Human Physiology - Daniela Sartori
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Transcript Human Physiology - Daniela Sartori
Chapter 15
Lecture
Outline
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Chapter 15 Outline
Defense
Mechansims
Functions of B Lymphocytes
Functions of T Lymphocytes
Active and Passive Immunity
Tumor Immunology
Diseases Caused By Immune System
15-2
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 and changes with exposure
15-3
Innate (Nonspecific) Immunity
15-4
Innate Immunity
Distinguishes
between “self” and “non-self” by
recognizing molecules called PAMPs=pathogenassociated molecular patterns
Is 1st line of defense against invading pathogens
Includes epithelial barriers, high acidity of gastric juice,
phagocytosis, interferons, and fever
15-5
Activation of Innate Immunity
Is
triggered in response to pathogen-associated
molecular patterns (PAMPs) produced only by
microorganisms
Best known are lipopolysaccharide (LPS) from gram
neg. bacteria and peptidoglycan from gram pos.
bacteria
Some immune cells have receptors for PAMPs
displayed on their surfaces
Receptors called Toll receptors
Ten different Toll receptors identified in humans
15-6
Phagocytosis continued
Is
performed by 3 classes of phagocytic cells:
Neutrophils - 1st to arrive at infection sites
Mononuclear phagocytes - macrophages and
monocytes
Organ-specific phagocytes in liver, spleen, lymph
nodes, lungs, and brain
Fixed phagocytes line sinusoids of liver, spleen,
and lymph nodes and remove pathogens
15-7
Phagocytosis continued
Connective
tissue and
blood contain mobile
leukocytes (WBCs)
These are attracted
to infection
(chemotaxis) by
chemokines
WBCs from blood exit
capillaries by
extravasation
(diapedesis) and ingest
pathogens
15-8
Phagocytosis continued
Pseudopods
from
phagocyte
surround pathogen
Forming a
vacuole
Vacuole
fuses with
lysosomes
which digest
pathogen
15-9
Fever
Appears
to be component of innate immunity
Occurs when hypothalamic thermostat is reset
upwards by interleukin-1 and other cytokines
(endogenous pyrogens)
Pyrogens are released by WBCs in response to
endotoxin from gram negative bacteria
Cytokines also increase sleepiness and a fall in the
plasma Fe concentration, which functions in
inhibiting bacterial activity
15-10
Interferons
Are
polypeptides produced by cells infected with virus
that provide short-acting, non-specific resistance to
viral infection in nearby cells
3 types: alpha, beta, and gamma interferon
15-11
The Life Cycle
of HIV: HIV
contains RNA.
Once inside the
host, viral RNA is
transcribed by
reverse
transcriptase into
cDNA. The genes
in cDNA direct
synthesis of new
viral particles
15-12
15-13
Adaptive (Specific) Immunity
15-14
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
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, and bind to, different
antibodies)
15-16
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
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
15-18
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, and lymph nodes with self-replacing
colonies
15-19
T Lymphocytes (T cells)
Develop
from lymphocytes that seed thymus
Do not secrete antibodies
Attack infected host cells, cancer cells, and foreign
cells
Thus they provide cell-mediated immunity
Supply 65 – 85% of lymphocytes for blood and most of
lymphocytes in germinal centers of lymph nodes and
spleen
15-20
B Lymphocytes (B cells)
Fight
bacterial infections by secreting antibodies into
blood and lymph
Thus provide humoral immunity
15-21
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
Secondary Lymphoid Organs
Consist
of lymph nodes, spleen, tonsils, and Peyer’s
patches
Located in areas where antigens could gain entry to
blood or lymph
Lymphocytes migrate constantly through blood and
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
Local Inflammation
Occurs
when bacteria enter a break in the skin
Inflammatory reaction is initiated by nonspecific
mechanisms of phagocytosis and complement
activation
Complement activation attracts phagocytes to area
15-24
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
And promotes phagocytic activity of neutrophils,
macrophages, and monocytes (= opsonization)
15-25
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
15-26
Local Inflammation continued
Mast cells secrete heparin,
histamine, prostaglandins,
leukotrienes, cytokines, and
TNF-a
These produce redness,
warmth, swelling, pus, and
pain
Recruit more leukocytes
If infection continues,
endogenous pyrogens are
released
15-27
B Lymphocytes (B cells)
Have
antibodies on
surface that are
receptors for
antigens
When bound to
antigen, are
stimulated to
divide and
secrete
antibodies
15-28
B Lymphocytes (B cells) continued
When
B cells divide,
some progeny
become memory cells
Others become
plasma cells that
produce about
2000
antibodies/sec that
are specific for
original antigen
This provides
active immunity
15-29
B Lymphocytes (B cells) continued
Binding
of B cells to antigen also triggers a cascade of
reactions that activate complement proteins
Complement proteins can kill antigen-bearing cells
and promote phagocytosis
15-30
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
15-32
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
region that confers
antibody specifity
All antibodies consists
of four polypeptide
chains: 2 heavy and 2
light chains, as seen in
the diagram below.
