Transcript the immune system: innate and adaptive body

THE IMMUNE SYSTEM:
INNATE AND ADAPTIVE
BODY DEFENSES
INNATE (NONSPECIFIC) DEFENSES
• Includes two lines of defense:
– First Line of Defense:
• External Surface Barriers: Skin and Mucosae
– Second Line of Defense:
• Antimicrobial proteins
• Phagocytes
• Inflammation
Adaptive (Specific) Defense System
• Third Line of Defense:
– Takes considerably more time to mount than
the innate response
– Attacks particular foreign substances
(antigens)
INNATE (NONSPECIFIC) DEFENSES
• External Surface Barriers: Skin and Mucosae
• Skin, a highly keratinized epithelial membrane, represents a physical barrier
to most microorganisms and their enzymes and toxins
• Mucous membranes line all body cavities open to the exterior and function
as an additional physical barrier
• Secretions of the epithelial tissues include:
– Acidity of the skin secretions (pH 3 to 5)
» Inhibits bacterial growth
– Sebum contains chemicals that are toxic to bacteria
– Vaginal secretions of adult female are also very acidic
– Stomach:
» Mucosa secretes a concentrated hydrochloric acid solution and proteindigesting enzyme (both kill microorganisms)
– Saliva:
» Cleanses the oral cavity and teeth
– Lacrimal fluid of the eye contain lysozyme
» Enzyme that destroys bacteria
– Mucus (sticky):
» Traps many microorganisms that enter the digestive and respiratory
passageways (hairs, cilia)
INTERNAL DEFENSES:
CELLS AND CHEMICALS
• Nonspecific cellular and chemical devices to
protect itself:
– Recognize surface carbohydrates, proteins unique to
infectious organisms (bacteria, viruses, and fungi)
• Phagocytes, natural killer cells, antimicrobial
proteins, and fever
• The inflammatory response enlists
macrophages, mast cells, all types of white
blood cells, and dozens of chemicals that kill
pathogens and help repair tissue
• Fever
PHAGOCYTES
• Confront microorganisms that branch the
external barriers
– Macrophages are the main phagocytes of the
body
• Derive form white blood cells called monocytes that leave the
bloodstream, enter the tissues, and develop into
macrophages
– Free macrophages (alveolar macrophages of the lungs and
dendritic cells of the epidermis) wander throughout the tissue
spaces
– Fixed macrophages (Kupffer cells in the liver and microglia of
the brain) are permanent residents of particular organs
• All macrophages are similar structurally and functionally
PHAGOCYTES
• Neutrophils:
– Most abundant type of white blood cell
– Become phagocytic on encountering infectious material in the tissues
– Are the first responders and become phagocytes when they encounter
infectious material
• Eosinophils:
– Another type of white blood cell
– Are weakly phagocytic but are important in defending the body against
parasitic worms
• Mast cells:
– Role in allergies
– Have the ability to bond with, ingest, and kill a wide range of bacteria
– Normally not included as a phagocyte but they share their capabilities
Mechanism of Phagocytosis
• A phagocyte engulfs
particulate matter
much the way an
amoeba ingests a
food particle
• The phagosome thus
formed is then fused
with a lysosome to
form a
phagolysosome
Mechanism of Phagocytosis
• Pathogens can sometimes elude capture because
phagocytes cannot bind to their capsules (example:
pneumococcus)
– Adherence is both more probable and more efficient when
complement proteins and antibodies coat foreign particles,
a process called opsonization
• Coating provides sites to which the phagocytes receptors can bind
• Exception: Neutrophils produce antibiotic-like chemicals
(defensins) that pierce the pathogen’s membrane
– Unhappily, the neutrophils also destroy themselves in the
process, whereas macrophages, which rely only on
intracellular killing, can go on to kill another day
PHAGOCYTOSIS BY MACROPHAGES
Natural Killer Cells (NK)
• Are able to lyse and kill cancer cells and virally infected cells
before the adaptive immune system has been activated
• Are a small group of large granular lymphocytes
– UNLIKE lymphocytes of the adaptive immune system, which recognize
and react only against specific virus-infected or tumor cells, Natural
Killer cells are far less picky
• Detect the lack of “SELF” cell surface receptors and by recognizing
certain surface sugars on the target cell
• Name “natural” reflects this non-specificity of these cells
• Are not phagocytic
• Mode of killing involves an attack on the target cell’s membrane and
release of cytolytic chemicals called perforins
– Shortly after perforin release, channels appear in the target cell’s
membrane and its nucleus disintegrates
• Also secrete potent chemical that enhance the inflammatory
response
Inflammation: Tissue Response to Injury
• Occurs any time the body tissues are injured
by physical trauma, intense heat, irritating
chemicals, or infection by viruses, fungi, or
bacteria:
– The four cardinal signs of acute inflammation are
redness, heat, swelling, and pain
– Chemicals cause dilation of surrounding blood
vessels to increase blood flow to the area and
increase permeability, which allows fluid containing
clotting factors and antibodies to enter the tissues
– Soon after inflammation the damaged site is
invaded by neutrophils and macrophages
Inflammation Process
• Begins with a flood of inflammatory chemicals released into the
extracellular fluid
