Chapter 43: Internal Defense

Immune Response – fight antigens

• Nonspecific (innate)– general

• Specific (adaptive or acquired) – tailor made– Antibodies

Fig. 43-2

INNATE IMMUNITY

Recognition of traitsshared by broad rangesof pathogens, using asmall set of receptors

•

•Rapid response

•Recognition of traitsspecific to particularpathogens, using a vastarray of receptors

•Slower response

ACQUIRED IMMUNITY

Pathogens(microorganisms

and viruses)

Barrier defenses:SkinMucous membranesSecretions

Internal defenses:Phagocytic cellsAntimicrobial proteinsInflammatory responseNatural killer cells

Humoral response:Antibodies defend againstinfection in body fluids.

Cell-mediated response:Cytotoxic lymphocytes defendagainst infection in body cells.

Nonspecific defense

• Skin• Mucus membranes• Acid secretions / enzymes of stomach• Hairs in nose• Phagocytes

Cytokines – signaling molecules

• Interferons• Interleukins• Tumor necrosis factors

• Interferons– Secreted by cells infected with viruses, parasites– Produced by macrophages– Type I interferons

• Inhibit viral replication– Viruses exposed to Type I interferon can’t infect other cells as

well• Activate natural killer cells

– Type II interferons• Specific immune system• Enhance activities of other immune cells• Stimulate macrophages to destroy tumor cells and

virus-infected cells

• Interleukins– Secreted by macrophages and lymphocytes– Regulate actions between lymphocytes and other

body cells– Interleukin-1 can reset body’s thermostat in

hypothalamus resulting in fever

• Tumor necrosis factors (TNFs)– Secreted by macrophages and lymphocytes– Stimulate immune cells for inflammation– Kill tumor cells

Complement system• Complements actions of other defenses• 20+ proteins in body fluids• Inactive until body exposed to antigen• Sometimes activated directly OR by binding of antigen

to antibody• Nonspecific• 4 actions:

– Lyse pathogen cell wall– Coat pathogen (phagocytes can work more easily)– Attract WBCs to infected site– Increase inflammation by stimulating release of histamine

Phagocytosis

• Nonspecific• Phagocytes =

– neutrophils (~20 bacteria)– Macrophages (~100 bacteria)

• Endocytosis

Fig. 43-3

Microbes

PHAGOCYTIC CELL

Vacuole

Lysosomecontaining enzymes

Natural Killer (NK) Cells

• Large, granular lymphocytes• Bone marrow• Nonspecific and specific• Release cytokines and enzymes to destroy

target cells

Inflammation • Heat, redness, edema, pain• Regulated by plasma proteins, cytokines, platelet

substances, basophils, mast cells• Blood vessels dilate• Increase capillary permeability• Increase blood flow – lots neutrophils, phagocytes,

platelets, basophils, mast cells to infected area• Mast cells release histamine, serotonin• Increase blood flow skin warm, appears red• Phagocytes go out of capillaries to infected tissue

(phagocytosis)

• Edema – fluid and antibodies leave circulation to enter tissues

• Swelling = increased volume of fluid in area• Pain – from edema and action of enzymes in

plasma

Fig. 43-8-3

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary

Phagocytic cellRed blood cells

Fluid

Phagocytosis

Fever

• Body’s thermostat in hypothalamus reset• Higher temp. interferes with growth and

replication of some pathogens– Lysosomes break down, destroying cells infected

by viruses

• Increased temp. promotes T cell activity and production of antibodies

• Increased phagocytosis

Specific immune response

• 2 types– Antibody-mediated immunity– Cell-mediated immunity

Fig. 43-16

Humoral (antibody-mediated) immune response

B cell

Plasma cells

Cell-mediated immune response

Key

Stimulates

Gives rise to

+

+

++

+

+

+Memory B cells

Antigen (1st exposure)

Engulfed by

Antigen-presenting cell

MemoryHelper T cells

Helper T cell Cytotoxic T cell

MemoryCytotoxic T cells

ActiveCytotoxic T cells

Antigen (2nd exposure)

Secretedantibodies

Defend against extracellular pathogens by binding to antigens,thereby neutralizing pathogens or making them better targetsfor phagocytes and complement proteins.

Defend against intracellular pathogensand cancer by binding to and lysing theinfected cells or cancer cells.

