CHAPTER 21 The Lymphatic & Immune System I. Introduction A. System diverse: components = mobile cells & organs 1. Lymphatic drainage vessels & lymph nodes 2. Spleen & blood 3. MALT: lymph tissue associated with mucosal tissues: GALT (tonsils, appendix, Peyer’s patches, small collections of lymphatic cells), nasal/respiratory system, urogenital tracts 4. Reticuloendothelial system: macrophages wherever found (Kupffer cells, dust cells, etc) 5. Nonspecific defenses: physical barriers & internal ones centered on inflammation, phagocytosis and complement activation B. Most of these components can be classified as 1. Transport/location: lymph nodes, spleen, blood & lymphatic vessels 2. Effecter system: phagocytosis, inflammation, complement activation, fever, etc 3. Recognition/effecter integration system: antigen presenting cells & lymphocytes C. Most of these systems are positive feedback control systems: consequences =? D. Principles of cell-to-cell “converstations” 1. A normal appearance: glycocalyx with glycoprotein array specific for your genetic makeup = MHC on all nucleated cells 2. Abnormal internal cellular activities (cancer, viral infection) will change the “look” of the MHCs on the involved cells, in particular Class I MHCs 3. Eating abnormal foods (bacteria, viral particles) by certain cells (antigen presenting cells) will change the look of the MHCs on the phagocytizing cells, in particular Class II MHCs 4. Lymphocytes (T cells) will respond to these changed appearances by touching the affected cells (recognition) and responding appropriately by secretion of compounds that affect the behavior of other cells in very specific ways (effecter integration) 5. B lymphocytes wait to catch their specific antigen (defined later); once the antigen is caught by the B cells (recognition), these cells respond by secreting specific compounds (effecter integration); major type of compound is antibody 6. Each of these events requires a receptor of some type on the cell membrane and a ligand (“receptee” for want of a better term) that may be associated with a cell membrane (Class I and II & some antigens) or soluble (some antigens) 7. Depending upon the particular secreted compound following the recognition event, the effect can be strictly local on the particular cell involved or system-wide
8. Basic elements = recognition (receptor/ligand) and secretion E. Antigens 1. Originally, ANTIbody GENerating molecules 2. Broader definition now; includes activation of both T and B lymphocytes 3. Ligand (“receptee”) 4. Non-self: a. Body learns to recognize non-self b. Development of tolerance in late prenatal & early postnatal periods c. Compounds not tolerated become antigens, or not-self 5. Protein or large carbohydrate a. Simple: single molecule b. Complex: membrane, bacteria, virus, parasite, etc c. Carbohydrates often have many repeating units 6. Other types of antigens a. Hapten b. Autoantigen: altered self, cross-reacting self, normally hidden self (eg: DNA) c. Heterophile antigen: cross-reacting; group A Streptococcus & heart muscle d. Alloantigen: A,B,O and other blood groups, MHC glycoproteins e. Allergen: stimulates too much immunoglobin E production 7. Antigenic determinant or epitope a. The specific part of the antigen that fits into the T or B cell receptor b. For B cells, each epitope causes a particular antibody to be produced c. Can be similar as in a large carbohydrate d. Can be different as in a protein 8. Areas of recognition (react with T and B cells) a. Antigens in lymph drainage: lymph nodes b. Antigens in blood: spleen c. Antigens at mucosal surfaces: MALT 9. Examples of a few specific antigens a. Pathogens: bacterial, viral, fungal, protozoan b. Toxins: tetanus, diphtherial, etc c. Heavy metals & poison ivy (haptens) F. Cell receptors, briefly 1. Whether B lymphocyte or T lymphocyte, the cell is preprogrammed to respond to a specific antigenic determinant BEFORE it ever has an opportunity to interact with it 2. B cell a. Receptor is antibody molecule on cell membrane b. Two sites for antigen-receptor interaction 3. T cell
a. b.