• Toll-like receptors (TLRs):
– Macrophages and certain cells lining the gastrointestinal tract and
respiratory tracts bear these surface membrane receptors
– Ten types have been identified:
• Each recognizing a specific class of attacking microbe
– Example:
» One type response to glycolipid in cell walls of tuberculosis bacterium
» One type response to a component of gram-negative bacteria such as
salmonelle
– Triggers release of cytokines that promote inflammation and attracts
WBCs
• Injured and stressed tissue cells, phagocytes, lymphocytes, mast
cells, and blood proteins are all sources of inflammatory mediators
– Histamine, kinins, prostaglandins
Inflammation Process
• All chemicals produced cause small blood vessels in
the injured area to dilate
– Local hyperemia results (accounting for the redness and
heat of an inflamed region)
• Swelling presses on adjacent nerves contributing to pain
– Pain also results from the release of bacterial toxins, lack of nutrition
to cells in the area, and the sensitizing effects of released
prostaglandins and kinins
» Aspirin and some other anti-inflammatory drugs produce their
analgesic (pain-reducing) effects by inhibiting prostaglandin
synthesis
– Increases the permeability of local capillaries
• Exudate fluid:
– Contains clotting factors (gel like substances that isolate the area,
preventing the spread of harmful agents) and antibodies
– Dilutes the harmful substances
– Brings in large quantities of oxygen and nutrients needed for repair
EVENTS IN INFLAMMATION
PHAGOCYTE MOBILIZATION
• Soon after inflammation begins, the
damaged area is invaded by more
phagocytes—neutrophils lead, followed
by macrophages
– If inflammation was provoked by pathogens
• A group of plasma proteins is activated
• Lymphocytes and antibodies invade the injured
site
PHAGOCYTE MOBILIZATION
• 1.Leukocytosis:
– Chemicals called
leukocytosis-inducing
factors released by injured
cells promote:
• Rapid release of
neutrophils from red bone
marrow
• Within a few hours the
number of neutrophils in
blood increases 4 to 5 fold
– Increase in WBCs
– Characteristic of
inflammation
PHAGOCYTE MOBILIZATION
• 2.Margination
(pavementing):
– Neutrophils adhesion
molecules (CAMs)
help them cling to the
inner walls of the
capillaries and postcapillary venules
PHAGOCYTE MOBILIZATION
• 3.Diapedesis
(emigration):
– Continued chemical
signaling prompts the
neutrophils to squeeze
through the capillary
walls
PHAGOCYTE MOBILIZATION
• 4.Chemotaxis:
– Neutrophils usually migrate
randomly, but inflammatory
chemicals act as homing
devices (chemotactic
agents)
• Attract the neutrophils and
other WBCs to the site of
the injury
– Within an hour after the
inflammatory response
has begun, neutrophils
have collected at the site
and are devouring any
foreign material present
PHAGOCYTE MOBILIZATION
PHAGOCYTE MOBILIZATION
• Monocytes follow neutrophils into the
injured area:
– Develop large numbers of lysosomes with
insatiable appetites
– Replace the neutrophils in the battlefield
– Central actors in the final disposal of cell
debris as an acute inflammation subsides,
and they predominate at suites of
prolonged, or chronic, inflammation
PHAGOCYTE MOBILIZATION
• The ultimate goal of an inflammatory
response is to clear the injured area of
pathogens, dead tissue cells, and any
other debris so that tissue can be
repaired
• Once this is accomplished, healing usually
occurs quickly
HOMEOSTATIC IMBALANCE
• In severely infected areas, the battle takes a
considerable toll on both sides, and creamy,
yellow pus, a mixture of dead or dying
neutrophils, broken-down tissue cells, and
living and dead pathogens, may accumulate
in the wound
• If the inflammatory mechanism fails to clear
the area of debris, the sac of pus may be
walled off by collagen fibers, forming an
abscess
– Surgical drainage of abscesses is often necessary
before healing can occur
HOMEOSTATIC IMBALANCE
• Tuberculosis bacilli:
– Some escape resistant to digestion by macrophages
– Escape the effects of antibiotics by remaining
enclosed within the macrophage host (infectious
granulomas)
• Tumorlike growth can develop
– Central region of infected macrophages surrounded by
uninfected macrophages encased by an outer fibrous capsule
• Could harbor these pathogens for years without symptoms
– Could break out and become active
Antimicrobial proteins
• Enhance the innate defenses by
attacking microorganisms directly or
by hindering their ability to reproduce
– Interferon
– Complement proteins
Interferon
•
•
Virally infected cells can do
little to save themselves, some
can secrete small proteins to help
protect cells that have not yet
been infected
Small proteins produced by
virally infected cells that help
protect surrounding healthy
cells
– Interferon diffuses to nearby
cells, where they stimulate
synthesis of a protein known as
PKR, which then “interferes” with
viral replication in the still-healthy
cells by blocking protein synthesis
at the ribosomes
•
•
Not virus specific
Produced against a particular
virus—protects against a variety of
other viruses
INTERFERON MECHANISM
Interferon
• Family of related proteins, produced by a variety of
body cells, each having a slightly different
physiological effect
• Lymphophytes secrete gamma (immune) interferon
• Most other leukocytes secrete alpha interferon
