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Chapter 22
The Lymphatic System
Lecture Outline
Principles of Human Anatomy and Physiology, 11e
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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.
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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
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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.
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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
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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
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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).
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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
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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.
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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)
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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.
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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
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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.
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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).
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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
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Lymphatic Organs and Tissues
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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
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• 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
Principles of Human Anatomy and Physiology, 11e
Thymus Gland
Figure 22.5
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• 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
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Thymus Gland
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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)
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Lymph Nodes
• Flow is in one direction
– afferent vessels lead
in
– sinuses lead to
efferent vessels that
exit at hilus
• Only nodes filter lymph
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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
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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
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Spleen
Figure 22.7
•
•
•
•
5 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)
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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.
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Clinical Application
• The spleen is often damaged in abdominal trauma. A
splenectomy may be required to prevent excessive
bleeding.
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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
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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).
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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
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NONSPECIFIC RESISTANCE: INNATE DEFENSES
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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 (1.53.0) kills many bacteria and destroys most of their toxins; vaginal
secretions also are slightly acidic.
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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
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Second Line of Defense: Internal Defenses
• The second line of defense involves internal antimicrobial
proteins, phagocytic and natural killer cells, inflammation,
and fever.
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Internal Defenses
• Antimicrobial proteins discourage microbial growth
– interferons
– complement proteins
– transferrins
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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.
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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.
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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
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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.
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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
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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
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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
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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
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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
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Review
• Table 22.1 summarizes the components of nonspecific
resistance.
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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.
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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).
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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
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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.
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APCs and MHC-II
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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
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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
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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
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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
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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
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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
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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”.
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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
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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.
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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.
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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.
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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.
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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
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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 TH cells and longlived memory TH cells
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Overview of Mature T Cells
1. Helper T (TH) 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 (TC) 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.
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Helper T Cells
• Display CD4 on surface so also known as T4 cells or TH
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)
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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
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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
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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.
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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
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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.
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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
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Graft Rejection
• After organ transplant, immune system has both cellmediated 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
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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
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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 selfantigen, 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.
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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
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Antibodies
• An antibody is a protein that can combine specifically with
the antigenic determinant on the antigen that triggered its
production.
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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.
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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
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Antibodies
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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)
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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 …
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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.
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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
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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
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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.
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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
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SELF-RECOGNIZITON AND SELF-TOLERANCE
• T cells undergo both positive and negative selection to
ensure that they can recognize self-MHC antigens (selfrecognition) 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).
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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
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Development of Self-Recognition & Immunological Tolerance
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Tumor Immunotherapy
• Cells with antitumor activity are injected into bloodstream of
cancer patient
– culture patient’s inactive cytotoxic T cells with interleukin2
– called lymphokine-activated killer cells (LAK)
• Can cause tumor regression, but has severe complications
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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.
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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
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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.
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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.
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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.
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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.
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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 12-72 hours after exposure to an
allergen and occur when allergens are taken up by antigenpresenting cells that migrate to lymph nodes and present
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Hypersensitivity Reactions
• Type IV (cell-mediated) reactions or delayed hypersensitivity
reactions usually appear 12-72 hours after exposure to an
allergen and occur when allergens are taken up by antigenpresenting 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.
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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.
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