+

+ +

Lymphocytes

• 3 types:– T cells– B Cells– NK cells

Natural Killer cells

• Kill virally infected and tumor cells

B cells• Antibody-mediated immunity• Mature into plasma cells (produce specific

antibodies)• Encode a receptor that binds to a specific

antigen– B cell receptors bind to antigen B cell activated– Divides rapidly differentiate into plasma cells

which produce antibody– Antibody binds to antigen that originally activated

B cells

• Some become memory B cells– Continue to make small amounts of antibody after

infection has been overcome

Fig. 43-19-3

Antigen-presenting cell Bacterium

Peptideantigen

Class II MHCmolecule

TCR CD4

Helper T cell

B cell

Activatedhelper T cell

Cytokines

+ Secretedantibodymolecules

Clone of memoryB cells

Clone of plasma cells

Fig. 43-14

B cells thatdiffer inantigen specificity

Antibodymolecules

Antigenreceptor

Antigen molecules

Clone of memory cells Clone of plasma cells

Role of B Cells Animation

T cells

• Cell-mediated immunity• “T” = thymus-derived• Thymus make T cells immunocompetent• In thymus – cells divided many times, develop

specific surface proteins with distinctive receptor sites

• Attack body cells infected by invading pathogens, foreign cells, cancer cells

• T cell antigen receptor (TCR)– Distinguishes T cells– Allows T cells to recognize specific antigens

• 2 main types– CD8 T cells (surface marker CD8)

• Cytotoxic T cells (killer T cells)• Recognize/destroy foreign antigens• Targets virus-infected cells, cancer cells, foreign tissue

grafts• Kill by releasing variety of cytokines and enzymes to lyse cells

Fig. 43-18-3

Cytotoxic T cell

Perforin

Granzymes

TCRCD8

Class I MHCmolecule

Targetcell

Peptideantigen

Pore

Released cytotoxic T cell

Dying target cell

– CD4 T cells (surface marker CD4)• Helper T cells• Secrete substances that activate or enhance immune

responses• 2 subsets

– T helper 1 – cell-mediated– T helper 2 – antibody- mediated : stimulate B cells divided and

produce antibodies

Fig. 43-17

Antigen-presentingcell

Peptide antigen

Cell-mediatedimmunity (attack on

infected cells)

Class II MHC moleculeCD4

TCR (T cell receptor)

Helper T cell

Humoralimmunity

(secretion ofantibodies byplasma cells) Cytotoxic T cell

Cytokines

B cell

Bacterium

+

+ +

+

Fig. 43-12

Infected cell

Antigenfragment

Class I MHCmolecule

T cellreceptor

(a)

Antigenassociateswith MHCmolecule

T cellrecognizescombination

Cytotoxic T cell (b) Helper T cell

T cellreceptor

Class II MHCmolecule

Antigenfragment

Antigen-presentingcell

Microbe

1

11

2

22

Major Histocompatibility complex

• MHC antigens – cell surface proteins – Help vertebrates distinguish self vs. nonself– Coded for by set of closely linked genes = Major

histocompatibility complex (MHC)• Humans MHC = HLA (human leukocyte antigen)• Polymorphic• Many combination not likely for people to have

same combo (except identical twins)

Antibody-mediated Immunity

• (humoral immunity)• B cells responsible

– Produce surface receptors– Bind to particular antigen– B cell activates

• Foreign antigen displayed on immune cell surface

• Contacts helper T cell (has complementary receptors)

• Macrophage secretes IL-1 – activated helper T cells

• (T cells do not recognize an antigen presented alone)

• Antibody receptor of B cell binds with complementary antigen

• Inside B cell – antigen degraded peptide fragments

• B cells display fragments on surface• Activated helper T binds with B cells• Activated helper T releases interleukins which,

with antigen, activate B cell• B cell increases in size mitosis• Each new cells makes antibodies specific to

antigen from original B cell

• Some cells of B cell clone plasma cells– Secrete antibody specific to antigen – Plasma cells do not leave lymph nodes– Antibodies can pass out of lymph tissue to

infected area

• Some B cells memory B cells– Live and make antibody after infection gone– Same pathogen enters later circulating

