Defense against the dark arts. Section 1: Lymphatic System Anatomy Lymphatic system includes cells,...

Defense against the dark arts

Section 1: Lymphatic System Anatomy

• Lymphatic system includes cells, tissues, and organs responsible for defending the body against:– Environmental hazards (such as various pathogens)– Internal threats (such as cancer cells)

• Lymphatics – Network of lymphatic vessels• Contains lymphocytes surrounded by lymph (fluid

similar to interstitial fluid)– Also includes array of lymphoid organs and tissues

Section 1: Lymphatic System Anatomy

• Lymphocytes (primary cells of lymphatic system)– Respond to: • Invading pathogens (such as bacteria and viruses)• Abnormal body cells (such as virus-infected or cancer

cells)• Foreign proteins (such as bacterial toxins)

– Mostly produced in lymphoid organs and tissues but also in red bone marrow

Figure 19 Section 1

The components of the lymphatic system

Lymphatic Vessels andLymph Nodes

Cervical lymph nodes

Thoracic duct

Right lymphatic duct

Axillary lymph nodesLymphatics of mammary gland

Cisterna chyli

Lymphatics of upper limb

Lumbar lymph nodes

Pelvic lymph nodes

Inguinal lymph nodes

Lymphatics of lower limb

Tonsil

Thymus

Spleen

Appendix

Mucosa-associatedlymphoid tissue(MALT) in digestive,respiratory, urinary,and reproductivetracts

Lymphoid Tissuesand Organs

Lymph

Lymphocyte

Module 19.1: Lymphatic capillaries

• Lymphatic vessels– Carry lymph from peripheral tissues to venous

system– Network begins with lymphatic capillaries

(smallest vessels)• Collect interstitial fluid (then called lymph) and

transport it to larger lymphatic vessels– Larger vessels are similar in structure to veins• Have valves

Figure 19.1 1

The flow of interstitial fluid into lymphatic capillaries, where it is called lymphArteriole

Smooth muscle

Endothelial cells

Lymphatic capillary

Blood capillaries

Loose connectivetissue

Venule Interstitialfluid

Lymphflow

Figure 19.1 3 – 4

Valve in lymphatic vessel LM x 65

Lymphatic vessel

Lymphatic valve

Lymphatic vessel

Vein

Artery

To larger lymphatic vesselsthat deliver lymph to the venous system

The flow of lymph from lymphatic capillaries tolarger lymphatic vessels on the way to the venous system

Vein

Artery

Lymphatic vessel

Lymphatic valve

From lymphaticcapillaries

Module 19.1: Lymphatic capillaries

• Lymphatic capillaries– Present in almost every tissue, alongside

cardiovascular capillaries• Differ from blood capillaries

1. Originate as pockets rather than continuous tubes2. Have larger diameters3. Have thinner walls

» Basal lamina is incomplete or absent4. Typically have a flattened or irregular outline in sectional

view5. Endothelial cells overlap to form one-way valves

» Collect fluids as well as larger solutes

Figure 19.1 2

The structure of lymphatic capillaries

Lymphflow

InterstitialfluidInterstitial

fluid

Looseconnective

tissue

Bloodcapillary

Looseconnective

tissueLymphaticcapillary

To largerlymphatics

Overlappingendothelial cells

Incomplete or absentbasal lamina

Lymphocyte

Sectional view

Module 19.1 Review

a. What is the function of lymphatic vessels?

b. What structure prevents the backflow of lymph in some lymphatic vessels?

c. What is the function of overlapping endothelial cells in lymphatic capillaries?

Module 19.2: Lymphatic vessels

• Lymphatic vessel location– Superficial lymphatics• Subcutaneous layer deep to skin• Areolar tissues of mucous membranes (digestive,

respiratory, urinary, and reproductive tracts)• Areolar tissues of serous membranes (pleural,

pericardial, and peritoneal cavities)

– Deep lymphatics• Accommodate deep arteries and veins supplying

skeletal muscles and other torso organs

Figure 19.2 1

Some characteristics of superficial and deep lymphatics

Lymphatic Vessels

Superficial Lymphatics Deep Lymphatics

Are located in the subcutaneous layer deep to the skin;in the areolar tissues of the mucous membranes liningthe digestive, respiratory, urinary, and reproductivetracts; and in the areolar tissues of the serousmembranes lining the pleural, pericardial, andperitoneal cavities

Accompany deep arteries and veinssupplying skeletal muscles and otherorgans of the neck, limbs, and trunk,and the walls of visceral organs

Deep inguinallymph nodes andlymphatic vessels

Superficial inguinallymph nodes andlymphatic vessels


• Large lymphatic vessels– Lymphatic trunks (drain lymph from large body

regions)• Jugular trunks• Subclavian trunks• Bronchomediastinal trunks• Lumbar trunks• Intestinal trunk

– Cisterna chyli• Expanded chamber receiving lymph from lumbar trunks

and intestinal trunk


• Large lymphatic vessels (continued)– Lymphatic ducts (empty into subclavian veins)• Right lymphatic duct

– Drains lymph from right arm, right upper torso, right head and neck

• Thoracic duct– Drains lymph from rest of body

» Left arm, lower limbs, lower torso, upper left torso, left head and neck

Figure 19.2 2

Drainage ofthoracic duct

Drainage of rightlymphatic duct

Areas of the body drained by the right lymphaticand thoracic ducts

Figure 19.2 3

Cisterna chyli

Thoracic duct

Thoraciclymph nodes

Parietalpleura (cut)

Diaphragm

Left jugular trunk

Left subclavian trunkThoracic duct enteringleft subclavian vein

Left bronchomediastinal trunk

Collects lymph from the trunkslabeled below

Thoracic Duct

Intestinal trunk

Interior vena cava (cut)

Right lumbar trunk

Left lumbar trunk

Superior vena cava (cut)

Rib (cut)

Azygos vein

Right jugular trunk

Right subclavian trunk

Right lymphatic duct enteringright subclavian vein

Right bronchomediastinal trunk

Is formed by the merging of thetrunks labeled below

Right Lymphatic Duct

The relationship between the right lymphatic and thoracic ducts and the venous system

Right internaljugular vein

Brachiocephalicveins

Left internaljugular vein


• Lymphedema– Blockage of lymphatic

drainage– Interstitial fluids

accumulate and affected area swells

– Most often seen in limbs– Can become permanent

and lead to infection• Interstitial fluid is

stagnant and pathogens accumulate

Module 19.2 Review

a. Name the two large lymphatic vessels into which the lymphatic trunks empty.

b. Explain lymphedema.