Receptor is a molecule similar to an antibody One site for antigen-receptor interaction
II. Immunity A. All aspects involved in protecting the health of the organism B. Can be a passive physical or chemical barrier: first line of defense C. Can be a nonspecific response (all targets) attacked by the effecter systems alone: second line of defense D. Can be a specific response (labeled target) involving the recognition/integration system in addition to the effecter system: third line of defense III. The lymphatic system A. Functions 1. Distribute (lymph vessels) & provide sites for cells involved in specific immunity (lymphocytes, macrophages, dendritic cells) 2. Return fluid from interstitial spaces to blood 3. Absorb/distribute compounds too large to enter blood capillaries (fat absorption from gut into lacteal lymph capillaries) B. Lymph capillaries (Fig 21-3) 1. Blind sacs 2. Delicate walls with endothelial cells that overlap to form flaps that operate as one-way valves 3. Basement membrane incomplete or absent; no filtering 4. Large particles (bacteria, cancer cells, virus) can easily enter 5. Fluid entering is same as interstitial fluid in composition 6. Internal valves like veins C. Lymph circulation 1. One way draining body tissues a. Superficial lymphatics b. Deep lymphatics: body cavitites 2. Lymphatic trunks 3. Right lymphatic duct: drains R arm, R side of head & thorax, empties into R subclavian vein 4. Thoracic duct: several trunks empty into expanded inferior portion (cisterna chyli) especially intestinal lymphatic trunks carrying fat absorbed by lacteal lymph capillaries; rest of lymphatic trunks drain into the thoracic duct before it empties into the L subclavian vein 5. Lymphedema: 1. Temporary: immobility, surgery, infectious 2. Permanent 6. Filariasis: roundworm & elephantiasis D. Lymphocytes: all made in the bone marrow, all look alike
1. T cells a. Thymus educated: only 20% make it out alive! b. 80% of circulating lymphocytes c. Several subtypes i. Tc - Cytotoxic - CD8 marker glycoprotein - Cell-mediated immunity - Recognize processed antigen especially viral proteins or infected cells - Kill infected cells ii. Th - Helper - Recognize processed antigen presented by antigenpresenting cells (APCs) - Stimulate activation of both T and B cells - Secrete lymphokines - CD4 marker glycoprotein iii. Ts - Suppressor - Inhibit activation of both B and T cells - CD8 marker glycoprotein iv. Several more subtypes not on this list (ex: Th1 & Th2 cells) 2. B cells a. Bone marrow educated b. 10-15% circulating lymphocytes c. Produce antibody d. Activated ones producing antibody = plasma cells e. Humoral immunity 3. NK cells a. Large granular lymphocytes b. 5-10% circulating lymphocytes c. Attack, non-specifically, foreign cells, body cells infected with virus or cancerous cells d. Immunological surveillance 4. Lifespan: 4-20 years 5. Circulation a. Wander among lymphoid tissues b. T:B cell ratio Blood: 8:1 Spleen: 1:1 Bone marrow: 1:3 E. Lymphopoiesis in bone marrow F. Maturation & development of tolerance
1. Stromal cells & B cell: IL7 2. NK: ? 3. Thymus & T cells a. Blood-thymus barrier b. Seven thymic hormones: roles ? c. Again, only 20% live d. Apoptosis: cell suicide rate = 80% G. Lymphoid tissues 1. Germinal centers: clonal expansion not lymphopoiesis 2. MALT (GALT) a. Tonsils b. Nodule lymphoid tissue with deep crypts on mucosal surface c. Drainage through cervical lymph nodes & mediastinal lymph nodes d. Palatine (adenoid),lingual, pharyngeal, tubal e. Few individual cells to nodules all along gut f. Peyer’s patches & appendix: fused lymphoid nodules g. Appendicitis, tonsillitis h. All other mucosal surfaces also have lymphoid nodules: name these mucosal surfaces 3. Lymph nodes a. Stroma = trabeculae & reticular connective tissue, blood vessels b. Parenchyma = lymphocytes, macrophages, dendritic cells c. Blood supply: high endothelial venules d. Lymph supply: afferent & efferent vessels e. Lymph flow - Afferent to subcapsular space: encounter dendritic cells (antigen presenting cells) - Outer cortex: B cells & germinal centers - Deep cortex: T cells & cells leaving the blood (lymphocytes & monocytes) - Medulla: B cells & germinal centers in medullary cords - Efferent lymph vessels f. Lymph examined at successive on way to thoracic duct g. Collections of lymph nodes at critical points: cervical, inguinal, axillary, mesenteric, mediastinal h. Lymphadenopathy: inflamed, infection, cancerous i. Lymph nodes & cancer - Lymphoma: cancer originating in a lymph node - Fluid draining from primary cancer can carry metastasizing cells 2. Thymus a. Gradual involution b. Stroma = septa & reticular connective tissue, blood vessels
