Chapter 22: The Lymphatic System and Immunity

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Immunity or Resistance

 Ability to ward off damage or disease through our defenses   2 types of immunity Innate or nonspecific immunity – present at birth   No specific recognition of invaders, no memory component 1 st and 2 nd line of defenses  Adaptive or specific immunity  Specific recognition of invaders with a memory component Copyright 2009, John Wiley & Sons, Inc.

Lymphatic system structure and function

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Consists of lymph, lymphatic vessels, structures and organs containing lymphatic tissue, red bone marrow

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2.

3.

Functions of the lymphatic system

Drain excess interstitial fluid Transport dietary lipid Carry our immune responses Copyright 2009, John Wiley & Sons, Inc.

Components of the Lymphatic System

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Lymphatic vessels and lymph circulation

 Vessels begin as lymphatic capillaries  Closed at one end  Unite to form large lymphatic vessels  Resemble veins in structure but thinner walls and more valves  Passes through lymph nodes  Encapsulated organs with masses and B and T cells Copyright 2009, John Wiley & Sons, Inc.

Lymphatic capillaries

 Slightly large diameter that blood capillaries  Unique one-way structure  Permits interstitial fluid to flow in but not out  Anchoring filaments pull openings wider when interstitial fluid accumulates  Small intestine has lacteal for dietary lipid uptake  Chyle is lymph with lipids Copyright 2009, John Wiley & Sons, Inc.

Lymphatic Capillaries

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Lymph trunks and ducts

 Vessels unite to form lymph trunks  Principal trunks are the lumbar, intestinal, bronchomediastinal, subclavian and jugular  Passes from lymph trunks into 2 main channels (thoracic and right lymphatic ducts) before draining into venous blood Copyright 2009, John Wiley & Sons, Inc.

Routes for drainage of lymph

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Formation and flow of lymph

  More fluid filters out of blood capillaries than returns to them by reabsorption Excess filtered fluid – about 3L/day – drains into lymphatic vessels and become lymph  Important function of lymphatic vessels to return lost plasma proteins to blood stream   Contain valves Same 2 “pumps” aiding venous return also used   Skeletal muscle pump – milking action Respiratory pump – pressure changes during breathing Copyright 2009, John Wiley & Sons, Inc.

Relationship of the Lymphatic System to the Cardiovascular System

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Lymphatic tissues and organs

 2 groups based on function 1.

  Primary lymphatic organs Sites where stem cells divide and become immunocompetent Red bone marrow and thymus 2.

  Secondary lymphatic organs Sites where most immune response occurs Lymph nodes, spleen, lymphatic nodules Copyright 2009, John Wiley & Sons, Inc.

Thymus and Medulla

 Thymus    Outer cortex composed of large number of T cells     Immature T cells migrate here from red bone marrow where they proliferate and begin to mature Dendritic cells derived from monocytes assist in T cell maturation Specialized epithelial cells help educate T cells through positive selection – only about 25% survive Macrophages clear out dead and dying cells Medulla   More mature T cells migrate here from cortex More epithelial cells, dendritic cells and macrophages Thymus shrinks with age from 70g in infants to 3g in old age Copyright 2009, John Wiley & Sons, Inc.

Thymus

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Lymph nodes

    Located along lymphatic vessels Scattered throughout body Stroma – supporting connective tissue  Capsule, trabeculae, reticular fibers and fibroblasts Parenchyma – functional part  Outer cortex – aggregates of B cells called lymphatic nodules (follicles) – site of plasma cell and memory B cell formation   Inner cortex – mainly T cells and dendritic cells Medulla – B cells, antibody producing plasma cells from cortex, and macrophages Copyright 2009, John Wiley & Sons, Inc.

Structure of a Lymph Node

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Lymph

  Lymph flows through a node in 1 direction only  Enters through afferent lymphatic vessels      Directs lymph inward Lymph enters sinuses (irregular channels) Into medulla Medullary sinuses drain into efferent lymphatic vessels Conveys lymph, antibodies and activated T cells out of the node Lymph nodes function as a filter  Foreign substances trapped  Destroyed by macrophages or immune response of lymphocytes Copyright 2009, John Wiley & Sons, Inc.

Spleen

   Largest single mass of lymphatic tissue in the body Stroma – capsule, trabeculae, reticular fibers, and fibroblasts Parenchyma  White pulp – lymphatic tissue (lymphocytes and macrophages)   B cells and T cells carry out immune function Red pulp Copyright 2009, John Wiley & Sons, Inc.