– Used to treat genital warts and hepatitis C (spread by blood
and sexual intercourse)
• Fibroblasts secrete beta interferon
– Active in reducing inflammation
• Besides anti-viral effects, activates Macrophages
and Natural Killer Cells
COMPLEMENT
• Complement (fills up or completes) refers to
a group of about 20 plasma proteins that
provide a major mechanism for destroying
foreign pathogens in the body
– Normally circulate in the blood in an inactive state
– C1 through C9
– B, D, and P, plus several regulatory proteins
• Activation unleashes chemical mediators that
amplify virtually all aspects of the inflammatory
process
• Non-specific defense mechanism
COMPLEMENT
• Can be activated by two
pathways:
– Classical: involves
antibodies, water-soluble
protein molecules that the
adaptive immune system
produces to fight off foreign
invaders
– Alternative: triggered
when factors B, D, and P
interact with
polysaccharide molecules
present on the surface of
certain microorganisms
– Each mechanism
involves a cascade
EVENTS AND RESULTS OF
COMPLEMENT ACTIVATION
Fever
• Abnormally high body temperature, is a
systemic response to microorganisms
• Systemic (whole body rather than to one of its
parts) response to invading microorganisms
• The hypothalamus (body temperature) is reset in
response to chemicals called pyrogens,
secreted by leukocytes and macrophages
exposed to foreign substances in the body
• High fevers are dangerous
– Denature proteins
Innate/Adaptive Defenses
• Unlike the innate system, which is
always ready and able to react, the
adaptive system must “meet” or be
primed by an initial exposure to a
specific foreign substance (antigen) before
it can protect the body against that
substance, and this priming takes precious
time
ADAPTIVE (SPECIFIC) DEFENSES
• Aspects of the Adaptive Immune Response
– It is specific:
• Recognize and destroy the specific antigen that initiated the
response
– It is systemic:
• Not limited (restricted) to the initial infection site
– It has “memory”:
• After an initial exposure the immune response is able to
recognize the same antigen and mount a faster and stronger
defensive attack
ADAPTIVE DEFENSES
• Humoral (humors: fluids) immunity:
– Antibody-mediated immunity
– Provided by antibodies present in the body’s
“humors” or fluids
– Produced by B lymphocytes
– Circulate freely in the blood and lymph
– Mark bacteria, bacterial toxins, viruses for
destruction by phagocytes or complement
ADAPTIVE DEFENSES
• Cellular (cell-mediated) immunity:
– Protective factor is a living cell
– Cellular targets:
• Virus-infected tissue cells
• Parasite-infected tissue cells
• Cancer cells of foreign graft
– Lymphocytes act either:
• Directly by lysing the foreign cells
• Indirectly by releasing chemical mediators that enhance the
inflammatory response or activate other lymphocytes or
macrophages
– Associated with T lymphocytes and has living cells as
its protective factor
ANTIGENS
• Substances that can mobilize the
immune system and provoke an
immune response
– Ultimate targets of all immune responses
• Most are large, complex molecules (both
natural and synthetic) that are not normally
present in the body (NONSELF)
• Can be complete or incomplete
COMPLETE ANTIGENS
• Two important functional properties are:
– 1. Immunogenicity:
• ability to stimulate the proliferation of specific lymphocytes
and antibodies
– 2. Reactivity:
– Ability react with the activated lymphocytes and produced
antibodies
• Limitless variety:
– All foreign proteins, nucleic acids, some lipids, and
many large polysaccharides
• Proteins are the strongest antigens
– Pollen, microorganisms, fungi, viruses
ANTIGENS
• Haptens are incomplete antigens that are not
capable of stimulating the immune response, but if
they interact with proteins of the body they may be
recognized as potentially harmful
– Small peptides, nucleotides, and many hormones—are NOT
immunogenic
– Certain chemicals: antibiotics, chemicals in poison ivy, animal
dander, detergents, cosmetics, etc.—NOT immunogenic
• BUT, if they link up with the body’s own proteins, the adaptive
immune system may recognize the combination as foreign and
mount an attack that is harmful rather than protective
(allergies)
– Have reactivity but NOT immunogenicity
ANTIGENIC DETERMINANTS
• Specific part of an
antigen that has
immunogenic
properties:
– Bind to free antibodies
or activated
lymphocytes in much
the same manner as
an enzyme binds to a
substrate
ANTIGENIC DETERMINANTS
• Large proteins have hundreds of chemically
different antigenic determinants, which
accounts for their high immunogenicity and
reactivity
• Large simple molecules such as plastics, which
have many identical, regularly repeating
units, have little or no immunogenicity
– Such substances are used to make artificial implants
ANTIGENIC DETERMINANTS
Self-Antigens: MHC Proteins
• The external surface of all our cells are dotted with a
huge variety of protein molecules
– These self-antigens are not foreign or antigenic to us, BUT they
are strongly antigenic to other individuals
• MHC proteins: major histocompatibility complex
– Group of glycoproteins: surface proteins that mark a cell as
SELF
• Coded for by genes
• Only identical twins have the same gene code
• Two major groups:
– Class I: found on virtually all body cells
– Class II: found only on certain cells that act in the immune
