Transcript Our Body’s Defenses - Bio-Guru

Our Body’s Defenses
Chapter 43
Composition of Mammalian Blood
Differentiation of blood cells
(release Histamine in
response to tissue injury)
The Kidneys
convert a
plasma protein
into a hormone
called
erythropoietin,
which
stimulates the
bone marrow to
produce
erythrocytes
(Destroy larger invaders by
Secreting destructive enzymes)
(Become macrophages
“big eaters”)
(Phagocytes)
THE FIRST LINE OF DEFENSE
Non-Specific
The First Line of Defense
Skin and Mucous membranes
Physical barriers
• Skin is a barrier when intact. Bacteria and viruses cannot
penetrate it
• Mucous membranes of various internal tracts (G.I., Respiratory,
Urogenital) prevent entry of various microbes
Chemical barriers
• The skin’s sebaceous glands and sweat glands maintain skin’s
pH at 3 to 5 – too acidic for “visiting” microbes – normal flora of
skin are unaffected, but usually not harmful (opportunistic)
• Saliva, tears and mucous contain antimicrobial agents and
enzymes like lysozymes
• Mucus in the upper respiratory tract, ear wax traps microbes
• Stomach acid kills pathogens (although some survive - viruses
like Hepatitis A, certain bacteria like E.coli and parasitic worms)
THE SECOND LINE OF DEFENSE
Non-Specific a.k.a Innate
The Second Line of Defense
Phagocytic WBCs, Inflammatory response, Antimicrobial proteins
• Neutrophils, Eosinophils, Natural Killer
cells, Monocytes (macrophages)
• Chemicals such as
– Histamine released by mast cells and
basophils
– pyrogens such as Interleukin 1
– Chemokines such as Interleukins 1 and 2
• Complement system, interferons
White Blood Cells (Leukocytes)
• are far fewer than RBCs (only 10% of blood cells - the
remaining 90% is RBCs)
• have nuclei and other organelles
• participate in protecting the body from infection
• consist of:
Granulocytes (three types) whose cytoplasm is filled with granules
– neutrophils, basophils, eosinophils Second Line of Defense (non-specific)
Agranulocytes
– monocytes with relatively clear cytoplasm Second Line of Defense
(non-specific)
– lymphocytes (T-cells, B-cells, Natural killer cells, etc)
Specific defense (Immune System)
(Non-specific defense)
Granulocytes vs.
Agranulocytes
Granulocytes are a type of white
Blood cell (Leukocyte) that
attacks and destroys foreign
substances. They have specific
granules in their cytoplasm.
The three different types of
granulocytes have different
types of specific granules.
They are spherical in shape,
contain nuclei.
- neutrophils,
- eosinophils, and
- Basophils
Monocytes and macrophages are
agranulocytes.
NEUTROPHILS (Granulocytes)
• The most common type of
Phagocyte it makes up 50 to
70% of the White Blood Cells in
the body. Neutrophils circulate
freely through blood vessels, and
they can squeeze between cells
in the walls of a capillary to reach
the site of infection. They then
engulf and destroy any
pathogens they encounter.
• They move form blood vessels to
injured tissues due to chemotaxis
– response to chemical signals
sent by damaged cells
Neutrophils self-destruct as they
phagocytose invaders – live only
for a few days
EOSINOPHILS (Granulocytes)
• About 1.5% of leukocytes
• Attack larger parasites
such as blood flukes
(Platyhelminthes)
• Adhere to the external wall of
parasite and release
destructive enzymes
• Do not have good phagocytic
skills
• their numbers increase
sharply in certain diseases,
especially infections by
parasitic worms.
Basophils (Granulocytes)
• Basophils comprise less than 1% of
normal blood leukocytes
• Not phagocytic
• Basophils leave the blood and
accumulate at the site of infection or
other inflammation.
• There they discharge the contents of
their granules, releasing histamine
and heparin.
• Histamine triggers blood vessel
dilation – so more leukocytes can get
to the site of injury and heparin is an
anticoagulant that helps the blood
flow easily to site of injury.
•The number of basophils
increases during infection.
MONOCYTES (Agranulocytes)
• Only constitute 5% of
the leukocytes, but
very effective
• Long-lived, excellent
phagocytes
• Some microbes can
evade them
• They circulate in the
blood for some time,
then they migrate into
body tissues and
become
macrophages
Monocytes or Macrophages also release
IL1 which induces fever and also stimulates
an immune response
MACROPHAGES (Agranulocytes)
• Phagocytes - they consume
and destroy any pathogens
they encounter. They also
rid the body of worn out cells
and cellular debris
• Some Macrophages are
stationed in the tissues of the
body*, awaiting pathogens,
while others move through
the tissues and seek out
pathogens.