Red Pulp

 Red pulp – blood-filled venous sinuses and splenic (Bilroth’s) cords – red blood cells, macrophages, lymphocytes, plasma cells, and granulocytes   Macrophages remove ruptured, worn out or defective blood cells Storage of up to 1/3 of body’s platelet supply  Production of blood cells during fetal life Copyright 2009, John Wiley & Sons, Inc.

Structure of the Spleen

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Lymphatic nodules

 Not surrounded by a capsule  Scattered throughout lamina propria of mucous membranes lining GI, urinary, reproductive tract  Mucosa-associated lymphatic tissue (MALT) of respiratory tract   Most small and solitary Some larger – tonsils, Peyer’s patches, appendix Copyright 2009, John Wiley & Sons, Inc.

Innate immunity

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First line of defenses: Skin and mucous membranes

 Provide both physical and chemical barriers  Physical barriers  Epidermis – closely packed, keratinized cells  Periodic shedding   Mucous membranes  Mucus traps microbes and foreign substances Nose hairs trap and filter  Cilia of upper respiratory tract propel trapped particles up and out Copyright 2009, John Wiley & Sons, Inc.

Innate Immunity

  Fluids   Lacrimal apparatus of eye   Washing action of tears Lysozyme breaks down bacterial cell walls – also present in saliva, perspiration, nasal secretions, and tissue fluids Saliva washes mouth   Urine cleanses urinary system Vaginal secretions, defecation and vomiting Chemicals   Sebaceous (oil) glands secrete sebum – protective film, acid Perspiration, gastric juice, vaginal secretions – all acidic Copyright 2009, John Wiley & Sons, Inc.

Second line of defenses: Internal defenses

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2.

Antimicrobial substances Interferons   Produced by lymphocytes, macrophages, and fibroblasts infected by viruses Prevents replication in neighboring uninfected cells Complement    Proteins in blood plasma and plasma membranes “complement” or enhance certain immune reactions Causes cytolysis of microbes, promotes phagocytosis, contributes to inflammation Copyright 2009, John Wiley & Sons, Inc.

Internal Defenses

3.

 Iron-binding proteins Inhibit growth of bacteria by reducing available iron 4.

  Antimicrobial proteins (AMPs) Short peptides that have a broad spectrum of antimicrobial activity Can attract dendritic cells and mast cells that participate in immune responses Copyright 2009, John Wiley & Sons, Inc.

Internal Defenses

  Natural Killer (NK) cells  Lymphocyte but not a B or T cell    Ability to kill wide variety of infected body cells and certain tumor cells Attack any body cell displaying abnormal or unusual plasma membrane proteins Can release perforin (makes perforations) or granzymes (induce apoptosis) Phagocytes    Neutrophils and macrophages (from monocytes) Migrate to infected area 5 steps in phagocytosis Copyright 2009, John Wiley & Sons, Inc.

Phagocytosis of a microbe

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5 KILLING Digested microbe in phagolysosome Residual body (indigestible material)

Inflammation

  Nonspecific, defensive response of body to tissue damage 4 signs and symptoms – redness, pain, heat and swelling  Attempt to dispose of microbes, prevent spread, and prepare site for tissue repair  3 basic stages    Vasodilation and increased blood vessel permeability Emigration Tissue repair Copyright 2009, John Wiley & Sons, Inc.

Vasodilation and increased permeability of blood vessels

 Increased diameter of arterioles allows more blood flow through area bringing supplies and removing debris  Increased permeability means substances normally retained in the blood are permitted to pass out – antibodies and clotting factors  Histamine, kinins, prostaglandins (PGs), leukotrienes (LTs), complement Copyright 2009, John Wiley & Sons, Inc.

Inflammation

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Emigration of phagocytes

 Depends on chemotaxis  Neutrophils predominate in early stages but die off quickly  Monocytes transform into macrophages   More potent than neutrophils Pus – pocket of dead phagocytes and damaged tissue Copyright 2009, John Wiley & Sons, Inc.

Adaptive immunity

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Ability of the body to defend itself against specific invading agents Antigens (Ags) – substances recognized as foreign and provoking an immune response

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Distinguished from innate immunity by

 Specificity  Memory Copyright 2009, John Wiley & Sons, Inc.

