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1 Principles of Human Anatomy and Physiology, 11e1 Chapter 22 The Lymphatic System Lecture Outline

2 Principles of Human Anatomy and Physiology, 11e2 INTRODUCTION The ability to ward off the pathogens that produce disease is called resistance. Lack of resistance is called susceptibility. Resistance to disease can be grouped into two broad areas. Nonspecific resistance to disease includes defense mechanisms that provide general protection against invasion by a wide range of pathogens. Immunity involves activation of specific lymphocytes that combat a particular pathogen or other foreign substance. The body system that carries out immune responses is the lymphatic system.

3 Principles of Human Anatomy and Physiology, 11e3 Chapter 22 The Lymphatic System Resistance is the ability to ward off disease –lack of resistance is termed susceptibility Nonspecific resistance to disease –general defensive mechanisms effective on a wide range of pathogens (disease producing microbes) Specific resistance or immunity is ability to fight a specific pathogen –cell-mediated immunity –antibody-mediated immunity

4 Principles of Human Anatomy and Physiology, 11e4 LYMPHATIC SYSTEM STRUCTURE AND FUNCTION The lymphatic system consists of a fluid called lymph flowing within lymphatic vessels, several structures and organs that contain lymphatic tissue (specialized reticular tissue containing large numbers of lymphocytes), and bone marrow, which is the site of lymphocyte production (Figure 22.1). Interstitial fluid and lymph are very similar. Their major difference is location. The lymphatic system functions to drain interstitial fluid, return leaked plasma proteins to the blood, transport dietary fats, and protect against invasion by nonspecific defenses and specific immune responses.

5 Principles of Human Anatomy and Physiology, 11e5 Lymphatic System Organs, vessels and a fluid called lymph –similar to interstitial fluid Organs involved –red bone marrow –thymus –spleen –lymph nodes –diffuse lymphatic tissue tonsils, adenoids & peyers patches

6 Principles of Human Anatomy and Physiology, 11e6 Functions of the Lymphatic System Draining excess interstitial fluid & plasma proteins from tissue spaces Transporting dietary lipids & vitamins from GI tract to the blood Facilitating immune responses –recognize microbes or abnormal cells & responding by killing them directly or secreting antibodies that cause their destruction

7 Principles of Human Anatomy and Physiology, 11e7 Lymphatic Vessels and Lymph Circulation Lymphatic vessels begin as blind-ended lymph capillaries in tissue spaces between cells (Figure 22.2). Interstitial fluid drains into lymphatic capillaries, thus forming lymph. Lymph capillaries merge to form larger vessels, called lymphatic vessels, which convey lymph into and out of structures called lymph nodes (Figure 22.1).

8 Principles of Human Anatomy and Physiology, 11e8 Lymphatic Vessels & Circulation Capillaries that begin as closed-ended tubes found in spaces between cells Combine to form lymphatic vessels –resemble veins with thin walls & more valves Fluid flows through lymph nodes towards large veins above the heart –lymph emptied into bloodstream

9 Principles of Human Anatomy and Physiology, 11e9 Lymphatic Capillaries Lymphatic capillaries have a slightly larger diameter than blood capillaries and have overlapping endothelial cells which work as one-way valves for fluid to enter the lymphatic capillary. Anchoring filaments attach endothelial cells to surround tissue (Figure 22.2). A lymphatic capillary in the villus of the small intestine is the lacteal. It functions to transport digested fats from the small intestine into blood.

10 Principles of Human Anatomy and Physiology, 11e10 Lymphatic Capillaries Found throughout the body except in Avascular tissue (cartilage, epidermis & cornea) Structure is designed to let tissue fluid in but not out –anchoring filaments keep tube from collapsing under outside pressure –overlapping endothelial cells open when tissue pressure is high (one-way valve)

11 Principles of Human Anatomy and Physiology, 11e11 Lymph Trunk and Ducts The principal lymph trunks, formed from the exiting vessels of lymph nodes, are the lumbar, intestinal, bronchomediastinal, subclavian, and jugular trunks (Figure 22.3). The thoracic duct begins as a dilation called the cisterna chyli (Figure 22.4) and is the main collecting duct of the lymphatic system. The thoracic duct receives lymph from the left side of the head, neck, and chest, the left upper extremity, and the entire body below the ribs. It drains lymph into venous blood via the left subclavian vein.

12 Principles of Human Anatomy and Physiology, 11e12 Lymph Trunks & Ducts Vessels unite to form trunks & thoracic ducts Right side head, arm & chest empty into right lymphatic duct and rest of body empties into thoracic duct Lymph is dumped directly into left & right subclavian veins

13 Principles of Human Anatomy and Physiology, 11e13 Right Lymphatic Duct (Figure 22.3) The right lymphatic duct drains lymph from the upper right side of the body. It drains lymph into venous blood via the right subclavian vein.

14 Principles of Human Anatomy and Physiology, 11e14 Formation and Flow of Lymph Interstitial fluid drains into lymph capillaries. The passage of lymph is from arteries and blood capillaries (blood) to interstitial spaces (interstitial fluid) to lymph capillaries (lymph) to lymphatic vessels to lymph trunks to the thoracic duct or right lymphatic duct to the subclavian veins (blood) (Figure 22.4). Lymph flows as a result of the milking action of skeletal muscle contractions and respiratory movements. It is also aided by lymphatic vessel valves that prevent backflow of lymph. An excessive accumulation of interstitial fluid may be caused by an obstruction to lymph flow (Clinical Application).

