Topic Number Eleven

The Immune System

The Immune system1. Innate Immunity: Nonspecific Defenses

Defenses against any pathogen

It does not confer long-lasting or protective immunity to the host

2. Adaptive immunity: Specific Defenses

Immunity, resistance to a specific pathogen.

1. First Line of Defense: Non-specific natural barriers which restrict entry of pathogen.

Examples: Skin and mucous membranes.

2. Second Line of Defense: Innate non-specific immune defenses provide rapid local response to pathogen after it has entered host.

Examples: Fever, phagocytes (macrophages and neutrophils), inflammation, and interferon.

3. Third line of defense: Antigen-specific immune responses, specifically target and attack invaders that get past first two lines of defense.

Examples: Antibodies and lymphocytes.

Three Lines of Defense Against Infection

Three Lines of Defense Against Infection

First Line of Defense:1. Skin

Intact skin, keratin (waterproof), form physical barriers that prevent the entry of microorganisms and viruses

Secretions from the skin

Sebum: Oily substance produced by sebaceous glands that forms a protective layer over skin. Contains unsaturated fatty acids which inhibit growth of certain pathogenic bacteria and fungi

Also include proteins such as lysozyme, an enzyme that digests the cell walls of many bacteria

Infections are rare in intact skin. Exceptions:

Hookworms can penetrate intact skin

Dermatophytes: “Skin loving” fungi

Normal microbiota compete with pathogens.

2. Mucous membranes

Saliva: Washes microbes from teeth and mouth mucous membranes.

Mucus: Thick secretion that traps many microbes.

Urination: Cleanses urethra.

Vaginal Secretions: Remove microbes from genital tract.

II. Second Line of Defense

1. Phagocytosis

Phagocytosis is carried out by white blood cells: macrophages, neutrophils, and occasionally eosinophils.

Wandering macrophages: Originate from monocytes that leave blood and enter infected tissue, and develop into phagocytic cells.

Fixed Macrophages (Histiocytes): Located in liver, nervous system, lungs, lymph nodes, bone marrow, and several other tissues.

Process of Phagocytosis

Antimicrobial Proteins1. The complement system

About 30 serum proteins activated in a cascade

Effects of Complement Activation

1.Opsonisation - enhancing phagocytosis of antigens

2.Chemotaxis - attracting macrophages and neutrophils

3.Cell Lysis - rupturing membranes of foreign cells

4.Clumping of antigen-bearing agents

Effects of Complement Activation

II. Interferons: Antiviral proteins that interfere with viral multiplication.

–Have no effect on infected cells.

–Host specific, but not virus specific.

Interferon alpha and beta: Produced by virus infected cells and diffuse to neighboring cells. Cause uninfected cells to produce antiviral proteins (AVPs).

Interferon gamma: Produced by lymphocytes. Causes neutrophils to kill bacteria.

Interferons (IFNs)

Inflammatory Response

Promote changes in blood vessels that allow more fluid, more phagocytes, and antimicrobial proteins to enter the tissues

Functions of Inflammation

1. Destroy and remove pathogens

2. If destruction is not possible, to limit effects by confining the pathogen and its products.

3. Repair and replace tissue damaged by pathogen and its products.

Major events in the local inflammatory responsePathogen Pin

Macrophage

Chemical signals

Capillary

Phagocytic cells

Red blood cell

Bloodclottingelements

Blood clot

Phagocytosis

Fluid, antimicrobial proteins, and clotting elements move from the blood to the site.Clotting begins.

2Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable.

1Chemokines released by various kinds of cells attract more phagocytic cells from the bloodto the injury site.

3 Neutrophils and macrophagesphagocytose pathogens and cell debris at the site, and the tissue heals.

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Adaptive Immunity: Specific Defenses of the Host

Third line of defense. Involves production of antibodies and generation of specialized lymphocytes against specific antigens

Terminology

Antigen (Ag): is any foreign molecule That is specifically recognized by lymphocytes and elicits a response from them

Antibody (Ab): Proteins made in response to an Ag; can combine with that Ag.

