Resistance of the Body to

Infection:
II. Immunity and Allergy
IMMUNITY.. .
The human body has the ability to resist almost all types of organisms or toxins
that tend to damage the tissues and organs. This capability is called immunity.
ACQUIRED
IMMUNITY.. . Much of the
immunity is acquired immunity that does not develop until after the body is
first attacked by a bacterium, virus, or toxin; often, weeks or months are
required for the immunity to develop. INNATE
IMMUNITY.. .
An additional element of immunity that results from general processes, rather
than from processes directed at specific disease organisms, is called innate
immunity, which includes the following aspects:
1. Phagocytosis of bacteria and other invaders by white blood cells
and cells of the tissue macrophage system.
2. Destruction of swallowed organisms by the acid secretions of the
stomach and the digestive enzymes.
3. Resistance of the skin to invasion by organisms.
4. Presence in the blood of certain chemicals and cells that attach to
foreign organisms or toxins and destroy them. Some of these are:
(A) Lysozyme, a mucolytic polysaccharide that attacks bacteria and causes
them to dissolute.
(B) Basic polypeptides, which react with and inactivate certain types of
gram-positive bacteria.
(C) The complement complex , a system of about 20 proteins that can be
activated in various ways to destroy bacteria.
(D) Natural killer lymphocytes that can recognize and destroy foreign cells,
tumor cells, and even some infected cells.
This innate immunity makes the human body resistant to diseases such as
some paralytic viral infections of animals, hog cholera, cattle plague, and
distemper—a viral disease that kills a large percentage of dogs that become
afflicted with it. Likewise, many animals are resistant or even immune to
many human diseases, such as poliomyelitis, mumps, human cholera,
measles, and syphilis, which are very damaging or even lethal to humans.
ACQUIRED (ADAPTIVE) IMMUNITY
In addition to its generalized innate immunity, the human body has the ability
to develop extremely powerful specific immunity against individual invading
agents such as lethal bacteria, viruses, toxins, and even foreign tissues from
other animals. This ability is called acquired or adaptive immunity. Acquired
immunity is caused by a special immune system that forms antibodies
and/or activated lymphocytes that attack and destroy the specific invading
organism or toxin.
Acquired immunity can often bestow an extreme degree of protection. For
example, certain toxins, such as the paralytic botulinum toxin or the
tetanizing toxin of tetanus, can be protected against in doses as high as
100,000 times the amount that would be lethal without immunity. It is for
this reason that the treatment process known as immunization is so
important in protecting people against disease and against toxins.
BASIC TYPES OF ACQUIRED IMMUNITY:
HUMORAL
CELL-MEDIATED

Two basic but closely allied types of acquired immunity occur in

the body.
Humoral immunity
In one of these, the body develops circulating antibodies, which are globulin
molecules in the blood plasma capable of attacking the invading agent. This
type of immunity is called humoral immunity or B-cell immunity because B
lymphocytes produce the antibodies.
Acquired immunity
The second type of acquired immunity is achieved through formation of large
numbers of activated T lymphocytes, which are specifically crafted in the
lymph nodes to destroy the foreign agent. This type of immunity is called cell-
mediated immunity or T-cell immunity because the activated lymphocytes
are T lymphocytes. Both the antibodies and activated lymphocytes are formed
in the lymphoid tissues of the body.
 BOTH TYPES OF ACQUIRED IMMUNITY
ARE INITIATED BY ANTIGENS
Because acquired immunity does not develop until after invasion by a foreign
organism or toxin, it is clear that the body must have some mechanism for
recognizing this invasion. Each toxin or organism almost always contains one
or more specific chemical compounds in its makeup that is (are) different from
all other compounds. In general, these are proteins or large polysaccharides
that initiate the acquired immunity; these substances are called antigens
(antibody generators).
For a substance to be antigenic, it usually must have a high molecular weight
of 8000 or more. Furthermore, the process of antigenicity usually depends on
regularly recurring molecular groups, called epitopes, on the surface of the
large molecule. This factor also explains why proteins and large
polysaccharides are almost always antigenic because both these substances
have this stereochemical characteristic.