Maturation of T cells and B cells

 Both develop from pluripotent stem cells originating in red bone marrow  B cells complete their development in red bone marrow   T cells develop from pre-T cells that migrate from red bone marrow to the thymus  Helper T cells (CD4 T cells) and cytotoxic T cells (CD8 T cells) Immunocompetence – ability to carry out adaptive immune response  Have antigen receptors to identify specific antigen Copyright 2009, John Wiley & Sons, Inc.

Cell-mediated and antibody-mediated immunity

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2 types of adaptive immunity

    Cell-mediated   Cytotoxic T cells directly attack invading antigens Particularly effective against intracellular pathogens, some cancer cells and foreign tissue transplants Antibody-mediated   B cells transform into plasma cells making antibodies (Abs) or immunoglobulins Works against extracellular pathogens in fluids outside cells Helper T cells aid in both types 2 types of immunity work together Copyright 2009, John Wiley & Sons, Inc.

Clonal selection

  Process by which a lymphocyte proliferates and differentiates in response to a specific antigen  Clone – population of identical cells all recognizing the same antigen as original cell Lymphocyte undergoes clonal selection to produce   Effector cell – active helper T cell, active cytotoxic T cell, plasma cell, die after immune response Memory cell – do not participate in initial immune response, respond to 2 nd invasion by proliferating and differentiating into more effector and memory cells, long life spans Copyright 2009, John Wiley & Sons, Inc.

Antigens

 Antigens have 2 characteristics   Immunogenicity – ability to provoke immune response Reactivity – ability of antigen to react specifically with antibodies it provoked   Entire microbes may act as antigen Typically, just certain small parts of large antigen molecule triggers response (epitope or antigenic determinant) Copyright 2009, John Wiley & Sons, Inc.

Diversity of antigen receptors

   Human immune system able to recognize and bind to at least a billion different epitopes Result of genetic recombination – shuffling and rearranging of a few hundred versions of several small gene segments Major Histocompatibility Complex Antigens  MHC or human leukocyte antigens (HLA)    Normal function to help T cells recognize foreign or self Class I MHC (MHC-I) – built into all body cells except RBCs Class II MHC (MHC-II) – only on antigen presenting cells Copyright 2009, John Wiley & Sons, Inc.

Pathways of antigen processing

 B cells can recognize and bind to antigens  T cells must be presented with processed antigens    Antigenic proteins are broken down into peptide fragments and associated with MHC molecules Antigen presentation – antigen-MHC complex inserted into plasma membrane Pathway depends on whether antigen is outside or inside body cells Copyright 2009, John Wiley & Sons, Inc.

Exogenous and Endogenous Antigens

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Exogenous antigens – present in fluid outside body cells

 Antigen-presenting cells (APCs) include dendritic cells, macrophages and B cells  Ingest antigen, process, place next to MHC-II molecule in plasma membrane, and present to T cells

Endogenous antigens – antigens inside body cells

 Infected cell displays antigen next to MHC-I Copyright 2009, John Wiley & Sons, Inc.

Exogenous Antigens

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Exogenous antigen 1 Phagocytosis or endocytosis of antigen 5 Vesicles containing antigen peptide fragments and MHC-II molecules fuse fragments bind to MHC-II molecules Key: Antigen peptide fragments MHC-II self-antigen Antigen presenting cell (APC) Digestion of antigen into Packaging of MHC-II molecules into a vesicle 7 Vesicle undergoes exocytosis and antigen –MHC-II complexes are inserted into plasma membrane 3 Synthesis of MHC-II molecules Endoplasmic reticulum APCs present exogenous antigens in association with MHC-II molecules

Endogenous Antigens

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Cell-mediated immunity

 Activation of T cells   First signal in activation   T-cell receptors (TCRs) recognize and bind to a specific foreign antigen fragments that are presented in antigen-MHC complexes CD4 and CD8 proteins are coreceptors Second signal required for activation  Costimulation – 20 known substances (cytokines, plasma membrane molecules)   May prevent immune response from occurring accidentally Anergy – recognition without costimulation (in both B and T cells) leads to prolonged state of inactivity Copyright 2009, John Wiley & Sons, Inc.