*Some macrophages are permanent
residents of specific tissues – alveolar
macrophages in lungs, Kupffer’s cells in
the liver, histiocytes in connective tissue,
mesangial cells in the kidney and
microglial cells in the brain.
Pus
• Accumulates at site of infection
• Consists of dead phagocytic cells (like
neutrophils and macrophages)
• Also contains fluids and proteins that
leaked from capillaries
• Absorbed by body eventually
Natural Killer Cell ( non-specific
Lymphocyte)
• Do not kill the
pathogen directly
• Their specific function
is to destroy virusinfected body cells
and cancerous cells
• They attack the
infected cell’s
membrane and cause
it to lyse
Summary of Functions of WBCs
• Leukocytes can squeeze between cells lining walls of
blood vessels by diapedesis and attack bacteria and
debris.
• Neutrophils and monocytes are phagocytic, with
monocytes engulfing the larger particles.
• Eosinophils moderate allergic reactions as well as
defend against parasitic infections.
• Basophils migrate to damaged tissues and release
histamine to promote inflammation and heparin to inhibit
blood clotting.
• Lymphocytes are the major players in specific immune
reactions and some produce antibodies.
The Second Line of Defense in Action
The Inflammatory Response IS A NONSPECIFIC DEFENSE REACTION OF THE BODY
TO TISSUE DAMAGE.
1. Despite the initial defenses of the skin and mucous membranes, pathogens
sometimes enter the body.
2. When pathogens enter the body, the immune system has a second line of
defense. The body's second line of defense acts when tissues are injured.
3. The mast cells found in connective tissues and basophils release a chemical called
HISTAMINE, when injured - which starts a series of changes called the inflammatory
response.
4. Histamine increases blood flow to the injured area and increases the permeability of
the surrounding capillaries, as a result, fluid and white blood cells (WBC) leak from
blood vessels into nearby tissue.
The Second Line of Defense in Action –
cont’d.
6.
7.
8.
9.
Pathogens are attacked by phagocytic white blood
cells (leukocytes) such as Neutrophils and Monocytes
in response to chemokines – chemical signals
Certain toxins released by pathogens may raise body
temperature, but leukocytes can do the same by
releasing molecules called pyrogens – fevers inhibit
microbial growth, speed up chemical reactions and
tissue repair
Antimicrobial agents collectively called the
complement system lyse invading cells
Inteferons are proteins secreted by virus-infected cells
that limit cell-to-cell spread of the virus
Mast Cells
(Not WBC, but helps with the body’s Defenses)
• A mast cell (or mastocyte) is a resident cell of
several types of tissues and contains many
granules rich in histamine and heparin.
• Although best known for their role in allergy and
anaphylaxis, mast cells play an important
protective role as well, being intimately involved
in wound healing and defense against
pathogens.
The Allergic Response is
initiated by plasma cells that
produce antibodies for
specific allergens. Some of
the antibodies can be
attached to special cells
called mast cells, that
produce histamine. This
causes most of the
symptoms associated with
allergies.
THE FINAL LINE OF DEFENCE
Specific Immunity
LYMPHOCYTES
LYMPHOCYTES ARE WBCs THAT ACTIVATE THE
SPECIFIC IMMUNE RESPONSE.
There are TWO Main Types of Lymphocytes:
- B Cells and
- T Cells.
(NKCs are also lymphocytes, but non-specific,
usually involved in second line of defense)
These WBCs accumulate in the Lymph and Lymph
Nodes, where they clean out the lymph fluid by
eating and destroying and foreign cells.
Lymphocytes are also found in the Spleen and Blood.
Lymphocytes Development
•Lymphocytes, like all other blood
cells, differentiate from pluripotent
blood cells in bone marrow or
fetal liver
•Lymphocytes that continue to
mature in bone marrow, turn into
B cells (“B” for “bursa” or bone)
•Lymphocytes that move to the
thymus, develop into T cells (“T”
for “thymus”)
•Both B and T cells populate
lymph nodes, the spleen and
other organs of the lymphatic
system
B Cells and T Cells
• Circulate in blood and lymph but
concentrated in lymph nodes, spleen and
other lymphatic regions
• Both cells deal with specific microbes or
foreign bodies – specificity!