LYMPHOCYTES ARE RESPONSIBLE FOR
ACQUIRED IMMUNITY
Acquired immunity is the product of the body’s lymphocytes. In people who
have a genetic lack of lymphocytes or whose lymphocytes have been
destroyed by radiation or chemicals, no acquired immunity can develop.
Within days after birth, such a person dies of fulminating bacterial infection
unless he or she is treated by heroic measures. Therefore, it is clear that
lymphocytes are essential to the survival of humans.
Location of lymphocytes
Lymphocytes are located most extensively in the lymph nodes, but are also
found in special lymphoid tissues such as the spleen, submucosal areas of
the gastrointestinal tract, thymus, and bone marrow. The lymphoid tissue is
distributed advantageously in the body to intercept invading organisms or
toxins before they can spread too widely.
Mechanism of invasion
In most cases, the invading agent first enters the tissue fluids and then is carried by
lymph vessels to the lymph node or other lymphoid tissue. For example, the lymphoid
tissue of the gastrointestinal walls is exposed immediately to antigens invading from the
gut. The lymphoid tissue of the throat and pharynx (including the tonsils and adenoids) is
well located to intercept antigens that enter by way of the upper respiratory tract. The
lymphoid tissue in the lymph nodes is exposed to antigens that invade the peripheral
tissues of the body, and the lymphoid tissue ofthe spleen, thymus, and bone marrow
plays the specific role of intercepting antigenic agents that have succeeded in reaching
the circulating blood.
T and B Lymphocytes promote Cell-
Mediated and Humoral Immunity
Although most lymphocytes in normal lymphoid tissue look alike when
studied under a microscope, these cells are distinctly divided into two major
populations. One of the populations, the T lymphocytes, is responsible for
forming the activated lymphocytes that provide cell-mediated immunity, and
the other popula- tion, the B lymphocytes, is responsible for forming
antibodies that provide humoral immunity.
Both types of lymphocytes are derived originally in the embryo from
multipotent hematopoietic stem cells that form common lymphoid progenitor
cells as one of their most important offspring as they differentiate. Almost all
the lymphocytes that are formed eventually end up in the lymphoid tissue,
but before doing so, they are further differentiated or preprocessed in the
following ways:
The lymphoid progenitor cells that are eventually destined to form activated
T lymphocytes first migrate to and are preprocessed in the thymus gland;
thus, they are called T lymphocytes to designate the role of the thymus. They
are responsible for cell-mediated immunity.
The other population of lymphocytes—the B lymphocytes that are destined to
form antibodies—are preprocessed in the liver during mid–fetal life and in the
bone marrow in late fetal life and after birth. This population of cells was first
discovered in birds, which have a special preprocessing organ called the bursa
of Fabricius. For this reason, these lymphocytes are called B lymphocytes to
designate the role of the bursa, and they are responsible for humoral
immunity.
Figure 35-1 shows the two lymphocyte systems for formation, respectively, of
(1) Activated T lymphocytes
(2) Antibodies
 PREPROCESSING OF T AND B LYMPHOCYTES
Although all lymphocytes in the body originate from lymphocyte-committed
stem cells of the embryo, these stem cells are incapable of forming activated T
lymphocytes or antibodies directly. Before they can do so, they must be
further differentiated in appropriate processing areas, as follows:
Thymus Gland Preprocesses T .Lymphocytes.
The T lymphocytes, after origination in the bone
marrow, first mi- grate to the thymus gland. Here they divide rapidly
and, at the same time, develop extreme diversity for reacting against
different specific antigens. That is, one thymic lymphocyte develops
specific reactivity against one antigen, and then the next lymphocyte
develops specificity against another antigen. This process continues
until there are thousands of different types of thymic lymphocytes with
specific reactivities against many thousands of different antigens. These
different types of preprocessed T lymphocytes now leave the thymus
and spread via the blood throughout the body to lodge in lymphoid
tissue everywhere.
The thymus also makes certain that any T lymphocytes leaving the thymus will
not react against proteins or other antigens that are present in the body’s own
tissues; otherwise, the T lymphocytes would be lethal to the person’s own
body in only a few days. The thymus selects which T lymphocytes will be
released by first mixing them with virtually all the specific self-antigens from
the body’s own tissues. If a T lymphocyte reacts, it is destroyed and
phagocytized instead of being released, which happens in to up to 90% of the
cells. Thus, the only cells that are finally released are those that are
nonreactive against the body’s own antigens—they react only against antigens
from an outside source, such as from a bacterium, toxin, or even transplanted
tissue from another person.
