death). Instead, the 3 L of fluid enters the lymphatic capillaries & is called Lymph (lymph passes through the lymphatic vessels back into blood). 2. Protect against pathogens & cancer cells -nonspecific defenses: general protection, does not distinguish threat specifics -specific defenses = immune response, identify and defend against one particular threat 3. Fat absorption -absorbs fats from the digestive tract lymphatic vessels called lacteals (located in lining of small intestine) -lymph called chyle (milky appearance because of fat content) (Immunity = resistance to infection through activation of specific defenses) Lymphatic System Components: 1. Lymph: fluid similar to plasma but less proteins 2. Lymphatic vessels: carry lymph from tissues to veins 3. Lymphoid tissues and organs: site of development of lymphocytes and screening for pathogens 4. Lymphatic capillary: beginning of lymphatic system of vessels, lined with flattened endothelium lacking a basement membrane 5. Lymph node: encapsulated mass of lymphatic tissue found among lymph vessels 6. Lymphatic nodule: small accumulation of lymphatic tissue lacking a distinct boundary 7. Lymphoid follicle: lymphatic nodules that are found within lymph nodes & the spleen 8. Lymphatic sinus: channels in a lymph node crossed by a reticulum of cells & fibers 9. Lymphocytes and Phagocytes: provide defense *Lymphatic capillaries are found in most tissues of the body except: CNS, bone marrow, cartilage, epidermis, cornea. Lymph: -lymph originates as fluid lost from blood capillaries -consists of water plus solutes from two sources: – Plasma: ions, nutrients, gases, some proteins – Cells: hormones, enzymes, waste products -collected in lymphatic capillaries -fluid, solutes, large objects driven into lymphatic capillary by pressure in interstitial space (arteries, skeletal muscle) Lymphatic Vessels: - histologically most like veins -lymphatic capillaries are more permeable than blood capillaries (lack basement membrane) - all three tunics - large ones have vasa vasorum -overlapping endothelial cells create one way mini-valves (allows fluid to enter capillaries but prevents it from passing back into interstitial spaces) - many anastomoses - lymph nodes present along vessels - converge, return fluid to blood stream: lymphatic capillaries → lymphatic collecting vessels → lymphatic trunks (jugular, subclavian, bronchomediastinal, intestinal, lumbar) → lymphatic ducts (Right lymphatic duct, thoracic duct)→ large veins OR: lymphatic capillaries → lymphatic collecting vessels → lymphatic trunks (jugular, subclavian, bronchomediastinal, intestinal, lumbar) → large veins Note: Jugular trunks drain: head & neck Subclavian trunks drain: upper limbs, superficial thoracic wall, & mammary glands Bronchomediastinal trunks drain: thoracic organs & deep thoracic wall Intestinal trunks drain: abdominal organs (intestines, stomach, pancreas, spleen, liver) Lumbar trunks drain: lower limbs, pelvic & abdominal walls, pelvic organs (ovaries, testes, kidneys, adrenal glands) Right lymphatic duct: drains right side of head, right-upper limb, right thorax Thoracic duct: drains remainder of the body Note: Cisterna Chyli: in some case, the lymphatic trunks form a sac Disorder: Lymphangitis = inflammation of a lymphatic vessel, due to toxins or infection, vasa vasorum swell with blood due to pressure, appears as red line under skin Lymphoid Cells: A. Macrophages: are monocytes that leave blood & enter tissues Phagocytosis: have an increase number of lysosomes Outlive neutrophils: accumulate in tissues after neutrophils & responsible for phagocytic activity in late stages of infection, including cleanup. T cell activation Produce chemicals that enhance immune response: interferons, prostaglandins, complement Sinuses: if microbes to enter the blood or lymphatic system, macrophages wait to phagocytize them in enlarged spaces called sinuses Sometimes given specific names: dust cells in lungs, kupffer cells in liver, & microglia in CNS B. Dendritic cells: large motile cells with long cytoplasmic extensions Scattered throughout most tissue: except brain In the skin called: Langerhans cells Antigen presentation: take in foreign antigens by endocytosis C. Lymphocytes: (3 classes) 1. T cells – “Thymus dependent”: stem cells give rise to pre-T cells, which migrate to thymus and are processed into T cells by thymosin (hormone produced by thymus) Cell-mediated immunity: immune response that does not involve antibodies or complement Cytotoxic T cells: kill “foreign” cells directly (by lysis or producing cytokines) Helper T cells: activate T & B cells Suppressor T cells: inhibit T & B cells 2. B cells – “Bone marrow derived”: stem cells give rise to pre-B cells, which are processed in red bone marrow into B cells When activated → plasma cell or memory B cell - plasma cell → secretes antibodies, antibodies bind specific antigens (foreign molecules) (antibody mediated or humoral immunity) - memory B cell → responds to antigen that was previously reacted to 3. Natural Killer Cell: attack abnormal cells: cancer cells, or virus-infected cells (nonspecific defense) Do not exhibit memory response: part innate immunity - defend the host from infection by other organisms, in a non-specific manner Lymphocytes constantly circulate between blood, lymph, tissues; can survive 20+ years Lymphopoiesis = production of lymphocytes - occurs in bone marrow, thymus, and lymphoid tissues -Hemocytoblast → Lymphoid stem cell - one type of lymphoid stem cell stays in bone marrow → B cells and NK cells - one type migrates to thymus → T cells Both B and T cells can divide to produce more of same type (clones) Both can migrate to all lymphoid tissues for division and development Lymphoid Tissue: - reticular CT (fine collagen fibers) & lymphocytes & other lymphoid cells (macrophages, dendritic cells) - functions: 1. Proliferation site for lymphocytes 2. Surveillance point for lymphocytes and macrophages - two types: lymphoid follicles and lymphoid organs 1. Lymphoid Follicles / Nodules - CT packed with lymphocytes (T, B, and dendritic cells) - no capsule - germinal center in middle: dividing B cells - germinal center surrounded by dendritic cells, T cells and some macrophages - special lymphoid nodule/follicle collections: *in loose CT of digestive, respiratory, urinary, reproductive *found within lymph nodes & spleen A. MALT (mucosa-associated lymphoid tissue): -deep to intestinal epithelium, made up of individual nodules called Peyer’s Patches: lymphatic nodules found small intestine & appendix -nonencapsulated lymphatic tissue -follicles associated with and found in & beneath mucous membranes lining the respiratory, digestive, reproductive, and urinary tracts B. Appendix: tubular offshoot of beginning portion of large intestine (walls have lymphatic nodules) C. Tonsils: large nodules in pharynx, have crypts to trap bacteria → encourage development of immunity 5 Total: 2 palatine tonsils: lymphoid masses 1 pharyngeal (adenoid): closely aggregated lymphatic nodules 2 lingual tonsils: loosely associated lymphatic nodules 2. Lymphoid Organs - have fibrous CT capsule around outside - contain many lymphoid follicles - include: lymph nodes, thymus, and spleen A. Lymph nodes - bean shaped, 1-25mm - have associates blood vessels and nerves structure: -capsule: CT, surrounds outside -trabeculae: folds of capsule creating partitions inside (forms internal skeleton) -cortex = outer edge -superficial cortex = lymphoid follicles: B cells & dendritic cells -deep cortex = T cells, transit between lymph and blood -medulla = center: houses B & plasma cells -sinuses: spaces throughout, house macrophages, allow lymph flow through node Lymph flow through node:(lymph nodes are the only structures to filter lymph) -lymph enters via afferent vessels (many) -flows slowly through sinuses where it is surveyed for pathogens and antigens Macrophages engulf pathogens Dendritic cells bind antigens and stimulate lymphocytes -“clean” lymph exits via efferent vessels (few) *Lymph nodes clustered mostly along lymphatic trunks: function to purify lymph before returning it to blood If pathogen detected: -lymphocytes increase in number (rapid clonal division of B & T cells) - causes node to swell = buboes (Yersinia pestis → Bubonic plague) Lymphadenopathy = chronic enlargement of lymph nodes, due to infection or cancer Cancer often metastasizes in lymph vessels: blood capillaries restrict access of cells but lymphatic capillaries do not B. Thymus -glandular -located superior to heart - T cells mature in cortex and migrate to medulla to enter blood Thymus produces hormones: thymosin & thymopoietin both promote development and maturation of lymphocytes (mostly the T cells in thymus) Thymus most