response
ADAPTIVE (SPECIFIC) DEFENSES
• Cells of the Adaptive Immune System
– Three cell types:
• Two types of lymphocytes:
– B lymphocytes (B cells)
» Oversees humoral immunity
– T lymphocytes (T cells)
» Non-antibody-producing
» Constitute the cell-mediated arm of adaptive
immunity
• Antigen-presenting cells (APCs)
– Do not respond to specific antigens but instead play
essential auxiliary roles
LYMPHOCYTES
• Originate in the red bone marrow from
hematopoietic stem cells
• When released from bone marrow, the
immature lymphocytes are essentially
identical
– Maturation (into T cells / B cells) depends
on where in the body they become
immunocompetent, that is, able to recognize a
specific antigen by binding to it
LYMPHOCYTES
•
T cells mature in the Thymus
under direction of thymic
hormone
– Positive selection produces selfMHC restricted T cells
• Those cells that are able to
recognize SELF are allowed to
continue the maturation process
• Those that fail undergo apoptosis
(programmed death of cells)
– Negative selection identifies T
cells that are self-tolerant
• Those that react too vigorously
with self MHC are selected
against and eliminated
• This ensures that the T cells
surviving this second screening
process exhibit self tolerance
(relative unresponsiveness to self
antigens)
T CELL SELECTION IN THE THYMUS
LYMPHOCYTES
• B cells become immunocompetent and
self-tolerant in bone marrow
– Mechanism is not completely understood but
appears to be very similar to the thymus
Lymphoid Organs
• Location where lymphocytes become
immunocompetent
– Primary lymphoid organs:
• Thymus
• Bone marrow
– Secondary lymphoid organs:
• All other organs
LYMPHOCYTES
•
•
When B or T cells become immunocompetent, they display a unique
type of receptor on their surface:
– Enable the lymphocyte to recognize and bind to a specific antigen
• Once these receptors appear, the lymphocyte is committed to react
to one distinct antigenic determinant, and one only, because all of
its antigen receptors are the same
Lymphocytes become immunocompetent before meeting the antigens
they may later attack
– It is our genes, not antigens, that determine what specific foreign
substances our immune system will be able to recognize and
resist
– Only some of the antigens our lymphocytes are programmed to
resist will ever invade our bodies:
• Only some of our immunocompetent cells are mobilized in our
life-time
– Others are forever idle
LYMPHOCYTES
• Immunocompetent (still
immature) T cells and B
cells are exported to the
lymph nodes, spleen,
and other secondary
lymphoid organs, where
the encounters with
antigens occur
– When the lymphocytes
complete their
differentiation into fully
functional—mature,
antigen-activated—T cells
and B cells
LYMPHOCYTE TRAFFIC
Antigen-Presenting Cells
APC
• Engulf antigens and present fragments of these antigens on
their surface where they can be recognized by T cells
– They present antigens to the cells that will destroy them
– Examples:
• Dendritic cells in connective tissues
• Langerhan’s cells of the skin epidermis
– Also secrete soluble proteins that activate T cells
• Macrophages (lymphoid organs and connective tissues
– Also secrete soluble proteins that activate T cells
• Activated B lymphocytes
• Activated T cells, in turn, release chemicals that rev up the
mobilization and maturation of dendritic cells and
macrophages and secrete bactericidal chemicals
– Interaction between various lymphocytes, and between lymphocytes
and APCs, underlie virtually all phases of the immune response
HUMORAL IMMUNE RESPONSE
• Humoral refers events taking place in
blood or body fluids
• The first encounter between an
immunocompetent but naïve B lymphocyte
and an invading antigen, usually takes
place in the spleen or in a lymph node,
but it may happen in any lymphoid
tissue
• Activated when antigens bind to its surface
receptors
HUMORAL IMMUNE RESPONSE
• Clonal selection is the
process of the B cell
growing and multiplying to
form an army of cells that
are capable of recognizing
the same antigen
• The resulting family of identical
cells, all descended from the
same ancestor cell, is called a
clone
• It is the antigen that does the
selecting in clonal selection by
“choosing” a lymphocyte with
complementary receptors
Clonal selection of a B Cell
stimulated by Antigen Binding
HUMORAL IMMUNE RESPONSE
Clonal Selection and Differentiation of B Cells
• Most cells of the clone become plasma cells
– Plasma cells are the antibody-secreting cells of
the humoral response
• Although B cells secrete limited amounts of antibodies,
plasma cells develop the elaborate internal machinery
(largely rough endoplasmic reticulum) needed to secrete
antibodies at the unbelievable rate of about 2000
molecules per second
– Each plasma cell functions at this pace for 4-5 days and then
dies
– The secreted antibodies, each with the same antigen-binding
properties as the receptor molecules on the surface of the
parent B cell, circulate in the blood or lymph, where they bind to
free antigens and mark them for destruction by other specific or
nonspecific mechanisms
HUMORAL IMMUNE RESPONSE
Clonal Selection and Differentiation of B Cells
• The clones that do
not become plasma
cells develop into
memory cells
– Mount an almost
immediate humoral
response if they
encounter then same