antibody targets it for destruction – Same time memory cells divided plasma

cells

Helper T Cell Activation

Fig. 43-9

Antigen-bindingsite

Antigen-binding site

Antigen-bindingsite

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

T cell

chain chain

Disulfide bridge

Cytoplasm of T cell

(b) T cell receptor

Cytoplasm of B cell

(a) B cell receptor

B cell

V

V

C C

V

V

C C C C

VV

Fig. 43-9a

Antigen-bindingsite

Antigen-binding site

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

Cytoplasm of B cell

(a) B cell receptor

B cell

V

V

C C

V

V

C C

Fig. 43-9b

Antigen-bindingsite

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

T cell

chain chain

Disulfide bridge

Cytoplasm of T cell

(b) T cell receptor

C C

VV

Antibodies

• (immunoglobulin, Ig)• 2 main functions

– Combines with antigen– Activate processes to destroy antigen

• Labels antigen for destruction• Doesn’t destroy antigen directly

Structure of Antibody

• 4 polypeptide chains– 2 identical long chains heavy chains– 2 identical short chains light chains

• Can bind with different affinities– During immune response, higher affinity

antibodies are made

Antigenic determinant

• Give antigen specific shape to be recognized by antibody

• Usually antigen has many different antigenic determinants– Many antibodies can bind to antigen

Fig. 43-10

Antigen-binding sites

Antigen-bindingsites

Epitopes(antigenicdeterminants)

Antigen

Antibody B

Antibody CAntibody A

CC

CV

V

V

V

C

5 Classes of Antibodies

• Unique AA sequences in heavy chain• 1. IgG – human ~ 75%

– Gamma globulin fraction of plasma– Interact with macrophages, activate complement

system

• 2. IgM– Interact with macrophages, activate complement

system– Defend against pathogens in blood

• 3. IgA– Mucus, tears, saliva, milk– Body openings

• 4. IgD– Low concentration in plasma– Helps activate B cells after antigen binding

• 5. IgE– Low concentration in plasma– Can bind to mast cells, cells with histamine

(allergy)– Parasitic worms

Fig. 43-20a

DistributionClass of Immuno-

globulin (Antibody)

IgM(pentamer)

J chain

First Ig classproduced afterinitial exposure toantigen; then itsconcentration inthe blood declines

Promotes neutraliza-tion and cross-linking of antigens;very effective incomplement systemactivation

Function

Fig. 43-20b

Distribution FunctionClass of Immuno-

globulin (Antibody)

IgG(monomer)

Most abundant Igclass in blood;also present intissue fluids

Promotes opsoniza-tion, neutralization,and cross-linking ofantigens; less effec-tive in activation ofcomplement systemthan IgM

Only Ig class thatcrosses placenta,thus conferringpassive immunityon fetus

Fig. 43-20c

Distribution FunctionClass of Immuno-

globulin (Antibody)

IgA(dimer)

J chain

Secretorycomponent

Present insecretions suchas tears, saliva,mucus, andbreast milk

Provides localizeddefense of mucousmembranes bycross-linking andneutralization ofantigens

Presence in breastmilk conferspassive immunityon nursing infant

Fig. 43-20d

Distribution FunctionClass of Immuno-

globulin (Antibody)

IgE(monomer)

Present in bloodat low concen-trations

Triggers release frommast cells andbasophils of hista-mine and otherchemicals that causeallergic reactions

Fig. 43-20e

Distribution FunctionClass of Immuno-

globulin (Antibody)

IgD(monomer)

Trans-membraneregion

Present primarilyon surface ofB cells that havenot been exposedto antigens

Acts as antigenreceptor in theantigen-stimulatedproliferation anddifferentiation ofB cells (clonalselection)

Antibody + Antigen activates other defense mechanisms

• 1. inactivate pathogen or its toxin– Ex: virus may not be able to attach to host

• 2. stimulates phagocytic cells to ingest the pathogen

• 3. complement proteins destroy pathogens– IgG and IgM Fc fragments bind to phagocytes for

destruction

Monoclonal Antibodies

• = identical antibodies produced by cells cloned from a single cell

• Steps:– Inject specific antigen into mice– Mice make antibodies– Collect mice B cells– Mix B cells (can only live in culture a few

generations) with lymphoma cells (can live in tissue culture indefinitely)

– Cells induced to fuse hybrid cells = hybridomas• Have properties of 2 parent cells• B cells – secrete antibodies• Cancer cells – cultured indefinitely

– Select hybrid cells making specific antibody• Clone them• Cells of clone make large amounts of specific antibody

Antibodies Animation

Cell – Mediated Immunity

• T cells and APCs responsible• T cells destroy virus-infected cells, altered cells