Module 19.3: Lymphocytes

• Lymphocytes– Account for 20%–30% of circulating leukocytes• Most lymphocytes are out in lymphatic tissues• Three classes circulate in blood

1. T cells (80% of circulating lymphocytes)» Cell-mediated immunity

2. B cells (10%–15% of circulating lymphocytes)» Antibody-mediated immunity

3. NK cells (5%–10% of circulating lymphocytes)» Immunological surveillance


• All lymphocytes are sensitive to specific chemicals (antigens)– Antigens can be:• Pathogens• Parts or products of pathogens• Other foreign compounds

– Are usually proteins but can be other common organic molecules as well

– Stimulate an immune response that leads to destruction of target compound or organism


• Lymphocyte classes– T cells (three major

categories)1. Cytotoxic T cells

– Attack foreign cells or virus-infected body cells» Commonly use

direct contact2. Helper T cells

– Stimulate T cell and B cell activation and function

3. Suppressor T cells– Inhibit T cell and B cell

activation and function– Work with helper T cells

to control immune response sensitivity


• Lymphocyte classes (continued)– B cells

• When stimulated, become plasma cells that produce and secrete antibodies– Antibodies then

circulate in body fluids to attack targets throughout the body

– NK (natural killer) cells• Attack foreign cells,

virus-infected body cells, and cancer cells

• Provide continuous monitoring of peripheral tissues

Figure 19.3 1

The three classes of lymphocytes circulating in the bloodstream

Classes of Lymphocytes

T Cells B Cells NK Cells

Account for approximately 80 percent of circulatinglymphcytes; are of three major types

Attack foreign cellsor body cellsinfected by viruses,commonly by directcontact; are theprimary cellsinvolved in theproduction ofcell-mediatedimmunity (cellularimmunity)

Stimulate theactivationand functionof both T cellsand B cells

Inhibit the activationand function of bothT cells and B cells;the interplaybetween suppressorT cells and helper Tcells helps establishand control thesensitivity of theimmune response

Cytotoxic T Cells Helper T Cells Suppressor T Cells Plasma Cells

When stimulated candifferentiate into plasmacells, which produce andsecrete antibodies; aresaid to be responsible forantibody-mediatedimmunity (humoralimmunity) becauseantibodies circulate widelyin body fluids

Account for 10–15 percentof circulating lymphocytes

Account for 5–10 percent of circulating lymphocytes;perform immunesurveillance,attacking foreigncells, body cellsinfected withviruses, and cancercells that appear innormal tissues


• Lymphopoiesis (lymphocyte production)– Occurs mainly in red bone marrow• Lymphocyte stem cells

– Develop from hemocytoblasts– Produce all lymphocyte types from two groups

1. Group migrates to thymus » Isolated by blood–thymus barrier» Become T cells and reenter bloodstream2. Group remains in bone to finish development» Become B cells and NK cells

– Mature T cells and B cells can reproduce

Module 19.3 Review

a. Identify the three main classes of lymphocytes.

b. Which cells are responsible for antibody-mediated immunity?

c . What tissues are involved in lymphopoiesis?

Module 19.4: Lymphatic tissues and organs

• Lymphatic tissues– Connective tissues dominated by lymphocytes• May form aggregations of lymphocytes (lymphoid

nodules)– Examples:• Aggregated lymphoid nodules (Peyer patches)

– Deep to epithelium in small intestine• Mucosa-associated lymphoid tissue (MALT)

– Protect epithelia of digestive, respiratory, urinary, and reproductive tracts

Figure 19.4 1

A photomicrograph and a drawing of aggregated lymphoid nodules in the intestinal mucosa

An aggregated lymphoid nodule in the intestinal mucosaIntestinal lumen

Mucousmembrane

of intestinal wall

Germinal center

Aggregatedlymphoid nodule

in intestinal mucosa

Underlyingconnective tissue Aggregated lymphoid

nodules LM x 20


• Tonsils– Lymphoid nodules in pharynx wall• Inflammation of tonsils = tonsillitis

– Palatine (posterior, inferior margin of oral cavity)• Paired

– Pharyngeal (posterior, superior wall of pharynx)• Often called adenoid• Single

– Lingual (deep to epithelium at base of tongue)• Paired

Figure 19.4 2

The location and histology of tonsils

LM x 40Pharyngeal tonsil

The location of the tonsils

Germinal centers within nodules

Pharyngeal epithelium

Pharyngeal tonsil

Hard palatePalatine tonsilLingual tonsil


• Lymph nodes– Small lymphoid organs surrounded by fibrous

connective tissue capsule– Diameter range 1–25 mm (about 1 in.)– Large lymph nodes (lymph glands) located in neck,

groin, axillae– Function as filters, removing 99% of pathogens from

lymph before fluid returns to bloodstream


• Pathway through lymph node– Afferent lymphatics (afferens, to bring to) bring lymph to node on

opposite side from hilum (indentation)– Subcapsular space

• Macrophages and dendritic cells (immune response)– Outer cortex

• B cells in germinal centers– Deep cortex

• T cells– Medullary sinus

• B cells and plasma cells – Exit node through efferent (efferens, to bring out) lymphatics

Figure 19.4 3

Start

The functional anatomy of lymph nodes

Path of Lymph Flow through a Lymph Node

Efferent lymphatics (efferens, to bring out)leave the lymph node at the hilum. Thesevessels collect lymph from the medullary sinusand carry it toward the venous circulation.

Lymph continues into the medullary sinus atthe core of the lymph node. This regioncontains B cells and plasma cells.

Lymph then flows through lymph sinuses in thedeep cortex, which is dominated by T cells.

Lymph next flows into the outer cortex, whichcontains B cells within germinal centers thatresemble those of lymphoid nodules.

The afferent vessels deliver lymph to thesubcapsular space, a meshwork of reticularfibers, macrophages, and dendritic cells.Dendritic cells are involved in the initiation ofthe immune response.

Afferent lymphatics (afferens, to bring to)carry lymph to the lymph node from peripheraltissues. The afferent lymphatics penetrate thecapsule of the lymph node on the side oppositethe hilum.