antigen again at some
future time
Clonal selection of a B Cell
stimulated by Antigen Binding
HUMORAL IMMUNE RESPONSE
Immunological Memory
• The primary immune
response (explained on the
previous slides) occurs on
first exposure to a particular
antigen with a lag time of
about 3-6 days
– Allowing time for the few B
cells specific for that antigen
to proliferate and for their
offspring to differentiate into
plasma cells
– After the mobilization period,
plasma antibody levels rise,
reach peak levels in about 10
days, and then decline
Primary and Secondary Humoral Responses
HUMORAL IMMUNE RESPONSE
Immunological Memory
•
•
•
•
•
When re-exposed to the same antigen, whether it’s the second or the
twenty-second time, a secondary immune response occurs
– It is faster, more prolonged, and more effective, because the
immune system has already been primed to the antigen, and sensitized
memory cells are already in place (on alert)
Within hours after recognition of the old antigen, a new army of plasma
cells is being generated
– Within 2-3 days the antibody concentration in the blood rises steeply
Secondary antibodies not only bind with greater affinity, but their
blood levels remain high for weeks to months
Memory cells persist for long periods in humans and many retain their
capacity to produce powerful secondary humoral responses for life
The same general phenomena occur in the cellular immune response:
A primary response sets up a pool of activated lymphocytes (in this
case, T cells) and generates memory cells that can then mount
secondary responses
Active Humoral Immunity
• Active Humoral
Immunity:
– When B cells encounter
antigens and produce
antibodies against them
• 1.Naturally acquired
when you get a bacterial
or viral infection, during
which time you may
develop symptoms of the
disease and suffer a little
(or a lot)
• 2.Artifically acquired
when you receive
vaccines
TYPES OF ACQUIRED IMMUNITY
Active Humoral Immunity
• Active immunity occurs when the body
mounts an immune response to an antigen
– Naturally acquired active immunity occurs when a
person suffers through the symptoms of an infection
– Artificially acquired active immunity occurs when a
person is given a vaccine
• Once it was realized that secondary
responses are so much more vigorous than
primaries, the race was on to develop
vaccines to “prime” the immune response by
providing a first meeting with the antigen
VACCINES
• Most contain dead or attenuated (living, but extremely
weakened) pathogens, or their components
• Two benefits:
– 1.They spare us most of the symptoms and discomfort of the disease
that would otherwise occur during the primary response
– 2.Their weakened antigens provide functional antigenic determinants
that are both immunogenic and reactive
• Vaccine booster shots: may intensify the immune response at
later meetings with the same antigen
• Shortcomings:
– Lots of antibodies are formed that provide immediate protection,
but cellular immunological memory is only poorly established
– In rare cases, vaccines cause the very disease they are trying to
prevent because the attenuated antigen isn’t weakened enough
– Vaccines may trigger an allergic response
Passive Humoral Immunity
• Passive humoral immunity
– Differs from active
immunity:
• In the antibody source:
– Instead of being made by
your plasma cells, the
antibodies are harvested
from the serum of an
immune human or animal
donor
• In the degree of protection
it provides:
– Your B cells are NOT
challenged by antigens
– Immunological memory
does NOT occur
– Protection provided by the
“borrowed” antibodies ends
when they naturally degrade
in the body
TYPES OF ACQUIRED IMMUNITY
Passive Humoral Immunity
• Occurs when a person is given preformed antibodies
– Naturally acquired passive immunity occurs when a mother’s
antibodies enter fetal circulating through the placenta
– Artificially acquired immunity occurs when a person is given
preformed antibodies that have been harvested from another
person
• Some diseases are rapidly fatal and would kill a person before
active immunity could be established
– The denoted antibodies provide immediate protection, but their effect is
short-lived (2-3 weeks)
» Gamma globulin
» Antivenom (snake bites)
» Antitoxin (tetanus)
» Rabies
» Botulism
ANTIBODIES
• Also called immunoglobulins
– Constitute the gamma globulin part of blood
proteins
• Proteins secreted by activated B cells
or plasma cells in response to an
antigen that are capable of binding to
that antigen
ANTIBODIES
• The basic antibody
structure consists of
four looping
polypeptide chains
linked together by
disulfide bonds:
– Two identical chains
(Heavy: H chains) contain
approximately 400 amino
acids
– Two identical chains
(Light: L chains) fewer
amino acids
• Flexible at the hinge
region
ANTIBODIES
• V region: Variable
region: the H and L
chains combine to
form an antigenbinding site shaped to
fit a specific antigenic
determinant
ANTIBODIES
• C region: forms the stem of
the antibody:
– Determines the antibody class
– Common function in all
antibodies
– Effector region dictates:
• 1.The cells and chemicals the
antibody can bind to
• 2. How the antibody class
functions in antigen
elimination
– Example: some antibodies
can fix complement, some
circulate in blood, some in
body secretions, some cross
the placental barrier, etc.