15 Principles of Human Anatomy and Physiology, 11e15 Formation & Flow of Lymph Fluid & proteins escaping from vascular capillaries is collected by lymphatic capillaries & returned to the blood Respiratory & muscular pumps promote flow of lymphatic fluid Lymphatic vessels empty into subclavian veins

16 Principles of Human Anatomy and Physiology, 11e16 Lymphatic Organs and Tissues

17 Principles of Human Anatomy and Physiology, 11e17 Lymphatic Organs & Tissues Widely distributed throughout the body Primary lymphatic organs –provide environment for stem cells to divide & mature into B and T lymphocytes red bone marrow gives rise to mature B cells thymus is site where pre-T cells from red marrow mature Secondary lymphatic organs & tissues –site where most immune responses occur lymph nodes, spleen & lymphatic nodules

18 Principles of Human Anatomy and Physiology, 11e18 Thymus Gland Figure 22.5 Large organ in infants (70 g) but atrophied as adult (3 g) 2 lobed organ located in mediastinum Capsule & trabeculae divide it into lobules Each lobule has cortex & medulla Cortex –tightly packed lymphocytes & macrophages Medulla –reticular epithelial cells produces thymic hormones –Hassall’s corpuscles

19 Principles of Human Anatomy and Physiology, 11e19 Thymus Gland Large organ in infants (70 g) but atrophied as adult (3 g) 2 lobed organ located in mediastinum Capsule & trabeculae divide it into lobules Each lobule has cortex & medulla Cortex –tightly packed lymphocytes & macrophages Medulla –reticular epithelial cells produces thymic hormones –Hassall’s corpuscles

20 Principles of Human Anatomy and Physiology, 11e20 Lymph Nodes - Overview Lymph nodes are encapsulated oval structures located along lymphatic vessels (Figures 22.1a and 22.6). They contain T cells, macrophages, follicular dendritic cells, and B cells. Lymph enters nodes through afferent lymphatic vessels, is filtered to remove damaged cells and microorganisms, and exits through efferent lymphatic vessels. Foreign substances filtered by the lymph nodes are trapped by nodal reticular fibers. Macrophages then destroy some foreign substances by phagocytosis and lymphocytes bring about the destruction of others by immune responses. Lymph nodes are the site of proliferation of plasma cells and T cells. Knowledge of the location of the lymph nodes and the direction of lymph flow is important in the diagnosis and prognosis of the spread of cancer by metastasis; many cancer cells are spread by way of the lymphatic system, producing clusters of tumor cells where they lodge. (Clinical Application)

21 Principles of Human Anatomy and Physiology, 11e21 Lymph Nodes Flow is in one direction –afferent vessels lead in –sinuses lead to efferent vessels that exit at hilus Only nodes filter lymph

22 Principles of Human Anatomy and Physiology, 11e22

23 Principles of Human Anatomy and Physiology, 11e23 Lymph Nodes Bean-shaped organs, up to 1 inch long, located along lymphatic vessels –scattered throughout body but concentrated near mammary glands, axillae & groin Stroma is capsule, trabeculae & reticular fibers Parenchyma is divided into 2 regions: –cortex lymphatic nodules with germinal centers containing dendritic cells –antigen-presenting cells and macrophages B cells proliferate into antibody-secreting plasma cells –medulla contains B cells & plasma cells in medullary cords

24 Principles of Human Anatomy and Physiology, 11e24 Metastasis Through Lymphatic System Characteristic of malignant tumors Spread of disease from one organ to another –cancer cells travel via blood or lymphatic system –cells establish new tumors where lodge Secondary tumor sites can be predicted by direction of lymphatic flow from primary site Cancerous lymph nodes are firm, enlarged and nontender -- infected lymph nodes are not firm and are very tender

25 Principles of Human Anatomy and Physiology, 11e25 Spleen Figure inch organ between stomach & diaphragm Hilus contains blood & lymphatic vessels Stroma consists of capsule, trabeculae, fibers & fibroblasts Parenchyma consists of white pulp and red pulp –white is lymphatic tissue (lymphocytes & macrophages) around branches of splenic artery –red pulp is venous sinuses filled with blood & splenic tissue (splenic cords)

26 Principles of Human Anatomy and Physiology, 11e26 Spleen The red pulp consists of venous sinuses filled with blood and splenic cords consisting of RBCs, macrophages, lymphocytes, plasma cells, and granulocytes. Macrophages remove worn-out or defective RBCs, WBCs, and platelets. The spleen stores blood platelets in the red pulp. The red pulp is involved in the production of blood cells during the second trimester of pregnancy.

27 Principles of Human Anatomy and Physiology, 11e27 Clinical Application The spleen is often damaged in abdominal trauma. A splenectomy may be required to prevent excessive bleeding.

