Chapter 43

Chapter 43

The Body’s Defenses

(The Immune System)

Reconnaissance, Recognition, and Response

• The immune system recognizes foreign bodies and responds with the production of immune cells and proteins

• Innate immunity- is present before any exposure to pathogens and is a nonspecific responses to pathogens and consists of external barriers plus internal cellular and chemical defenses

• Acquired immunity- develops after exposure to agents such as microbes, toxins, or other foreign substances. It involves a very specific response to pathogens

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.

Innate Immunity-Barrier Defenses

• Include the skin and mucous membranes of the respiratory, urinary, and reproductive tracts

• Mucus traps and allows for the removal of microbes

• The low pH of skin and the digestive system prevents growth of microbes

Innate Immunity-Cellular Innate Defenses

• White blood cells (leukocytes) engulf pathogens in the body

• A white blood cell engulfs a microbe, then fuses with a lysosome to destroy the microbe

• Macrophages are part of the lymphatic system and are found throughout the body

• Types of white blood cells:

– Neutrophil

– Eosinophil

– Basophil

– Lymphocyte(natural-killer cells, T cells, B cells)

– Monocytes

– Macrophages

– Dendritic cells

Adenoid

Tonsil

Lymphnodes

Spleen

Peyer’s patches(small intestine)

Appendix

Lymphaticvessels Lymph

nodeMasses ofdefensive cells

Bloodcapillary

Lymphaticvessel

Tissuecells

Interstitial fluid

Innate Immunity-Antimicrobial Proteins

• Attack microbes directly or impede their reproduction

• Interferon proteins provide defense against viruses and helps activate macrophages

Innate Immunity-Inflammatory Responses

• Following an injury, mast cells release histamine, which promotes changes in blood vessels; this is part of the inflammatory response

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary

Phagocytic cellRed blood cells

Innate Immunity-Inflammatory Responses

• Increases local blood supply and allow more phagocytes and antimicrobial proteins to enter tissues

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary

Phagocytic cellRed blood cells

Fluid

Innate Immunity-Inflammatory Responses

• Pus- a fluid rich in white blood cells, dead microbes, and cell debris, accumulates at the site of inflammation

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary

Phagocytic cellRed blood cells

Fluid

Phagocytosis

Innate Immunity-Natural Killer Cells

• All cells in the body (except red blood cells) have a class 1 MHC (major histocompatibility) protein on their surface

• Cancerous or infected cells no longer express this protein; natural killer (NK) cells attack these damaged cells, causing them to lyse

Innate Immune System Evasion by Pathogens

• Some pathogens avoid destruction by modifying their surface to prevent recognition or by resisting breakdown following phagocytosis

• Example: Tuberculosis (TB), kills more than a million people a year

Acquired immunity, lymphocyte receptors provide pathogen-specific recognition

• White blood cells (lymphocytes) recognize and respond to antigens, foreign molecules

• Lymphocytes that mature in the thymus are called T cells, and those that mature in bone marrow are called B cells

• Lymphocytes have an enhanced response to a foreign molecule encountered previously

• B cells and T cells have receptor proteins that can bind to foreign molecules

• Each individual lymphocyte is specialized to recognize a specific type of molecule

• Cytokines are secreted by macrophages and dendritic cells to recruit and activate lymphocytes

Antigen Recognition by Lymphocytes

• A single B cell or T cell has about 100,000 identical antigen receptors

Antigen-bindingsite

Antigen-binding site

Antigen-bindingsite

Disulfidebridge

VariableregionsConstantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

T cell

chain chainDisulfide bridge

Cytoplasm of T cell

(b) T cell receptor

Cytoplasm of B cell

(a) B cell receptor

B cell

VV

C C

VV

C C C C

VV

Antigen-bindingsite

Antigen-binding site

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

Cytoplasm of B cell

(a) B cell receptor

B cell

VV

C C

VV

C C

Antigen-bindingsite

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

T cell

chain chainDisulfide bridge

Cytoplasm of T cell

(b) T cell receptor

C C

VV

• All antigen receptors on a single lymphocyte recognize the same epitope, or antigenic determinant, on an antigen

Antigen-binding sites

Antigen-bindingsites

Epitopes(antigenicdeterminants)

Antigen

Antibody B

Antibody CAntibody A

CC

CV

V

VV

C

• B cells give rise to plasma cells, which secrete proteins called antibodies or immunoglobulins

Antigen-binding sites

Antigen-bindingsites

Epitopes(antigenicdeterminants)

