White Blood Cells
Immune System
Chapters 33 and 34
1
• The main components of the immune system are lymphocytes,
lymphoid tissue, and lymphoid organs, such as the spleen, lymph
nodes, and thymus. The immune system protects our body from
foreign organisms by fighting infections and conferring immunity to
disease. As with other body systems, the immune system must also
maintain homeostasis or have some sort of regulation between
recognizing material that is “self” (from the body) from material that
is “non-self”(foreign). Obviously, the immune system must launch
an appropriate immune response against invading antigens.
Inappropriate immune responses include hypersensitivities,
allergies, and autoimmunity. Diminished immune responses are
also detrimental to the body, such as overall immune deficiency and
AIDS.
3
• The word antigen means anything that
can elicit an immune response. It can be
a protein or a polysaccharide on the
surface of (or released by) a cell
bacterium, fungus, virus, etc. An antigen
is a substance that is recognized as
foreign by the host immune system.
4
• In this photo, you see a bacterial
cell with several antigens
protruding from the cell
membrane. Any of these antigens
can cause an immune response.
Notice that antibody A is only
recognizing, and binding to, the
antigen depicted as a red triangle.
Notice that antibody B recognizes
and binds to the antigen depicted
as a peach circle. Antibodies are
specific; they can only
recognize and bind to one
particular antigen.
• The immune system may not necessarily react to, or recognize, the
entire polysaccharide or antigenic proteins. Rather, the immune
cells may react to only a particular site, perhaps a certain sugar or
chain of amino acids on the entire antigenic molecule. These
smaller sites on the larger antigenic proteins or
5
polysaccharide are called epitopes.
Tolerance
• If I took your cells and injected them into
another person, they would likely a elicit
an immune response because your
glycoproteins are antigenic it to someone
else. However, your own immune system
does not react to your antigens.
Tolerance to self antigens sometimes
malfunctions and becomes the mechanism
for autoimmune diseases. We say this
tolerance is to self antigens.
7
How does tolerance happen?
• The immune cells may not express
receptors to self antigens
• T cells do not respond to self antigens
– The thymus kills self reactive lymphocytes
– Other immune cells inactivate
lymphocytes that could be reactive to your
own cells
8
Formed Elements
• Formed elements are red blood cells, platelets,
and white blood cells. The prefix “leuko” means
white and the suffix “cyte” means cell.
Therefore, “leukocyte” means white blood cell.
White blood cells contain nuclei and organelles,
so of all the formed elements, WBCs are the
only formed elements that are true cells. Red
blood cells lack nuclei and organelles and
platelets are only fragments of a larger cell.
9
White blood cells
• WBCs defend your body against foreign materials, such as bacteria,
viruses, or cells from another person. They remove toxins, wastes,
and they also remove damaged or dying cells. For example, old red
blood cells must be removed from the circulation and macrophages
(a type of WBC) help do this. A typical µl of blood contains 6-9000
white blood cells. However, white blood cells circulating in your
blood only represent a fraction of the total number present in your
body. White blood cells only use the circulatory system to get to
their final destination. When needed, they migrate out of the
bloodstream and reside in the connective tissues found throughout
our body. To remember how many of the white blood cells are
neutrophils, basophiles, etc., remember 60-30-6-3-1.
11
Of the white blood cells in the
circulation:
• 60% are neutrophils
• 30% are lymphocytes (this includes B
cells and T cells together)
• 6% are monocytes
• 3% are eosinophiles
• 1% are basophiles
If these numbers change, it could suggest
pathology.
12
WBCs in order of abundance:
Never (neutrophils
Let (lymphocytes)
Monkeys (monocytes)
Eat (eosinophils)
Bananas (basophils)
How do I remember the
relative percentages?
60 + 30 + 6 + 3 +1
(i.e., 60% neutrophils, 30%
lymphocytes, 6% monocytes, 3%
eosinophils & 1% basophils)
13
White Blood Cell Count
• When a person has a blood test, in addition to RBC
information, a “white blood cell count” can be ordered to
report the total number of WBCs present.
• A slightly more expensive test, but much more
informative, is a “white blood cell count with differential”.
This test will tell you the total number of WBCs as well
as how many of each type of WBC is present.
• Usually one orders the cheaper test unless there is a
reason to be suspicious of a WBC disorder.