28 Principles of Human Anatomy and Physiology, 11e28 Lymphatic Nodules Concentrations of lymphatic tissue not surrounded by a capsule scattered throughout connective tissue of mucous membranes –mucosa-associated lymphoid tissue (MALT) Peyer’s patches in the ileum of the small intestine Appendix Tonsils form ring at top of throat - Figure 23.2 –adenoids (pharyngeal tonsil) –palatine tonsils (on each side wall) –lingual tonsil in the back of the tongue

29 Principles of Human Anatomy and Physiology, 11e29 DEVELOPMENT OF THE LYMPH TISSUES Lymphatic vessels develop from lymph sacs, which develop from veins. Thus, they are derived from mesoderm. Lymph nodes develop from lymph sacs that become invaded by mesenchymal cells (Figure 22.8).

30 Principles of Human Anatomy and Physiology, 11e30 Developmental Anatomy Begins to develop by 5th week Lymphatic vessels develop from lymphatic sacs that arise from veins Jugular sac & cisterna chyli form thoracic duct Sacs develop into lymph nodes Spleen develops in gastric mesentery Thymus is outgrowth of 3rd pharyngeal pouch

31 Principles of Human Anatomy and Physiology, 11e31 NONSPECIFIC RESISTANCE: INNATE DEFENSES

32 Principles of Human Anatomy and Physiology, 11e32 First Line of Defense: Skin and Mucous Membranes Nonspecific resistance refers to a wide variety of body responses against a wide range of pathogens (disease producing organisms) and their toxins. Mechanical protection includes the intact epidermis layer of the skin (Figure 5.1), mucous membranes, the lacrimal apparatus, saliva, mucus, cilia, the epiglottis, and the flow of urine. Defecation and vomiting also may be considered mechanical processes that expel microbes. Chemical protection is localized on the skin, in loose connective tissue, stomach, and vagina. The skin produces sebum, which has a low pH due to the presence of unsaturated fatty acids and lactic acid. Lysozyme is an enzyme component of sweat that also has antimicrobial properties. Gastric juice renders the stomach nearly sterile because its low pH ( ) kills many bacteria and destroys most of their toxins; vaginal secretions also are slightly acidic.

33 Principles of Human Anatomy and Physiology, 11e33 Skin & Mucous Membranes Mechanical protection –skin (epidermis) closely packed, keratinized cells shedding helps remove microbes –mucous membrane secretes viscous mucous cilia & mucus trap & move microbes toward throat –washing action of tears, urine and saliva Chemical protection –sebum inhibits growth bacteria & fungus –perspiration lysozymes breakdown bacterial cells –acidic pH of gastric juice and vaginal secretions destroys bacteria

34 Principles of Human Anatomy and Physiology, 11e34 Second Line of Defense: Internal Defenses The second line of defense involves internal antimicrobial proteins, phagocytic and natural killer cells, inflammation, and fever.

35 Principles of Human Anatomy and Physiology, 11e35 Internal Defenses Antimicrobial proteins discourage microbial growth –interferons –complement proteins –transferrins

36 Principles of Human Anatomy and Physiology, 11e36 Antimicrobial Proteins Body cells infected with viruses produce proteins called interferons (IFNs). –Once produced and released from virus-infected cells, IFN diffuses to uninfected neighboring cells and binds to surface receptors, inducing uninfected cells to synthesize antiviral proteins that interfere with or inhibit viral replication. –INFs also enhance the activity of phagocytes and natural killer (NK) cells, inhibit cell growth, and suppress tumor formation; they may hold promise as clinical tools in AIDS and cancer treatment once they are more fully understood.

37 Principles of Human Anatomy and Physiology, 11e37 Antimicrobial Proteins A group of about 20 proteins present in blood plasma and on cell membranes comprises the complement system –when activated, these proteins “complement” or enhance certain immune, allergic, and inflammatory reactions.

38 Principles of Human Anatomy and Physiology, 11e38 Natural Killer Cells & Phagocytes NK cells kill a variety of microbes & tumor cells –found in blood, spleen, lymph nodes & red marrow –attack cells displaying abnormal MHC antigens Phagocytes (neutrophils & macrophages) –ingest microbes or particulate matter –macrophages developed from monocytes fixed macrophages stand guard in specific tissues –histiocytes in the skin, kupffer cells in the liver, alveolar macrophages in the lungs, microglia in the brain & macrophages in spleen, red marrow & lymph nodes wandering macrophages in most tissue

39 Principles of Human Anatomy and Physiology, 11e39 Phagocytosis Phagocytes are cells specialized to perform phagocytosis and include neutrophils and macrophages. –The four phases of phagocytosis include chemotaxis, adherence, ingestion, digestion and killing. (Figure 22.9). –After phagocytosis has been accomplished, a phagolysosome (Figure 22.9) is formed. –The lysosome in the phagolysosome, along with lethal oxidants produced by the phagocyte, quickly kills many types of microbes. Some of the reasons why a microbe may evade phagocytosis include: capsule formation, toxin production, interference with lysozyme secretion, and the microbe’s ability to counter oxidants produced by the phagocytes.