15-33
Diversity of Antibodies
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
Each
15-34
Antibody Diversity continued
2
mechanisms might account for diversity
If a few hundred genes code for Heavy chains and a few
hundred for Light chains, different combinations could lead to
millions of different antibodies
Recombination of these in developing lymphocytes of
marrow produces antigen-independent diversity
Diversity further increases via somatic hypermutation in
which there is a high rate of single base pair mutations
Occurs as B cells undergo proliferation in 2o lymphoid
tissues in response to foreign antigens
Antigen-dependent diversification also occurs in genetic
recombination—there is a switch in constant regions of
heavy chains of antibodies so that IgM are converted to
IgA or IgE=class switch recombination.
15-35
Complement System
15-36
The Complement System
Is
part of nonspecific defense system
Activity is triggered by binding of antibodies to antigens
(classic pathway) and by unique polysaccharide
coating of bacteria (alternative pathway)
Binding of antibodies to antigens does not by itself
destroy antigens or pathogens
Antibodies label targets for complement system attack
and also stimulate opsonization (the ability of
antibodies to stim. phagocytosis)
15-37
The Complement System continued
Is
a series of proteins whose activation forms a
membrane attack complex which perforates a cell
causing it to undergo lysis
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
15-38
The Complement System continued
In
classic pathway, antibody-antigen binding activates
C1
C1 hydrolyzes C4 into C4a and C4b
C4b binds to cell membrane and becomes active,
splitting C2 into C2a and C2b
C2a attaches to C4b and cleaves C3 into C3a and
C3b
Alternate pathway also cleaves C3 (and so
converges with classic pathway at this step)
C3b converts C5 to C5a and C5b
15-39
Fixation of Complement Proteins
15-40
Membrane Attack Complex
C5b
and C6 - C9 are inserted into bacterial cell membrane,
forming membrane attack complex
This creates large pore in membrane, causing osmotic
influx of H2O, lysis, and cell death
15-41
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 (opsonization)
C3a and C5a stimulate mast cells to release histamine
Which increases blood flow and capillary
permeability, bringing in more phagocytes
15-42
T Cells
15-43
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 and cause lysis
Also secrete granzymes which cause destruction of
victim's DNA
15-44
Helper and Suppressor T Cells
Helper
T-cells carry CD4
surface marker
Indirectly participate by
enhancing responses of
both killer T-cells and Bcells
Regulatory T-cells
decrease responses of
killer T-cells and B cells
Carry CD25 surface
marker (and CD4)
Help protect against
autoimmune responses
15-45
Lymphokines
Are
cytokines
secreted by
lymphocytes
Usually called
interleukin-1,
2, 3 . . . or IL1, IL-2 . . .
