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Antibodies

Immunoglobulins

Gamma globulin part of blood proteins

Produced by activated B cells/plasma cells in


response to specific antigen

Five classes of antibodies:

IgM, IgA, IgD, IgE, IgG

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Classes of Antibodies

IgM

A pentamer; first antibody released

Potent agglutinating agent

Readily fixes and activates complement

IgA (secretory IgA)

Monomer or dimer; in mucus and other secretions

Helps prevent entry of pathogens

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Copyright 2006 Pearson Education, Inc., publishing as Benjamin Cummings

Table 21.3

Classes of Antibodies

IgD

Monomer attached to the surface of B cells

Functions as a B cell receptor

IgG

Monomer; 7585% of antibodies in plasma

From secondary and late primary responses

Crosses the placental barrier

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Classes of Antibodies

IgE

Monomer active in some allergies and parasitic


infections

Causes mast cells and basophils to release


histamine

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Table 21.3

Basic Antibody Structure

Consists of four looping polypeptide chains linked


together with disulfide bonds

Two identical heavy (H) chains and two identical


light (L) chains

The four chains bound together form an antibody


monomer

Each chain has a variable (V) region at one end


and a constant (C) region at the other

Variable regions of the heavy and light chains


combine to form the antigen-binding site

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Antigen-binding
site

Heavy chain
variable region
Heavy chain
constant region
Light chain
variable region
Light chain
constant region
Disulfide bond

Hinge
region
Stem
region

(a)

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Figure 21.14a

Antibody Structure

Antibodies responding to different antigens have


different V regions but the C region is the same for
all antibodies in a given class

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Antibody Structure

C regions form the stem of the Y-shaped antibody


and:

Determine the class of the antibody

Serve common functions in all antibodies

Dictate the cells and chemicals that the antibody


can bind to

Determine how the antibody class will function in


elimination of antigens

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Mechanisms of Antibody Diversity

Plasma cells make over a billion types of


antibodies

However, each cell only contains 100,000 genes


that code for these polypeptides

To code for this many antibodies, somatic


recombination takes place:

Gene segments are shuffled and combined in


different ways by each B cell as it becomes
immunocompetent

Information of the newly assembled genes is


expressed as B cell receptors and as antibodies

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Antibody Diversity

Random mixing of gene segments makes unique


antibody genes that:

Code for H and L chains

Account for part of the variability in antibodies

V gene segments, called hypervariable regions,


mutate and increase antibody variation

Plasma cells can switch H chains, making two or


more classes with the same V region

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Antibody Targets

Antibodies do not destroy antigen; they inactivate


and tag it for destruction

Form antigen-antibody (immune) complexes

Ab mechanisms:

Neutralization

Agglutination

Precipitation

Complement fixation

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Adaptive defenses

Humoral immunity
Antigen

Antigen-antibody
complex

Antibody

Inactivates by
Neutralization
(masks dangerous
parts of bacterial
exotoxins; viruses)

Agglutination
(cell-bound antigens)

Enhances

Fixes and activates


Precipitation
(soluble antigens)

Enhances

Phagocytosis

Complement

Leads to

Inflammation

Cell lysis

Chemotaxis

Histamine
release

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Figure 21.15

Monoclonal Antibodies

Commercially prepared antibodies are used:

To provide passive immunity

In research, clinical testing, and cancer treatment

Monoclonal antibodies are pure antibody


preparations

Specific for a single antigenic determinant

Produced from descendents of a single cell

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Monoclonal Antibodies

Hybridomas cell hybrids made from a fusion of a


tumor cell and a B cell

Have desirable properties of both parent cells


indefinite proliferation as well as the ability to
produce a single type of antibody

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Cell-Mediated Immune Response

Only respond to processed ag usually presented


on cell surface; Must recognize both ag & MHC to
respond

Types:

CD4 cells ; helper T cells (TH)

CD8 cells ; cytotoxic T cells (TC)

Suppressor T cells (TS) or T regulatory

Memory T cells

Many more subtypes that are relatively < numbers

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Importance of Cellular Response