14
Leucopenia
• Leucopenia means an absolute decrease in white
blood cell numbers. The disorder may affect any of the
specific types of white blood cells, but most often it
affects neutrophils, which, under normal healthy
conditions, is the most abundant. A number of
conditions may cause leucopenia, including aplastic
anemia, treatment with chemotherapeutic drugs,
irradiation, and idiosyncratic drug reactions.
16
Idiosyncratic Drug Reactions
• Idiosyncratic is a term used to describe drug reactions
that are different from the effects obtained in most
persons and that cannot be explained in terms of
allergies. In other words, a patient reacts very badly to a
particular drug for no known reason. They probably
have a different gene expression than other people.
• A number of drugs can cause idiosyncratic reactions,
such as chloramphenicol, which is used as an antibiotic.
Obviously, if a person has a reduced white blood cell
count, they would be more prone to infection.
17
Leukocytosis
• Leukocytosis is a term to describe
excessive numbers of white blood
cells.
• Leukocytosis is normal when you are
fighting an infection.
• Leukocytosis also occurs with leukemia,
except that with leukemia, the excessive
white blood cells are not normal, or
functional.
18
Leukemia
• Leukemia is a word to describe uncontrolled
production of white blood cells of a myelogenous or
lymphogenous cell lines. What does that mean?
Remember that the hemocytoblast is a multipotent stem
cell that gives birth to any type of blood cell. If it
differentiates into a myelogenous cell line, it will
further differentiate into neutrophils, eosinophiles,
basophiles, macrophages, and monocytes. If it
differentiates into a lymphogenous cell line, it will
further differentiate into either a B cell or a T cell.
20
Genesis of Blood Products
T-Cell
CFU-T
B-Cell
CFU-B
Pluripotent
Stem Cell
Lymphoid
Stem Cell
eosinophil
CFU-Eosin
basophil
CFU-Bas
neutrophil
CFUGM
Myeloid
Stem Cell
macrophage
platelets
CFU-MEG
BFU-E
Copyright © 2006 by Elsevier, Inc.
monocyte
21
erythrocyte
• A cancer-causing mutation in the myelogenous or
lymphogenous cell lines causes leukemia which is
characterized by greatly increased numbers of abnormal
white blood cells. The leukemic cells from the bone
marrow may reproduce so greatly that they invade the
bone marrow where they are being made, and
overwhelm normal white blood cells that are trying to
develop. Although there are greater numbers of
white blood cells in circulation during leukemia,
these cells are not functioning properly.
22
• Additionally, the cancerous cells within the bone marrow
consume too many of the nutrients, impeding the
development of normal blood cells (including platelets
and red blood cells).
• Almost all types of cancer cause both anorexia ( a
reduction in food intake caused primarily by diminished
appetite) and cachexia ( a metabolic disorder of
increased energy expenditure leading to weight loss
greater than that caused by decreased food intake
alone). In other words, the cancer cells are too
metabolically active and consume too many nutrients.
23
Genesis of Blood Products
T-Cell
CFU-T
B-Cell
CFU-B
Pluripotent
Stem Cell
Lymphoid
Stem Cell
eosinophil
CFU-Eosin
basophil
CFU-Bas
neutrophil
CFUGM
Myeloid
Stem Cell
macrophage
platelets
CFU-MEG
BFU-E
Copyright © 2006 by Elsevier, Inc.
monocyte
24
erythrocyte
TYPES OF WHITE BLOOD CELLS
•
•
•
•
•
Basophiles (mast cells)
Eosinophils
Neutrophils
Monocytes (macrophages)
Lymphocytes
– T cells and B cells
• discussed later in this lecture
25
Types of WBCs
•
Can be classified based
on the appearance of
granules when viewed
under the light
microscope.
1. Granulocytes-PMN’s
–
Contain visible granules.
Includes:
•
•
•
Basophils
Eosinophils
Neutrophils
2. Agranulocytes
–
Do not contain visible
granules. Includes:
•
•
Lymphocytes
Monocytes
26
Granulocytes Basophils
• Contain granules that appear deep
purple or blue
• This enhances the local inflammation
initiated by mast cells
• IgE antibody binds to allergen, and this
complex sticks to basophils or mast
cells and leads to rupture and release
of histamine (vasodilator and
increases capillary permeability) and
heparin (anti-coagulant).