c. Parenchyma = cortex & medulla T cells & reticular epithelial cells d. Cortex: blood thymus barrier & thymus hormones (thymosins) from reticular epithelial cells that isolate & influence maturing T cells e. Medulla: T cells can enter/leave blood or exit by efferent lymph vessels f. Hassall’s corpuscles: reticular epithelial cells in medulla; function ? 3. Spleen a. Functions - Remove abnormal RBCs (red pulp) - Store iron (red pulp) - Respond to antigens in blood (white pulp) b. Stroma = trabecular & reticular connective tissue & blood vessels c. Parenchyma - Red pulp: macrophages, sinusoidal capillaries & venous drainage - White pulp: surrounds trabecular arteries, lymphocytes, macrophages, like lymphoid nodules d. Thin capsule around organ: can rupture from trauma; intraabdominal bleeding e. Swollen during infectious mononucleosis IV. Chemical & physical nonspecific body defenses A. Mechanical barriers 1. Unbroken skin & mucosa 2. Sloughing of surface cells (normal & handwashing) 3. Vomiting, diarrhea, voiding urine 4. Cough, sneeze B. Chemical barriers 1. Lysozyme: tears, sweat & saliva 2. Sebum: acidic 3. Mucous +/- cilia: entrapment & movement 4. Acidity: gastric 5. Digestive enzymes of mouth, stomach & duodenum C. Ecological: normal bacterial flora of skin, large intestine & other mucous membranes V. Nonspecific effecter systems A. Phagocytosis 1. Removal of cell debris & foreign compounds/particles 2. Microphages: ready to go, no activation period a. Neutrophils: acute inflammation, bacteria b. Eosinophils: antibody coated items, decrease inflammation c. Short life span (hours)
3. Macrophages a. Derived from monocytes b. Require a period of activation c. Macrophage phagocytosis (reticuloendothelial) system d. Longer life span (days - months) e. Functions: i. Destroy phagocytized material ii. Release toxic chemicals: tumor necrosis factor, NO, H2O2 iii. Present portions of digested antigen to a Th cell on Class II MHCs iv. Release some lymphokines 4. Phagocytes’ capabilities a. Margination in response to endothelial signals b. Diapedesis c. Chemotaxis d. Adhesion to target i. Required before eating ii. Inhibited by bacterial capsules & slime layers iii. Enhanced by opsonization Particle coated with antibody Particle covered with complement B. Immunological surveillance & NK cells 1. NK respond to a variety of unusual antigens on the cell surface a. Cancer cells display tumor specific antigens on the cell surface b. Virally-infected cells will be covered with viral proteins 2. On activation the golgi apparatus secretes many perforin filled vesicles 3. After exocytosis the perforins adhere to the target cell membrane & form pores in the cell membrane 4. The target cell can no longer maintain its internal environment & dies C. Interferons 1. Small proteins released by macrophages, lymphocytes & virallyinfected cells 2. All interfere with viral replication, not viral entry, in other cells 3. Interferon alpha: source = leukocytes, additional action = attract NK cells 4. Interferon beta: source = fibroblasts & many other virally infected cells, act like interferon alpha 5. Interferon gamma: source = T & NK cells, additional action = stimulate macrophages 6. An example of a cytokine: compound released by one cell to influence the behavior of another; local effect D. Complement