15-46
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 and
dendritic cells
15-47
Dendritic Cells
Originate
in marrow, then migrate to most tissues
Prominent where pathogens might enter body
Engulf protein antigens, partially digest them, and
display polypeptide fragments on surface for T cells to
"see"
15-48
Dendritic Cells continued
Fragments
are
associated on surface
with histocompatibility
antigens which are
necessary to activate
T-cells
To increase chance of
interacting with correct
T-cells, dendritic cells
migrate to secondary
lymphoid organs
Where secrete
chemokines to
attract T-cells
15-49
Histocompatibility Antigens
15-50
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 the major histocompatibility complex (MHC)
The 4 genes have multiple alleles creating many
possible MHC types
15-51
MHC
MHC
genes produce 2 types of cell surface molecules:
class-1 and class-2
Class-1s are made by all cells except RBCs
Class-2s are made only by antigen-presenting cells
and B-cells
These present class-2s, together with foreign
antigens, to helper T-cells
This is the only way to activate helper T-cells
so they can promote B-cell activity
15-52
MHC continued
In
order for killer and helper T-cells to function they
require co-presentation of antigen with a specific MHC
marker
Killer T-cells are activated to kill victim cell only by copresentation of antigen and class-1 marker
Helper T-cells require antigen and class-2 marker
15-53
MHC continued
Co-presentation
requirement comes from presence of different
coreceptors on killer and helper T cells
Killer T coreceptor CD8 interacts only with class-1s
Helper T coreceptor CD4 interacts only with class-2s
15-54
Interactions Between Antigen
Presenting Cells and Lymphocytes
15-55
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 T-cells bind and are activated
Can now promote B-cell activity
15-56
The interaction of an
antigen-presenting
cell (a macrophage
in this example), Tcells, and B-cells:
Contact between a
macrophage and a T-cell
requires helper T-cell
interact with antigen and
Class 2-MHC molecule.
The helper T-cell is now
activated and able to
interact with B-cell
15-57
Macrophage-T cell Interaction
When
macrophages and T cells form a complex,
macros secrete IL-1 and Tumor Necrosis Factor
(which is good at killing cancer cells)
IL-1 stimulates cell division and proliferation of
helper T-cells
Activated helpers secrete M-CSF and gammainterferon and IL-2
Promotes activity of macrophages
Activated helpers activate B cells
15-58
Killer T cell Activity
Killer
Ts destroy
infected cells if
class-1 markers
are present
15-59
Helper T cell-B cell Interactions
Activated
helper Ts promote humoral response of B cells by
binding to their surface antigens and MHC class 2s
This stimulates proliferation of Bs, their conversion to plasma
cells, and their secretion of antibodies
15-60
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)
15-61
Active Immunity
15-62
Primary and 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 and
decline after a few
weeks
Subsequent exposure to
same antigen causes
secondary response
Antibody production is
much more rapid and
sustained
15-63
Clonal Selection Theory
Is
mechanism by which secondary immune responses
are produced
Each B cell produces only 1 kind of antibody and
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 and secrete
antibodies
Some become memory cells that can be
stimulated to produce antibodies in the secondary
response
15-64
The clonal
selection theory
as applied to Blymphocytes
15-65
15-66
Germinal Centers
Develop
in lymph nodes and spleen from a cloned and
activated B-cell
Which proliferate and undergo hypermutation
Generating and secreting diverse antibodies for
the secondary immune response
15-67
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
15-68
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
15-69
Immunological Tolerance continued
2
possible mechanisms for tolerance:
Clonal deletion : tolerance occurs because T cells
that recognize self-antigens are destroyed
Clonal anergy: lymphocytes directed against selfantigens are present throughout life but don't attack
self-antigens
Central tolerance: mechanisms that occur in
thymus or bone marrow (T-cells by apoptosis; Bcells by clonal deletion and anergy
Peripheral tolerance: involves complex mech.