Trabeculae

Germinalcenter

Hilum

Lymph nodeartery and vein

Lymph nodes

Lymph node

Lymph vessel

Module 19.4 Review

a. Define tonsil.

b. Name the lymphoid tissue that protects epithelia lining the digestive, respiratory, urinary, and reproductive tracts.

Module 19.5: Thymus

• Function of the thymus and age-related effects– Produces several hormones (thymosins)

important in functional T cell development• More important in children

– Size is largest (40 g) before puberty – Diminishes in size and becomes fibrous (involution)

• After age 50, size can be <12 g and secretions decline– May lead to increased susceptibility to disease

Module 19.5: Thymus

• Structure of the thymus– Bilobed gland in mediastinum, posterior to sternum• Left and right lobes with smaller partitions (septa)

dividing it into lobules• Each lobule contains:

– Cortex (reticular epithelial cells and lymphocytes)» Has blood–thymus barrier to isolate developing T cells

– Medulla (reticular epithelial cells and lymphocytes organized into thymic corpuscles)» Developed T cells enter bloodstream (no barrier)

Figure 19.5 2

Septa

Lobule

Left lobe

Right lobe

The surface anatomyof the thymus

Figure 19.5 3 – 4

The histology of the thymus

Medulla Septa Cortex

Lobule

Thymus gland LM x 50

Lobule

Lymphocytes

Thymiccorpuscle

Reticular epithelialcells

Thymic corpuscle LM x 532

Module 19.5 Review

a. Where is the thymus located?

b. Which cells constitute and maintain the blood–thymus barrier?

c. Describe the gross anatomy of the thymus.

Module 19.6: Spleen

• Similar to a lymph node: filters blood for the body to prevent pathogens from reaching vital organs

• Extremely delicate tissue– If damaged or ruptured it is

to difficult to fix surgically and a slenectomy is usually done

Figure 19.6 1

A transverse section of the trunk showing the location ofthe spleen within the abdominopelvic cavity

Stomach

Rib

Pancreas

Aorta

Kidneys

Liver

Diaphragm

Gastrosplenic ligament

Gastric area

Diaphragmatic surfaceof the spleen

Hilum

Renal area

Spleen

Spleen

Module 19.6: Spleen

• Internal functional anatomy– Outer capsule of collagen and elastic fibers• Protects but overall spleen structure is delicate

– Damage can necessitate removal (splenectomy)

– Trabeculae • Fibrous partitions that allow room for blood vessels

– Pulp (cellular components allowing identification and removal of damaged or infected cells in bloodstream)• Red pulp (large quantities of RBCs)• White pulp (resemble lymphoid nodules with lymphocytes,

macrophages, and dendritic cells)

Figure 19.6 4

Central artery in splenic nodule

White pulp of splenic nodule

Capsule

Trabecula

Trabecular artery

Fibrous partitions within which bloodvessels travel

Trabeculae

Red pulp

The histological appearance of the spleen LM x 50

Figure 19.6 5

Module 19.6 Review

a. What is the function of the spleen?

b. Describe red pulp and white pulp found in the spleen.

.

Section 2: Nonspecific Defenses

• Two complementary mechanisms work to fight infection, illness, and disease1. Specific defenses (protect against particular

threats)• Depend on specific lymphocyte activities• Produce state of protection (immunity or specific

resistance)

Section 2: Nonspecific Defenses

• Two complementary mechanisms work to fight infection, illness, and disease (continued)

2. Nonspecific defenses (present from birth and do not distinguish one type of threat from another)• Physical barriers• Phagocytes• Immunological surveillance• Interferons• Complement• Inflammatory response• Fever

Animation: Immunity: Nonspecific Defenses

Module 19.7: Physical barriers and phagocytes

• Physical barriers– Integumentary system• Secretions from sebaceous and sweat glands wash away

microorganisms and chemical agents– May also contain bactericidal chemicals, destructive enzymes

(lysozymes), and antibodies

• Hair provides protection from mechanical abrasion and prevents hazardous materials or insects from contacting skin• Multiple layers of epithelial cells with keratin that are

connected with desmosomes

Figure 19.7 1

Structures in the skin that constitutea physical barrier

Duct of eccrinesweat gland

Hair Secretion

Epithelium

Keratinizedcells

DesmosomesSebaceousgland

The epithelial covering of the skinhas multiple layers, a coating ofkeratinized cells, and a network ofdesmosomes that lock adjacentcells together.

The hairs on most areas of yourbody’s surface provide someprotection against mechanicalabrasion (especially on the scalp),and they often prevent hazardousmaterials or insects fromcontacting your skin.

Most epithelia are protected byspecialized accessory structures andsecretions. The epidermal surfacealso receives the secretions ofsebaceous and sweat glands. Thesesecretions, which flush the surface towash away microorganisms andchemical agents, may also containbactericidal chemicals, destructiveenzymes (lysozymes), andantibodies.


• Physical barriers (continued)– Other epithelial linings • Found along digestive, respiratory, urinary, and

reproductive tracts• Cells provide physical barrier• Secretions (mucus, enzymes, stomach acid) often ensnare,

destroy, or wash away pathogenic material

Figure 19.7 2

Epithelial cells tiedtogether by tightjunctions andsupported by afibrous basal lamina

Basal lamina

Tight junctionsMucus coating

Secretory cell

Mucus bathes most surfaces of yourdigestive tract, and your stomachcontains a powerful acid that candestroy many pathogens. Mucusmoves across the lining of therespiratory tract, urine flushes theurinary passageways, and glandularsecretions do the same for thereproductive tract. Special enzymes,antibodies, and an acidic pH add tothe effectiveness of these secretions.

The barrier provided by the epithelia lining the digestive, respiratory, urinary, and reproductive tracts


• Phagocytes– Engulf and destroy foreign compounds and pathogens– “First line of cellular defense” against pathogenic invasion– Types

1. Neutrophils (in bloodstream and tissues)– Phagocytize cellular debris or bacteria

2. Eosinophils (less abundant)– Phagocytize foreign compounds and antibody-coated pathogens

3. Macrophages (derived from monocytes)– Fixed (permanent residents of certain organs)– Free (travel throughout body)

Figure 19.7 3

Neutrophils areabundant, mobile,and quick tophagocytize cellulardebris or invadingbacteria. Theycirculate in thebloodstream androam throughperipheral tissues,especially at sitesof injury orinfection.

