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