(cancer cells), foreign grafts• Steps:

– Virus invades body cells– Viral proteins displayed on cell surface of APC– T cells with specific receptor to that antigen become

activated– T cell grows in size clone of helper T cells, cytotoxic T

cells and memory T cells

– Cytotoxic T cells leave lymph nodes infected area

– Combine with antigen on target cell– Releases cytotoxic proteins to destroy cell– Disengages from target and seeks new one

Cytotoxic T Cells animation

Long-term Immunity and Immunological Memory

• Memory B and memory T cell responsible• Primary Response vs. Secondary Response

Primary Response• 1st exposure to antigen• 3-14 days for specific antibodies• Injection of antigen• Brief latent period antigen is recognized and

appropriated lymphocytes form clones• Logarithmic phase antibody concentration

rises rapidly for several days (mostly IgM)• Decline phase antibody concentration

decreases to very low level

Secondary Response• 2nd injection of same antigen• More rapid• Shorter latent period memory B and T cells already

bear antibodies to that antigen• Less antigen needed for response• More antibodies made with higher affinity (mostly IgG)• Why we don’t usually suffer same disease many times• No symptoms• Booster shots – elicit secondary response to reinforce

immunological memory

Active immunity• Developed after exposure to antigens• Naturally or artificially induced• Immunization - Exposed to vaccine

– Virus attenuated • Sabin polio, measles

– Killed pathogens ( still have antigens)• Whooping cough, Typhoid fever

– Toxins from pathogens (altered so no destruction, same antigens)

• Tetanus, botulism

Passive Immunity

• Individual is given antibodies actively produced by another organism

• “borrowed immunity” – effects don’t last– Used to boost body’s defense temporarily

• Natural passive immunity– Mom baby– Through placenta– Until baby’s own immune system matures– IgA in breast milk

Cancer• Precancer cells – different surface proteins

(antigens) • Dendritic cells recognize, present cancer antigen

to T cells• T cell activates clone cytotoxic T cells, make

interleukins to attract macrophages and NK cells• Cytotoxic T cells make interferons for antitumor

effect• Macrophages make TNF to inhibit tumor growth

Graft Rejection and Transplants

• MHC antigens same only for identical twins• Hard to find matches because so many

possibilities for MHC antigens• Graft rejection – immune response against a

foreign graft/transplant– T cells attack transplanted tissue, destroy in a week

• To prevent rejection– Drugs – suppress immune system

• Xenotransplantation – process to transplant animal parts to humans– Genetic engineered pigs– Artificial organs

Allergic reactions

• Hypersensitivity results in the manufacture of antibodies against mild antigens, called allergens, that normally do not stimulate an immune response

• Ex: dust mites, pollen

Common allergic reaction:Ex: hayfever to ragweed pollen

• Sensitization• Activation of mast cells• Allergic response prolonged (maybe)

Sensitization

• Macrophages degrade allergen, present fragments of it to T cells

• Activated T cells stimulate B cells into plasma cells and produce IgE

• IgE antibodies attach to receptors on mast cells (at C region – V region is left open to attach to allergen)

Activation of Mast cells

• Allergens attach to IgE on mast cells stimulating mast cells to release histamine and serotonin that cause inflammation

• Blood vessels dilate• Capillaries more permeable edema, red• Nasal passages swollen, irritated• Noses run, sneeze, eyes water

Allergic response is prolonged (maybe)

• Chemical from mast cells lure certain WBCs to inflamed area

• WBCs release compounds that damage tissue and prolong reaction

Fig. 43-23

Allergen

IgE

Granule

Mast cell

Histamine

Hives

• Allergen/IgE reaction happens in skin• Histamine released by mast cells causes

swollen red welts (hives)

Systemic anaphylaxis

• Dangerous allergic reaction that can occur when a person develops an allergy to a specific drug, venom or food

• In minutes widespread reaction• Mast cells give off much histamine

vasodilation and permeability• So much plasma may be last from blood that

circulatory shock and death can occur in minutes

Antihistamines

• Drugs that block the effects of histamines• Compete for same receptors on target cells as

histamine• Not totally effective because mast cells

release substances other than histamine for reaction

Autoimmunity

• T cells react immunologically against self• Ex:

– Rheumatoid arthritis– Multiple sclerosis– Systemic lupus erythematosus– Insulin-dependent diabetes– Psoriasis– Scleroderma