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Chapter 15
Immune System
15-1
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Chapter 15 Outline
Innate
Immunity
Adaptive Immunity
Complement System
T Cells
Histocompatibility Antigens
Interactions Between Antigen-Presenting Cells &
Lymphocytes
Active Immunity
Passive Immunity
Immune System & Cancer
Diseases Caused By Immune System
15-2
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Defense Mechanisms
Against
pathogens constitute the immune system
Can be grouped into 2 categories:
Innate (nonspecific) immunity is inherited as part of
structure of each organism
Adaptive (specific) immunity is a function of
lymphocytes & changes with exposure
15-3
Innate Immunity
15-4
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Innate Immunity
Is
1st line of defense against invading pathogens
Includes epithelial barriers, high acidity of gastric juice,
phagocytosis, & fever
15-5
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Phagocytosis
Is
triggered in response to pathogen-associated
molecular patterns (PAMPs) produced only by
microorganisms
Best known are lipopolysaccharide (LPS) from
gram-bacteria & peptidoglycan from gram+s
15-6
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Phagocytosis continued
Is
performed by 3 classes of phagocytic cells:
Neutrophils - 1st to arrive at infection sites
Mononuclear phagocytes - macrophages &
monocytes
Organ-specific phagocytes in liver, spleen, lymph
nodes, lungs, & brain
Fixed phagocytes line sinusoids of liver, spleen, &
lymph nodes & remove pathogens
15-7
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Phagocytosis continued
 Connective
tissue &
blood contain mobile
leukocytes (WBCs)
 These are attracted
to infection
(chemotaxis) by
chemokines
 WBCs from blood exit
capillaries by
extravasation
(diapedesis) & ingest
pathogens
Fig 15.1
15-8
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Phagocytosis continued
 Pseudopods
from
phagocyte
surround pathogen
 Forming a
vacuole
 Vacuole
fuses with
lysosomes
which digest
pathogen
Fig 15.2
15-9
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Fever
Appears
to be component of innate immunity
Occurs when hypothalamic thermostat is reset
upwards by IL1- & other cytokines (endogenous
pyrogens)
Pyrogens are released by WBCs in response to
endotoxin from gram– bacteria
15-10
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Interferons
Are
polypeptides produced by cells infected with virus
that provide short-acting, non-specific resistance to
viral infection in nearby cells
3 types: a, , g, interferon
15-11
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Fig 15.3
15-12
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15-13
Adaptive Immunity
15-14
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Adaptive Immunity
Is
acquired ability to defend against specific pathogens
by prior exposure to those pathogens
Is mediated by production of specific antibodies by
lymphocytes
15-15
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Antigens
Are
molecules that elicit production of antibodies that
specifically bind those antigens
Are usually large molecules that are foreign to the
body
Immune system can distinguish “self” molecules from
non-self antigens
Normally makes antibodies only against non-self
antigens
Large, complex molecules can have a number of
antigenic determinant sites (different sites that
stimulate production of, & bind to, different antibodies)
15-16
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Haptens
Are
small non-antigenic molecules that become
antigens when bound to proteins (form an antigenic
determinant site)
Useful for creating antibodies for research and
diagnosis
15-17
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Immunoassays
 Are
tests that use
specific antibodies
to identify a
particular antigen
 The binding of
antibody to antigen
causes clumping
(agglutination)
which can be
visualized
Fig 15.4
15-18
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Lymphocytes
Are
derived from stem cells in bone marrow
Which replace selves by cell division so are not
depleted
Lymphocytes produced by this process seed
thymus, spleen, & lymph nodes with self-replacing
colonies
15-19
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T Lymphocytes (T cells)
Develop
from lymphocytes that seed thymus
Do not secrete antibodies
Attack infected host cells, cancer cells, & foreign cells
Thus they provide cell-mediated immunity
Supply 65 – 85% of lymphocytes for blood & most of
lymphocytes in germinal centers of lymph nodes &
spleen
15-20
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B Lymphocytes (B cells)
Fight
bacterial infections by secreting antibodies into
blood & lymph
Thus provide humoral immunity
15-21
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Thymus
Is
located below the thyroid gland
Grows during childhood, gradually regresses after
puberty
Contains T cells that supply other tissues
T cells can be depleted, e.g. by AIDs or
chemotherapy