BASIC ANTIBODY STRUCTURE
ANTIBODIES
• Grouped into five classes:
– Antibodies are divided into five classes:
• Based on the C regions in their heavy (H) chains (structure): IgM,
IgA, IgD, IgG, IgE
– Remember the name MADGE
– All have the same Y-shape structure (are monomers)
– Different biological roles and locations in the body:
•
•
•
•
IgM: released to the blood by plasma cells
IgA: primarily in mucus and other secretions
IgD: bound to B cell receptor
IgG: most abundant antibody in the plasma
– Only class that crosses the placental barrier
• IgE: almost never found in the blood
– Involved in some allergies
Mechanism of Antibody Diversity
• Embryonic cells contain a few hundred
gene segments that are shuffled and
combined to form all of the different B cells
that are found in the body
Antibody Targets and Functions
Antigen-antibody (immune) complexes
•
•
Though antibodies cannot
themselves destroy antigens,
they can inactivate them and
tag them for destruction
Complement fixation and
activation:
– Used against cellular antigens
(bacteria, mismatched Red Blood
Cells)
– Occurs when complement (C
regions) binds to antibodies
attached to antigens, and leads to
lysis of the cell
– Molecules released amplify the
inflammatory response, promote
phagocytosis via opsonization
(coating of foreign antigens that
makes them more susceptible)
Antibody Targets and Functions
Antigen-antibody (immune) complexes
• Neutralization:
– Occurs when antibodies
block specific sites on
viruses or bacterial
exotoxins (toxic chemicals
secreted by bacteria)
• Loses its toxic effects
because it cannot bind to
receptors on tissue cells to
cause injury
– The antigen-antibody
complexes are eventually
destroyed by phagocytes
– Occurs when antibodies block
specific sites on viruses or
bacterial exotoxins, causing
them to lose their toxic effects
Antibody Targets and Functions
Antigen-antibody (immune) complexes
• Agglutination occurs when
antibodies cross-link to
antigens on cells, causing
clumping:
– Because antibodies have
more than one antigenbinding site, they can
bind to the same
determinant on more
than one antigen at a
time
• Consequently, antigenantibody complexes
can be cross-linked into
large lattices
– Basis of blood typing
Antibody Targets and Functions
Antigen-antibody (immune) complexes
• Precipitation:
– Occurs when soluble
molecules are crosslinked into large
complexes that settle
out of solution
• More easily captured
and engulfed by
phagocytes than are
freely moving antigens
Antibody Targets and Functions
Antigen-antibody (immune) complexes
• A quick way to remember how antibodies
work is to remember they have a PLAN of
action—Precipitation, Lysis (by
complement), Agglutination, and
Neutralization
MECHANISM OF ANTIBODY ACTION
Monoclonal Antibodies
• Produced by descendents of a single cell
• Produce a single type of antibody
• Are commercially prepared antibodies specific for a
single antigenic determinant
• Used to diagnose:
–
–
–
–
–
Pregnancy
STDs
Types of cancer
Hepatitis
Rabies
• Used to treat:
– Leukemia (WBC)
– Lymphomas (Lymph nodes)
CELL-MEDIATED IMMUNE RESPONSE
• Despite their immense versatility,
antibodies provide only partial
immunity
– Their prey is the obvious pathogen
– They are fairly useless against infectious
microorganisms like the tuberculosis bacillus
which quickly slips inside body cells to
multiply there
– In these cases, the cell-mediated arm of
adaptive immunity comes into play
CELL-MEDIATED IMMUNE RESPONSE
•
•
The T cells that mediate cellular
immunity are a diverse lot, much more
complex than B cells in both
classification and function
There are two major types of effector T
cells based on which of a pair of structurally
related cell differentiation glycoproteins
(CD4 or CD8) is displayed by a mature T cell
–
These glycoprotein surface receptors, which
are distinct from the T cell antigen receptors,
play a role in interactions between a tissue
cell and other cells or foreign antigens
•
•
CD4 cells (T4 cells) are primarily helper T cells
(TH)
CD8 cells (T8 cells) are cytotoxic T cells (T C)
–
•
•
Role is to destroy any cells in the body that
harbor anything foreign
In addition to these two major groups of
T cells, there are suppressor T cells (TS),
memory T cells, and some fairly rare
subgroups
The stimulus for clonal selection and
differentiation of T cells is binding of antigen,
although their recognition mechanism is
different from B cells
T CELL TYPES
COMPARISON
•
•
HUMORAL RESPONSE
Antibodies produced by plasma
cells
– Specialized to latch onto bacteria
and soluble foreign molecules in
extracellular environments (body
secretions, tissue fluid, blood,
lymph)
– Never invade solid tissue lesion is
present
•
•
Antibody production and pathogen
multiplication are in a race against
each other
Forming antibody-antigen
complexes does not destroy the
antigens
– Prepares them for destruction by
innate defenses and activated T
cells
•
•
•
•
CELLULAR RESPONSE
In contrast to B cells and
antibodies, T cells cannot “see”
antigens
T cells can recognize and respond
only to processed fragments of
protein antigens displayed on
body cell surfaces (APCs and
others) and then only under
specific circumstances
T cells are best suited for cell-tocell interactions
– Most of their direct attacks on
antigens (mediated by the
cytotoxic T cells) target body cells:
• Infected by viruses or bacteria
• Abnormal or cancerous body cells
• Cells of infused or transplanted
foreign tissues
Clonal Selection and Differentiation of T Cells
• The stimulus for clonal selection and
differentiation of T cells is the same in B
cells and T cells—binding of antigen
• However, the mechanism by which T cells
recognize “their” antigen is very
different than that seen in B cells and
has some unique restrictions