The Origin of the word Bursa
• In birds, the bursa of
Fabricius is the site of
hematopoiesis. It is a
specialized lymphatic organ
necessary for B cell
development in birds.
• Mammals generally do not
have an equivalent organ;
the bone marrow is often
both the site of
hematopoiesis and B cell
development.
The lymphatic system
Consists of organs, ducts, and nodes. It transports a watery
clear fluid called lymph. This fluid distributes immune
cells and other factors throughout the body. It also
interacts with the blood circulatory system to drain fluid
from cells and tissues. The lymphatic system contains
immune cells called lymphocytes, which protect the body
against antigens (viruses, bacteria, etc.) that invade the
body.
Main functions of lymphatic system:
• to collect and return interstitial fluid, including plasma
protein to the blood, and thus help maintain fluid balance,
• to defend the body against disease by producing
lymphocytes,
• to absorb lipids from the intestine and transport them to
the blood.
The Lymphatic System
So how does this 3rd line of
defense or specific immunity
work?
Cell-surface proteins
• All cells, bacteria, viruses, fungi, yeast, etc. have
proteins on their surface.
• These proteins may help with facilitated
diffusion, active transport, cell-to-cell
communication, etc.
• But some of these proteins are used for cell-tocell recognition.
• Foreign proteins that initiate the immune
response are called ANTIGENS
• These antigens are found on viruses, bacteria,
parasitic worms, pollen, fungi, protozoa, etc.
Specific Immunity – The Final Line of Defense
• Antigens cause B lymphocytes to
produce ANTIBODIES
• The term antigen is a contraction of
ANTIBODY GENERATOR
• Each antigen has a specific shape and
several specific sides or sub-shapes called
epitopes.
• The antibodies that B cells produce bind to
specific antigens and specific epitopes of
the antigens only (Shape matters)
Antibodies
•
•
•
•
Group of Globular proteins found in blood serum called Immunoglobulins (Ig)
Each is made up of 4 polypeptide chains – 2 identical light and 2 identical heavy
chains, held together with disulfide bridges
Some amino acid regions of the chains are constant and found in every antibody,
whereas others are vary between different antibodies
The variable regions that form the arms of the Y-shaped molecule are the antigen
binding sites
Epitope
• An epitope is a
surface feature of
a 3-dimensional
antigen
• In other words, it
is one part of a
larger molecule –
the antigen.
• Antibodies are
made to recognize
each epitope of
each antibodies.
How Antibodies work
The binding of antibodies to antigens tags foreign cells and molecules for
destruction by phagocytes, or the complement system of proteins.
Opsonization: to
make pathogen
ready for
phagocytosis
The classical complement pathway, resulting in
the lysis of a target cell
Antibody
molecules
attach to the
antigens on the
pathogen’s
membrane.
Complement
proteins link
two antibody
molecules.
Activated complement
proteins attach to the
pathogen’s membrane in
step-by-step sequence,
forming a membrane attack
complex (MAC)
MAC pores in
the membrane
cause cell
lysis.
Two Groups of Antibodies
• Polyclonal antibodies are a mixed group of
antibodies – each one binds to a separate
epitope of an antigen. Antibodies made in our
bodies are usually polyclonal.
• Monoclonal Antibodies – are a group of
antibodies that recognize and bind to only ONE
epitope of an antigen. They are made in labs,
using mice, cell cultures, etc.
The most common example of
antigens and antibodies
ABO Blood Group
• Type A blood has A antigens on red blood cells and antiB antibodies in the plasma.
• Type B blood has B antigens on red blood cells and antiA antibodies in the plasma.
• Type AB blood has both A and B antigens, but no
antibodies in the plasma.
• Type O blood has neither antigen, but both types of
antibodies in the plasma.
• Adverse transfusion reactions are avoided by preventing
the mixing of blood that contains matching antigens and
antibodies.
– Adverse reactions are due to the agglutination of red blood cells.
Rh Blood Group
• The Rh factor was named after the rhesus
monkey.
• If the Rh factor surface protein is present on red
blood cells, the blood is Rh positive; otherwise it
is Rh negative.
• There are no corresponding antibodies in the
plasma unless a person with Rh-negative blood
is transfused with Rh-positive blood; the person
will then develop antibodies for the Rh factor.