These can only be replenished up to late childhood
After that, repopulation is accomplished by
production in secondary lymphoid organs
15-22
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Secondary Lymphoid Organs
Consist
of lymph nodes, spleen, tonsils, & Peyer’s
patches
Located in areas where antigens could gain entry to
blood or lymph
Lymphocytes migrate constantly through blood &
lymph from one lymphoid organ to another
Enhances chance that antibody will encounter its
antigen
Spleen filters blood; other lymphoid organs filter
lymph
15-23
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Local Inflammation
Occurs
when bacteria enter a break in the skin
Inflammatory reaction is initiated by nonspecific
mechanisms of phagocytosis & complement activation
Complement activation attracts phagocytes to area
15-24
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Local Inflammation continued
As
inflammation progresses, B cells produce
antibodies against bacterial antigens
Attachment of antibodies to antigens amplifies
nonspecific responses because of complement
activation
& promotes phagocytic activity of neutrophils,
macrophages, & monocytes (= opsinization)
15-25
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Local Inflammation continued
 In
inflamed area,
leukocytes attach to
surface of endothelial
cells
 Move by chemotaxis
to inflamed site
 Neutrophils arrive 1st,
then monocytes, then
T cells
 Undergo
extravasation
Fig 15.6
15-26
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Local Inflammation continued
 Mast
cells secrete
heparin, histamine,
prostaglandins,
leukotrienes, cytokines,
& TNF-a
 These produce
redness, warmth,
swelling, pus, & pain
 Recruit more
leukocytes
 If infection continues,
endogenous pyrogens
are released
Fig 15.5
15-27
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B Lymphocytes (B cells)
Have
antibodies on
surface that are
receptors for
antigens
When bound to
antigen, are
stimulated to
divide & secrete
antibodies
Fig 15.8
15-28
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B Lymphocytes (B cells)
 When
B cells divide,
some progeny
become memory cells
 Some become
plasma cells that
produce about
2000
antibodies/sec that
are specific for
original antigen
 This provides
active immunity
Fig 15.7
15-29
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B Lymphocytes (B cells)
Binding
of B cells to antigen also triggers a cascade of
reactions that activate complement proteins
Complement proteins can kill antigen-bearing cells
& promote phagocytosis
15-30
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Antibodies
Are
proteins called immunoglobulins
Part of gamma globulin class of plasma proteins
Antibodies have same basic structure but their
differences provide for antibody specificity
15-31
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15-32
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Antibody Structure
 Is
in shape of “Y”
 2 long heavy (H) chains are
joined to 2 shorter light (L)
chains
 When cleaved, stalk of Y
becomes crystallizable
fragment (Fc)
 Fc is constant among
different antibodies
 Arms of Y contain antigenbinding fragment (Fab)
 Fab contains a variable
Fig 15.10
region that confers
antibody specifity
15-33
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Antibody Diversity
person has about 1020 antibody molecules
With a few million different specificities
Likely there is an antibody specific for any antigen a
person might encounter
2 mechanisms might account for diversity
If a few hundred genes code for Hs & a few hundred
for Ls, different combinations of these could lead to
millions of different antibodies
Mutations could increase diversity, especially with
age
Each
15-34
Complement System
15-35
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The Complement System
Is
part of nonspecific defense system
Activity is triggered by binding of antibodies to antigens
(classic pathway) & by bacterial coat polysaccharides
(alternative pathway)
Binding of antibodies to antigens does not by itself
destroy antigens or pathogens
Antibodies label targets for complement system attack
& also stimulate opsonization
15-36
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The Complement System continued
Is
a series of proteins whose activation forms a
membrane attack complex which perforates a cell
causing it to lyse
Complement proteins can be subdivided into 3
functional groups:
C1 - recognition
C4, C2, C3 - activation
C5-C9 - attack (complement fixation)
These form the membrane attack complex
15-37
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The Complement System continued
In
classic pathway antibody-antigen binding activates
C1
C1 hydrolyzes C4 into C4a & C4b
C4b binds to cell membrane & becomes active,
splitting C2 into C2a & C2b
C2a attaches to C4b & cleaves C3 into C3a & C3b
Alternate pathway also cleaves C3 (& so
converges with classic pathway at this step)
C3b converts C5 to C5a & C5b
15-38
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Fixation of Complement Proteins