40 Principles of Human Anatomy and Physiology, 11e40 Phagocytosis Chemotaxis –attraction to chemicals from damaged tissues, complement proteins, or microbial products Adherence –attachment to plasma membrane of phagocyte Ingestion –engulf by pseudopods to form phagosome Digestion & killing –merge with lysosome containing digestive enzymes & form lethal oxidants –exocytosis residual body

41 Principles of Human Anatomy and Physiology, 11e41 Inflammation Damaged cell initiates Signs of inflammation –redness –heat –swelling –pain –Loss of function may be a fifth symptom, depending on the site and extent of the injury. Function is to trap microbes, toxins or foreign material & begin tissue repair

42 Principles of Human Anatomy and Physiology, 11e42 Stages of Inflammation The three basic stages of inflammation are vasodilation and increased permeability of blood vessels, phagocyte migration, and tissue repair (Figure 22.10). Vasodilation & increased permeability of vessels –caused by histamine from mast cells, kinins from precursors in the blood, prostaglandins from damaged cells, and leukotrienes from basophils & mast cells –occurs within minutes producing heat, redness & edema –pain can result from injury, pressure from edema or irritation by toxic chemicals from organisms –blood-clotting factors leak into tissues trapping microbes Phagocyte emigration –within an hour, neutrophils and then monocytes arrive and leave blood stream (emigration) Tissue repair

43 Principles of Human Anatomy and Physiology, 11e43 Abscesses and Ulcers Pus is dead phagocytes, damaged tissue cells & fluid Abscess is accumulation of pus in a confined space not open to the outside –pimples & boils Ulcer is an open sore People with poor circulation (diabetics with advanced atherosclerosis) –stasis ulcers in tissues of legs due to poor oxygen & nutrient supply to tissues

44 Principles of Human Anatomy and Physiology, 11e44 Fever Abnormally high body temperature that occurs because the hypothalamic thermostat is reset Occurs during infection & inflammation –bacterial toxins trigger release of fever-causing cytokines such as interleukin-1 Benefits –intensifies effects of interferons, inhibits bacterial growth, speeds up tissue repair

45 Principles of Human Anatomy and Physiology, 11e45 Review Table 22.1 summarizes the components of nonspecific resistance.

46 Principles of Human Anatomy and Physiology, 11e46 SPECIFIC RESISTANCE: IMMUNITY Immunity is the ability of the body to defend itself against specific invading agents. –bacteria, toxins, viruses, cat dander, etc. Differs from nonspecific defense mechanisms –specificity----recognize self & non-self –memory----2nd encounter produces even more vigorous response Antigens are substances recognized as foreign by the immune responses. The branch of science that deals with the responses of the body when challenged by antigens is called immunology.

47 Principles of Human Anatomy and Physiology, 11e47 Maturation of T Cells and B Cells Both T cells and B cells derive from stem cells in bone marrow (Figure 22.11). B cells complete their development in bone marrow (Figure 22.11). T cells develop from pre-T cells that migrate to the thymus. Before T cells leave the thymus or B cells leave bone marrow, they acquire several distinctive surface proteins; some function as antigen receptors, molecules capable of recognizing specific antigens (Figure 22.12).

48 Principles of Human Anatomy and Physiology, 11e48 Maturation of T and B Cells T cell mature in thymus –cell-mediated response killer cells attack antigens helper cells costimulate T and B cells –effective against fungi, viruses, parasites, cancer, and tissue transplants B cells in bone marrow –antibody-mediated response plasma cells form antibodies –effective against bacteria

49 Principles of Human Anatomy and Physiology, 11e49 Types of Immune Response Cell-mediated immunity (CMI) refers to destruction of antigens by T cells. –particularly effective against intracellular pathogens, such as fungi, parasites, and viruses; some cancer cells; and foreign tissue transplants. –CMI always involves cells attacking cells. Antibody-mediated (humoral) immunity (AMI) refers to destruction of antigens by antibodies. –works mainly against antigens dissolved in body fluids and extracellular pathogens, primarily bacteria, that multiply in body fluids but rarely enter body cells. Often a pathogen provokes both types of immune response.

50 Principles of Human Anatomy and Physiology, 11e50 APCs and MHC-II

51 Principles of Human Anatomy and Physiology, 11e51 Antigens Molecules or bits of foreign material –entire microbes, parts of microbes, bacterial toxins, pollen, transplanted organs, incompatible blood cells Required characteristics to be considered an antigen –immunogenicity = ability to provoke immune response –reactivity = ability to react to cells or antibodies it caused to be formed Get past the bodies nonspecific defenses –enter the bloodstream to be deposited in spleen –penetrate the skin & end up in lymph nodes –penetrate mucous membrane & lodge in associated lymphoid tissue

52 Principles of Human Anatomy and Physiology, 11e52 Chemical Nature of Antigens/Epitopes Large, complex molecules, usually proteins –if have simple repeating subunits are not usually antigenic (plastics in joint replacements) –small part of antigen that triggers the immune response is epitope antigenic determinant Hapten is smaller substance that can not trigger an immune response unless attached to body protein –lipid of poison ivy

53 Principles of Human Anatomy and Physiology, 11e53 Diversity of Antigen Receptors Immune system can recognize and respond to a billion different epitopes -- even artificially made molecules Explanation for great diversity of receptors is genetic recombination of few hundred small gene segments Each B or T cell has its own unique set of gene segments that codes its unique antigen receptor in the cell membrane