T cells are best suited for cell-to-cell interactions,


and target:

Cells infected with viruses, bacteria, or


intracellular parasites

Abnormal or cancerous cells

Cells of infused or transplanted foreign tissue

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Adaptive defenses

Cellular immunity
Immature
lymphocyte
Red bone marrow

T cell
receptor
Class II MHC
protein

T cell
receptor

Maturation

CD4
cell

Thymus
Activation

APC
(dendritic cell)

Class I MHC
protein

CD8
cell
Activation

Memory
cells
CD4

APC
(dendritic cell)
CD8

Lymphoid
tissues and
organs

Helper T cells
(or regulatory T cells)

Effector
cells
Blood plasma

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Cytotoxic T cells

Figure 21.16

Comparison of Humoral and Cell-Mediated


Response

Antibodies of the humoral response

The simplest ammunition of the immune response

Targets

Bacteria and molecules in extracellular


environments (body secretions, tissue fluid, blood,
and lymph)

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Comparison of Humoral and Cell-Mediated


Response

T cells of the cell-mediated response

Recognize and respond only to processed fragments


of antigen displayed on the surface of body cells

Targets

Body cells infected by viruses or bacteria

Abnormal or cancerous cells

Cells of infused or transplanted foreign tissue

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Antigen Recognition

Immunocompetent T cells are activated when their


surface receptors bind to a recognized antigen
(nonself)

T cells must simultaneously recognize

Nonself (the antigen)

Self (an MHC protein of a body cell)

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MHC Proteins

Two types of MHC proteins are important to T cell


activation

Class I MHC proteins - displayed by all cells except


RBCs

Class II MHC proteins displayed by APCs


(dendritic cells, macrophages and B cells)

Both types are synthesized at the ER and bind to


peptide fragments

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Class I MHC Proteins

Bind with fragment of a protein synthesized in the


cell (endogenous antigen)

Endogenous antigen is a self-antigen in a normal


cell; a nonself antigen in an infected or abnormal
cell

Informs cytotoxic T cells of the presence of


microorganisms hiding in cells (cytotoxic T cells
ignore displayed self-antigens)

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Cytoplasm of any tissue cell


2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.

Endogenous antigen
self-protein or foreign
(viral or cancer) protein

Cisternae of
endoplasmic
reticulum (ER)
3 Endogenous
antigen peptide is
loaded onto class
I MHC protein.
4 Loaded MHC protein
migrates in vesicle to
the plasma membrane,
where it displays the
antigenic peptide.

Transport
protein
(ATPase)

Plasma membrane of a tissue cell

Antigenic peptide

Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.

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Figure 21.17a

Class II MHC Proteins

Bind with fragments of exogenous antigens that


have been engulfed and broken down in a
phagolysosome

Recognized by helper T cells

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Cytoplasm of APC

1a

Class II MHC is
synthesized in ER.

Invariant chain
prevents class II
MHC from binding
to peptides in the ER.

Vesicle fuses with


phagolysosome. Invariant
chain is removed, and
antigen is loaded.

2a

Cisternae of
endoplasmic
Phagosome
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.

Class II MHC
is exported
from ER in a
vesicle.

2b

Phagosome merges
with lysosome, forming
a phagolysosome;
antigen is degraded.

Extracellular
antigen
Extracellular fluid

Lysosome

Plasma membrane of APC

Vesicle with
loaded MHC
migrates to the
plasma
membrane.

Antigenic peptide

(b) Exogenous antigens are processed and displayed on class II MHC of


antigen-presenting cells (APCs).
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Figure 21.17b

T Cell Activation

APCs (most often a dendritic cell) migrate to


lymph nodes and other lymphoid tissues to
present their antigens to T cells

T cell activation is a two-step process


1.

Antigen binding

2.