Clonal Selection and Differentiation of T Cells
Antigen Recognition and MHC Restriction
• Like B cells, immunocompetent T cells are
activated when the variable regions of their
surface receptors bind to a “recognized”
antigen
• However, T cells must accomplish double
recognition:
– They must simultaneously recognize nonself (the
antigen) and self (a MHC protein of a body cell)
– Two types of MHC (Major Histocompatibility Complex)
proteins are important to T cell activities
Clonal Selection and Differentiation of T Cells
Antigen Recognition and MHC Restriction
• Class I MHC proteins:
– Displayed by virtually all body
cells except red blood cells
and are always recognized by
CD8 T cells (cytotoxic T cells:
TC)
– Pick up peptide fragments in
the ER:
• May be derived from selfproteins
• Or from ENDOGENOUS
ANTIGENS (foreign) : viral
proteins or cancer proteins
made within the cell
– Migrates to the plasma
membrane to display its
attached protein fragment
– Widely distributed
MHC class I proteins pick up
peptide fragments in the ER
Clonal Selection and Differentiation of T Cells
Antigen Recognition and MHC Restriction
•
Class II MHC proteins:
– Typically found only on the
surface of mature B cells, some T
cells, and antigen-presenting
cells, where they enable the cells
of the immune system to
recognize one another
– Like Class I MHC, synthesized at
the ER and bind to peptide
fragments
• EXOGENOUS ANTIGENS
(foreign): antigens that have been
phagocytosed and broken down in
the phagolysosome vesicle
• Class II MHC protein moves from
the ER through the Golgi
apparatus and into a
phagolysosome
• Ultimately attach to cell surface for
recognition by CD4 (T4 cells:
helper T cells: TH)
MHC class II proteins pick up peptide
fragments from endocytosed vesicles
Clonal Selection and Differentiation of T Cells
Antigen Recognition and MHC Restriction
Role of MHC Proteins in the Immune Response
• Provide the means for signaling to
immune system cells that infectious
microorganisms are hiding in body
cells
T Cell Activation
• Two-Step Process:
– Antigen binding
– Co-stimulation
Antigen Binding
• T cell antigen receptors
(TCRs) bind to an
antigen-MHC complex
on the surface of a
body cell
– Helper T cells (CD4)(T4
cells)(TH) can bind only to
antigens linked to class II
MHC proteins
– Cytotoxic T cells
(CD8)(T8 cells)(TC)
activated by antigen
fragments complexed with
class I MHC proteins
Cloning Selection of TC and TH Cells
• Both cells are stimulated to
proliferate (clone) and
complete their differentiation
when they bind to parts of
foreign antigens complexed to
MHC proteins
• Immunocompetent TC cells
are activated when they bind
to endogenous antigens
(nonself)—part of a virus in this
example—complexed to a
class I MHC protein
• Activation of TH cells is similar,
except that the processed
antigen is complexed with a
class II MHC protein
Clonal selection of cytotoxic (Tc) and helper (TH) T cells
involves simultaneous recognition of self and antiself
Co-stimulation (a)
•
Before a T cell can proliferate and
form a clone, it must recognize one
or more co-stimulatory signals
–
–
–
Other receptors on an APC (antigenpresenting cell)
Cytokine chemicals: proteins produced
by WBCs which regulate immune
responses
Interleukins chemicals: enable
communication between WBCs in
immune response reactions
•
•
Stimulates mitosis
Once activated, a T cell enlarges
and proliferates to form a clone of
cells that differentiate and perform
functions according to their T cell
class
–
Once they have done their job, the
effector T cells are unnecessary and
thus disposable
CENTRAL ROLE OF HELPER T CELLS
Specific T Cell Roles(b)
• Helper T cells (TH) (primed
by APC presentation of
antigen) stimulate
proliferation of other T cells
and B cells that have already
become bound to antigen
– Without TH there is NO
immune response
– Their cytokines furnish the
chemical help needed to
recruit other immune cells to
fight off intruders, prodding the
B cells into more rapid
divisions
– Signal for antibody formation
to begin
– Unleash the protective
potential of B cells
CENTRAL ROLE OF HELPER T CELLS
Specific T Cell Roles
• Cytotoxic T cells (TC), also
called killer T cells, are the
only T cells that can directly
attack and kill other cells
displaying antigen to which
they have been sensitized
– Circulate in and out of the
blood and lymph
– Main targets are virus-infected
cells, but they also attack
tissue cells infected by certain
intracellular bacteria or
parasites, cancer cells, and
foreign cells introduced into
the body by blood transfusions
or organ transplants
– Induce target cell lysis
Cytotoxic T cells attack infected
and cancerous cells
Specific T Cell Roles
• Suppressor T cells (TS) release cytokines that suppress the
activity of both B cells and other types of T cells
– Regulatory cells
– Though to be vital for winding down and finally stopping the immune
response after an antigen has been inactivated or destroyed
– Helps prevent runaway or unnecessary immune system activity
– Because of their inhibitory role, presumed to be important in preventing
autoimmune reactions
– Activation process is still hypothetical
• Gamma delta T cells (Tgd):
– Found in the intestine and are more similar to NK (natural killer) cells
than other T cells
• Without helper T cells there is no adaptive immune response
because the helper T cells direct or help complete the
activation of all other immune cells
PRIMARY IMMUNE RESPONSE
Organ Transplants and Prevention of Rejection
•
Grafts:
–
–
–
–
Autografts are tissue grafts transplanted from one body site to another in the same parson
Isografts are grafts donated to a patient by a genetically identical individual such as an
identical twin
Allografts are grafts transplanted from individuals that are not genetically identical but belong
to the same species