Fig 15.12
15-39
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Membrane Attack Complex
 C5b
& C6 - C9 are inserted into bacterial cell membrane,
forming membrane attack complex
 This creates large pore in membrane, causing osmotic
influx of H20, lysis, & cell death
Fig 15.13
15-40
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Complement Fragments
That
are liberated during activation have a number of
effects, including
Attracting phagocytes (chemotaxis)
Phagocytes have receptors for C3b which can serve as
bridge to victim cell
C3a & C5a stimulate mast cells to secrete histamine
Which increases blood flow & capillary permeability,
bringing in more phagocytes
15-41
T Cells
15-42
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Killer or Cytotoxic T Cells
Carry
CD8 cell surface marker
Destroy body cells that possess foreign antigens
Usually from a pathogen, but can be from
malignancy or self cells never seen by immune
system
Kill by cell-mediated destruction
That is, must be in contact with victim cell
Kill by secreting perforins which create a pore in
victim's membrane & cause lysis
Also secrete granzymes which cause destruction of
victim's DNA
15-43
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Helper & Suppressor T Cells
 Helper
Ts carry CD4
surface marker
 Indirectly participate
by enhancing
responses of both
killer T cells & B cells
 Suppressor Ts
decrease responses
of killer Ts & B cells
Fig 15.14
15-44
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Lymphokines
 Are
cytokines
secreted by
lymphocytes
 Usually called
interleukin-1,
2, 3 . . . or IL1, IL-2 . . .
15-45
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T Cell Receptor Proteins
Only
protein antigens are recognized by most T cells
T cell receptors cannot bind to free antigens
T cells respond to foreign antigens when they are
presented on surface of antigen-presenting cells
Chief antigen presenting cells are macrophages &
dendritic cells
15-46
Histocompatibility Antigens
15-47
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Dendritic Cells
Originate
in marrow, then migrate to most tissues
Prominent where pathogens might enter body
Engulf protein antigens, partially digest them, & display
polypeptide fragments on surface for T cells to "see"
15-48
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Dendritic Cells continued
 Fragments
are
associated on surface
with histocompatibility
antigens which are
necessary to activate
Ts
 To increase chance of
interacting with correct
T cells, dendritics
migrate to secondary
lymphoid organs
 Where secrete
chemokines to
attract Ts
Fig 15.15
15-49
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Histocompatibility Antigens
Are
on surface of all body's cells except mature RBCs
Also called human leukocyte antigens (HLAs)
Are coded for by group of 4 genes on chromosome 6
called major histocompatibility complex (MHC)
4 genes have multiple alleles creating many
possible MHC types
15-50
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MHC
MHC
genes produce 2 types of cell surface molecules:
class-1 & class-2
Class-1s are made by all cells except RBCs
Class-2s are made only by antigen-presenting cells
& B cells
These present class-2s together with foreign
antigen to helper Ts
 This is only way to activate helper Ts so they
can promote B cell activity
15-51
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MHC continued
In
order for killer & helper Ts to function they require
co-presentation of antigen with a specific MHC marker
Killer Ts are activated to kill victim cell only by copresentation of antigen & class-1 marker
Helper Ts require antigen & class-2 marker
15-52
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MHC continued
 Co-presentation
requirement comes from presence of different
coreceptors on killer & helper T cells
 Killer T coreceptor CD8 interacts only with class-1s
 Helper T coreceptor CD4 interacts only with class-2s
Fig 15.16
15-53
Interactions Between Antigen
Presenting Cells & Lymphocytes
15-54
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T Cell Response to a Virus
When
virus infects body it is phagocytized by
macrophage or dendritic cell
Its partially-digested polypeptide fragments are
antigens that are displayed on surface
Form a complex with class-2 MHC molecules that
macrophages present to helper T cells
 Helper Ts bind & are activated
 Can now promote B cell activity
15-55
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Fig 15.17
15-56
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Macrophage-T cell Interaction
When
macrophages & T cells complex, macros
secrete IL-1 & TNF (good at killing cancer cells)
IL-1 stimulates cell division & proliferation of helper
Ts
Activated helpers secrete M-CSF & g- interferon & IL-2
Promotes activity of macrophages
Activated helpers activate B cells
15-57
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Killer T cell Activity
Killer
Ts destroy
infected cells if
class-1 markers
are present
Fig 15.18
15-58