Eosinophils, whichare less abundantthan neutrophils,phagocytize foreigncomponds orpathogens that havebeen coated withantibodies.

Types of Phagocytes

There are two major classes of macrophages derived from themonocytes of the circulating blood. This collection of phagocyticcells is called the monocyte–macrophage system, or thereticuloendothelial system.

Fixed macrophages are permanentresidents of specific tissues and organsand are scattered among connectivetissues. They normally do not move withinthese tissues.

Free macrophages travelthroughout the body, arriving at thesite of an injury by migrating throughadjacent tissues or by recruitmentfrom the circulating blood.

12 μm 8–10 μm

Figure 19.7 4

Module 19.7 Review

a. Define chemotaxis.

b. How does the integumentary system protect the body?

c. Identify the types of phagocytes in the body, and differentiate between fixed macrophages and free macrophages.

Module 19.8: Immunological surveillance

• Immunological surveillance– Constant monitoring of normal tissues by NK cells• Normal cells are generally ignored by immune system• Cancer cells often contain tumor-specific antigens

– NK cells recognize as abnormal and destroy

• NK cells recognize bacteria, foreign cells, virus-infected cells, and cancer cells


• Steps of NK recognition and destruction1. Presence of unusual plasma membrane activates

NK cell• NK cell adheres to target cell

2. Golgi apparatus moves within NK cell near target cell• Produces many secretory vesicles containing perforins

3. Perforins release from NK cell and arrive at target cell4. Perforins create pores in target cell membrane

• Target cell can no longer maintain its internal environment and disintegrates

Figure 19.8 1

The steps by which NK cells recognize and kill target cells

Step 1: If a cell hasunusual components in itsplasma membrane, an NKcell recognizes that othercell as abnormal. Suchrecognition activates theNK cell, which thenadheres to its target cell.

Step 2: The Golgi apparatusmoves around the nucleus untilthe maturing face points directlytoward the abnormal cell. A floodof secretory vesicles is thenproduced at the Golgi apparatus.These vesicles, which containproteins called perforins, travelthrough the cytoplasm toward thecell surface.

Step 3: The perforinsare released at the cellsurface by exocytosisand diffuse across thenarrow gap separatingthe NK cell from itstarget.

Step 4: As a result of thepores made of perforinmolecules, the target cellcan no longer maintainits internal environment,and it quicklydisintegrates.

Golgi apparatus

NK cell Abnormalcell

Abnormalcell

Perforinmolecules

NK cell

Pores produced by theinteraction of perforinmolecules


• NK cells also destroy abnormal cells– Abnormal daughter cells

occur during cell division– Some abnormal cells

become cancer cells

Figure 19.8 2

Daughter cells

Daughter cells

Stem cell

Abnormal cellNK cell identifies anddestroys abnormal cell

The process whereby NK cells detectand destroy abnormal cellsresulting from faultycell division


• Immunological escape– Immunological surveillance by NK cells is not

perfect• Primary tumors may be surrounded by a capsule and

escape detection– Released malignant cells may be detected and destroyed

• Daughter tumor cells sometimes do not display tumor-specific antigens or secrete chemicals that kill NK cells– Cancer cells can spread and create secondary tumors

Figure 19.8 3

The cells within a primarytumor may grow rapidly,and if the tumor has a surrounding capsule, thecells within may notprovoke a massiveresponse by NK cells.

As malignant tumorcells begin migratinginto surroundingtissues, they can bedetected anddestroyed by NK cells.

Sometimes a daughter cell will beproduced that either does notdisplay tumor-specific antigens, orthat secretes chemicals thatdestroy NK cells. Such a cell willsurvive and be free to grow anddivide.

Once immunologicalescape has occurred,cancer cells canmultiply and spreadwithout interference byNK cells. They can thenmove throughout thebody, establishingpotentially lethalsecondary tumors.

NK cell

The process of immunological escape

Module 19.8 Review

a. Define immunological surveillance.

b. How do NK cells detect cancer cells?

c. If NK cells are engaged in immunological surveillance, how do cancer cells spread?

Module 19.9: Interferons and the complement system

• Interferons– Small proteins released by activated lymphocytes,

macrophages, and virus-infected tissues– Trigger antiviral proteins in cytoplasm of nearby

cells• Do not prevent entry of viruses but interfere with viral

replication

– Also stimulate activities of macrophages and NK cells


• Interferons (continued)– Three types

1. Alpha (α) interferons (produced by virus-infected cells)– Attract and stimulate NK cells and give viral resistance

2. Beta (β) interferons (secreted by fibroblasts)– Slow inflammation in damaged area

3. Gamma (γ) interferons (secreted by T cells and NK cells)– Stimulate macrophage activity

Figure 19.9 1

Three of the types of interferons

Alpha (α)-interferonsare produced by cellsinfected with viruses.They attract and stimulate NK cells and enhance resistance to viral infection.

Beta (β)-interferons,secreted by fibroblasts,slow inflammation in adamaged area.

Gamma()-interferons,secreted by T cells andNK cells, stimulatemacrophage activity.


• Complement system (complements antibody action)– 11 plasma proteins that interact to attach to foreign cells– Two pathways of activation

1. Classical pathway (most rapid and effective)– Complement proteins attach to antibody already bound to pathogen– Attached protein activates and initiates cascade to activate and

attach other complement proteins

2. Alternative pathway– Several complement proteins (notably properdin) activate in plasma

after contacting foreign materials


• Complement system effects– Pore formation (formed by many complement proteins)

• Destroys integrity of target cell– Enhanced phagocytosis

• Attracts phagocytes and makes target cells easier to engulf– = Opsonization

– Histamine release• By mast cells and basophils• Increases inflammation and blood flow to region

Animation: Immunity: Complement

Module 19.9 Review

a. Define interferons.

b. Briefly explain the role of complement proteins.

c. What is the effect of histamine released by complement system activation?