active in early childhood, atrophies with age C. Spleen - located lateral to stomach Functions: -remove abnormal blood cells -store iron from recycled RBCs for reuse -initiate immune response by B & T cells in response to antigens in blood (have high conc. of T cells & B cells) -store platelets (acts as a blood reservoir) Structure: -Red pulp: sinusoids filled with RBCs, platelets, and macrophages which phagocytize old RBCs and pathogens -White pulp: lymphoid follicles containing lymphocytes, await antigen to activate Spleen cleans blood: - blood flows slowly through sinusoids - macrophages and lymphocytes detect and destroy foreign cells and antigens Spleen = mostly sinusoids -bleeds profusely when damaged -to fragile to stitch tears -splenectomy to prevent fatal hemorrhaging -liver and bone marrow can take over functions Defense against pathogens: 1st line: prevent entry → skin & mucosa 2nd line: general antimicrobial actions when first line has been penetrated [nonspecific defense = innate defense (born with it)] 3rd line: precision assault on a specific pathogen (immune response) 1) Skin, hair, secretions 2) Macrophages , neutrophils, eosinophils 3) NK cells 4) Antiviral chemicals 5) Antibacterial proteins 6) Restrict spread of injury 7) Accelerate metabolism 1. Physical Barriers A. Cutaneous Membrane (Skin): -impenetrable layers of keratinized cells -impermeable to water and chemicals -acid pH due to sebum -high salt due to perspiration (acid & salt inhibit microbe growth) B. Mucosa: -produces antimicrobial secretions: -acid: inhibit microbe growth -lysozyme: lyse bacterial cell walls -mucus: traps microbes 2. Phagocytes A. Microphages neutrophils and eosinophils: -either phagocytose pathogen or -secrete defensins on pathogen: defensins cause membrane pores that cause lysis of target cell B. Macrophages phagocytose pathogens, cell debris and other foreign material -fixed macrophages: non-traveling, associated with specific tissue or organ (e.g. microglia) -free macrophages: travel throughout body via blood All phagocytes: -emigrate from capillaries -display chemotaxis (move toward chemical signals to site where microbe is) -have receptors to bind target for phagocytosis Phagocytosis 1. phagocytic cell adheres to target via receptors 2. pseudopods form around target to engulf 3. target internalized in phagosome → fused with lysosome 4. target digested in phagolysosome: -small solutes diffuse into cytoplasm for use (amino acids, glucose. etc.) -undigestable = residual body 5. enzymes neutralized, residual body exocytosed 3. Immunological Surveillance -monitoring of tissues by NK cells for abnormal cells (cancer or virus infected) -abnormal cells express abnormal antigens on surface → detected by NK cells -NK cell binds abnormal cell and releases perforins from Golgi -perforins assemble on target membrane creating pores → lysis of target 4. Interferons = antiviral cytokines (cytokines = chemicals used for cell to cell communication) = proteins released by activated lymphocytes, macrophages, or virusinfected cells Three types: -α interferons: produced by leukocytes to attract and stimulate NK cells -β interferons: produced by virus infected cells to trigger neighboring cells to produce antiviral proteins to slow viral replication -γ interferons: produced by T and NK cells to stimulate macrophage activity 5. Complement - 11 complement proteins + 9 other factors (C1 – C9) & regulators act in cascade to cause foreign cell lysis (often target bacteria) 6. Inflammation -localized redness, swelling, heat, and pain in response to any tissue damage Functions: 1. Help prevent injury/infection from spreading 2. Disposes of cell debris 3. Sets the stage for repair Inflammation Events: 1.) Histamine is released by mast cells in response to change in the local environment and triggers an acceleration of blood flow to the area (vasodilation). 2.) Clotting factors and complement enter the site. A clot forms around the injury and complement lyses bacteria and attracts phagocytes. 3.) The local temperature rises due to the increase blood flow, which accelerates enzymatic reactions to enhance killing of pathogens. 4.) Neutrophils arrive, emigrate and chemotax, and are activated to produce the respiratory burst releasing toxic compounds to kill pathogens. They also release cytokines to attract other phagocytes. 