Co-stimulation

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T Cell Activation: Antigen Binding

CD4 and CD8 cells bind to different classes of


MHC proteins (MHC restriction)

CD4 cells bind to antigen linked to class II MHC


proteins of APCs

CD8 cells are activated by antigen fragments


linked to class I MHC of APCs

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T Cell Activation: Antigen Binding

Dendritic cells are able to obtain other cells


endogenous antigens by

Engulfing dying virus-infected or tumor cells


Importing antigens through temporary gap junctions
with infected cells

Dendritic cells then display the endogenous


antigens on both class I and class II MHCs

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T Cell Activation: Antigen Binding

TCR that recognizes the nonself-self complex is


linked to multiple intracellular signaling pathways

Other T cell surface proteins are involved in


antigen binding (e.g., CD4 and CD8 help maintain
coupling during antigen recognition)

Antigen binding stimulates the T cell, but costimulation is required before proliferation can
occur

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T Cell Activation: Co-Stimulation

Requires T cell binding to other surface receptors on an


APC

Dendritic cells and macrophages produce surface B7


proteins when innate defenses are mobilized

B7 binding with a CD28 receptor on a T cell is a crucial costimulatory signal

Cytokines (interleukin 1 and 2 from APCs or T cells)


trigger proliferation and differentiation of activated T cell

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T Cell Activation: Co-Stimulation

Without co-stimulation, anergy occurs

T cells

Become tolerant to that antigen

Are unable to divide

Do not secrete cytokines

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T Cell Activation: Co-Stimulation

T cells that are activated

Enlarge, proliferate, and form clones

Differentiate and perform functions according to


their T cell class

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T Cell Activation: Co-Stimulation

Primary T cell response peaks within a week

T cell apoptosis occurs between days 7 and 30

Effector activity wanes as the amount of antigen


declines

Benefit of apoptosis: activated T cells are a hazard

Memory T cells remain and mediate secondary


responses

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Adaptive defenses

Cellular immunity
1 Dendritic cell

Viral antigen

Dendritic
cell

T cell receptor
(TCR)
Clone
formation

Class lI MHC
protein
displaying
processed
viral antigen
CD4 protein

engulfs an
exogenous antigen,
processes it, and
displays its
fragments on class
II MHC protein.
2 Immunocompetent

CD4 cell recognizes


antigen-MHC
complex. Both TCR
and CD4 protein bind
Immunocom- to antigen-MHC
complex.
petent CD4
T cell

Costimulation
also required

3 CD4 cells are

activated,
proliferate (clone),
and become memory
and effector cells.
Helper T
memory cell

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Activated
helper
T cells
Figure 21.18

Cytokines p. 818

Chemicals produced by different cells, including


activated T cells & macrophages, that influence:

Cell development

Differentiation

Immune reponses IL2 stimulates activated T cells


to proliferate; given theraputically to CA pts

Include:

IFN, IL1-IL8, IL10-IL13; MIF, TNF, Perforin,


Lymphotoxin, Inflammatory factors

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Cytokines

IL-2 is a key growth factor, acting on cells that


release it and other T cells

Encourages activated T cells to divide rapidly

Used therapeutically to treat melanoma and kidney


cancers

Other cytokines amplify and regulate innate and


adaptive responses

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Helper T Cells (TH)

Regulatory cells that play a central role in the


immune response

Once primed by APC presentation of antigen, they:

Chemically or directly stimulate proliferation of


other T cells

Stimulate B cells that have already become bound


to antigen

Without TH, there is no immune response

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Helper T Cells

Cause dendritic cells to express co-stimulatory


molecules required for CD8 cell activation

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TH cell help in cell-mediated immunity


CD4 protein

Helper T cell

Class II MHC
protein
APC (dendritic cell)

1 Previously

activated TH cell
binds dendritic cell.
2 TH cell stimulates

IL-2

dendritic cell to express


co-stimulatory
molecules (not shown)
needed to activate CD8
cell.
3 Dendritic cell can

Class I
MHC protein
(b)

CD8
protein

CD8 T cell

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now activate CD8 cell


with the help of
interleukin 2 secreted
by TH cell.
Figure 21.19b

Helper T Cells

Interact directly with B cells displaying antigen


fragments bound to MHC II receptors

Stimulate B cells to divide more rapidly and begin


antibody formation

B cells may be activated without TH cells by


binding to T cellindependent antigens

Most antigens require TH co-stimulation to activate


B cells

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TH cell help in humoral immunity


Activated helper
T cell

1 TH cell binds with the

Helper T cell
CD4 protein

self-nonself complexes of a
B cell that has encountered
its antigen and is displaying
it on MHC II on its surface.