Module 19.10: Inflammation and fever

• Inflammatory response– Localized tissue response that produces:• Local swelling• Redness• Heat• Pain

– Complex process of inflammation can be triggered by:• Cells that are damaged from any source release

prostaglandins, proteins, and potassium ions• Foreign proteins or pathogens


• The events in inflammation– Tissue damage causes chemical change in interstitial fluid– Mast cell activation• Release of histamine and heparin

– Causes:» Increased blood flow to area» Clot formation» Phagocyte attraction (removes debris and activates specific

defenses)– Tissue repair• Pathogen removal, clot erosion, scar tissue formation


• Fever– Maintenance of body temperature >37.2°C (99°F)– Pyrogens (pyro-, fever or heat, + -gen, substance)• Reset temperature thermostat in hypothalamus

– Raises body temperature

• Functions– May inhibit some viruses and bacteria– Increases metabolic rate which may accelerate tissue defenses

and repair process

Figure 19.10 3

Interferons

Immunological Surveillance

Phagocytes

Physical Barriers

A summary of the body’s nonspecific defenses

Prevent approach ofand deny access topathogens

Duct of eccrinesweat gland

Secretions

Epithelium

Hair

Remove debrisand pathogens

Neutrophil Eosinophil MonocyteFree

macrophageFixed

macrophage

Destroysabnormal cells

Natural killer cell

Lysedabnormalcell

Increase resistance ofcells to viral infection;slow the spread ofdisease

Interferons released by activatedlymphocytes, macrophages, orvirus-infected cells

Figure 19.10 3

Fever

Inflammatory Response

Complement System

Lysedpathogen

Complement

Attacks and breaks down thesurfaces of cells, bacteria, andviruses; attracts phagocytes;stimulates inflammation

Multiple effects

Mast cell

Mobilizes defenses;accelerates repairs;inhibits pathogens

Body temperature rises above 37.2°C in response to pyrogens

• Blood flow increased• Phagocytes activated• Damaged area isolated by clotting reaction• Capillary permeability increased• Complement activated• Regional temperature increased• Specific defenses activated

A summary of the body’s nonspecific defenses

Module 19.10 Review

a. List the body’s nonspecific defenses.

b. A rise in the level of interferons in the body suggests what kind of infection?

c. What effects do pyrogens have in the body?

Section 3: Specific Defenses

• Specific defenses– Coordinated activities of T cells and B cells• Produce immunity

– Specific resistance against potentially dangerous antigens

• T cells (cell-mediated immunity)– Defend against abnormal cells and pathogens inside cells

• B cells (antibody-mediated immunity)– Defend against antigens and pathogens in body fluids

The various forms of immunity

Specific Defenses (Immunity)

Respond to threats on anindividualized basis

Aquired ImmunityIs not present at birth; is acquiredagainst a specific antigen only uponexposure to that antigen or receipt ofantibodies from someother source

Passive ImmunityProduced bytransfer ofantibodies fromanother source

NaturallyacquiredpassiveimmunityConferred bytransfer ofmaternalantibodies acrossplacenta or inbreast milk

Artificiallyacquiredpassiveimmunity

Conferred byadministration ofantibodies tocombat infection

Active Immunity (Immune Response)

Develops inresponse to antigenexposure

Naturallyacquiredactiveimmunity

Artificially acquiredactive immunity

Develops afterexposure toantigens inenvironment

Develops afteradministration of an antigen(usually throughvaccination). Theseactivities stimulate animmune response andpromote immunity to thatparticular antigen.

Geneticallydetermined—noprior exposureor antibodyproductioninvolved

Innate Immunity

Figure 19 Section 3 1

Section 3: Specific Defenses

• Properties of immunity1. Specificity• T cells and B cells bind only one antigen

2. Versatility• Millions of lymphocytes, each sensitive to a different

antigen3. Immunologic memory• Memory cells “remember” antigens for future attacks

4. Tolerance• Ignoring normal “self” tissues

Module 19.11: Triggering an immune response

• Phagocytes activated by antigen exposure stimulate specific immune responses

• To trigger a response, antigens or antigenic fragments must appear in plasma membranes from:– Infecting cells or being “processed” by

phagocytes• = Antigen presentation

Figure 19.11 1

An overview of the immune response

Antigens or AntigenicFragments in Body FluidsMost antigens must eitherinfect cells or be“processed” byphagocytes before specificdefenses are activated. Thetrigger is the appearanceof antigens of antigenicfragments in plasmamembranes;this is called antigenpresentation.

Specific Defenses

Antigenpresentationtriggers specificdefenses, or animmune response.

Cell-MediatedImmunity

Direct Physical andChemical Attack

Phagocytesactivated

T cellsactivated

Communicationand feedback

Destructionof antigens

Activated T cells findthe pathogens andattack them throughphagocytosis or therelease of chemicaltoxins.

Attack by CirculatingAntibodies

Antibody-MediatedImmunity

Activated Bcells giverise to cellsthat produceantibodies.


• Major histocompatibility complex (MHC) proteins– Genetically determined membrane glycoproteins

present on all cells• Synthesis controlled by portion of chromosome 6

– = Major histocompatibility complex

– Foreign antigens are attached to newly synthesized MHC proteins and appear on cell surface

– T cells bind antigen-MHC complex and become activated


• MHC proteins– Two classes

1. Class I MHC proteins– Present on all cells– Create complex when cell is infected with bacteria or viruses

2. Class II MHC proteins– Only in membranes of antigen-presenting cells (APC)

» Examples: monocyte–macrophages, dendritic cells– Create complex with phagocytized pathogens

Figure 19.11 2

The events of antigen presentation in an infected body cell

The abnormalpeptides aredisplayed by ClassI MHC proteins onthe plasmamembrane.

After export to theGolgi apparatus,the MHC proteinsreach the plasmamembrane withintransport vesicles.

Antigen presentationby Class I MHCproteins is triggeredby viral or bacterialinfection of a bodycell.

The infection resultsin the appearance ofabnormal peptides inthe cytoplasm.

The abnormalpeptides areincorporated intoClass I MHC proteinsas they aresynthesized at theendoplasmicreticulum.

Plasma membrane

Viral or bacterialpathogen

Transportvesicle

Endoplasmicreticulum

Figure 19.11 3

Lysosomal actionproduces antigenicfragments.

Lysosome

Phagocytic cell

Nucleus Endoplasmicreticulum

The endoplasmicreticulum producesClass II MHC proteins.

Antigenic fragmentsare bound to Class IIMHC proteins.