27
BASOPHILES
• Basophiles migrate to injury sites and release the contents of their
granules. The granules contain histamine and heparin among
other components. Histamine is a vasodilator and increases
capillary permeability. Collectively this means the capillary will
have more blood flow through it and the capillary itself will be more
leaky, to allow more white blood cells to reach the tissue infection.
Heparin is an anticoagulant, so the blood will be less likely to clot,
allowing better movement of the white blood cells to the infection
site. When a basophile leaves the circulation and enters the
tissues, it is called a mast cell. The function of the basophiles
augments the inflammation response initiated by the mast cells.
Remember “B for basophiles and B for begin”, as in beginning the
inflammatory response. Basophils and mast cells bind to an IgE
antibody/antigen complex to begin the anti-inflammatory
response known as an allergic reaction.
28
Granulocytes Eosinophils
• have reddish-orange staining granules (Eos
is the Greek goddess of dawn) and a bilobed
nucleus.
• Move into tissues after several hours and
survive from minutes to days.
• They will phagocytize antibody-coated
material, but their main method of attack is
the exocytosis of toxic compounds onto the
surface of their target.
• Important defenders against large, multicellular parasites such as flukes or parasitic
worms. They  in # dramatically during a
parasitic infection.
• Prevent excess spreading of local
inflammatory factors.
29
EOSINOPHILES
• Eosinophils attach themselves to parasites, particularly
parasitic flukes invading the GI tract. They release
hydrolytic substances and digest the parasite from
the outside. During a parasitic infection, there is an
increase in eosinophil numbers. Eosinophiles also
seem to play a role in preventing the excessive
spreading of local inflammatory factors (cytokines)
from mast and basophiles. Clearly, if the mast cells
and basophiles were left unchecked, then widespread
histamine and heparin release would cause excessive
vasodilatation. This is what happens during
anaphylactic shock.
30
Cytokines
• Soluble molecules
released mainly by
leukocytes to
communicate and
coordinate / direct the
immune response
• Include:
– Interleukins (IL-1, IL-2,
etc.)
– Chemokines: signals for
leukocyte extravasation
and migration within
tissues (chemotaxis)
– Interferons
– Tumor necrosis factors
31
Granulocytes Neutrophils
• Cytoplasm is packed with pale
(“neutral colored”) granules that
contain bactericidal compounds
• Highly mobile and generally the
second WBC to arrive at an injury
site. (tissue macrophage is first)
• in the bloodstream for only about
few hrs; tissues for 4-5 days
• Opsonization- foreign bodies
bound to antibodies leads to more
“docking and destruction” (see
opsonization slide)
32
NEUTROPHILS (a type of phagocyte)
• Neutrophils are the most abundant of the
circulating white blood cells. This white
blood cell is extremely mobile and is the
first WBC to leave the circulation to
assist the macrophages in their fight of
an infection in the tissues. They are
excellent phagocytes; they ingest large
particles or even entire cells (such as
bacteria).
33
Agranulocytes Monocytes
• Almost twice as big as an RBC
• Nucleus is large and tends to be oval or
kidney-shaped
• Stay in blood for 24 hours and then
enter tissues.
• Once in tissues, they swell and become
tissue macrophages (takes 8 hours to
mature).
• APC- help initiate antibody formation
• Tissue macrophages- “Langerhans”
cells in skin, in lymph nodes, in lungs, in
liver (Kupffer cells).
• FIRST LINE OF DEFENSE- can
phagocytize far more bacteria.
34
MONOCYTES AND MACROPHAGES
(types of phagocytes)
• A monocyte that leaves the circulation and enters the
tissues is called a macrophage. A macrophage can
ingest many more foreign particles than a neutrophil
and is the first line of defense against invading
microbes, followed by neutrophils. The
macrophages and neutrophils are nonspecific
immune cells since they do not discriminate between
the types of material they ingest. They can engulf any
type of bacteria, other microbes, or even dead or dying
body cells. They both use opsonization to help engulf
foreign material.
35
Opsonization
• Opsonization means that when antibodies
(released by a mature B lymphocyte) bind to a
foreign particle (antigen), they bind the antigen
at the stem (Fc receptor) of the antibody. The
macrophage or neutrophil can grab onto this FC
receptor and more easily wrap itself around the
bacterium to engulf it. This is especially
important when the bacterium has a protective
capsule around it that prevents the phagocyte
from getting a grip on it. Opsonization with an
antibody helps it to grab on to the slippery
36
bacterium.