Most of the preprocessing of T lymphocytes in the thymus occurs shortly
before the birth of a baby and for a few months after birth. Beyond this
period, removal of the thymus gland diminishes (but does not eliminate) the
T-lymphocytic immune system. However, removal of the thymus several
months before birth can prevent development of all cell-mediated immunity,
including rejection of transplanted organs.
Liver and bone marrow preprocess B
lymphocytes
In humans, B lymphocytes are preprocessed in the liver during midfetal
life and in the bone marrow during late fetal life and after birth. B
lymphocytes are different from T lymphocytes in two ways:
1. Instead of the whole cell developing reactivity against the antigen, as
occurs for the T.lymphocytes, the B.lymphocytes actively secrete antibodies
that are the reactive agents. These agents are large proteins that are capable
of combining with and destroying the antigenic substance.
2. The B lymphocytes have even greater diversity than the T lymphocytes,
thus forming many millions of reactivities. After preprocessing, the B-
lymphocytes, like the T-lymphocytes, migrate to lymphoid tissue throughout
the body, where they lodge near but slightly removed from the T-lymphocyte
areas.
T-LYMPHOCYTES AND B-LYMPHOCYTE ANTIBODIES REACT
AGAINST SPECIFIC ANTIGENS—ROLE OF LYMPHOCYTE CLONES
When specific antigens come into contact with T and B lymphocytes in the
lymphoid tissue, some of the T lymphocytes become activated to form
activated T cells, and some of the B lymphocytes become activated to form
antibodies. The activated T cells and antibodies, in turn, react highly
specifically against the particular types of antigens that initiated their
development. The mechanism of this specificity is described next.
Millions of specific types of lymphocytes
are stored in lymphoid tissue
Millions of different types of preformed B lymphocytes and preformed T
lymphocytes capable of forming highly specific types of antibodies or T cells
are stored in the lymph tissue. Each of these preformed lymphocytes is
capable of forming only one type of antibody or one type of T cell with a
single type of specificity, and only the specific type of antigen can activate it.
Once the specific lymphocyte is activated by its antigen, it reproduces wildly,
forming tremendous numbers of duplicate lymphocytes.
If it is a B lymphocyte, its progeny will eventually secrete the specific type of
antibody that then circulates throughout the body. If it is a T lymphocyte, its
progeny are specific sensitized T cells that are released into the lymph,
carried to the blood, and then circulated through all the tissue fluids and back
into the lymph, sometimes circulating around and around in this circuit for
months or years.
All the different lymphocytes that are capable of forming one specific
antibody or T cell are called a clone of lymphocytes. That is, the lymphocytes
in each clone are alike, derived originally from one or a few early lymphocytes
of its specific type.
 ORIGIN OF THE MANY CLONES OF
LYMPHOCYTES
Only several hundred to a few thousand genes code for the millions of
different types of antibodies and T lymphocytes. At first, it was a mystery
how it was possible for so few genes to code for the millions of different
specificities of antibodies or T cells produced by the lymphoid tissue. This
mystery has now been solved.
The whole gene for forming each type of T cell or B cell is never present in the
original stem cells from which the functional immune cells are formed.
Instead, there are only gene segments—actually, hundreds of such segments
—but not whole genes. During preprocessing of the respective T- and B-cell
lymphocytes, these gene segments become mixed with one another in
random combinations, finally forming whole genes.
Once stimulated by binding to a foreign antigen, such as a component of
a bacterium or virus, a lymphocyte multiplies into a clone of identical
cells. Some of the cloned B cells differentiate into plasma cells that
produce antibody molecules.
Because there are several hundred types of gene segments, as well as
millions of different combinations in which the segments can be arranged in
single cells, one can understand the millions of different cell gene types that
can occur. For each functional T or B lymphocyte that is finally formed, the
gene structure codes for only a single antigen specificity. These mature cells
then become the highly specific T and B cells that spread to and populate the
lymphoid tissue.
MECHANISM FOR ACTIVATING LYMPHOCYTE CLONES
Each clone of lymphocytes is responsive to only a single type of antigen (or to
several similar antigens that have almost exactly the same stereochemical
characteristics). The reason for this is the following.