54 Principles of Human Anatomy and Physiology, 11e54 Major Histocompatibility Complex Antigens All our cells have unique surface markers (1000s molecules) –integral membrane proteins called HLA antigens MHC-I molecules are built into cell membrane of all cells except red blood cells Function –if cell is infected with virus MHC-I contain bits of virus marking cell so T cells recognize is problem Some cells also display MHC class II antigens. –MHC-II markers seen only on membrane of antigen presenting cells (macrophages, B cells, thymus cells) Function –if antigen presenting cells (macrophages or B cells) ingest foreign proteins, they will display as part of their MHC-II

55 Principles of Human Anatomy and Physiology, 11e55 Histocompatibility Testing Histocompatibility is a similarity of MHC antigens on body cells of different individuals –tissue typing must be done before any organ transplant –can help identify biological parents

56 Principles of Human Anatomy and Physiology, 11e56 Pathways of Antigen Processing B and T cells must recognize a foreign antigen before beginning their immune response –B cells can bind to antigen in extracellular fluid –T cells can only recognize fragments of antigens that have been processed and presented to them as part of a MHC molecule Helper T cells “see” antigens if part of MHC-II molecules on surface of antigen presenting cell Cytotoxic T cells “see” antigens if part of MHC-I molecules on surface of body cells

57 Principles of Human Anatomy and Physiology, 11e57 Processing of Exogenous Antigens Cells called antigen-presenting cells (APCs) process exogenous antigens (antigens formed outside the body) and present them together with MHC class II molecules to T cells. APCs include macrophages, B cells, and dendritic cells. The presentation of exogenous antigens together with MHCII molecules on antigen presenting cells alerts T cells that “intruders are present”.

58 Principles of Human Anatomy and Physiology, 11e58 Processing of Exogenous Antigens Foreign antigen in body fluid is phagocytized by APC –macrophage, B cell, dendritic cell (Langerhans cell in skin) Antigen is digested and fragments are bound to MHC-II molecules stuck into antigen presenting cell membrane APC migrates to lymphatic tissue to find T cells

59 Principles of Human Anatomy and Physiology, 11e59 Processing of Endogenous Antigens Endogenous antigens are synthesized within the body and include viral proteins or proteins produced by cancer cells Most of the cells of the body can process endogenous antigens Fragments of endogenous antigen are associated with MHCI molecules inside the cell. The antigen MHCI complex moves to the cell’s surface where it alerts T cells.

60 Principles of Human Anatomy and Physiology, 11e60 Cytokines & Cytokine Therapy Small protein hormones involved in immune responses –secreted by lymphocytes and antigen presenting cells Cytokine therapy uses cytokines (interferon) –alpha-interferon used to treat Kaposi’s sarcoma, genital herpes, hepatitis B and C & some leukemias –beta-interferon used to treat multiple sclerosis –interleukin-2 used to treat cancer (side effects) Table 22.2 describes some of the cytokines that participate in immune responses.

61 Principles of Human Anatomy and Physiology, 11e61 CELL-MEDIATED IMMUNITY Begins with activation of T cell by a specific antigen Result is T cell capable of an immune attack –elimination of the intruder by a direct attack In a cell-mediated immune response, an antigen is recognized (bound), a small number of specific T cells proliferate and differentiate into a clone of effector cells (a population of identical cells that can recognize the same antigen and carry out some aspect of the immune attack), and the antigen (intruder) is eliminated.

62 Principles of Human Anatomy and Physiology, 11e62 Activation, Proliferation, and Differentiation of T Cells T cell receptors recognize antigen fragments associated with MHC molecules on the surface of a body cell. Proliferation of T cells requires costimulation, by cytokines such as interleukin-1 (IL-1) and interleukin-2 (IL-2), or by pairs of plasma membrane molecules, one on the surface of the T cell and a second on the surface of an APC.

63 Principles of Human Anatomy and Physiology, 11e63 Activation, Proliferation & Differentiation of Cytotoxic T Cells Receptor on CD8 cell binds to foreign antigen fragment part of MHC-I Costimulation from helper T cell –prevents accidental immune response Proliferates & differentiates into population (clone) of Tc cells and memory Tc cells Occurs in secondary lymphatic organs such as lymph node

64 Principles of Human Anatomy and Physiology, 11e64 Activation, Proliferation & Differentiation of Helper T Cells Receptor on CD4 cell binds to foreign antigen fragment associated with MHC-II Costimulation with interleukin Proliferates & differentiates into population (clone) of T H cells and long- lived memory T H cells

65 Principles of Human Anatomy and Physiology, 11e65 Overview of Mature T Cells 1.Helper T (T H ) cells, or T4 cells, display CD4 protein, recognize antigen fragments associated with MHC-II molecules, and secrete several cytokines, most important, interleukin-2, which acts as a costimulator for other helper T cells, cytotoxic T cells, and B cells (Figure 22.14). 2.Cytotoxic T (T C ) cells, or T8 cells, develop from T cells that display CD8 protein and recognize antigen fragments associated with MHC-I molecules. 3.Memory T cells are programmed to recognize the original invading antigen, allowing initiation of a much swifter reaction should the pathogen invade the body at a later date.