MHC II protein
of B cell displaying
processed antigen

2 TH cell releases

T cell receptor (TCR)

IL- 4 and other


cytokines
B cell (being activated)
(a)
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interleukins as
co-stimulatory signals to
complete B cell activation.

Figure 21.19a

Roles of Cytotoxic T(TC) Cells

Directly attack and kill other cells- the only T cell


that directly kills

Activated TC cells circulate in blood and lymph


and lymphoid organs in search of body cells
displaying antigen they recognize

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Roles of Cytotoxic T(TC) Cells

Targets

Virus-infected cells

Cells with intracellular bacteria or parasites

Cancer cells

Foreign cells (transfusions or transplants)

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Cytotoxic T Cells

Bind to a self-nonself complex

Can destroy all infected or abnormal cells

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Cytotoxic T Cells

Lethal hit

Tc cell releases perforins and granzymes by


exocytosis

Perforins create pores through which granzymes


enter the target cell

Granzymes stimulate apoptosis

In some cases, TC cell binds with a Fas receptor on


the target cell, and stimulates apoptosis

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Adaptive defenses
Cytotoxic
T cell (TC)

Cellular immunity

1 TC binds tightly to
the target cell when it
identifies foreign antigen
on MHC I proteins.

granzyme molecules from its


granules by exocytosis.
Granule

Perforin
TC cell
membrane

Target
cell

2 TC releases perforin and

Target
cell
membrane
Perforin
pore
Granzymes

5 The TC detaches and

3 Perforin molecules
insert into the target
cell membrane,
polymerize, and form
transmembrane pores
(cylindrical holes)
similar to those
produced by
complement
activation.
4 Granzymes enter the
target cell via the pores.
Once inside, these
proteases degrade
cellular contents,
stimulating apoptosis.

searches for another prey.


(a) A mechanism of target cell killing by T C cells.
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Figure 21.20a

Natural Killer Cells

Recognize other signs of abnormality

Lack of class I MHC

Antibody coating a target cell

Different surface marker on stressed cells

Use the same key mechanisms as Tc cells for


killing their target cells

Non-specific (not considered a T cell)

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Regulatory T (TReg) Cells

Dampen the immune response:

by direct contact

by inhibitory cytokines

Important in preventing autoimmune reactions

T suppressor cells or Suppressor T cells

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Cell-mediated
immunity

Antigen (Ag) intruder

Humoral
immunity

Inhibits

Inhibits

Triggers

Adaptive defenses

Innate defenses
Surface Internal
barriers defenses

Ag-infected
body cell engulfed
by dendritic cell
Becomes
Ag-presenting cell
(APC) presents
self-Ag complex
Activates

Free Ags
may directly
activate B cell
Antigenactivated
B cells
Clone and
give rise to

Activates

Nave
Nave
CD8
CD4
T cells
T cells
Activated to clone
Activated to clone
and give rise to Induce and give rise to
co-stimulation
Memory
cytotoxic T cells
Activated
cytotoxic
T cells

Memory
helper T cells
Activated
helper
T cells

Memory
B cells

Plasma cells
(effector B cells)
Secrete

Cytokines stimulate

Together the nonspecific killers


and cytotoxic T cells mount a
physical attack on the Ag

Nonspecific killers
(macrophages and
NK cells of innate
immunity)

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Antibodies (Igs)
Circulating lgs along with
complement mount a chemical
attack on the Ag

Figure 21.21

Fig. 43-16
Humoral (antibody-mediated) immune response

Cell-mediated immune response


Key

Antigen (1st exposure)

Gives rise to

Engulfed by
Antigenpresenting cell

Stimulates

B cell

Helper T cell

Cytotoxic T cell

Memory
Helper T cells

Antigen (2nd exposure)


Plasma cells

Memory B cells

Memory
Cytotoxic T cells

Active
Cytotoxic T cells

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

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Defend against intracellular pathogens


and cancer by binding to and lysing the
infected cells or cancer cells.