Activation and clonal selection of helper T cells

      Most that display CD4 develop into helper T cells (CD4 T cells) Recognize exogenous antigen fragments associated with MHC-II molecules on the surface of an APC After activation undergoes clonal selection Makes active helper T cells and memory helper T cells Active helper T cells secrete variety of cytokines  Interleukin-2 (IL-2) needed for virtually all immune responses Memory helper T cells are not active cells – can quickly proliferate and differentiate if the antigen appears again Copyright 2009, John Wiley & Sons, Inc.

Activation and clonal selection of a helper T cell

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Activation and clonal selection of cytotoxic T cells

 Most that display CD8 develop into cytotoxic T cells (CD8 T cells)  Recognize antigens combined with MHC-I  Maximal activation also requires presentation of antigen with MHC-II to cause helper T cells to produce IL-2  Undergoes clonal selection  Active cytotoxic T cells attack body cells  Memory cytotoxic T cells do not attack but wait for a antigen to appear again Copyright 2009, John Wiley & Sons, Inc.

Activation and clonal selection of a cytoxic T cell

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Elimination of invaders

     Cytotoxic T cells migrate to seek out and destroy infected target cells Kill like natural killer cells Major difference is T cells have specific receptor for particular microbe while NK cells destroy a wide variety of microbe-infected cells 2 ways to kill cells  Granzymes cause apoptosis  Perforin and/ or granulysin causes cytolysis Immunological surveillance  Tumor antigens displayed on cancerous cells targeted by cytotoxic T cells, macrophages and natural killer cells Copyright 2009, John Wiley & Sons, Inc.

Activity of cytoxic T cells

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Antibody-mediated immunity

 Activation and clonal selection of B cells     During activation, antigen binds to B cell receptor (BCRs) Can respond to unprocessed antigen Response much more intense when B cell processes antigen  Antigen taken into B cell, combined with MHC-II, moved to plasma membrane, helper T cell binds and delivers costimulation (interleukin-2 and other cytokines) B cell undergoes clonal selection   Plasma cells secrete antibodies Memory B cells do not secrete antibodies but wait for reappearance of antigen Copyright 2009, John Wiley & Sons, Inc.

Activation and clonal selection of B cells

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Antibodies (Ab)

      Can combine specifically with epitope of the antigen that triggered its production Belong to group of glycoproteins called globulins  Ab are immunoglobulins (Igs) 4 polypeptide chains – 2 heavy (H) chains, 2 light (L) chains Hinge region – antibody can be T shape or Y shape Variable (V) region at tips of each H and L chain  2 antigen-binding sites - bivalent Constant (C) region – remainder of H and L chain  Same in each 5 classes – determines type of reaction Copyright 2009, John Wiley & Sons, Inc.

Chemical structure of the immunoglobin (IgG) class of antibody

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Antibody actions

     Neutralizing antigen Immobilizing bacteria Agglutinating and precipitating antigen Enhancing phagocytosis Activating complement      Defensive system of over 30 proteins Destroy microbes by causing phagocytosis, cytolysis, and inflammation Acts in a cascade – one reaction triggers another 3 different pathways ass activate C3 C3 then begins cascade that brings about phagocytosis, cytolysis, and inflammation Copyright 2009, John Wiley & Sons, Inc.

Complement activation and results of activation

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PHAGOCYTOSIS: Enhancement of phagocytosis by coating with C3b 4 C7 C6 C8 C9 Histamine Mast cell Microbe INFLAMMATION: Increase of blood vessel permeability and chemotactic attraction of phagocytes C5b C6 C7 C8 C9 Channel Microbial plasma membrane CYTOLYSIS: Bursting of microbe due to inflow of extracellular fluid through channel formed by membrane attack complex C5-C9 Membrane attack complex forms channel

Immunological memory

     Thousands of memory cells exist after initial encounter with an antigen Next time antigen appears can proliferate and differentiate within hours Antibody titer measure of immunological memory  Amount of Ab in serum Primary response Secondary response faster and stronger Copyright 2009, John Wiley & Sons, Inc.

Self-recognition and self-tolerance

   Your T cells must have   Self-recognition – be able to recognize your own MHC Self-tolerance – lack reactivity to peptide fragments from your own proteins Pre-T cells in thymus develop self-recognition via positive selection – cells that can’t recognize your own MHC undergo apoptosis Self-tolerance occurs through negative selection in which T and B cells that recognize self peptide fragments are eliminated   Deletion – undergo apoptosis Anergy – remian alive but are unresponsive Copyright 2009, John Wiley & Sons, Inc.

Development of self-recognition and self tolerance

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End of Chapter 22

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