• Erythroblastosis fetalis develops in Rh-positive
fetuses of Rh-negative mothers but can now be
prevented
“Self” Markers or MHC
• All our cells have surface glycoproteins called MHC
(Major Histocompatibility Complex) glycoproteins. They
are also known as HLA for Human Leukocyte Antigens
• There are 2 classes of MHC – Class I MHC and Class II
MHC
– Class I MHC glycoproteins are found on all nucleated
cells (almost all body cells) non-professional antigenpresenting cells
– Class II MHC glycoproteins are found only on a few
cell types like macrophages, B cells, activated T cells
and the cells that make up the interior of the thymus
professional antigen-presenting cells
MHCs and Chromosome 6
• The genes for both class I and class II MHC
proteins are on chromosome 6
• There are hundreds of different alleles for the
MHC genes, so no 2 people will have the same
type of MHC glycoproteins on their cells, unless
they are identical twins
• This leads to tissue rejection after organ
transplants (the “histo” in histocompatibility
means tissue)
Self vs. Non-self
• When lymphocytes mature, they will bear
receptors that are specific to different MHC
molecules
• All lymphocytes that bear receptors specific
for MHC molecules already present in the
body undergo apoptosis (programmed cell
death or suicide), so that your body is safe
from its own defense system
• A failure to destroy lymphocytes with “self”
receptors, will cause auto-immune diseases
like lupus, MS, etc.
What do the MHCs do?
• The job of MHC molecules is to “present”
antigens that cells may be housing due to an
infection or intrusion by foreign tissues to T
cells
Remember: An antigen is a foreign molecule
that does not belong to the host cell
• The antigens are “read” by T cells – there are
2 types of T cells:
– Helper T cells and
– Cytotoxic T cells
APCs (Antigen-Presenting Cells)
TC cells have receptors that bind to Class I MHC, while TH cells have
receptors that bind to Class II MHC
A non-professional APC
A professional APC
That phagocytized the
antigen
The Immune Response
Made up of two systems:
- humoral or circulating antibody system – B cell activation
- cell mediated immunity - T cell activation
• The humoral (antibody-mediated) system - B-Cells involved
– produces secreted antibodies (proteins) to destroy antigens.
Antibodies act on antigens in the serum and lymph. The
antibodies may either be attached to B-cell membranes or
free in the serum and lymph.
• The cell-mediated system – T-Cells involved
– T-cells act on antigens appearing on the surface of
individual cells. T-cells produce T-cell receptors which
recognize specific antigens bound to the antigen presenting
structures on the surface of the presenting cell – either a
body (non-professional) cell or a macrophage (professional).
The Cell-Mediated Response
1.
2.
3.
4.
5.
6.
7.
8.
9.
The invader or antigen is phagocytized by a macrophage which
then presents the antigen on its MHC II complex
The invader could also enter a regular body cell – which then
presents the antigen on its MHC I complex
The macrophage stimulates helper T cells with IL-1 and antigen
A Helper-T cell binds to the antigen presented by the macrophage
The Helper T cell releases IL-2
The infected body cell, along with the IL-2 from the Helper T cell
IL-2 stimulates cytotoxic T cells to develop into active killer cells
The Cytotoxic T-cells differentiate into Active cytotoxic T cells and
memory T cells
Active cytotic T cells or killer cells bind to their targets and release
Porforin, which makes the cell membrane porous. This lyses the
cell.
The Memory T cells persist in the body for many years and may
never be activated. However, in the event that the same foreign
organism returns, they will develop into Active Cytotoxic T Cells
much more rapidly than the original T-cells.
The Suppressor T Cell
A special T Cell called the Suppressor T cell
turns off the whole immune response
when the threat has passed – conserve
energy!
B Lymphocytes (B cells) and the Humoral
Response
1.
The invader or antigen is phagocytized by a macrophage which
then presents the antigen on its MHC II complex
The macrophage stimulates helper T cells with IL-1 and antigen
A Helper-T cell binds to the antigen presented by the macrophage
The Helper T cell releases IL-2
A specific B-cell clone will recognize and bind to FREE antigens –
bacteria, viruses, etc. that are circulating in the blood and tissue
fluids.
They are then stimulated by helper T cells and Interleukin-2 which
is released by the Helper T cells
The B cells that have been stimulated by the free antigens and
HelperT/IL-2, will differentiate into
2.
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–
–
8.
9.
Plasma Cells and
Memory Cells
Plasma cells produce antibodies that are specific to one epitope
on the free antigens that inactivated the B-cell
Memory cells are extremely long lived. They “hang out” in the
system. If they ever encounter the same antigen again, they
rapidly differentiate into plasma cells and produce the specific
antibodies again faster than before.
Memory B and Memory T cells
• Memory Cells persist in the body for many
years and may never be activated.