The helper T cells receptors recognize the self-nonself


complexes on the APC
The interaction activates the helper T cells (CD4+)
The helper T cell can then activate cytotoxic T cells
and B cells with the same receptors
Suppressor T cells
Memory T cells
Self protein
displaying T cell
an antigen receptor

Interleukin-2 Cytotoxic
stimulates T cell
cell division

Cell-mediated
immunity
(attack on
infected cells)

Interleukin-2
APC

Helper
T cell

activates
other T cells
and B cells

B cell

Interleukin-1
activates
helper T cell

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Humoral
immunity

(secretion of
antibodies by
plasma cells)

Figure 24.13B

Organ Transplants

The four major types of grafts are:

Autografts graft transplanted from one site on


the body to another in the same person

Isografts grafts between identical twins

Allografts transplants between individuals that


are not identical twins, but belong to same species

Xenografts grafts taken from another animal


species

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Prevention of Rejection

Tissue rejection inhibited by immunosuppressive


drugs

However, these drugs depress patients immune


system so it cannot fight off foreign agents

GVH

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Immunodeficiencies
Congenital/acquired

SCID genetic

< B and T cells

Abnormalities in interleukin receptors

Defective adenosine deaminase (ADA) enzyme

Metabolites lethal to T cells accumulate

Fatal if untreated; treatment is with bone marrow


transplants

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Acquired Immunodeficiencies

Hodgkins disease cancer of the lymph nodes


leads to immunodeficiency by depressing lymph
node cells

Acquired immune deficiency syndrome (AIDS)


cripples the immune system by interfering with the
activity of helper T (CD4) cells

Characterized by severe weight loss, night sweats,


and swollen lymph nodes

Opportunistic infections occur, including


pneumocystis pneumonia and Kaposis sarcoma

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AIDS
Caused by human immunodeficiency virus (HIV)
transmitted via body fluids blood, semen, and
vaginal secretions

HIV enters the body via:

Blood transfusions

Contaminated needles

Intimate sexual contact, including oral sex

HIV:

Destroys TH (CD4) cells

Depresses cell-mediated immunity

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AIDS

HIV multiplies in lymph nodes throughout the


asymptomatic period; Ab neg for wks after infect.

Symptoms appear in a few months to 10 years

Attachment

HIVs coat protein (gp120) attaches to the CD4


receptor

A nearby protein (gp41) fuses the virus to the


target cell

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AIDS

HIV enters the cell and uses reverse transcriptase


to produce DNA from viral RNA

This DNA (provirus) directs the host cell to make


viral RNA (and proteins), enabling the virus to
reproduce and infect other cells

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AIDS

HIV reverse transcriptase is not accurate and


produces frequent transcription errors

This high mutation rate causes resistance to drugs

Treatments include:

Reverse transcriptase inhibitors (AZT)

Protease inhibitors (saquinavir and ritonavir)

New drugs currently being developed that block


HIVs entry to helper T cells

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Autoimmune Diseases

Loss of the immune systems ability to distinguish


self from nonself

The body produces autoantibodies and sensitized


TC cells that destroy its own tissues

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Examples of Autoimmune Diseases

Multiple sclerosis

Myasthenia gravis

Graves disease

Type I (juvenile) diabetes mellitus

Systemic lupus erythematosus (SLE)

Glomerulonephritis

Rheumatoid arthritis

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Mechanisms of Autoimmune Diseases


Foreign antigens may resemble self-antigens

1.

Antibodies against the foreign antigen may cross-react


with self-antigen

New self-antigens may appear, generated by

2.

Gene mutations

Changes in self-antigens by hapten attachment or as a


result of infectious damage

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Mechanisms of Autoimmune Diseases


3.