66 Principles of Human Anatomy and Physiology, 11e66 Helper T Cells Display CD4 on surface so also known as T4 cells or T H cells Recognize antigen fragments associated with MHC-II molecules & activated by APCs Function is to costimulate all other lymphocytes –secrete cytokines (interleukin-2) autocrine function in that it costimulates itself to proliferate and secrete more interleukin (positive feedback effect causes formation of many more helper T cells)

67 Principles of Human Anatomy and Physiology, 11e67 Cytotoxic T Cells Display CD8 on surface Known as T8 or Tc or killer T cells Recognize antigen fragments associated with MHC-I molecules –cells infected with virus –tumor cells –tissue transplants Costimulation required by cytokine from helper T cell

68 Principles of Human Anatomy and Physiology, 11e68 Memory T Cells T cells from a clone that did not turn into cytotoxic T cells during a cell-mediated response Available for swift response if a 2nd exposure should occur

69 Principles of Human Anatomy and Physiology, 11e69 Details: Cytotoxic T Cells Cytotoxic T cells fight foreign invaders by killing the target cell (the cell that bears the same antigen that stimulated activation or proliferation of their progenitor cells) without damaging the cytotoxic T cell itself (Figure 22.15). –When cytotoxic T cells encounter a cell displaying a microbial antigen, they can release granzymes which trigger apoptosis (Figure 22.15a). The microbe is then destroyed by phagocytes. –Cytotoxic T cells can also bind to infected cells and release perforin and granulysin. Perforin causes cytolysis while granulysin destroys the microbe. –Cytotoxic T cells can also release lymphotoxin which activates damaging enzymes within the target cell. –When the cytotoxic T cell detaches from a target cell, it can destroy another cell.

70 Principles of Human Anatomy and Physiology, 11e70 Elimination of Invaders Cytotoxic T cells migrate to site of infection or tumor formation Recognize, attach & attack –secrete granules containing perforin that punch holes in target cell –secrete lymphotoxin that activates enzymes in the target cell causing its DNA to fragment –secrete gamma-interferon to activate phagocytic cells

71 Principles of Human Anatomy and Physiology, 11e71 Immunological Surveillance Immunological surveillance is carried out by cytotoxic T cells. –They recognize tumor antigens and destroy the tumor cell. –The immune system can recognize proteins in transplanted organs as foreign and mount a graft rejection. Success of a proposed organ or tissue transplant depends on histocompatibility. Tissue typing (histocompatibility testing) is done before any organ transplant. Organ transplant recipients also receive immunosuppresive drugs.

72 Principles of Human Anatomy and Physiology, 11e72 Immunological Surveillance Cancerous cell displays unusual surface antigens (tumor antigens) Surveillance = immune system finds, recognizes & destroys cells with tumor antigens –done by cytotoxic T cells, macrophages & natural killer cells –most effective in finding tumors caused by viruses Transplant patients taking immunosuppressive drugs suffer most from viral-induced cancers

73 Principles of Human Anatomy and Physiology, 11e73 Graft Rejection After organ transplant, immune system has both cell- mediated and antibody-mediated immune response = graft rejection Close match of histocompatibility complex antigens has weaker graft rejection response –immunosuppressive drugs (cyclosporine) inhibits secretion of interleukin-2 by helper T cells little effect on B cells so maintains some resistance

74 Principles of Human Anatomy and Physiology, 11e74 Antibody-Mediated Immunity The body contains not only millions of different T cells but also millions of different B cells, each capable of responding to a specific antigen. B cells sit still and let antigens be brought to them –stay put in lymph nodes, spleen or peyer’s patches Once activated, differentiate into plasma cells that secrete antibodies Antibodies circulate in lymph and blood –combines with epitope on antigen similarly to key fits a specific lock

75 Principles of Human Anatomy and Physiology, 11e75 Activation, Proliferation, and Differentiation of B Cells During activation of a B cell, an antigen binds to antigen receptors on the cell surface (Figure 22.16). B cell antigen receptors are chemically similar to the antibodies that will eventually be secreted by their progeny. Some antigen is taken into the B cell, broken down into peptide fragments and combined with the MHC-II self- antigen, and moved to the B cell surface. Helper T cells recognize the antigen-MHC-II combination and deliver the costimulation needed for B cell proliferation and differentiation. Some activated B cells become antibody-secretion plasma cells. Others become memory B cells.

76 Principles of Human Anatomy and Physiology, 11e76 Activation, Proliferation, & Differentiation of B Cells B cell receptors bind to antigen -- response more intense if on APC Helper T cell costimulates Rapid cell division & differentiation occurs –long-lived memory cells –clone of plasma cells produce antibody at 2000 molecules/sec for 4-5 days secrete only one kind antibody Antibody enters the circulation to attack antigen

77 Principles of Human Anatomy and Physiology, 11e77 Antibodies An antibody is a protein that can combine specifically with the antigenic determinant on the antigen that triggered its production.

78 Principles of Human Anatomy and Physiology, 11e78 Antibody Structure Antibodies consist of heavy and light chains and variable and constant portions (Figure 22.17). Based on chemistry and structure, antibodies are grouped into five principal classes each with specific biological roles (IgG, IgA, IgM, IgD, and IgE). Table 22.3 summarizes the structures and functions of these five classes of antibodies.