Complement: Serum proteins that bind to Ab in an Ag–Ab reaction; cause cell lysis

Antigenic Determinants

Antibodies recognize and react with antigenic determinants or epitopes on an antigen

Haptens

Haptens. A hapten is a molecule too small to stimulate antibody formation by itself. However. when the hapten is combined with a larger carrier molecule. usually a serum protein. the hapten and its carrier together form a conjugate that can stimulate an immune response.

Antibody Structure

The five classes of immunoglobulins

Lymphocytes

The vertebrate body is populated by two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells)

The plasma membranes of both B cells and T cells have about 100,000 antigen receptor that all recognize the same epitope

Lymphocyte Development

Arise from stem cells in the bone marrow

But they later develop into B cells or T cells, depending on where they continue their maturation

Bone marrow

Lymphoidstem cell

B cell

Blood, lymph, and lymphoid tissues(lymph nodes, spleen, and others)

T cell

Thymus

T Cell Receptors

V V

C C

The antigen receptors on B cells are called B cell receptors (or membrane immunoglobulins) and the antigen receptors on T cells are called T cell receptors

MHC

MHC molecules : Are encoded by a family of genes called the major histocompatibility complex and function in signaling between lymphocytes and cells expressing antigen.

Infected cells produce MHC molecules which bind to antigen fragments and then are transported to the cell surface in a process called antigen presentation

Infected cell

Antigenfragment

Class I MHCmolecule

T cellreceptor

(a) Cytotoxic T cell

A fragment offoreign protein(antigen) inside thecell associates withan MHC moleculeand is transportedto the cell surface.

1

The combination ofMHC molecule andantigen is recognizedby a T cell, alerting itto the infection.

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1

2

Class I MHC molecules, found on almost all uncleated cells of the body

Display peptide antigens to cytotoxic T cells

Class II MHC molecules, located mainly on dendritic cells (antigen-presenting cells), macrophages, and B cells

Display antigens to helper T cells

1

2

Microbe Antigen-presentingcell

Antigenfragment

Class II MHCmolecule

T cellreceptor

Helper T cell

A fragment offoreign protein(antigen) inside thecell associates withan MHC moleculeand is transportedto the cell surface.

1

The combination ofMHC molecule andantigen is recognizedby a T cell, alerting itto the infection.

2

(b)

Clonal selection theory

States that each lymphocyte has membrane-bound immunoglobulin receptors specific for a particular antigen and after the receptor is engaged, a clone of antibody-producing cells (plasma cell) and memory cells are produced. In the secondary immune response memory cells facilitate a faster, more efficient response

An

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con

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(arb

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nits

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104

103

102

101

100

0 7 14 21 28 35 42 49 56Time (days)

Antibodiesto A

Antibodiesto B

Primaryresponse toantigen Aproduces anti-bodies to A

2Day 1: First exposure toantigen A

1 Day 28: Second exposureto antigen A; firstexposure to antigen B

3 Secondary response to anti-gen A produces antibodiesto A; primary response to anti-gen B produces antibodies to B

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Clonal selection theory (Continued)

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3

B cell

Bacterium

Peptide antigen

Class II MHCmolecule

TCR

Helper T cell

CD4

Activated helper T cell Clone of memory

B cells

Cytokines

Clone of plasma cellsSecreted antibodymolecules

Endoplasmicreticulum of plasma cell

Macrophage

After a macrophage engulfs and degradesa bacterium, it displays a peptide antigencomplexed with a class II MHC molecule.A helper T cell that recognizes the displayed complex is activated with the aid of cytokines secreted from the macrophage, forming a clone of activated helper T cells (not shown).

1 A B cell that has taken up and degraded the same bacterium displays class II MHC–peptide antigen complexes. An activated helper T cellbearing receptors specific for the displayedantigen binds to the B cell. This interaction,with the aid of cytokines from the T cell,activates the B cell.

2 The activated B cell proliferatesand differentiates into memoryB cells and antibody-secreting plasma cells. The secreted antibodies are specific for the same bacterial antigen that initiated the response.