5.) Macrophages arrive to engulf pathogens and cell debris. 6.) Fibroblast are stimulated to create collagen patch (scar tissue) to reinforce the clot and begin repair. 7.) Mast cell chemicals trigger pain receptors. 8.) The specific/immune defenses are activated. Puss =dead WBCs, pathogens, debris: failure to clear abscess =puss walled off by CT Necrosis =tissue degeneration due to lysosomal enzymes released by damaged cells (injury gets worse before better) Apoptosis = controlled cell death (no necrosis) 7. Fever = elevated body temperature (>99°F/37.2C) - triggered by pyrogens(triggers rise in temperature); released into blood by leukocytes, mostly macrophages, upon exposure to foreign antigens - effect: increase metabolic rate to allow better defense and repair (rate 10% / 1°C) up to 104°F: safe & productive @106°F: nervous tissue dysfunctional @110°F: proteins denature = death Specific or Adaptive Defenses = The Immune Response T cells = cellular-mediated immunity; function to amplify the inflammatory response B cells = humoral immunity (antibody-mediated immunity); responsible for most complement activation/fixation - Each B cell covered in receptors that recognize and bind only one specific antigen Antigen = foreign substance that can activate the immune system and provoke an immune response -usually large complex molecules: proteins, nucleic acids, some lipids, some polysaccharides -Simple chemical structures like plastic and metal are not immunogenic / antigenic -Haptens: small molecules capable of combining with larger molecules, such as blood proteins, to stimulate an adaptive immune response 2 Types of antigens: a. Foreign antigens: are not produced by the body but are introduced from outside Ex: -bacteria, viruses, other microorganisms -Pollen, animal dander, foods, drugs--------can trigger overreaction of immune system called allergic reaction b. Self-antigens: -are molecules produced by body -response can be beneficial or harmful Ex: -tumor antigens---------beneficial -autoimmune disease-----harmful Overview & Comparison Between Nonspecific & Specific Immunity: Nonspecific: Also called Innate Immunity Non-specific ex: act on bacteria in general Non-memory ex: following first exposure to bacteria, body can take many days to destroy them and these bacteria can cause damage to tissues Includes: Mechanical mechanisms: such as, skin & mucous membranes Chemical mediators: such as, cytokines & histamine Interferon Cells: such as, neutrophils, macrophages, basophils, mast cells, eosinophils, NK cells Specific: Also called Adaptive Immunity Specific ex: act on specific kind of bacteria only Memory ex: following the second exposure to the same bacteria, the response is rapid and effective and no symptoms occur. Includes: B cells (humoral immunity) & T cells (cell-mediated immunity) Forms of Immunity: Properties of Immunity 1. Specificity: immune response targets particular antigens; each B and T cell responds to and destroys only one specific antigen. 2. Versatility: a large diversity of lymphocytes prescribed by genes exist to respond to almost any antigen; when a particular antigen is encountered the one lymphocyte specific to it divides by clonal selection to produce many cells specific to that particular antigen 3. Memory: response after second exposure to the same antigen is faster, stronger and lasts longer; during the initial exposure memory cells were created to respond quickly upon second exposure 4. Tolerance: immune system responds only to non-self antigens; B and T cells that recognize self antigens are destroyed by clonal deletion to insure self tolerance T Cells and Cell Mediated Immunity - Protects against intracellular antigens: targets virus, intracellular bacteria, or parasite infected cells, cancer cells, and cells of foreign grafts -3 main types of cells: 1. Cytotoxic T (TC) cells: carry out cell mediated immunity, physically attack foreign cells 2. Helper T (TH) cells: activate B and TC cells 3. Suppressor T (TS) cells: moderate the immune response by inhibiting TC and B cells -Activation of Lymphocytes: 1. Lymphocytes must be able to recognize the antigen 2. Do not recognize free antigen 3. Antigen must be bound to special glycoprotein receptors on target cell: Major Histocompatibility Complex (MHC) 4. After recognition, lymphocytes must increase in number to effectively destroy antigen -Antigenic Determinants: • • Antigenic determinants: specific regions of a given antigen recognized by a lymphocyte Activation can occur in two ways – Antigenic receptors (T-cell receptors and B-cell receptors) • Surface of lymphocyte that combines directly with antigenic determinant – Activation involving glycoproteins called major histocompatibility complex (MHC) molecules attached to plasma membranes. Have variable region that can bind to foreign and self antigens. Antigen Processing and MHC Class I Found on surface of nucleated cells: secreted by Golgi Bind endogenous antigens: contain small peptides present in cytoplasm Abnormal peptides (cancer, virus, bacterial) trigger cell destruction by TC cells Antigen Processing and MHCII Found on lymphocytes and antigen presenting cells (APC) (e.g. dendritic cells, Langerhans cells, macrophages, activated B cells) Bind exogenous antigens: materials that have been phagocytosed and broken down Activate TH cells which activate B cells and TC cells Each T cell detects only one antigen and only when it is in either class I MHC or class II MHC Costimulation: • In order for B or T cells to produce a response, there must be – Binding of the MHC class II/antigen complex to the T cell receptor – Costimulation • Costimulation: – By cytokines. Released by the macrophage of a cytokine that binds to a receptor on the helper T cell. – By surface molecules. Binding of two molecules (B7 and CD28) on the macrophage and Helper T cell. Helps to hold the cells together. b. molecule B7 on macrophages must bind with molecule CD28 on helper T cells before helper T cells can respond to the antigen. Class recognized is determined by CD (cluster of differentiation) markers on the T cell (glycoprotein receptors) CD8 → TC and TS; respond to antigen in class I MHC CD4 → TH; respond to antigen in class II MHC Ex: Helper T cells have a glycoprotein called CD4, which helps connect helper T cells to the macrophage by binding class II MHC molecules.---------------------for this reason, helper T cells are sometimes referred to as CD4, or T4 cells *If costimulation does not take place, cell exhibits anergy (B or T cell does not respond to an antigen). Activation of CD8 / TC cells / Killer T (Proliferation) 1. Cell finds target antigen in class I MHC 2. Tc Cell undergoes clonal selection: proliferation producing many identical cells (often requires stimulation from a TH cell that was activated by an APC) 3. Some clones remain inactive as memory Tc Cells 4. Some clones (active cells) destroy target cell: A. release perforin: lyse target B. release lymphotoxin: disrupt DNA C. induce apoptosis: “self destruct” Activation of initial cell and clonal selection take time: memory cells are ready to go upon second exposure to same antigen Ts Cells activate more slowly than Tc function to release inhibitory cytokines to reduce immune response Organ transplants Graft rejection: tissue typing = attempt to match MHC, but antigens in MHC will always be foreign, thus attacked; need immuno-suppressive drugs to suppress TC cell activity to save graft Activation of CD4 / TH cells (Proliferation) Activated TH cells secrete cytokines which coordinate specific and nonspecific defense: - stimulate production of memory T cells - accelerate production of active Tc cells - attract and stimulate macrophages and NK cells - promote activation of B cells resulting in antibody production B Cells and Antibody Mediated Immunity - targets bacteria, bacterial toxins, and free viruses Activation of B cells: T dependent antigens 1. B cells have antibodies (IgD) on surface as receptor for antigen: binding causes B cell to become Sensitized 2. Bound antigen is internalized and expressed back on surface in Class II MHC 3. A specific TH cell recognizes the antigen+MHC complex and releases cytokines to activate the B cell 4. Activated B cell proliferates (clonal selection) to produce memory B cells and plasma cells 5. Plasma cells secrete antibodies specific to original antigen, ~2000/sec, for 4-5 days, then die (apoptosis) Note: Antibodies = Immunoglobulins (Ig) = Gamma Globulins (bec. Found mostly in gamma globulin part of plasma proteins) *Note: Some B cells respond to T-independent antigens: they can self activate upon antigen binding without a TH cell T-independent activation is less common and produces much weaker response and less protection Initial exposure to antigen: ~5 