Xenografts are grafts taken from another animal species
•
•
•
Transplant success depends on the similarity of the tissues because cytotoxic T
cells, NK cells, and antibodies work to destroy foreign tissues
Following surgery the patient is treated with immunosuppressive therapy
involving drugs of the following categories:
–
–
–
1. Corticosteroid drugs to suppress inflammation
2. Antiproliferative drugs
3. Immunosuppressant drugs
•
•
•
Example: transplanting a baboon heart into a human being
Suppresses immune system
Increases susceptibility to viral and bacterial infections
Key to success is to provide enough immunosuppression to prevent rejection
but not enough to be toxic, and to use antibiotics to keep infection under
control
HOMEOSTATIC IMBALANCE
• Immunodeficiencies are any congenital or acquired
conditions that cause immune cells, phagocytes, or
complement to behave abnormally
– Severe combined immunodeficiency (SCID) is a congenital
condition that produces a deficit of B and T cells
• Little or no protection against disease-causing organisms of any
type
• Successful transplants of bone marrow tissue or cultured stem cells
from umbilical cord blood improve survival rates
• Genetic engineering using virus vectors is still experimental
– Acquired immune deficiency syndrome (AIDS) cripples the
immune system by interfering with helper T cells
HOMEOSTATIC IMBALANCE
• Autoimmune diseases occur when the immune system loses its
ability to differentiate between self and nonself and ultimately
destroys itself
– Hodgkin’s disease: cancer of the lymph nodes
• Leads to immunodeficiency by depressing lymph node cells
– AIDS (acquired immune deficiency syndrome)
• Cripples the immune system by interfering with the activity of helper T cells
(TH)
• HIV (human immunodeficiency virus) (RNA virus) coat glycoprotein fits into
the CD4 of TH receptor like a plug fits into a socket
– Once inside, HIV uses the enzyme reverse transcriptase to produce DNA from the
information encoded in its (viral) RNA
– This DNA inserts itself into the target cell’s DNA and directs the cell to produce
viral RNA and proteins so that the virus can multiply and infect other cells
» HIV reverse transcriptase enzyme is not very accurate and produces
errors frequently, causing HIV’s high mutation rate and its changing
resistance to drugs
AUTOIMMUNE DISEASES
•
•
•
Immune system loses its ability to distinguish self from foreign antigens
Immune system turns on itself
Body produces antibodies (autoantibodies) and sensitized TC cells that destroy
its own tissues
–
Multiple sclerosis: destroys the white matter of the brain and spinal cord
•
–
–
–
–
–
–
•
Injection of genetically engineered antibodies to the CD4 receptors on T H cells seem to stabilize the
condition
Myasthenia gravis: impairs communication between nerves and skeletal muscles
Grave’s disease: prompts the thyroid gland to produce excessive amounts of thyroxine
Type I (juvenile) diabetes mellitus: destroys pancreatic beta cells, resulting in a deficit of
insulin and inability to use carbohydrates
Systemic lupus erythematosus (SLE): systemic (whole body not part) disease that
particularly affects the kidneys, heart, lungs, and skin
Glomerulonephritis: severe impairment of renal function
Rheumatoid arthritis: systematically destroys joints
More recent is the drug thalidomide
–
–
Morning sickness drug for pregnant women (birth defects)
Inhibits the immune system’s production of TNF (Tumor necrosis factor: enhances
nonspecific killing)
HYPERSENSITIVITIES
ALLERGIES
• Allergies, are the result of the immune
system causing tissue damage as it
fights off a perceived threat that would
otherwise be harmless
– Term allergen is used to distinguish the
antigen from those producing essentially
normal responses
HYPERSENSITIVITIES
ALLERGIES
•
•
•
Immediate hypersensitivities (acute:
Type1) begin within seconds after
contact and last about half an hour
(pollen, bee sting, spider bite, food,
antibiotics, dust mites, etc.)
When IgE antibody molecules bind
to mast cells and basophils,
sensitization is complete
Most common type is anaphylaxis:
– Initial meeting with an allergen
produces no symptoms but it
sensitizes the person
– Anaphylaxis is triggered at later
encounters with the same allergen
• Induces an enzymatic
cascade that causes the mast
cells and basophils to
degranulate, releasing a flood
of histamine and other
inflammatory chemicals
MECHANISM OF AN ACUTE
ALLERGIC RESPONSE
HYPERSENSITIVITIES
ALLERGIES
•
•
•
•
Subacute hypersensitivities take 1-3 hours to occur and last 10-15
hours
Caused by antibodies IgG and IgM
Can be transferred via blood or serum
Type II:
– Stimulates phagocytosis and comlement-mediated lysis of the cellular antigens
– Transfusion of mismatched blood
•
Type III:
– Insoluble antigen-antibody complexes are widespread throughout the body and
blood
• Cannot be cleared
• Intense inflammatory reaction
• Cell lysis and killing that damages tissue
–
–
–
–
Farmer’s lung: inhaling moldy hay
Glomerulonephritis
Systemic lupus erythematosus
Rheumatoid arthritis
HYPERSENSITIVITIES
ALLERGIES
• Delayed hypersensitivities reactions take 1-3
days to occur and may take weeks to go away
• Type IV:
– Can be passively transferred in blood transfusions
– Contact dermatitis:
•
•
•
•
Poison ivy
Heavy metals ( lead, mercury, etc.)
Certain cosmetic and deodorant chemicals
Tuberculin test
DEVELOPMENTAL ASPECTS
OF THE IMMUNE SYSTEM
• Embryologic Development
– Stem cells of the immune system originate in
the liver and spleen during weeks 1-9 of
embryonic development; later the bone
marrow takes over this role
– In late fetal life and shortly after birth the
young lymphocytes develop self-tolerance
and immunocompetence
• Later in life the ability and efficiency of
our immune system declines