Macrophage: a wandering, walking cell. “Big eater”
capable of phagocytosis. Is a modified monocyte in
tissues
37
The difference between
macrophages and neutrophils
• Macrophages and neutrophils both use hydrolytic
enzymes to break apart the foreign particles that they
ingest. However, only the macrophage then takes some
of the particles of the antigen and embeds them in its cell
membrane, then goes to a lymphocyte to present the
antigen pieces to it. The lymphocyte then “feels” the
shapes of the antigen pieces, and launches further
defensive measures. Because of this, macrophages are
considered antigen presenting cells (APC), which
activate T cells and B cells into action.
38
Agranulocytes Lymphocytes
• Slightly larger than RBCs. In
blood smears, you typically only
see a thin halo of cytoplasm
around a relatively large nucleus.
• Continuously migrate from the
bloodstream thru peripheral
tissues and back into the
bloodstream.
• Circulating lymphocytes are only a minute fraction of the total #
in the body. Most are in other connective tissues and in
lymphatic organs.
• Circulating blood contains 2 classes:
– T cells: defend against foreign cells and tissues and coordinate the
immune response
– B cells: produce and distribute antibodies that attack foreign
materials
39
WBC Circulation and Movement—
mostly macrophage and neutrophils
• Use the bloodstream mainly to
travel from organ to organ or to
quickly go to areas of
invasion/injury.
• Characteristics of circulating
WBCs:
•
•
•
•
•
1. Margination
2. Diapedesis
3. Ameboid Motion
4. Chemotaxis
5. Phagocytosis
40
Bean Bag analogy for diapedesis
Interior of
blood
vessel
Interstitial space
41
INNATE IMMUNITY
(Nonspecific immune defenses)
– Simple barriers
– Inflammation
– Fever
– Antimicrobial substances (complement
proteins and interferons)
– Generic reactions to antigens and foreign
microbes
• Phagocytes (macrophages and monocytes)
• Basophils
• Eosinophils
43
ADAPTIVE (ACQUIRED) IMMUNITY
(specific)
• Cell mediated (T cells)
• Humoral mediated (B cells)
44
The Immune System
The body’s defense
against disease
45
Introduction
•
Detection, response
1. Innate Immunity, Nonspecific
defenses
– barriers
– inflammation
2. Adaptive Immunity, Specific
defenses
– recognition, destruction and
removal
– “cellular immunity” and “humoral
immunity”
– Memory cells (cells that remain for
years)
46
INNATE IMMUNITY
(Nonspecific immune defenses)
•
•
•
Simple barriers include cutaneous and mucous membranes. The
secretions from these membranes can prevent the spreading of invading
microbes.
Mucus can trap microbes, or serosal secretions may contain lysozymes
that can destroy the microbes.
Inflammation is also a nonspecific host defense.
–
•
•
The characteristics of inflammation include dolor (pain), calor (heat) rubor (redness),
and tumor (swelling).
Fever is another nonspecific host defense, and this elevates metabolic
rates for all cells of the body, including the activity of white blood cells.
Anti-microbial substances are also nonspecific. These include
complement proteins and interferons. Another non-specific defense is the
phagocytic white blood cells (neutrophils, tissue macrophages,
eosinophiles, and basophiles). These are generic in their responses to
invading microbes.
47
Inflammation
•3 stages of inflammation:
1.Vasodilation & increased permeability of blood vessels
2.Phagocyte migration & phagocytosis
3.Tissue repair
49
THE INFLAMMATORY REACTION
• Picture a knife protruding through the
integument system down to the dermis. The
mast cells and basophiles release copious
amounts of histamine and heparin in
response to the injury. These chemicals result
in dilation of the local blood vessels, leading to
increased blood flow and increased blood vessel
permeability. As a result, the area will become
red, swollen, warm, and painful to the touch.
50
• As a result of increased blood flow, there will be more white blood
cells, specifically monocytes and neutrophils, attracted to the injury
site. The macrophages in the dermis release cytokines. A cytokine
is a chemical which recruits more white blood cells to the injury
site. The increased blood flow will also bring with it more clotting
factors. A clot will form in the tissue that stops the bleeding into the
wound, but also walls off the wound to surrounding tissue so any
microbe introduced into the warm should be localized and prevent it
from spreading. When more white blood cells arrive at the injury
site, T cells and antibodies also arrive, providing specific
defenses against any microbe that entered the wound. The
macrophages and neutrophils will phagocytize any debris and
also aid in the repair of the tissue.