1. A group of 11 proteins secreted by the liver in an inactive form 2. Activation produces a cascade effect as the proteins are activated in a specific sequence (similar to the blood clotting proteins) 3. Functions of activated complement include a. Destruction of the target cell membrane: membrane attack complex creates pores in it b. Stimulates inflammation: histamine release c. Attracts phagocytes: neutrophils & macrophages d. Opsonize the target to enhance phagocytosis by enhancing adhesion 4. Pathways of activation a. Classic - Most rapid & effective - First component binds to an antibody molecule already attached to the target surface or an antigen b. Alternate Properdin pathway Exposure to common bacterial products causes properdin or factors B, D & P to react with C3 and the rest of the complement cascade E. Inflammation 1. Response to tissue injury of any cause 2. Signs: heat, pain, swelling, redness, loss of function 3. May cause much of the damage done by a disease (TB, rheumatic fever, autoimmune diseases) 4. Cause: any cell injury or cell necrosis, ischemia, reperfusion injury, trauma, surgery, infection, extreme temperature, etc,etc 5. Goals a. Temporary repair b. Prevent /slow spread of problem: clot formation, fibroblast activation c. Clean up area (phagocytosis) & repair it (regeneration/fibrosis) 6. Pivotal cell = mast cell (basophil in blood) a. Granules are filled with acute inflammatory compounds Histamine Serotonin Heparin b. Cell membrane of any damaged cell: synthesis using arachidonic acid to produce prostaglandins & leukotrienes; these are lipids 7. Sequence of events a. Release of acute inflammatory mediators from mast cells & other injured cells
b. Increased capillary permeability brings clotting factors, platelets & complement Area swells as interstitial fluid increases Capillary beds open fully (redder & hotter) as precapillary sphincters relax Kinens from damaged tissues & pressure from fluid activate pain neurons Phagocytes arrive: neutrophils go to work immediately & monocytes rev up. 8. Consequences a. Group of positive feedback cascades b. Defeat Continued stimulation of cascades leads to collateral tissue death Local (tissue necrosis) or organism consequences (death) +/- stimulation of specific immunity (peracute infections) c. Stalemate & evolution into chronic state Macrophages & fribroblast scarring become more evident Stimulation of specific immune system & inflammation Can cycle between chronic & acute; more scarring in each round d. Clearance Neutrophils clear area with minimal stimulation of specific immunity Specific immunity is stimulated by macrophages APC activity & organism is cleared Balance of fibrosis/regeneration depending upon amount of stroma replacing parenchyma in affected area F. Fever a. Pyrogen: fever inducing compound Endogenous: IL-1 from macrophages, inflammation Exogenous: bacterial toxins (endotoxin & exotoxins), drug contaminants b. Moderate fever: increase metabolism rate, unloading of O2 to tissues & may be too hot for pathogen VI. Specific recognition/integration immunity (macrophage as APC, T & B cells) A. Forms of immunity 1. Innate 2. Acquired a. Active: memory cells & antibodies, anamnestic response - Natural
- Artificial b. Passive: antibodies only, no anamnestic response Natural Artificial: RhoGAM, gamma globulin shot B. Properties of immunity 1. Specific response to an antigenic determinant by T or B cell: clone selection 2. Responsive: selected clones divide to produce two cell populations a. Active cells: make antibody (B), kill (Tc), or coordinate (Th) b. Memory cells: a few who do nothing at this time but are responsible for the faster, better response seen upon second exposures (anamnestic response) 3. Memory: anamnestic response 4. Tolerance to self antigens acquired during maturation in bone marrow or thymus C. Overview of immunity 1. One role of T and B cells is to increase the activity of the effecter systems a. Antibody & complement activation b. Antibody as opsonin for phagocytosis c. Cytokines released by T cells 2. A second role is to directly kill the antigen in cell-mediated immunity: Tc 3. A third is to coordinate the activity of the entire immune response (Th) D. Clone selection & clone expansion 1. Antigen recognition a. Tc & Class I MHCs: endogenous antigens b. Th & Class II MHCs: exogenous antigens after processing APC cells such as macrophages THE connection between nonspecific & specific immunity 2. Costimulation Full activation requires the presence of a second signal on cell membrane denoting “Kill me; I am infected/cancerous” or “I am an active phagocyte” E. Tc activation 1. Encounter virally-infected cell or cancerous cell displaying their antigenic determinant on MHC Class I 2. Second signal is also present on the target cell 3. Cells come into direct contact & Tc TCR interacts with the Class I; CD8 molecules stabilize the interaction. 4. The Tc cell is stimulated to divide repeatedly producing an active Tc cell population & a memory one