Antigen

Antibody B

Antibody CAntibody A

CC

CV

V

VV

C

Antigen-bindingsite

Antigen-binding site

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

Cytoplasm of B cell

(a) B cell receptor

B cell

VV

C C

VV

C C

• B cell receptors bind to specific, intact antigens

Antigen-bindingsite

Antigen-binding site

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

Cytoplasm of B cell

(a) B cell receptor

B cell

VV

C C

VV

C C

• Secreted antibodies (immunoglobulins) are free floating B cell receptors

Antigen-bindingsite

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

T cell

chain chainDisulfide bridge

Cytoplasm of T cell

(b) T cell receptor

C C

VV

• T cells can bind to an antigen that is free or on the surface of a pathogen molecules

Antigen-bindingsite

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

T cell

chain chainDisulfide bridge

Cytoplasm of T cell

(b) T cell receptor

C C

VV

• T cells bind to antigen fragments presented on a host cell-surface proteins- MHC

The Role of the MHC

• In infected cells, MHC molecules bind and transport antigen fragments to the cell surface, a process called antigen presentation

• A nearby T cell can then detect the antigen fragment displayed on the cell’s surface

Antigen

Top view: binding surfaceexposed to antigen receptors

Plasmamembrane ofinfected cell

AntigenClass I MHCmolecule

Class I MHC molecules- display peptide antigens to cytotoxic T cells

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

Microbe1

11

22 2

Class II MHC molecules- located on dendritic cells, macrophages, and B cells. These are antigen-presenting cells that display antigens to cytotoxic T cells and helper T cells

Lymphocyte Development

Origin of Self-Tolerance• As lymphocytes mature in bone marrow or

the thymus, they are tested for self-reactivity and destroyed if they test positive

Amplifying Lymphocytes by Clonal Selection• The binding of a lymphocyte to an antigen induces

the lymphocyte to divide rapidly- clonal selection• Two types of clones are produced: short-lived

activated effector cells and long-lived memory cells

B cells thatdiffer inantigen specificity

Antibodymolecules

Antigenreceptor

Antigen molecules

Clone of memory cells Clone of plasma cells

• The first exposure to a specific antigen represents the primary immune response

• During this time, effector B cells called plasma cells are generated, and T cells are activated to their effector forms

• In the secondary immune response, memory cells facilitate a faster, more efficient response

Animation: Role of B Cells

Primary vs Secondary immune response

Antibodiesto A Antibodies

to B

Secondary immune response toantigen A produces antibodies to A;primary immune response to antigenB produces antibodies to B.

Primary immune responseto antigen A producesantibodies to A.

Ant

ibod

y co

ncen

trat

ion

(arb

itrar

y un

its)

Exposureto antigen A

Exposure toantigens A and BTime (days)

104

103

102

101

100

0 7 14 21 28 35 42 49 56

Acquired immunity defends against infection of body cells and fluids

• Humoral immune response (extracellular pathogens) involves activation and clonal selection of B cells, resulting in production of secreted antibodies

• Cell-mediated immune response (intercellular pathogens and cancer) involves activation and clonal selection of cytotoxic T cells

• Helper T cells aid both responses

Humoral (antibody-mediated) immune response

B cell

Plasma cells

Cell-mediated immune response

Key

StimulatesGives 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.

+

+ +

Helper T Cells: A Response to Nearly All Antigens

• A surface protein called CD4 binds the class II MHC molecule

• This binding keeps the helper T cell joined to the antigen-presenting cell while activation occurs

• Activated helper T cells secrete cytokines that stimulate other lymphocytes

Animation: Helper T Cells

Antigen-presentingcell

Peptide antigen

Cell-mediatedimmunity (attack on

infected cells)

Class II MHC moleculeCD4TCR (T cell receptor)

Helper T cell

Humoralimmunity

(secretion ofantibodies byplasma cells) Cytotoxic T cell

Cytokines

B cell

Bacterium

+

+ +

+

Cytotoxic T Cells: A Response to Infected Cells

• Cytotoxic T cells are the effector cells in cell-mediated immune response

• Binding to a class I MHC complex on an infected cell activates a cytotoxic T cell and makes it an active killer

• The activated cytotoxic T cell secretes proteins that destroy the infected target cell

Animation: Cytotoxic T Cells

Cytotoxic T cell

PerforinGranzymes

TCRCD8

Class I MHCmolecule

Targetcell

Peptideantigen

Pore

Released cytotoxic T cell

Dying target cell

B Cells: A Response to Extracellular Pathogens

• The humoral response is characterized by secretion of antibodies by B cells

• Activation of B cells is aided by cytokines and antigen binding to helper T cells