51
Inflammation
52
ADAPTIVE (ACQUIRED) IMMUNITY
(non-specific)
• Adaptive immunity is from lymphocytes (B
cells and T cells). These cells attack in
different ways.
• T cell lymphocytes
– (cell-mediated immunity)
• B cell lymphocytes
– (humoral immunity)
55
• Both of these types of cells recognize antigens, but they can only
recognize whatever single antigen or epitope they were exposed to.
This is like a specific key (T cell or B cell) will unlock only a specific
lock (antigen) in your house. Each flu virus, bacterial infection, or
fungal infection you have ever had in your lifetime is like a different
lock in your body. This means we need millions of different types of
B and T cells in our body. When one specific B or T cell encounters
its antigen that it recognizes, it is activated and quickly creates
copies of itself, like duplicating keys. During the infection battle,
many of the duplicated B or T cells die, but a few continue to live on
as memory cells. These memory cells will allow you to mount a
quicker response and more aggressive response should you
ever become infected with the same antigen in the future.
56
Specific Host DefensesTriggering systems that
“recognize” the pathogen
•
•
•
•
Cell-Mediated Immunity
T lymphocytes
cell-to-cell combat
Originate in bone marrow and
matured in thymus.
most active against virallyinfected cells
Humoral Immunity
• B lymphocytes
• produce antibodies
•
most effective against bacteria, toxins
and viruses which are freely circulating
in body fluids
58
MEMORY CELLS
• In this picture, the cell at the top with a brown nucleus
represents a virgin cell. A virgin B or T cell is one that
has never been exposed to an antigen. When the
virgin lymphocyte encounters an antigen, it starts to
make clones of itself. Some of the clones will be
active cells (those shown with the red nucleus) and
fight the infection. The other clones (yellow nucleus)
will remain dormant and serve as memory cells.
When the infection has been conquered, the red
nucleated activated cells will die. But the yellow
nucleated memory cells will continue to live in the lymph
tissues.
59
• If the memory cells encounter the same antigen
again, they can quickly generate another army
of activated cells. Thus, the second response
to the antigen will be much faster and more
aggressive. Why? At the first exposure, a
single virgin cell had to replicate to create clones
of itself. With the second exposure, multiple
memory cells were available for cloning. Sheer
numbers dictate that the formation of activated
cells will occur more rapidly and more
abundantly.
60
Sequence of the body’s battle:
Dormant lymphocytes
Invasion of body by foreign antigen
Phagocytosis by macrophages
Presentation of antigen to lymphocytes
61
• Using a graph to describe a quicker response to a
second exposure to the same antigen, you’ll notice on
the x-axis, 7 days elapse after an antigen has been
introduced into the body. On the y-axis you’ll notice the
immune response. It is a gauge of intensity, and you’ll
notice there are no units associated with this axis. An
antigen (A) is introduced into the body on day five, and it
takes 7-10 days before your immune response reaches
its peak.
63
• If, at a later date, antigen A is reintroduced into your
body, because you caught the same cold again from
your child or spouse, you’ll notice the immune response
takes a much shorter time to respond to that antigen.
Additionally, it responds with more vigor. In other words,
the immune response occurs faster and with more
intensity. If however, you were exposed to a different
antigen, say antigen B, you’ll notice that your immune
response will again take 7-10 days upon first exposure to
this antigen to mount an impressive response worthy to
contain and eradicate antigen B.
64
ADAPTIVE (ACQUIRED) IMMUNITY
(specific)
• Cell mediated (T cells)
• Humoral mediated (B cells)
65
CELL MEDIATED IMMUNITY:
T CELLS
There are three main T cells:
• Helper T cells
• Cytotoxic T cells (Killer cells)
• Suppressor T cells.
66
•
•
•
•
CellMediated
immunity
T-cells
•
– kill infected cells
•
Helper Cells (two types)
– activate macrophages and B-cells
•
Suppressor Cells
– regulate activity
TH
TH
activation
activation
Antigen
presentation
Act over a short range
Interact with another cell in body
Can kill or signal other cells
Only recognize antigen when presented on
surface of target cell
Cytotoxic Cells
Antigen
presentation
TC
cytotoxicity
B
macrophage
Virally infected cell and
some tumor cells
67
HELPER T CELLS
• The helper T cell category is by far the most numerous.