Antigenic fragmentsare displayed by ClassII MHC proteins on theplasma membrane.

PlasmamembranePhagocytic APCs

engulf theextracellularpathogens.

The events of antigen presentation in a phagocytic cell

Module 19.11 Review

a. Describe antigen presentation.

b. What is the major histocompatibility complex (MHC)?

c. Where are Class I MHC proteins and Class II MHC proteins found?

Module 19.12: T cell activation by infected cells

• Inactive T cells must bind the specific MHC-antigen complex that the T cell is programmed to detect– = Antigen recognition– Two classes of T cell CD (cluster of differentiation)

markers can recognize antigens1. CD8 markers (on CD8 T cells)

– Respond to Class I MHC proteins

2. CD4 markers (on CD4 T cells)– Respond to Class II MHC proteins

Figure 19.12 1

The structures involved in the process ofantigen recognition

Inactive T cell

Receptor

Antigen

MHC protein

Antigenrecognition

protein

Infected body cell (including APCs)

Figure 19.12 2

CD (cluster of differentiation) markers, the membraneproteins involved in antigen recognition

CD MarkersThere are at least 70 differentCD markers, but only twoassociated with T cells areimportant to our discussion.

CD8 markers arefound on CD8 T cells.CD8 T cells respond toantigens presented byClass I MHC proteins.

CD4 markers arefound on CD4 T cells.CD4 T cells, discussedfurther in the nextmodule, respond toantigens presented byClass II MHC proteins.

CD4 MarkersCD8 Markers


• Steps of CD8 T cell activation1. Antigen recognition2. Costimulation• Physical or chemical stimulation of T cell in addition to

the Class I MHC molecule

3. T cell activation and cell division• Three CD8 T cells produced

1. Cytotoxic T cells (TC cells)

2. Memory TC cells

3. Suppressor T cells (TS cells)

Figure 19.12 3 – 4

Before activation can occur, a T cell mustbe chemically or physically stimulated bythe abnormal target cell. This vitalsecondary binding process, calledcostimulation, confirms the activationsignal. Costimulation is like the safety on agun: It helps prevent T cells frommistakenly attacking normal (self) tissues.

CD8 T cell

Antigen

T cellreceptor

CostimulationactivatesCD8 T cell

Costimulation

CD8

Class IMHC

Infected cell

Events in the stimulation and formation of cytotoxic, memory TC, and suppressor T cells

Activation andCell Division

Antigen Recognition

Antigen recognition occurswhen a CD8 T cell encountersan appropriate antigen on thesurface of another cell, boundto a Class I MHC protein.

Infectedcell

Viral orbacterialantigen

InactiveCD8T cell

Antigenrecognitionresults in T cellactivation and celldivision,producing threedifferent types ofCD8 T cells.

Cytotoxic T Cells Seek Out Antigen-Bearing Cells

Memory TC Cells Are Produced

Suppressor T Cells Provide a Delayed Suppression

Cytotoxic T cells, also called TC cells, seek out and destroyabnormal and infected cells. Cytotoxic T cells are highly mobile cellsthat roam throughout injured tissues. When a TC cell encounters itstarget antigens bound to Class I MHC proteins, it attacks the targetcell.

Memory TC cells are produced bythe same cell divisions that producecytotoxic T cells. Thousands of thesecells are produced, but they do notdifferentiate further the first time theantigen triggers an immuneresponse.

Memory TC cells(inactive)

Suppressor T cells (TS cells)suppress the responses of other Tcells and B cells by secretingsuppression factors that limit thedegree of immune system activation.Suppression does not occurimmediately, because suppressor Tcell activation takes much longerthan the activation of other types of Tcells, and so suppressor T cells actonly after the initial immune response.

SuppressorT cells

Disruption of cell metabolismthrough the release oflymphotoxin (lim-fō-TOK-sin)

Activation of genes within thetarget cell nucleus that resultsin the self-destruction of thecell through a process calledapoptosis (ap-op-TŌ-sis)

Destruction of target cellmembrane through therelease of perforins

The TC cell destroys the antigen-bearing cell. It may use severaldifferent mechanisms to kill thetarget cell.

Destruction of Target Cells


• CD8 T cell types1. Cytotoxic TC cells• Seek out and destroy abnormal and infected cells in

injured tissues– Target cells must have specific Class I MHC proteins– Destructive mechanisms

» Release of perforins» Activate target cell self-destruction genes for cell death

(apoptosis)» Disruption of cell metabolism with lymphotoxin


• CD8 T cell types (continued)2. Memory TC cells

• Produced but do not differentiate further during first antigen exposure

• Upon 2nd exposure to same antigen, memory TC cells become cytotoxic T cells

3. Suppressor T cells• Secrete suppression factors to limit responses of other T cells and B

cells• Also act only after first antigen exposure (initial immune response)

Module 19.12 Review

a. Identify the three major types of T cells activated by Class I MHC proteins.

b. Describe CD markers.

c. How can the presence of an abnormal antigen in the cytoplasm of a cell initiate an immune response?

Module 19.13: CD4 T cell and B cell activation

• B cell activation– Must bind specific antigen– Antigens are brought into cell through endocytosis and then placed

on surface of cell bound to Class II MHC proteins• = Sensitization

– Full activation occurs when activated helper T cell binds to sensitized B cell antigen-Class II MHC complex

– Activated B cells produce:• Memory B cells (inactive until 2nd exposure to antigen)• Plasma cells (activated B cells that produce antibodies)

Module 19.13: CD4 T cell and B cell activation

Animation: B Cell Sensitization

Figure 19.13

The process whereby stimulation of CD4 T cells results in the production of antibodies

Antigen Recognition by CD4 T Cell B Cell Sensitization

CD4 T Cell Activation and Cell Division

Antigens

Class II MHC

Antibodies

InactiveB cell

Antigens boundto antibodymolecules

SensitizedB cell

Foreign antigen

Antigen-presentingcell (APC)

APCClass II MHC

Antigen CostimulationCD4 protein

T cell receptorTH cell

InactiveCD4 (TH)cell

The Golgi apparatus ispackaging membranereceptors (red) that will beincorporated into the surfaceof the cell. These receptorsare essential to thecostimulation of B cells.

Memory TH cells(inactive)

Active helper T cells secretecytokines that stimulateboth cell-mediated andantibody-mediated immunity.