Release of novel self-antigens by trauma of a


barrier (e.g., the blood-brain barrier)

Also, some loss of T suppressor or T regulatory


functions

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Hypersensitivities

Immune responses to a perceived (otherwise harmless)


threat

Causes tissue damage

Different types are distinguished by

Their time course

Whether antibodies or T cells are involved

Antibodies cause immediate and subacute


hypersensitivities

T cells cause delayed hypersensitivity

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Immediate Hypersensitivity

Acute (type I) hypersensitivities (allergies) begin


in seconds after contact with allergen

Initial contact is asymptomatic but sensitizes the


person

Reaction may be local or systemic

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Immediate Hypersensitivity

The mechanism involves IL-4 secreted by T cells

IL-4 stimulates B cells to produce IgE

IgE binds to mast cells and basophils, resulting in a


flood of histamine release and inducing the
inflammatory response

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Immediate Hypersensitivity

Acute (type I) hypersensitivities begin in seconds


after contact with allergen- allergies

Anaphylaxis if systemic, life threatening

Release of histamine from basophils & mast cells

Release of inflammatory chemicals

Systemic or local responses

Shock, vasodilation, death;

RX: epinephrine

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Anaphylactic Shock

Systemic response to allergen that directly enters the blood

Basophils and mast cells are enlisted throughout the body

Systemic histamine releases may cause

Constriction of bronchioles

Sudden vasodilation and fluid loss from the bloodstream

Hypotensive shock and death

Treatment: epinephrine

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Immediate or Type I
Hypersensitivity

Requires sensitization

Sensitization stage
1 Antigen (allergen)
invades body.

IgE mediated
2 Plasma cells
produce large
amounts of class
IgE antibodies
against allergen.

3 IgE antibodies
attach to mast
cells in body tissues
(and to circulating
basophils).

Mast cell with


fixed IgE
antibodies
IgE
Granules
containing
histamine

Subsequent (secondary)
responses
4 More of
same antigen
invades body.

Antigen

5 Antigen combines
with IgE attached
to mast cells (and
basophils), which
triggers degranulation
and release of histamine
(and other chemicals).

Mast cell granules


release contents
after antigen binds
with IgE antibodies

Histamine

6 Histamine causes blood vessels to dilate and become


leaky, which promotes edema; stimulates secretion of
large amounts of mucus; and causes smooth muscles
to contract (if respiratory system is site of antigen
entry, asthma may ensue).

Outpouring of
fluid from
capillaries

Release
of mucus

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Constriction of small
respiratory passages
(bronchioles)

Figure 21.21

Subacute Hypersensitivities

Caused by IgM and IgG, and transferred via blood plasma


or serum

Onset is slow (13 hours) after antigen exposure

Duration is long lasting (1015 hours)

Cytotoxic (type II) reactions

Antibodies bind to antigens on specific body cells,


stimulating phagocytosis and complement-mediated lysis of
the cellular antigens

Example: mismatched blood transfusion reaction where


infused blood cells are destroyed

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Subacute Hypersensitivities

Immune complex (type III) hypersensitivity

Antigens are widely distributed through the body


or blood

Insoluble antigen-antibody complexes form

Complexes cannot be cleared from a particular area


of the body

Intense inflammation, local cell lysis, and death


may result

Example: systemic lupus erythematosus (SLE)

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Delayed Hypersensitivities (Type IV)

Slow Onset (13 days); Cell mediated

Delayed hypersensitivity, Td, & TC cells

Mediated by Cytokines from activated TC

RX: corticosteroids (Antihistamines no use)

Examples: contact dermatitis as in poison ivy

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Developmental Aspects

Immune system stem cells develop in the liver and


spleen by the ninth week

Later, bone marrow becomes the primary source of


stem cells

Lymphocyte development continues in the bone


marrow and thymus system begins to wane

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Developmental Aspects

TH2 lymphocytes predominate in the newborn, and


the TH1 system is educated as the person
encounters antigens

Tolerance occurs in the fetus

The immune system is impaired by stress and


depression

With age, the immune system begins to wane

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