As their name implies, they help the immune system
direct its response. Helper T cells are activated when
their receptors bind to an antigen on the surface of an
antigen presenting cell (macrophage). Helper T cells
unite cell mediated and humoral responses. When
the helper T cell is activated, it will replicate to create
many clones of itself, it recruits more white blood cells
into action, can stimulate cytotoxic T cells, and can
stimulate B cells to mature into plasma cells that can
then secrete antibodies.
68
Activation of Helper T-cells
Il-2
antigenpresenting
cell
antigen
Il-2 receptor
MHC II
Th
Th
CD4
proliferation
Th
Th
69
CYTOTOXIC T CELLS
(KILLER T CELLS)
• The cytotoxic T cell must have direct contact with its
target cell (a microorganism or a cell infected with a
virus). For this reason, cytotoxic T cells are also called
killer T cells. When a cytotoxic T cell binds to an antigen
on a virally infected cell, the cytotoxic T cell releases
hole-forming proteins on the surface of the infected
cell. These proteins are called perforins and they
literally create holes in the infected cell’s membrane.
This causes the infected cell to begin a process called
apoptosis. Apoptosis is cellular suicide (cell
mediated cell death). The infected cell starts to
degrade its nuclear DNA and cellular proteins. When the
process is over, the cell is dead and the virus cannot 70
exist without it.
Cytotoxic T-cells
• Cytotoxic T-Cells
recognize viral protein
fragments on surface of
infected cells.
• Cytotoxic T-Cells induce
infected cells to kill
themselves
– Bind to infected cells
– Induce cell death
– Punch holes in cell
membrane
Class I
MHC
infected
target
cell
Tc
CD8
Perforin discharge
71
• NOTE: without your helper T cells, your B cells
and cytotoxic T cells would be largely
unresponsive to the infection in your body. If
you could pretend to be HIV (the virus that
causes AIDS), which of the T cells would you
infect first and wipe out? If you guessed helper
T cells, if you would be correct. In fact, HIV
infects helper T cells and depletes their
population. All the while, the cytotoxic T cells
are unresponsive to the infection going on. HIV
is truly an insidious virus.
72
SUPPRESSOR T CELLS
• Suppressor T-cell function is not well
understood. But we do know they are
capable of suppressing the functions of
cytotoxic and helper T cells. They
prevent the cytotoxic T cells from
generating excessive immune reactions
that could destroy healthy surrounding
tissue.
73
HUMORAL IMMUNITY
• Humoral immunity is conferred by the B cells in your
body. It is called that because the B cells generate
antibodies that stay in the blood ( blood is a humor, or
fluid) and it is the antibodies that will latch onto a specific
antigen. B cells do not engage in cell to cell combat
like T cells. B cells provide protection against foreign
antigens that are in your circulation or outside of the cell.
These antigens may arise from bacteria, viruses, or
parasites, just to name a few. When the B cell becomes
activated by an antigen presenting cell (a macrophage)
or activated by a helper T cell, the B cell will mature
into a plasma cell.
74
• The plasma cell can make antibodies. Each antibody
made will only be able to recognize one specific antigen.
That means that you would need many different types of
B cells, each capable of making only one type of
antibody, to defend against the endless number of
foreign antigens you may encounter. When you come
into contact with an antigen for a second or third time,
the memory cells will allow you to respond much more
quickly and with greater quantity, including speeding up
the production of antibodies.
75
• Memory cells are what make a vaccine work. A vaccine
is made from a dead or weakened microbe, or just
portions of them (their epitopes). When introduced into
the body, these antigens stimulate the immune system.
Vaccines cause you to create memory cells. If you
should happen to come into contact with the antigen
later in life, your memory cells are already in place, and
can rapidly respond with great quantities of antibodies,
limiting how severe your illness will be. Remember, B
cells, T cells, memory cells, and antibodies can only
recognize one particular antigen.
76
• In this picture, you can see B cells with integral proteins of various
shapes. Notice that one B cells is square shaped and can recognize
only a square antigen. Once it binds its antigen, the B cell
becomes activated, and begins to replicate clones of itself.