79 Principles of Human Anatomy and Physiology, 11e79 Details: Antibody Structure Glycoproteins called immunoglobulins –4 polypeptide chains -- 2 heavy & 2 light chains –hinged midregion lets assume T or Y shape –tips are variable regions -- rest is constant region 5 different classes based on constant region –IgG, IgA, IgM, IgD and IgE tips form antigen binding sites

80 Principles of Human Anatomy and Physiology, 11e80 Antibodies

81 Principles of Human Anatomy and Physiology, 11e81 Antibody Actions Neutralization of antigen by blocking effects of toxins or preventing its attachment to body cells Immobilize bacteria by attacking cilia/flagella Agglutinate & precipitate antigens by cross-linking them causing clumping & precipitation Complement activation Enhancing phagocytosis through precipitation, complement activation or opsonization (coating with special substance)

82 Principles of Human Anatomy and Physiology, 11e82 Monoclonal Antibodies Antibodies against a particular antigen can be harvested from blood –different antibodies will exist for the different epitopes on that antigen Growing a clone of plasma cells to produce identical antibodies difficult –fused B cells with tumor cells that will grow in culture producing a hybridoma –antibodies produced called monoclonal antibodies Used clinically …

83 Principles of Human Anatomy and Physiology, 11e83 Clinical Application Monoclonal antibodies are important in measuring levels of a drug in a patient’s blood Diagnosis of pregnancy, allergies, and diseases such as hepatitis, rabies, and some sexually transmitted diseases. They have also been used in early detection of cancer and assessment of extent of metastasis. They may be useful in preparing vaccines to counteract transplant rejection, to treat autoimmune diseases, and perhaps to treat AIDS.

84 Principles of Human Anatomy and Physiology, 11e84 Role of Complement System in Immunity Complement system is made up of over 30 proteins (Figure 22.18). Many complement proteins are inactive and must be activated. Activated complement acts in a cascade that causes –inflammation: dilation of arterioles, release of histamine & increased permeability of capillaries –opsonization/phagocytosis: protein binds to microbe making it easier to phagocytize –cytolysis: a complex of several proteins can form holes in microbe membranes causing leakiness and cell rupture Complement may be activated by the classical pathway, alternative pathway, and the lectin pathway

85 Principles of Human Anatomy and Physiology, 11e85 Pathways of the Complement System Classical pathway begins with activation of C1 Alternate pathway begins with activation of C3 Lead to inflammation, enhanced phagocytosis or microbe bursting

86 Principles of Human Anatomy and Physiology, 11e86 Immunological Memory Immunological memory is due to the presence of long-lived antibodies and very long-lived lymphocytes that arise during proliferation and differentiation of antigen-stimulated B and T cells. –Immunization against certain microbes is possible because memory B cells and memory T cells remain after the primary response to an antigen (Figure 22.19). –The secondary response (immunological memory) provides protection should the same microbe enter the body again. There is rapid proliferation of memory cells, resulting in a far greater antibody titer (amount of antibody in serum) than during a primary response. Table 22.4 summarizes the various types of immunity.

87 Principles of Human Anatomy and Physiology, 11e87 Immunological Memory Primary immune response –first exposure to antigen response is steady, slow –memory cells may remain for decades Secondary immune response with 2nd exposure –1000’s of memory cells proliferate & differentiate into plasma cells & cytotoxic T cells antibody titer is measure of memory (amount serum antibody) –recognition & removal occurs so quickly not even sick

88 Principles of Human Anatomy and Physiology, 11e88 SELF-RECOGNIZITON AND SELF-TOLERANCE T cells undergo both positive and negative selection to ensure that they can recognize self-MHC antigens (self- recognition) and that they do not react to other self-proteins (tolerance). –Negative selection involves both deletion and anergy (Figure 22.20). –B cells develop tolerance Much research has centered on cancer immunology, the study of ways to use the immune system for detecting, monitoring, and treating cancer (Clinical Application).

89 Principles of Human Anatomy and Physiology, 11e89 Self-Recognition & Immunological Tolerance T cells must learn to recognize self (its own MHC molecules ) & lack reactivity to own proteins –self-recognition & immunological tolerance T cells mature in thymus –those can’t recognize self or react to it… destroyed by programmed cell death (apoptosis or deletion) inactivated (anergy) -- alive but unresponsive –only 1 in 100 emerges immunocompetent T cell B cells similarly develop in bone marrow

90 Principles of Human Anatomy and Physiology, 11e90 Development of Self-Recognition & Immunological Tolerance

91 Principles of Human Anatomy and Physiology, 11e91 Tumor Immunotherapy Cells with antitumor activity are injected into bloodstream of cancer patient –culture patient’s inactive cytotoxic T cells with interleukin- 2 –called lymphokine-activated killer cells (LAK) Can cause tumor regression, but has severe complications

92 Principles of Human Anatomy and Physiology, 11e92 STRESS AND IMMUNITY The field of psychoneuroimmunology (PNI) deals with common pathways that link the nervous, endocrine, and immune systems. PNI has shown that thoughts, feelings, moods, and beliefs influence the level of health and the course of a disease.

