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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