Additionally, that B cells that was stimulated will turn into a
plasma cell. It is the plasma cell that can now generate
antibodies that will specifically blind to that square shaped antigen.
This is similar to the T cells, which also only respond to one
particular antigen. You would need many different B cells and T
cells in order to fight al the invading microbes and other antigens
and that you might encounter throughout your life span.
78
Formation of Antibodies—Humoral
immunity
tiny fraction
of total
B-cells
antigen
activation
•Act to limit, inactivate
or aid in antigen
destruction
antigen
antibody
secreting
plasma
cell
79
ANTIBODIES
(immunoglobins)
• An antibody is a protein that is secreted into the
plasma by a plasma cell (mature B cell). They
are Y-shaped proteins with two long peptide
chains (dark brown in the picture) and two
short chains (blue). The stem region
determines the classification type of the
antibody. There are five main classes (Ig stands
for immunoglobulin): IgG, IgA, IgM, IgE, and
IgD. Remember this as GAMED.
80
• The arm regions that project outward from the stem of the antibody
consist of amino acids that allow the antibody to bind to one
particular antigen. There are usually only to variable regions, one
at the end of each arm, and it is here that the antibody gets its
specificity in binding to one particular epitope on an antigen. The
variable region is the part of the antibody that attaches to the
antigen. Although most antibodies only have two variable regions,
larger antibodies, such as IgM, have multiple binding sites for a
particular antigen. Levels of antibodies can be measured in the
serum. In fact, we can take a patient’s blood sample, loaded into a
gel, and separate the antibodies according to their size.
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Antibody specificity –
# binding sites -
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IgG
• IgG is the most abundant of all antibodies
and their functions include: opsonization,
neutralizing toxins and attacking
viruses. They can cross the placenta
and cause destruction of fetal red blood
cells. This is called hemolytic disease of
the newborn. IgG is the second antibody
made during an infection (IgM is the first.
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IgA
• These antibodies are found on the surface
of your body. They are found on
mucosal surfaces, sweat, tears,
bronchiole secretions, and even in your
saliva.
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IgM
• These antibodies are extremely large and can
have 10 binding sites. In other words, 10 of the
variable regions of each IgM antibody are
capable of binding the same antigen. They are
the first antibody that is produced, and they
can bind to antigens, covering up their toxinproducing sites, or just weigh the entire antigen
down so that it precipitates out of solution
(plasma) so the entire agglutinated compex can
be removed from the circulation.
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IgE
• These are the antibodies responsible for
causing your allergic reactions. If you
have severe allergies, IgE’s are not your
friend. They stimulate histamine release
from basophiles and mast cells. They are
also important in the lysis of parasitic
worms.
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IgD
• These antibodies are believed to help
activate B cells in some unknown
fashion.
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HOW ANTIBODIES ATTACK
• Because of the bivalent nature of the antibodies
(a stem and two arms, each attack in different
ways), they can inactivate the invading agent in
one of several ways:
–
–
–
–
–
Agglutination
Neutralization
Lysis
Opsonization
Complement Cascade
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Antigen-Antibody Complexes
Direct actions of
antibodies are:
•Agglutination
•Neutralization
•Opsonization (cover)
•Also, they participate
in amplification effects
by activating a group of
plasma proteins known
as “complement
proteins” which result
in destroying the
antigenic cell.
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Agglutination
• Multiple large particles with antigens on
their surfaces, such as bacteria or red
blood cells, are bound together into a
clump held together by the antibodies that
are attached to the surface antigens. This
large clump can then precipitate. In other
words, the antibody and antigen complex
becomes so large that it is rendered in
soluble and precipitates out of solution.
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Ag + Ab = Agglutination
Testing for Blood Types
Some viruses can
clump RBC’s!
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Neutralization
• Neutralization, in which the antibodies
don’t cover the entire cell; they just cover
the toxic sites of the antigen agent.
Neutralization is also a factor in hemolytic
disease of the newborn, during which a
mother is Rh negative and pregnant with
an Rh positive fetus.
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Lysis
• Some antibodies are capable of directly
attacking membranes of cellular microbes,
and therefore cause them to rupture (lyse).
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Opsonization
• This is when the antibody binds to an
antigen that the phagocytes are having
difficulty engulfing, such as a bacterium
with a capsule (like TB).