• Clonal selection of B cells generates antibody-secreting plasma cells, the effector cells of humoral immunity

Antigen-presenting cell

Endoplasmicreticulum ofplasma cell

Secretedantibodymolecules

Bacterium

B cellPeptideantigen

Class II MHCmolecule

TCR CD4

Helper T cellActivatedhelper T cell

Cytokines

Clone of memoryB cells

Clone of plasma cells

2 µm

+

5 Antibody Classes

• Polyclonal antibodies are the products of many different clones of B cells following exposure to a microbial antigen

• Monoclonal antibodies are prepared from a single clone of B cells grown in culture

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

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

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

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

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)

The Role of Antibodies in Immunity

• Neutralization- a pathogen can no longer infect a host because it is bound to an antibody

• Agglutination- clumping of bound antibodies to antigens increase phagocytosis

• Complement system- antibodies and proteins generate a membrane attack to lyse a cell

Animation: Antibodies

Viral neutralization

Virus

Opsonization

Bacterium

Macrophage

Activation of complement system and pore formation

Complement proteins

Formation ofmembraneattack complex

Flow of waterand ions

Pore

Foreigncell

Active and Passive Immunization

• Active immunity- develops in response to an infection or immunization (vaccination)

• Immunization- a nonpathogenic form or part of a microbe elicits an immune response to an immunological memory

• It is conferred naturally when IgG crosses the placenta from mother to fetus or when IgA passes from mother to infant in breast milk

• It can be conferred artificially by injecting antibodies into a nonimmune person

Passive immunity provides immediate, short-term protection

Immune Rejection

• Cells transferred from one person to another can be attacked by immune defenses

Blood Groups• Antigens on red blood cells determine whether a

person has blood type A (A antigen), B (B antigen), AB (both A and B antigens), or O (neither antigen)

• Antibodies to nonself blood types exist in the body

• Transfusion with incompatible blood leads to destruction of the transfused cells

Tissue and Organ Transplants

• MHC molecules are different among people

• Differences in MHC molecules stimulate rejection of tissue grafts and organ transplants

• Chances of successful transplantation increase if donor and recipient MHC tissue types are well matched

• Immunosuppressive drugs facilitate transplantation

Exaggerated, Self-Directed, and Diminished Immune ResponsesAllergies

• Allergies are exaggerated (hypersensitive) responses to antigens called allergens

• Allergies such as hay fever, IgE antibodies produced after first exposure to an allergen attach to receptors on mast cells

Allergen

IgE

GranuleMast cell

Histamine

The next time the allergen enters the body mast cells release histamine leading to typical allergy symptoms

An acute allergic response can lead to anaphylactic shock within seconds of allergen exposure

Autoimmune Diseases

• The immune system loses tolerance for self and turns against certain molecules of the body

• Examples: systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, and multiple sclerosis

Exertion, Stress, and the Immune System

• Moderate exercise improves immune system function

• Psychological stress has been shown to disrupt hormonal, nervous, and immune systems

Immunodeficiency Diseases

• Inborn immunodeficiency results from hereditary or developmental defects that prevent proper functioning of innate, humoral, and/or cell-mediated defenses

• Acquired immunodeficiency results from exposure to chemical and biological agents

• Acquired immunodeficiency syndrome (AIDS) is caused by a virus

Acquired Immune System Evasion by Pathogens

• Pathogens have evolved mechanisms to attack immune responses

Antigenic Variation

• Pathogens are able to change epitope expression and prevent recognition

• The human influenza virus mutates rapidly, and new flu vaccines must be made each year

Latency

• Some viruses may remain in a host in an inactive state

• Herpes simplex viruses can be present in a human host without causing symptoms

Attack on the Immune System: HIV

• Human immunodeficiency virus (HIV) infects helper T cells

• The loss of helper T cells impairs both the humoral and cell-mediated immune responses and leads to AIDS

• HIV uses antigenic variation and latency while integrated into host DNA

Animation: HIV Reproductive Cycle

Latency

Relative antibodyconcentration

AIDSH

elpe

r T c

ell c

once

ntra

tion

in b

lood

(cel

ls/m

m3 )

Helper T cellconcentration

Relative HIVconcentration

Years after untreated infection0 1 2 3 4 5 6 7 8 9 10

0

200

400

600

800

Cancer and Immunity

• The frequency of certain cancers increases when the immune response is impaired

• Two suggested explanations are

– Immune system normally suppresses cancerous cells

– Increased inflammation increases the risk of cancer