In the case of the B lymphocytes, each of these has on its cell surface
membrane about 100,000 antibody molecules that will react highly
specifically with only one type of antigen. Therefore, when the appropriate
antigen comes along, it immediately attaches to the antibody in the cell
membrane; this leads to the activation process.
In the case of the T lymphocytes, molecules similar to antibodies, called
surface receptor proteins (or T-cell receptors), are on the surface of the T-cell
membrane, and these are also highly specific for one specified activating
antigen. An antigen therefore stimulates only those cells that have
complementary receptors for the antigen and are already committed to
respond to it.
Role of macrophages in the activation process
Aside from the lymphocytes in lymphoid tissue, literally millions of
macrophages are also present in the same tissue. These macrophages line the
sinusoids of the lymph nodes, spleen, and other lymphoid tissue, and they lie in
opposition to many of the lymph node lymphocytes. Most invading organisms
are first phagocytized and partially digested by the macrophages, and the
antigenic products are liberated into the macrophage cytosol. The macrophages
then pass these antigens by cell to cell contact directly to the lymphocytes, thus
leading to activation of the specified lymphocytic clones. The macrophages, in
addition, secrete a special activating substance, interleukin-1, that promotes
still further growth and reproduction of the specific lymphocytes.
Role of T Cells in activation of B Lymphocytes
Most antigens activate both T lymphocytes and B lymphocytes at the same
time. Some of the T cells that are formed, called T-helper cells, secrete
specific substances (collectively called lymphokines) that activate the specific
B lymphocytes. Indeed, without the aid of these T-helper cells, the quantity of
antibodies formed by the B lymphocytes is usually small.
SPECIFIC ATTRIBUTES OF THE
B-LYMPHOCYTE SYSTEM—HUMORAL IMMUNITY
AND ANTIBODIES
Antibody formation by plasma cells
Before exposure to a specific antigen, the clones of B lymphocytes remain
dormant in the lymphoid tissue. On entry of a foreign antigen, macrophages
in lymphoid tissue phagocytize the antigen and then present it to adjacent B
lymphocytes. In addition, the antigen is presented to T cells at the same time,
and activated T-helper cells are formed. These helper cells also contribute to
extreme activation of the B lymphocytes.
The B lymphocytes specific for the antigen immediately enlarge and take on
the appearance of lymphoblasts. Some of the lymphoblasts further
differentiate to form plasmablasts, which are precursors of plasma cells. In the
plasmablasts, the cytoplasm expands, and the rough endoplasmic reticulum
proliferates vastly. The plasmablasts then begin to divide at a rate of about
once every 10 hours for about nine divisions, giving a total population of
about 500 cells for each original plasmablast in 4 days.
The mature plasma cell then produces gamma globulin antibodies at an
extremely rapid rate—about 2000 molecules per second for each plasma cell.
In turn, the antibodies are secreted into the lymph and carried to the
circulating blood. This process continues for several days or weeks until,
finally, exhaustion and death of the plasma cells occur.
Formation of memory cells enhances antibody
response to subsequent antigen exposure
A few of the lymphoblasts formed by activation of a clone of B lymphocytes
do not go on to form plasma cells but, instead, form moderate numbers of
new B lymphocytes similar to those of the original clone. In other words, the
B-cell population of the specifically activated clone becomes greatly
enhanced, and the new B lymphocytes are added to the original lymphocytes
of the same clone. They also circulate throughout the body to populate all the
lymphoid tissue; immunologically, however, they remain dormant until
activated once again by a new quantity of the same antigen.
These lymphocytes are called memory cells. Subsequent exposure to the
same antigen will cause a much more rapid and potent antibody response
this second time around because there are many more memory cells than
there were original B lymphocytes of the specific clone.
Figure 35-3 shows the differences between the primary response for forming
antibodies that occurs on first exposure to a specific antigen and the
secondary response that occurs after second exposure to the same antigen.
Note the 1-week delay in the appearance of the primary response, its weak
potency, and its short life. The secondary response, by contrast, begins
rapidly after exposure to the antigen (often within hours), is far more potent,
and forms antibodies for many months rather than for only a few weeks. The
increased potency and duration of the secondary response explain why
immunization is usually accomplished by injecting antigen in multiple doses,
with periods of several weeks or several months between injections.