3

Figure 43.17

Humoral and cell-mediated immunity

The humoral immune response involves the activation and clonal selection of B cells, resulting in the production of secreted antibodies

The cell-mediated immune response involves the activation and clonal selection of cytotoxic T cells

Humoral immune response Cell-mediated immune response

First exposure to antigen

Intact antigensAntigens engulfed and

displayed by dendritic cellsAntigens displayed

by infected cells

Activate Activate Activate

Gives rise to Gives rise to Gives rise to

B cellHelperT cell

CytotoxicT cell

Plasmacells

MemoryB cells

Active and memory helperT cells

Memory cytotoxic

T cells

Active cytotoxic

T cells

Secrete antibodies that defend againstpathogens and toxins in extracellular fluid

Defend against infected cells, cancer cells, and transplanted tissues

Secretedcytokinesactivate

The role of helper T cells in acquired immunity

Helper T cells produce CD4, a surface protein that enhances their binding to class II MHC molecule–antigen complexes on antigen-presenting cells

Activation of the helper T cell then occurs

Activated helper T cells secrete several different cytokines that stimulate other lymphocytes

After a dendritic cell engulfs and degrades a bacterium, it displays bacterial antigen fragments (peptides) complexed with a class II MHC molecule on the cell surface. A specific helper T cell binds to the displayed complex via its TCR with the aid of CD4. This interaction promotes secretion of cytokines by the dendritic cell.

Proliferation of the T cell, stimulatedby cytokines from both the dendritic cell and the T cell itself, gives rise toa clone of activated helper T cells(not shown), all with receptors for thesame MHC–antigen complex.

The cells in this clonesecrete other cytokines that help activate B cellsand cytotoxic T cells.

Cell-mediatedimmunity(attack on

infected cells)

Humoralimmunity

(secretion ofantibodies byplasma cells)

Dendriticcell

Dendriticcell

Bacterium

Peptide antigen

Class II MHCmolecule

TCR

CD4

Helper T cell

Cytokines

Cytotoxic T cell

B cell

1

2 3

1

2 3

Cytotoxic T cells

Bind to infected cells, cancer cells, and transplanted tissues

Binding to a class I MHC complex on an infected body cell

Activates a cytotoxic T cell and differentiates it into an active killer

Cytotoxic T cell

Perforin

Granzymes

CD8TCR

Class I MHCmolecule

Targetcell Peptide

antigen

Pore

ReleasedcytotoxicT cell

Apoptotictarget cell

Cancercell

CytotoxicT cell

A specific cytotoxic T cell binds to a class I MHC–antigen complex on a target cell via its TCR with the aid of CD8. This interaction, along with cytokines from helper T cells, leads to the activation of the cytotoxic cell.

1The activated T cell releases perforin molecules, which form pores in the target cell membrane, and proteolytic enzymes (granzymes), which enter the target cell by endocytosis.

2The granzymes initiate apoptosis within the target cells, leading to fragmentation of thenucleus, release of small apoptotic bodies, and eventual cell death. The released cytotoxic T cell can attack other target cells.

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The Results of Ag-Ab Binding

Binding of antibodies to antigensinactivates antigens by

Viral neutralization(blocks binding to host)

and opsonization (increasesphagocytosis)

Agglutination ofantigen-bearing particles,

such as microbes

Precipitation ofsoluble antigens

Activation of complement systemand pore formation

Bacterium

Virus Bacteria

Solubleantigens Foreign cell

Complementproteins

MAC

Pore

Enhances

Phagocytosis

Leads to

Cell lysis

Macrophage

Active and Passive Immunization

Active immunity: Develops naturally in response to an infection

Can also develop following immunization, also called vaccination

Passive immunity: Provides immediate, short-term protection

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

Can be conferred artificially by injecting antibodies into a nonimmune person

The allergic response

IgE antibodies produced in response to initial exposure to an allergen bind to receptors or mast cells.

1 On subsequent exposure to the same allergen, IgE molecules attached to a mast cell recog-nize and bind the allergen.

2 Degranulation of the cell,triggered by cross-linking of adjacent IgE molecules, releases histamine and other chemicals, leading to allergysymptoms.

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2

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Allergen

IgE

Histamine

Granule

Mast cell