Active helper T cells

Cytokines

An activated helper T cell Fluorescent LM x 400

B Cell Activation

Class II MHC Sensitized B cell

Antigen

T cell receptor

Helper T cell

Costimulationby cytokines

Cytokines

SensitizedB cell

Activehelper T cell

Division, Differentiation, and Antibody Production

Memory B cells remain inreserve to deal with subsequentinjuries of infections thatinvolve the same antigens. Onsubsequent exposure, thememory B cells respond bydifferentiating into plasma cellsthat secrete antibodies inmassive quantities.

Memory B cells(inactive)

ActivatedB cell

Celldivision

Stimulationby cytokines

Active B cells

Activehelper T cell Plasma cells

Antibodymolecules

Under stimulationby cytokines fromhelper T cells,clones of active Bcells differentiateinto plasmacells, eachcapable ofsecreting up to100 millionantibodymolecules eachhour.

Module 19.13 Review

a. Define sensitization.

b. Explain the function of cytokines secreted by helper T cells.

c. If you observed a higher-than-normal number of plasma cells in a sample of lymph, would you expect antibody levels in the blood to be higher or lower than normal?

Module 19.14: Antibodies

• Antibody molecules– Consist of two parallel polypeptide chains• One pair of heavy chains• One pair of light chains

– Each pair contains:• Constant segments

– On heavy chains, form the base of antibody molecule• Variable segments

– Free tips are antigen binding sites– Differences in amino acid sequences produce variability needed

for different antibodies

Figure 19.14 1

The structure of an antibody moleculeAntigen binding sites

Constantsegments

of lightand heavy

chains

Variablesegment

Antigenbinding

site

Disulfidebond

Heavy chain

Light chain

Binding sites that can activate the complement systemare covered when the antibody is secreted but becomeexposed when the antibody binds to an antigen.

Binding sites may also be present that attach thesecreted antibody to the surfaces of macrophages,basophils, or mast cells.


• Antigen-antibody complex– When a specific antibody binds to corresponding antigenic

determinant sites (binding sites) on antigen• Complete antigens

– Have at least two antigenic determinant sites, one for each binding site on antibody

– Large antigens (like bacteria) may have millions of antigenic determinant sites

• Partial antigens (haptens)– Do not have enough binding sites to bind antibody– Antibody may bind to hapten and carrier molecule

» Response will then be against body cell carrier molecule as well

Figure 19.14 2

The formation of an antigen-antibody complexCarriermolecule

Partial antigen(hapten)

Antibody

Antibody

Antigen-antibodycomplex

Antibodies bind not to the entireantigen, but to specific portions ofits exposed surface—regionscalled antigenic determinantsites.

A complete antigen is anantigen with at least two antigenicdeterminant sites, one for each ofthe antigen binding sites on anantibody molecule.

Partial antigens, or haptens, do notordinarily cause B cell activation.However, they may become attached tocarrier molecules, forming combinationsthat can function as complete antigens.The antibodies produced will attack boththe hapten and the carrier molecule. Ifthe carrier molecule is normally presentin the tissues, the antibodies may beginattacking and destroying normal cells.This is the basis for several drugreactions, including allergies topenicillin.

Figure 19.14 3

Antigen

AntibodiesAntigenic

determinant sites

A bacterium with numerous antigenicdeterminant sites, to which antibodies bind


• Five different classes of antibodies (immunoglobulins or Igs)– Differences in heavy-chain constant segments1. IgG (80% of all antibodies)

• Against many viruses, bacteria, and bacterial toxins

2. IgE• Attaches to basophil and mast cell surfaces

3. IgD• On B cell surface where it binds antigens in extracellular fluid• Plays role in B cell sensitization


• Five different classes of antibodies (continued)4. IgM • First class of antibody secreted after antigen

encountered– Production declines as IgG production increases

• Anti-A and anti-B antibodies are examples

5. IgA• Found primarily in glandular secretions such as mucus,

tears, saliva, and semen• Attack before pathogens gain internal access

Figure 19.14 4

The five classes of antibodies, or immunoglobulins (Igs)

Classes of Antibodies

IgG antibodiesaccount for 80 percentof all antibodies. IgGantibodies areresponsible forresistance againstmany viruses,bacteria, and baterialtoxins.

IgE attaches asan individualmolecule to theexposedsurfaces ofbasophils andmast cells.

IgD is an individualmolecule on thesurfaces of B cells,where it can bindantigens in the extracellular fluid. Thisbinding can play a rolein the sensitization ofthe B cell involved.

IgM is the first class ofantibody secreted after anantigen is encountered. IgMconcentration declines as IgGproduction accelerates. Theanti-A and anti-B antibodiesresponsible for theagglutination of incompatibleblood types are IgMantibodies.

IgA is found primarilyin glandular secretionssuch as mucus, tears,saliva, and semen.These antibodies attackpathogens before theygain access to internaltissues.


• Primary response– Antibody-mediated response to initial antigen

exposure– Is delayed due to time to activate specific B cells• Antibody titer (level of antibody activity) peaks

1–2 weeks after initial exposure

• Secondary response– From memory B cells for specific antigen– Antibody titers increase more rapidly and reach

higher concentrations

Figure 19.14 5 – 6

A primary antibody response, which occurs afteran initial exposure to an antigen

Time (weeks) Time (weeks)A secondary antibody response, which occurs afterthe eliciting antigen has been encountered before

IgMIgMIgG

IgG

Primary response Secondary response

Antib

ody

conc

entr

ation

in p

lasm

a

The time course and amount of antibody production for an initial exposure to an antigen and for asubsequent exposure to the same antigen

Module 19.14 Review

b. Describe the structure of an antibody.

c. Which would be more affected by a lack of memory B cells and memory T cells: the primary response or the secondary response?