Generation of lifelong Immunity by plasma
cells
When B lymphocytes encounter their associated antigens, become activated,
and undergo clonal expansion, they differentiate into short-lived or long-lived
plasma cells that produce large amounts of antibodies. The short-lived
plasma cells provide rapid protection but undergo apoptosis after a few days
of intense antibody secretion. However, the long-lived plasma cells reside in
tissues such as the bone marrow and gut associated lymphoid tissue and can
continue producing antibodies for many years, providing lifelong immunity
against infectious diseases such as measles and smallpox.
High titers of smallpox-specific antibodies, for example, have been detected
in the blood of subjects vaccinated in childhood, 70 years previously. Also,
older survivors of the 1918 H1N1 influenza virus pandemic were shown to
possess highly functional, virus-neutralizing antibodies to this virulent virus
90 years after they were infected. Thus, plasma cells that produce virus-
neutralizing antibodies can be sustained for many decades after exposure,
even into the tenth decade of life in humans.
 Nature of Antibodies
(Igs) that have molecular weights between 160,000 and 970,000 and
constitute about 20% of all the plasma proteins. All the immunoglobulins are
composed of combinations of light and heavy polypeptide chains. Most are a
combination of two light and two heavy chains, as shown in Figure 35-4.
However, some immunoglobulins have combinations of as many as 10 heavy
and 10 light chains, which give rise to high-molecular-weight
immunoglobulins. Yet, in all immunoglobulins, each heavy chain is paralleled
by a light chain at one of its ends, thus forming a heavy-light pair; there are
always at least two and as many as 10 such pairs in each immunoglobulin
molecule.
Figure 35-4 shows a designated end of each light and heavy chain, called the
variable portion; the remainder of each chain is called the constant portion.
The variable portion is different for each specific antibody, and it is this
portion that attaches specifically to a particular type of antigen. The
constant portion determines other properties of the antibody, establishing
such factors as antibody diffusivity in the tissues, adherence to specific
structures in the tissues, attachment to the complement complex, ease with
which the antibodies pass through membranes, and other biological
properties of the antibody. A combination of noncovalent and covalent
bonds (disulfide) holds the light and heavy chains together.
Specificity of Antibodies

Each antibody is specific for a particular antigen; this characteristic is a

result of the unique structural organization of amino acids in the variable
portions of the light and heavy chains. The amino acid organization has a
different steric shape for each antigen specificity, so when an antigen
comes into contact with it, multiple prosthetic groups of the antigen fit as
a mirror image with those of the antibody, thus allowing for rapid and
tight bonding between the antibody and antigen.
When the antibody is highly specific, there are so many bonding sites that the
antibody-antigen coupling is exceedingly strong, held together by
(1) Hydrophobic bonding.
(2) Hydrogen bonding.
(3) Ionic attractions.
(4) Van der Waals forces.
It also obeys the thermodynamic mass action law:
Ka is called the affinity constant and is a measure of how tightly the antibody
binds with the antigen.
Note especially in Figure 35-4 that there are two variable sites on the
illustrated antibody for attachment of antigens, making this type of antibody
bivalent. A small proportion of the antibodies, which consist of combinations
of up to 10 light and 10 heavy chains, has as many as 10 binding sites.
Five general classes of antibodies
There are five general classes of antibodies, respectively named:
1.IgM
2.IgG,
3.IgA

4.IgD
5.IgE
“Ig” stands for immunoglobulin, and
the other five letters designate the respective classes.
For the purpose of our limited discussion, two of these classes of antibodies
are of particular importance:
1.IgG, which is a bivalent antibody and constitutes about 75% of the
antibodies of the normal person, and
2.IgE, which constitutes only a small percentage of the antibodies but is
especially involved in allergies.
3.The IgM class is also interesting because a large share of the antibodies
formed during the primary response are of this type. These antibodies have
10 binding sites that make them exceedingly effective in protecting the body
against invaders, even though there are not many IgM antibodies.
Mechanisms of action of antibodies
Antibodies act mainly in two ways to protect the body against invading agents:
(1) By direct attack on the
invader. (2) By activation of the
complement system that then has multiple means of its own for destroying the
invader.