that produce anergy
15-70
Passive Immunity
15-71
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
15-72
Passive Immunity continued
Occurs
naturally before and after birth
Some antibodies from mother pass placenta to fetus
during pregnancy and provide passive immunity
During 1st 2-3 days of nursing, mother produces
colostrum which is rich in her antibodies and gives her
immunity to infant
Immunological competence (ability to mount a specific
immune response) does not develop until 1 month
after birth
15-73
15-74
Monoclonal Antibodies
In
a variation of passive immunity, animals (mice,
sheep, rabbits) are injected with antigens and used to
obtain monoclonal antibodies which are prod. by an
isolated pure clone of cells
A single B-cell is fused with a cancerous myeloma cell
to form a hybrid cell capable of dividing indefinitely
Result is a clone of cells that secretes monoclonal
antibodies specific for single antigenic determ. site
Use for diagnosis, lab tests, and medical treatment of
some cancers
15-75
The Production of Monoclonal Antibodies
15-76
Immune System and Cancer
15-77
Tumor Immunology
Believed
that tumor cells arise often but are normally
recognized and killed by immune system
When cancer develops, the immunological
surveillance system of T-cells and natural killer cells
has failed
Tumor biology is similar to and interrelated with
functions of immune system
Most tumors are clones of single cells whose mitosis is
not controlled by normal inhibitory mechanisms
15-78
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 and 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
15-79
Natural Killer (NK) Cells
Are
lymphocytes related to T-cells
Provide first line of cell-mediated defense
Considered to be part of the innate immune system
Possess an array of surface receptors that allow them
to fight viruses, bacteria, parasites and malignant cells
NK cells destroy tumors in a non-specific fashion;
backed up by specific response of killer T-cells
NKs are stimulated by interferon from T-cells
NKs attack cells that lack class-1 MHC antigens
Kill with perforins and granzymes
15-80
Immunotherapy for Cancer
Monoclonal
antibodies have been used
About 20-25% of breast cancer patients have HERZ
receptors on plasma membrane of tumor cells
Monoclonal antibodies for these receptors is commercially
available as Hereceptin, which blocks these receptors.
Human interferons obtained from genetically engineered
bacteria are now available
Have been used for treatment of some types of
lymphomas, renal carcinoma, and melanoma
15-81
Effects of Aging and Stress
Little
is known about why susceptibility to cancer is so
variable
Cancer risk increases 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
15-82
Diseases Caused By Immune
System
15-83
Diseases Caused by Immune System
Can
be grouped into 3 categories: autoimmune
diseases, immune complex diseases, and allergies
All caused by abnormal functioning of immune
system
15-84
Autoimmune Diseases
Are
produced by failure of immune system to
recognize and tolerate self-antigens
Autoreactive T-cells are formed and B-cells produce
autoantibodies
Afflicts women twice as often as men
15-85
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)
15-86
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
15-87
Autoimmune Diseases continued
Failure
of self-tolerance may be due to:
Antibodies being produced that are directed against
other antibodies
Happens with rheumatoid arthritis
15-88
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
15-89
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
15-90
Immune Complex Diseases
Involve
formation of immune complexes that are free
and not attached to a cell
These activate complement proteins and promote
inflammation
Can result from infections by bacteria, parasites,
viruses
Can result from formation of complexes between selfantigens and autoantibodies
This occurs in rheumatoid arthritis and lupus
15-91
Allergy (Hypersensitivity)
Is
an abnormal immune response to allergens
Comes in 2 forms: immediate and 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
15-92
Immediate Hypersensitivity
Dendritic
cells stimulate a class of helper Ts to
secrete interleukin-4 and -13 which cause B and
plasma cells to secrete IgE antibodies
IgE antibodies do not circulate in blood; are
attached to mast cells and basophils
When re-exposed to same allergen, antibodies on
mast cells and basophils bind it and stimulate
secretion of histamine, leukotrienes, and
prostaglandin D
Producing allergy symptoms
Histamine increases capillary permeability and
enhances immune response
15-93
Immediate Hypersensitivity continued
15-94
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
15-95