Module 19.15: Antibody defenses

• Antibody defenses– Neutralization

• Antibodies occupy binding sites on viruses and bacterial toxins preventing them from affecting body cells

– Prevention of pathogen adhesion• IgA antibodies in glandular secretions cover bacteria or

viruses preventing adhesion and infection of body cells– Activation of complement

• After antigen binding, complement also can bind to the antibody, accelerating the complement cascade


• Antibody defenses (continued)– Stimulation of inflammation• Basophil and mast cell stimulation to release chemicals

– Opsonization• Coating of pathogen with antibodies allows phagocytes

to bind easier

– Attraction of phagocytes• Attached antibodies attract eosinophils, neutrophils,

and macrophages


• Antibody defenses (continued)– Precipitation and agglutination• The linking of multiple pathogens by antibodies creating

an immune complex– When target antigen is on cell surface (like RBC) or virus

» = Agglutination

Module 19.15 Review

a. Define opsonization.

b. List the ways that antigen-antibody complexes can destroy target antigens.

c. Which cells are involved in the inflammatory response?

CLINICAL MODULE 19.16: Allergies

• Allergies– Inappropriate or excessive immune responses to antigens

(allergens)– Sensitization and activation of B cells to allergens leads to

production of large quantities of IgE– Reactions may be:

• Localized (inflammation, pain, itching at contact area)– Example: hypersensitivity reaction of allergic rhinitis (hay fever and

other environmental allergies)

• Systemic (allergen in bloodstream, symptoms widespread)– Example: anaphylaxis (circulating allergen causing widespread

vasodilation through mast cell activation)

Figure 19.16

The events that result in an allergy

First Exposure Allergen fragment

AllergensMacrophage TH cell activation

B cell sensitizationand activation

Plasma cell

IgE antibodies

Subsequent Exposure

Allergen

IgE

Granules

Massivestimulation of

mast cellsand basophils

Sensitization ofmast cells andbasophils

Release of histamines, leukotrienes,and other chemicals that

cause pain and inflammation

Localized Allergic Reactions Systemic Allergic Reactions

If the allergen is at the bodysurface: localized inflammation,pain, and itchingExample: allergic rhinitis

If the allergen is in thebloodstream: itching, swelling,and difficulty breathing (due toairway constriction)Example: anaphylaxis

CLINICAL MODULE 19.16 Review

a. Define allergy and allergen.

b. What is anaphylaxis?

c. Which chemicals do mast cells and basophils release when stimulated in an allergic reaction?

Module 19.17: Integrated defense responses

• Exposure to antigens triggers both specific and nonspecific defenses– Neither branch works alone– Many times, activities from each branch will

enhance the other

• Responses will vary based on antigen type

Figure 19.17 1

The relationships among the elements of the nonspecific defenses and the specific defenses (immune response)

Antigens

Trigger

Nonspecific Defenses

Specific Defenses (Immune Response)Antigen

presentationby APCs

NK cellsMacrophages

Complementsystem

Activation by Class I MHC Proteins Activation by Class II MHC Proteins

Antigen andClass I MHCProtein

Indicates that thecell is infected orotherwise abnormal

Antigen andClass II MHCProtein

CD8 T cells CD4 T cells

Indicates thepresence ofpathogens,toxins, or foreignproteins

CytotoxicT Cells

MemoryTc Cells

SuppressorT Cells

Attack anddestroy infectedand abnormalcells displayingantigen

Awaitreappearanceof the antigen

Control ofmoderateimmune responseby T cells and Bcells

Direct physicaland chemicalattack

Direct physicaland chemicalattack

Attack bycirculatingproteins

Destructionof Antigens

Helper T Cells

Stimulate immuneresponse by Tcells and B cells

Activationof B cells

Awaitreappearance ofthe antigen

Memory TH Cells

Production ofplasma cells

Production of memory Bcells

Secretion ofantibodies

Figure 19.17 2

Antigenpresentation

BACTERIA

An overview of the course of eventsinvolved in overcoming a bacterial infection

Phagocytosis bymacrophages and APCs

Activation ofcytotoxic T cells

Activation ofhelper T cells

Activation of B cells

Destruction ofbacteria by

cell lysis

Antibodyproduction byplasma cells

Opsonizationand phagocyte

attraction

Formation ofantigen-antibody

complexes

Figure 19.17 3

Antigenpresentation

An overview of the course of events involved in overcoming a viral infection

VIRUSES

Infection oftissue cells

Infection of or uptakeby APCs

Release ofinterferons

Appearance of antigenin plasma membrane

Activation ofhelper T cells

Activation ofcytotoxic T cells

Stimulationof NK cells

Increasedresistance toviral infection

and spread

Destruction ofviruses or

prevention ofvirus entry into cells

Antibodyproduction byplasma cells

Destruction ofvirus-infected cells

Activation of B cells

Module 19.17 Review

a. Identify the type of T cell whose plasma membrane contains CD8 markers and the type with CD4 markers.

b. Which cells can be activated by direct contact with virus-infected cells?

c. Which cells produce antibodies?

CLINICAL MODULE 19.18: Immune disorders

• Excessive or misdirected immune responses– Autoimmune disorders• Activated B cells make antibodies against “self”

antigens or body cells and tissues– = Autoantibodies

• Likely arise from body cell antigens being too similar to specific foreign antigen


• Excessive or misdirected immune responses (continued)– Autoimmune disorders (continued)• Examples:

– Thyroiditis (inflammation resulting from autoantibodies attacking thyroglobin)

– Rheumatoid arthritis (autoantibodies attack connective tissues around joints)

– Insulin-dependent diabetes mellitus (autoantibodies attack pancreatic islet cells)

– Multiple sclerosis (autoantibodies attack myelin)


• Excessive or misdirected immune responses (continued)– Graft rejection• Recipient cytotoxic T cells become activated and attack

MHC proteins of donated material • Reduction in immune response sensitivity

(immunosuppression) by drugs can increase transplant success– Example: cyclosporin A (CsA) inhibits helper T cells

– Allergies


• Inadequate immune responses– Immunodeficiency diseases• Result from:

1. Problems with lymphoid organ and tissue development2. An infection with a virus that depresses immune function

» Example: Acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV) that infects CD4 T cells

3. Treatment with, or exposure to, immunosuppressive agents like radiation or drugs


• Inadequate immune responses (continued)– Age-related reductions in immune activity• T cells become less responsive

– Fewer cytotoxic T cells respond» Possibly related to thymus involution

• B cell response also less due to number of helper T cells reduced– Vaccinations highly recommended

• NK cells reduced and immune surveillance compromised– Increased incidence of cancer

CLINICAL MODULE 19.18 Review

a. Define autoimmune disorders.

b. Describe immunosuppression.

c. Provide a plausible explanation for the increased incidence of cancer in the elderly.

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