Direct action of antibodies on invading agents
Figure 35-5 shows antibodies (designated by the red Y- shaped bars) reacting
with antigens (designated by the shaded objects). Because of the bivalent
nature of the antibodies and the multiple antigen sites on most invading agents,
the antibodies can inactivate the invading agent in one of several ways, as
follows:
1. Agglutination, in which multiple large particles with antigens on their
surfaces (e.g., bacteria or red cells) are bound together into a clump.
2. Precipitation, in which the molecular complex of soluble antigen (e.g.,
tetanus toxin) and antibody becomes so large that it is rendered insoluble and
precipitates.
3. Neutralization, in which the antibodies cover the toxic sites of the
antigenic agent.
4. Lysis, in which some potent antibodies are occasionally capable of directly
attacking membranes of cellular agents and thereby cause rupture of the
agent.
These direct actions of antibodies often are not strong enough to play a
major role in protecting the body against the invader. Most of the protection
occurs through the amplifying effects of the complement system.
COMPLEMENT SYSTEM FOR ANTIBODY ACTION
The main function of the complement system is to enhance (complement)
the actions of antibodies and phagocytic cells in neutralizing and destroying
pathogens, removing damaged cells from the body, and promoting
inflammation.
Complement is a collective term that describes a system of about 20 proteins,
many of which are enzyme precursors. The principal actors in this system are 11
proteins designated C1 through C9, B, and D, shown in Figure 35-6.
All these are present normally among the plasma proteins in the blood, as
well as among the proteins that leak out of the capillaries into the tissue
spaces. The enzyme precursors are normally inactive but can be activated by
the so-called classical pathway.
Classical Pathway
The classical pathway is initiated by an antigen-antibody reaction. That is,
when an antibody binds with an antigen, a specific reactive site on the
constant portion of the antibody becomes uncovered, or activated, and this in
turn binds directly with the C1 molecule of the complement system. This sets
into motion a cascade of sequential reactions, shown in Figure 35-6, beginning
with activation of the proenzyme C1.
The C1 enzymes that are formed then activate successively increasing
quantities of enzymes in the later stages of the system so that from a small
beginning, an extremely large, amplified reaction occurs. Multiple end
products are formed, as shown at the right in the figure, and several of these
have important effects that help prevent damage to the body’s tissues caused
by the invading organism or toxin. Among the more important effects are the
following:
1. Opsonization and phagocytosis:
One of the products of the complement cascade, C3b, strongly activates
phagocytosis by neutrophils and macrophages causing these cells to engulf
the bacteria to whichthe antigen-antibody complexes are attached. This
process is called opsonization. It often enhances the number of bacteria that
can be destroyed by many hundredfold.
2. Lysis:
One of the most important of all the products of the complement cascade is
the membrane attack complex (also called the cytolytic complex), which is a
combination of multiple complement factors designated as C5b6789. This
membrane attack complex inserts itself into the lipid bilayer of the cell
membrane, creating pores that are permeable to ions and causing osmotic
rupture of the cell membranes of bacteria or other invading organisms.
3. Agglutination:
The complement products also change the surfaces of the invading
organisms, causing them to adhere to one another, thus promoting
agglutination.
4. Neutralization of viruses:
The complement enzymes and other complement products can attack the
structures of some viruses and thereby render them nonvirulent.
5. Chemotaxis:
Fragment C5a initiates chemotaxis of neutrophils and macrophages, thus
causing large numbers of these phagocytes to migrate into the tissue area
adjacent to the antigenic agent.
6. Activation of mast cells and basophils:
Fragments C3a, C4a, and C5a activate mast cells and basophils, causing them
to release histamine, heparin, and several other substances into the local
fluids. These substances, in turn, cause increased local blood flow, increased
leakage of fluid and plasma protein into the tissue, and other local tissue
reactions that help inactivate or immobilize the antigenic agent. These same
factors play a major role in inflammation and allergy.
7. Inflammatory effects:
In addition to inflammatory effects caused by activation of the mast cells
and basophils, several other complement products contribute to local
inflammation. These products cause;
(1) the already increased blood flow to increase still further;
(2) the capillary leakage of proteins to be increased;
(3) the interstitial fluid proteins to coagulate in the tissue spaces, thus
preventing movement of the invading organism through the tissues.