days B cell → plasma cell ~10 days to peak antibody levels (titer) in blood antibodies (IgM) circulate ~ 2 weeks Second exposure: memory cell → plasma cell ~1-2 days peak titer ~ 2-3 days, higher level antibodies (IgG) circulate weeks – months Antibody (Ab) Structure: -two identical heavy chains (H) -two identical light chains (L) all held together by disulfide bonds -hinge region: flexibility -constant segments (C): -determine class of antibody molecule -have sites for complement binding (Fc region) -variable segments (V): -determine antigen specificity of antibody -make up antigen binding sites (2 per molecule) Humans produce 100million-1billion different Ab’s that each bind a different antigen Classes of Antibodies/Immunoglobulins: (5 classes: IgG, IgM, IgA, IgE, IgD) IgG antibodies • Monomer • most common • produced upon second exposure • produced at high levels • provides resistance against viruses, bacteria, toxins • can cross placenta (provides protection to fetus & newborn) IgM antibodies • Pentamer • first class produced upon initial exposure • forms immune complexes (agglutination) IgA antibodies • Dimer • in secretions (found in: saliva, tears, mucous membranes, colostrums, milk) IgD antibodies • Monomer • on surface of B cells as receptor • sensitizes or activates B cell upon antigen binding IgE antibodies • Monomer • on mast cells and basophils as receptor • triggers histamine release upon antigen binding (stimulates inflammatory response) Antigen-Antibody Complexes: -antibodies bind antigen via antigen binding sites -antigen gets bound by its antigenic determinant site / epitope complete antigen = two epitopes bound to the two antigen binding sites incomplete antigen / hapten = only one epitope bound to one site (small molecules), can lead to allergies (combine with body proteins e.g. latex) Effects of Antibody Binding: 1. Agglutination and Precipitation 2. Opsonization (opsonins = substances that make an antigen more susceptible to phagocytosis) 3. Neutralization: a. prevent attachment of pathogens, b. inactivate toxins 4. Complement fixation: (Antigen binds to an antibody, as a result, the antibody can activate complement proteins, which can produce inflammation, chemotaxis, & lysis) 5. Stimulate inflammation (IgE on Mast cell) (When an antigen binds to antibody, it triggers a release of chemicals that cause inflammation) 6. Ab-dependent cell mediated cytotoxicity Immune Disorders: 1. Autoimmune Disorders -immune response targets normal body cells, autoantibodies produced Ex: Insulin dependent diabetes mellitus /Type I (attack cells of pancreas) Multiple sclerosis (attack white matter of CNS - demyelination) Rheumatoid arthritis (attack joints) Graves Disease (attack thyroid) Celiac Disease (attack lining of small intestine) Lupus (attack tissues & cells) 2. Immunodeficiency Diseases -immune system fails to develop or immune responses are blocked -due to: genetics/development, infection by virus, exposure to radiation/drugs Ex: SCID (severe combined immunodeficiency disorder) “Bubble Boy”: born without B or T cells Hodgkins Disease: lymph node cancer = ↓ B and T cells AIDS (acquired immune deficiency syndrome): virus (HIV) infects CD4 (TH) cells and replicates causing cell lysis. -TH cells necessary for both TC and B cell activation -↓ TH = patient has poor cell mediated and antibody mediated immunity -patient dies of opportunistic infections Allergies = excessive immune response to non-harmful antigens, results in tissue damage 1. Immediate Hypersensitivity (most common) antibody based (antigen = allergen) A. Anaphylaxis: -initial expose produces IgE -IgE binds Mast cells/basophils -2nd exposure, allergen binds IgE, triggers release of histamine & heparin → inflammation (ex: runny eyes and nose) Anaphylactic shock = allergen circulates in blood → body wide inflammation (↓ BP = shock) B. Atopy = full blown allergic response upon 1st exposure 2. Delayed Hypersensitivity -cell mediated -TC, TH, & macrophages activated by allergen resulting in cell death & local inflammation (e.g. poison ivy) Age Related Changes: - thymus size ↓, less T cells produced - ↓TH cells = less B and TC cell activation = ↓ immunity overall - ↓B cells = ↓ antibodies = ↑ susceptibility to viral and bacterial infections - ↑ chance of cancer (↓ NK & TC cells) Overview Summary of Body Defense *Nonspecific defense and immunity are linked*