93 Principles of Human Anatomy and Physiology, 11e93 Aging With advancing age, the immune system functions less effectively. Individuals become more susceptible to infections and malignancies Response to vaccines is decreased Produce more autoantibodies Reduced immune system function –T cells less responsive to antigens –age-related atrophy of thymus –decreased production of thymic hormones –B cells less responsive –production of antibodies is slowed

94 Principles of Human Anatomy and Physiology, 11e94 AIDS: Acquired Immunodeficiency Syndrome AIDS is a condition in which a person experiences a telltale assortment of infections as a result of the progressive destruction of immune cells by the human immunodeficiency virus (HIV). Although HIV has been isolated from several body fluids, the only documented transmissions are by way of blood, semen, vaginal secretions, and breast milk from an infected nursing mother. It does not appear that people become infected as a result of routine, nonsexual contacts. The AIDS virus is generally thought to be quite fragile outside of the body and easily eliminated with standard disinfecting techniques. At present, the only means of preventing AIDS is to block transmission of the virus, including abstinence from sex with infected individuals, use of condoms during intercourse, use of sterile hypodermic needles, and avoidance of pregnancy in HIV-infected women. Until there is an effective drug therapy or an effective vaccine, preventing the spread of AIDS must rely on education and safer sexual practices.

95 Principles of Human Anatomy and Physiology, 11e95 HIV HIV is a form of retrovirus with a protein coat wrapped by an envelope of glycoproteins (Figure 22.21). HIV enters T cells where it sheds its protein coat. New HIV DNA is produced in the T cell along with new protein coats and then released. The T cells are ultimately destroyed. Common signs and symptoms of infection are fever, fatigue, rash, headache, joint pain, sore throat, and swollen lymph nodes. The infected individual ultimately develops antibodies to HIV. Progression to AIDS occurs because of reduced numbers of T cells and resulting immunodeficiency. AIDS lowers the body’s immunity by decreasing the number of helper T cells; the result is progressive collapse of the immune system, making the person susceptible to opportunistic infections (invasion of normally harmless microorganisms that now proliferate wildly because of the defective immune system). Treatment of HIV infection with reverse transcriptase inhibitors and protease inhibitors has shown to delay the progression of HIV infection to AIDS.

96 Principles of Human Anatomy and Physiology, 11e96 Hypersensitivity Reactions A person who is overly reactive to a substance that is tolerated by most others is said to be hypersensitive (allergic). Whenever an allergic reaction occurs, there is tissue injury. The antigens that induce an allergic reaction are called allergens.

97 Principles of Human Anatomy and Physiology, 11e97 Hypersensitivity Reactions There are four basic types of hypersensitivity reactions. Type I (anaphylaxis) reactions are the most common and occur with a few minutes after a person sensitized to an allergen is reexposed to it. Anaphylaxis results from the interaction of allergens with IgE antibodies on the surface of mast cells and basophils. In anaphylactic shock, which may occur in a susceptible individual who has just received a triggering drug or been stung by a wasp, wheezing and shortness of breath as airways constrict are usually accompanied by shock due to vasodilation and fluid loss from blood. This is a life-threatening emergency.

98 Principles of Human Anatomy and Physiology, 11e98 Hypersensitivity Reactions Type II (cytotoxic) reactions are caused by antibodies (IgG or IgM) directed against a person’s blood cells or tissue cells. The reaction of antibodies and antigens usually leads to activation of complement. Type II reaction, which may occur in incompatible blood transfusion reactions, damage cells by causing lysis. Type III (immune complex) reactions involve antigens (not part of a host tissue cell), antibodies (IgA or IgM), and complement. Some type II conditions include glomerulonephritis, systemic lupus erythematosus, and rheumatoid arthritis. Type IV (cell-mediated) reactions or delayed hypersensitivity reactions usually appear hours after exposure to an allergen and occur when allergens are taken up by antigen- presenting cells that migrate to lymph nodes and present the allergen to T cells. Intracellular bacteria, such as the one that causes tuberculosis, trigger this type of cell-mediated immune response.

99 Principles of Human Anatomy and Physiology, 11e99 Hypersensitivity Reactions Type IV (cell-mediated) reactions or delayed hypersensitivity reactions usually appear hours after exposure to an allergen and occur when allergens are taken up by antigen- presenting cells that migrate to lymph nodes and present the allergen to T cells. Intracellular bacteria, such as the one that causes tuberculosis, trigger this type of cell-mediated immune response.

100 Principles of Human Anatomy and Physiology, 11e100 Immune Disease In an autoimmune disease the immune system fails to display self-tolerance and attacks the person’s own tissue. Infectious mononucleosis is a contagious disease primarily affecting lymphatic tissue throughout the body but also affecting the blood. It is caused by the Epstein-Barr virus which multiplies in B cells. There is no cure, and treatment consists of watching for and treating complications. Usually the disease runs its course in a few weeks. Lymphomas are cancers of the lymphatic organs especially the lymph nodes. The two main types are: Hodgkin disease and non-Hodgkin lymphoma. Systemic lupus erythematosus is a chronic autoimmune, inflammatory disease that affects multiple body syystems.

101 Principles of Human Anatomy and Physiology, 11e101 end


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