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Helper T cell-B cell Interactions
 Activated
helper Ts promote humoral response of B cells by
binding to their surface antigens & MHC class 2s
 This stimulates proliferation of Bs, their conversion to plasma
cells, & their secretion of antibodies
Fig 15.20
15-59
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Destruction of T cells
Activated
Ts must be destroyed after infection is over
Occurs because Ts produce a surface receptor called
FAS
FAS production increases during infection
After a few days, Ts begin to produce FAS ligand
Binding of FAS to FAS ligand triggers apoptosis (cell
suicide)
15-60
Active Immunity
15-61
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Primary & Secondary Responses
 On
1st exposure to
pathogen, there is latency
of 5-10 days before
specific antibodies are
made (= primary
response)
 Antibody levels plateau
after few days & decline
after a few weeks
 Subsequent exposure to
same antigen causes
secondary response
 Antibody production is
much more rapid &
sustained
Fig 15.22
15-62
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Clonal Selection Theory
 Is
mechanism by which secondary responses are produced
 Each B cell produces only 1 kind of antibody & related
antigen receptor (on its surface)
 Exposure to its antigen stimulates a B cell to divide until a
large population of genetically identical cells (clones) is
produced
 Some of these become plasma cells & secrete antibodies
 Some become memory cells that can be stimulated to
produce antibodies in the secondary response
15-63
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Fig 15.23
15-64
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15-65
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Active Immunity
Development
of a secondary response provides active
immunity
Immunizations induce primary responses by
inoculating people with pathogens whose virulence
has been attenuated or destroyed (vaccinations)
Cause development of B cell clones that can
provide secondary response
15-66
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Immunological Tolerance
Ability
to produce antibodies against non-self antigens
while tolerating self-antigens (immunological
competence) occurs during 1st month of life
Tolerance requires continuous exposure to an
antigen
Some self-antigens, such as lens protein in eye, are
normally hidden from blood
Exposure to such self-antigens results in production
of autoantibodies
Killer T cells that attack self-antigens are called
autoreactive T cells
15-67
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Immunological Tolerance continued
2
possible mechanisms for tolerance:
Clonal deletion theory: tolerance occurs because T
cells that recognize self-antigens are destroyed
Good evidence this occurs in thymus
Clonal anergy: lymphocytes directed against selfantigens are present throughout life but don't attack
self-antigens
Mechanism not understood
Appears to underlie tolerance in B cells
15-68
Passive Immunity
15-69
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Passive Immunity
Is
immune protection produced by transfer of
antibodies to a recipient from a donor
Donor was actively immunized
Person who receives these ready-made
antibodies is passively immunized
 Used to treat snakebite, rabies, tetanus,
hepatitis
15-70
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Passive Immunity
Occurs
naturally before & after birth
Some antibodies from mother pass placenta to fetus
during pregnancy & provide passive immunity
During 1st 2-3 days of nursing, mother produces
colostrum which is rich in her antibodies & gives her
immunity to infant
Immunological competence (ability to mount a specific
immune response) does not develop until 1 month
after birth
15-71
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15-72
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Monoclonal Antibodies
Commercially
prepared for use in research &
diagnostic tests
Exhibit specificity for only 1 antigenic determinant
Animal (usually mouse) is injected with antigen, & its B
cells harvested from spleen
Bs are hybridized with cancerous myeloma cells to
make them immortal
Individual Bs are screened & 1 that produces right
antibody is selected
This 1 is allowed to multiply in culture & its clones
(= hybridoma) are source of large quantity of
antibodies
15-73
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Fig 15.24
15-74
Immune System & Cancer
15-75
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Tumor Immunology
Thought
that tumor cells arise often but are normally
recognized & killed by immune system
When cancer develops, the immunological
surveillance system of T & natural killer cells, has
failed
Tumor biology is similar to & interrelated with functions
of immune system
Most tumors are clones of single cells whose mitosis is
not controlled by normal inhibitory mechanisms
15-76
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Tumor Immunology continued
Tumor
cells dedifferentiate (become less specialized