• However, in the event that the same
foreign organism returns, they will develop
into Plasma Cells much more rapidly than
the original B-Cells or T-cells.
Helper T cells bind to class II MHC molecules found on macrophages and lymphocytes.
The macrophage also stimulates the helper T cells with IL-1 and antigen
IL-2 stimulates B cells that
have already made contact
with free antigens to
differentiate into Plasma cells
Produces cytokine IL-2 in
response to IL-1 and antigen
Cytokines stimulate other
lymphocytes
Self-stimulation
With IL-2
Produces cytokine IL-2, in
response to IL-1 and antigen
Cytokines stimulate other
lymphocytes
Memory Cells persist in the body for many years and may never be activated.
However, in the event that the same foreign organism returns, they will develop
into Plasma Cells much more rapidly than the original B-Cells or T—cells.
A special T cell called the suppressor T cell “turns off” the
immune system, once the antigen has been eliminated
IL-2 stimulates cytotoxic
T cells that are already
stimulated by an infected
or tumor cell to develop
into active killer cells
Active killer cells bind to their
targets and release Porforin,
which makes the cell membrane
porous. This lyses the cell
APCs (Antigen-Presenting Cells)
TC cells have receptors that bind to Class I MHC, while TH cells have
receptors that bind to Class II MHC
A non-professional APC
A professional APC
Immune Responses
• When B or T cells become activated the first
time, their actions constitute a primary immune
response, after which some cells remain as
memory cells.
• If the same antigen is encountered again, more
numerous memory cells can mount a more rapid
response, known as the secondary immune
response.
– The ability to produce a secondary immune response
may be long-lasting.
IMMUNITY
• Active immunity is achieved by recovering from an infectious disease such
as measles
• Active immunization can be acquired artificially through vaccination.
Vaccines can be made of:
- Inactivated bacterial toxins (tetanus)
- Killed microbes (flu, cholera, bubonic plague, and hepatitis A)
- Parts of microbes (HPV)
- Living but weak (attenuated) microbes (measles, mumps, polio)
These can no longer cause disease, but can act as antigens and stimulate
the immune response to produce antibodies and more importantly, memory
cells.
• Passive immunity is what is transferred from one person to another – such
as from mother to her fetus or from a nursing mother to her child. It can also
be transferred from one animal immune to a disease, to another, through an
injection.
Blood Groups and Transfusions
Antigens and Antibodies
• Clumping of red blood cells following
transfusion is called agglutination.
• Agglutination is due to the interaction of
proteins on the surfaces of red blood cells
(antigens) with certain antibodies carried in
the plasma.
• Only a few of the antigens on red blood cells
produce transfusion reactions.
– These include the ABO group and Rh group.
Hemostasis
• Hemostasis refers to the stoppage
of bleeding.
• Following injury to a vessel, three
steps occur in hemostasis:
1. blood vessel spasm,
2. platelet plug formation, and
3. blood coagulation.
1. Blood Vessel Spasm
• Cutting a blood vessel causes the muscle
in its walls to contract in a reflex, or
engage in vasospasm.
• This reflex lasts only a few minutes, but it
lasts long enough to initiate the second
and third steps of hemostasis.
2. Platelet Plug Formation
• Platelets stick to the exposed edges of
damaged blood vessels, forming a net with
spiny processes protruding from their
membranes.
• A platelet plug is most effective on a small
vessel.
3. Blood Coagulation
Blood coagulation is the most effective means of hemostasis. Blood coagulation
is very complex and uses clotting factors.
a. Damaged tissues release a chemical called tissue thromboplastin, which
activates the first in a series of factors leading to the production of
prothrombin activator.
b. Prothrombin activator converts prothrombin in the plasma into thrombin.
This in turn, catalyzes a reaction that converts fibrinogen into fibrin.
c. The major event in blood clot formation is the conversion of soluble
fibrinogen into net like insoluble fibrin causing the blood cells to catch.
d. The amount of prothrombin activator formed is proportional to the amount of
tissue damage.
e. Once a blood clot forms, it promotes still more clotting through a positive
feedback system.
f. After a clot forms, fibroblasts invade the area and produce fibers throughout
the clots.
A clot that forms abnormally in a vessel is a thrombus; if
it dislodges, it is an embolus.
Clotting in a Nutshell
Damaged tissue

Thromboplastin

Prothrombin activator

Thrombin

Fibrinogen (soluble) into
Fibrin (insoluble)

Net-like Clot
THE END