5. The active Tc cells kill the target(s) by a. Producing lymphotoxins that disrupt the cell membrane b. Release of perforin like the NK cell c. Activation of apoptosis 6. Graft (organ) rejection F. Th activation 1. As above but reaction is with Class II MHCs on APCs and second signal is also required 2. Result is the secretion of an array of cytokines that a. Stimulate T cell division b. Enhancing phagocytosis recruitment & action c. Attract NK cells & up-regulate their activity d. Promote B cell division & antibody production G. B cell activation 1. Antigenic determinant attaches to the antibody molecule of the B cell surface = sensitization 2. The B cell processes & presents fragments of the antigen on class II MHCs 3. Th cells recognizes the antigen on the class II MHC & stimulates the further activation of the B cell 4. The B cell repeatedly divides producing two populations: active & memory 5. The active population develop into plasma cells & secrete an antibody H. Antibody 1. Functions a. Neutralization: binding b. Agglutination & precipitation: immune complex c. Activate complement d. Attract phagocytes e. Opsonize f. Stimulate inflammation g. Prevent adhesion 2. Classes of antibody (immunoglobin) a. IgG Cross placenta Mature antibody response (2nd) Neutralize toxin (tetanus) Remove microbes by activating complement & opsonization b. IgE Attach to basophiils & mast cells Recognition causes degranulation of mast/basophil Important in allergy & large parasitic infections
c. IgD The B cell receptor Sensitizes the B cell d. IgM - First antibody made in the 1st reponse - Activates complement - Can’t cross placenta - Agglutinate, opsonize, neutralize e. IgA Found on mucosal surfaces: respiratory, urogenital, intestinal Prevents attachment of pathogen - Neutralize, agglutinate 3. Compare primary to secondary response with regard to: a. Antibody class: M versus G b. Time of response: 2-3 weeks versus 1 week c. Amount of antibody produced d. Fig 21-27 VII. Fig 22-20 and 21-21 How T cells are activated; 1 and 2 should only be Th cells interacting with the APC. Fig 21.23 how B cells are activated VIII. Neonatal immunity A. Protection may not be complete 1. Mother’s vaccination/disease history 2. Colostrum quantity & quality 3. Exposure: immune system immature at birth B. Series of artificial active immunity activations required IX. Immune disorders A. Too little 1. Congential 2. Acquired: radiation, cancer trt, cancer invasion, organ transplants, HIV, stress (glucocorticoids depress inflammation, phagocytosis, interleukin secretion) B. Misdirected: autoimmune disease, many 1. Females > males 2. Waxing/waning character 3. Rheumatoid arthritis 4. Insulin-dependent diabetes: changes in the structure of selfantigens; viral infection alters the antigens of the beta cells that are then destroyed by the immune system
5. Thyroiditis 6. Multiple sclerosis 7. Guillian-barre: temporary 8. Myasthenia gravis 9. Lupus erythematosis: abnormal exposure of self-antigens; DNA 10. Rheumatoid arthritis: heart tissue antigens are similar to Streptococcus antigens aand there is a cross-reaction between antibody made against Streptococcus and heart antigens C. Too much 1. Type I a. Immediate b. IgE antibodies on mast/basophils c. Inflammation & bronchioloar constriction & mucous production d. Local antigen exposure: angioedema, hay fever, asthma e. Generalized by antigen in blood stream (bee sting, injection) f. Anaphylaxis: hypotension due to vasodilation 2. Type II a. Antibody dependent cytotoxicity b. Antibody + cell+ complement = cell lysis c. Cell = RBC 3. Type III a. Immune complex disease b. Antigen/antibody reactions occur too fast for clearing c. Complement activation & inflammation where these complexes get trapped (local = glomerulonephritis; general = serum sickness) 4. Type IV a. Delayed or cell-mediated b. Tc activation c. Tuberculin test, graft rejections