like cells of an embryo)
As dedifferentiate, produce surface antigens that are
normally recognized by immunological surveillance
& destroyed
Because were absent at the time immunological
competence was established
Body treats these antigens as foreign
Presence of these antigens provides basis of
laboratory diagnostic tests for some cancers
15-77
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Natural Killer (NK) Cells
Are
lymphocytes related to T cells
Provide first line of cell-mediated defense
NK cells destroy tumors in a non-specific fashion;
backed up by specific response of killer Ts
NKs are stimulated by interferon from T cells
NKs attack cells that lack class-1 MHC antigens
Kill with perforins & granzymes
15-78
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Immunotherapy for Cancer
Most
strategies involve boosting, or directing, patients
own immune responses
Interferons & interleukins have been useful in
treatment of some forms of cancer
E.g. interleukin-2, which activates both killer T & B
cells, has shown promise
15-79
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Effects of Aging and Stress
Little
is known about why susceptibility to cancer is so
variable
Cancer risks increase with age
One factor may be that aging lymphocytes
accumulate genetic errors that decrease
effectiveness
Thymus function declines with age
Tumors grow faster in stressed animals
Stress hormones (corticosteroids) cause decreased
immune function
15-80
Diseases Caused By Immune
System
15-81
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Diseases Caused by Immune System
Can
be grouped into 3 categories: autoimmune
diseases, immune complex diseases, & allergies
All caused by abnormal functioning of immune
system
15-82
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Autoimmune Diseases
Are
produced by failure of immune system to
recognize & tolerate self-antigens
Autoreactive T cells are formed & B cells produce
autoantibodies
Afflicts women twice as often as men
15-83
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Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
An antigen that does not normally circulate in blood
being presented to immune system
E.g. in Hashimoto's thyroiditis, antibodies are
stimulated to attack thyroglobulin (which is
normally hidden from immune surveillance)
15-84
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Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
Combination of a self-antigen, that is otherwise
tolerated, with a foreign hapten
E.g. in thrombocytopenia (low platelet count),
platelets are destroyed because they combine
with victim's medications
15-85
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Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
Antibodies being produced that are directed against
other antibodies
Happens with rheumatoid arthritis
15-86
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Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
Antibodies against foreign antigens cross-reacting
with self-antigens
This can happen with rheumatic fever
15-87
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Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
Self-antigens being presented to helper T cells
together with class-2 MHC molecules
This happens in Type I diabetes
15-88
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Immune Complex Diseases
Involve
formation of immune complexes that are free &
not attached to a cell
These activate complement proteins & promote
inflammation
Can result from infections by bacteria, parasites,
viruses
Can result from formation of complexes between selfantigens & autoantibodies
This occurs in rheumatoid arthritis & lupus
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Allergy (Hypersensitivity)
Is
an abnormal immune response to allergens
Comes in 2 forms: immediate & delayed
hypersensitivity
Immediate is due to abnormal B cell response to
allergen; causes effects in secs to mins
Caused by foods, bee stings, pollen
Delayed is abnormal T cell response that causes
symptoms 24-72 hrs after exposure
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Immediate Hypersensitivity
Dendritic
cells stimulate a class of helper Ts to secrete
interleukin-4 & -13 which cause B & plasma cells to
secrete IgE antibodies
Do not circulate in blood; are attached to mast cells
& basophils
When re-exposed to same allegen, antibodies on
mast cells & basophils bind it & stimulate secretion
of histamine, leukotrienes, & prostaglandin D
Producing allergy symptoms
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Immediate Hypersensitivity continued
Fig 15.26
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Delayed Hypersensitivity
Symptoms
take longer to develop (hrs to days)
Is a cell-mediated T cell response
Symptoms caused by secretion of lymphokines, not
histamine
Antihistamines provide little benefit
Examples include contact dermatitis caused by poison
ivy, oak, or sumac
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