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Complement Cascade
• The antibody not only binds to the
bacteria, but also pops the cell membrane
of the invading organism.
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Antibody Production
• When one becomes infected, 1st Ab
produced is class IgM. IgG is made
later
• The levels of Abs and specific Abs
can be measured in the serum (liquid
portion of blood)
• Ab levels can be used to monitor the
immune response
– Antibody titer
• A secondary/ memory response will
produce Abs more quickly and in
greater quantity
• Memory cells are the basis for
vaccines. Vaccines are dead or
weakened microbes or antigens
which are introduced into the body to
stimulate an immune system.
Memory cells are formed, ready and
waiting for possible next exposure
later in life.
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PATHOLOGICAL STATES OF
THE IMMUNE SYSTEM
HYPERSENSITIVITY AND ALLERGIES
• A child ingests a peanut for the first time, and is not aware that he is allergic to the
proteins on them.
• A macrophage ingests the peanut antigens, and break them down.
• Some of the peanut antigens are embedded into the cell membrane of the
macrophage.
• The antigenic peptide from the peanut is presented to a T helper cell and activates it.
• The activated T helper cell now releases many cytokines.
• The cytokines activate cytotoxic T cells.
• The T helper cell activates B cells.
• The B cells replicate clones of themselves
– Some of these clones become memory cells
– Some of these clones mature into plasma cells
• Plasma cells secrete IgE antibodies
• IgE antibodies bind to mast cells and basophiles
• The mast cells and basophils release histamine granules
• Severe vasodilatation occurs
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• Anaphylactic shock: blood pressure drops
1st Exposure – Sensitization
APC Processes Ag
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1st Exposure – Sensitization
B Cells Activated to Make Ab (IgE!)
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2nd Exposure Mast cells/ Basophils bind Ag
via IgE on their surface & degranulate
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Regulation (homeostasis)
– “self” and “nonself”
– inappropriate
immune responses
• Excessive
(hypersensitivities:
allergies,
autoimmunity)
• Diminished
(Immune
deficiency: HIV
AIDS)
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AUTOIMMUNITY
• Autoimmunity describes the loss of self tolerance by the
lymphocytes. The T cells and B cells now attack the body’s own
tissues. For some reason, women are more afflicted with
autoimmune disorders than men.
•
•
•
•
•
•
•
•
Examples of autoimmune diseases
Graves’ disease
Myasthenia Gravis
Systemic Lupus Erythematosus (SLE, or “Lupus”)
Rheumatoid arthritis
Multiple sclerosis
Hashimoto’s thyroiditis
Insulin-dependent diabetes mellitus.
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Autoimmunity
•
•
•
•
•
Affects 5% of the developed world
Disproportionately affects women
Loss of self tolerance
Patients can have auto-reactive T cells and Abs
Often treated with immunosuppressant drugs
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GRAVES’ DISEASE
• This is an autoimmune disorder in which
antibodies called TSI ( thyroid
stimulating immunoglobulin) stimulate
the thyroid inappropriately and this leads
to hyperthyroidism.
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HASHIMOTO’S THYROIDITIS
• Another autoimmune disorder of the
thyroid, except the antibodies destroy the
thyroid gland and this leads to
hypothyroidism.
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MYASTHENIA GRAVIS
• Antibodies destroy the nicotinicacetylcholine receptor on the surface of
skeletal muscle. As a consequence, the
patient has progressive muscle
weakness due to the loss of nervous
stimulation of the muscle cells.
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INSULIN-DEPENDENT
DIABETES MELLITUS
• Antibodies destroy the beta cells of the
islets of Langerhans in the pancreas.
This leads to the inability for insulindependent cells of the body to import
glucose from the plasma.
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MULTIPLE SCLEROSIS
• Antibodies attack the myelin sheath
around neurons, leading to a decline in
the speed of the action potential.
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SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
• This is a chronic inflammatory disease
that affects many systems of the body.
The initial manifestation is a red rash
around the nose and mouth and almost
looks like a butterfly mask on the
patient’s face.
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RHEUMATOID ARTHRITIS
• This is a collagen disease and often ends
up deforming the patient’s joints. This
is one the antibodies chronically attack
and destroy the collagen within the joints
of the patient. The patient ends up with
hands and feet severely flexed and curled.
Extension of the joints is extremely
difficult, if not impossible.
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