Wed 12 Jan 2011
Mechanisms of the immune system
Nonspecific, innate immunity
Most microorganisms encountered in daily life are repelled
before they cause detectable signs and symptoms of disease. These potential
pathogens, which include viruses,
are quite diverse, and therefore a nonspecific defense system that diverts all
types of this varied microscopic horde equally is quite useful to an organism.
The innate immune system provides this kind of nonspecific protection through a
number of defense mechanisms, which include physical barriers such as the skin,
chemical barriers such as antimicrobial proteins that harm or destroy invaders,
and cells that attack foreign cells and body cells harbouring infectious
agents. The details of how these mechanisms operate to protect the body are
described in the following sections.
External barriers to infection
The skin and the mucous membrane linings of the respiratory,
gastrointestinal, and genitourinary tracts provide the first line of defense
against invasion by microbes or parasites.
Human skin has a tough outer layer of cells that produce keratin. This layer of cells, which is constantly
renewed from below, serves as a mechanical barrier to infection. In addition,
glands in the skin secrete oily substances that include fatty acids,
such as oleic acid,
that can kill some bacteria; skin glands also secrete lysozyme, an enzyme (also present in tears and
saliva) that can break down the outer wall of certain bacteria. Victims of
often fall prey to infections from normally harmless bacteria, illustrating the
importance of intact, healthy skin to a healthy immune system.
Like the outer layer of the skin but much softer, the mucous membrane
linings of the respiratory, gastrointestinal, and genitourinary tracts provide a mechanical barrier of
cells that are constantly being renewed. The lining of the respiratory tract
has cells that secrete mucus (phlegm), which traps small particles.
Other cells in the wall of the respiratory tract have small hairlike
projections called cilia, which steadily beat in a sweeping movement
that propels the mucus and any trapped particles up and out of the throat and
nose. Also present in the mucus are protective antibodies, which are products
of specific immunity. Cells in the lining of the gastrointestinal tract secrete
mucus that, in addition to aiding the passage of food, can trap potentially
harmful particles or prevent them from attaching to cells that make up the
lining of the gut. Protective antibodies are secreted by cells underlying the
gastrointestinal lining. Furthermore, the stomach lining secretes hydrochloric acid that is strong enough to kill many microbes.
Chemical barriers to infection
Some microbes penetrate the body's protective barriers and
enter the internal tissues. There they encounter a variety of chemical
substances that may prevent their growth. These substances include chemicals
whose protective effects are incidental to their primary function in the body,
chemicals whose principal function is to harm or destroy invaders, and
chemicals produced by naturally occurring bacteria.
Chemicals with incidental protective
Some of the chemicals involved in normal body processes are
not directly involved in defending the body against disease. Nevertheless, they
do help repel invaders. For example, chemicals that inhibit the potentially
damaging digestive enzymes
released from body cells which have died in the natural course of events also
can inhibit similar enzymes produced by bacteria, thereby limiting bacterial
growth. Another substance that provides protection against microbes
incidentally to its primary cellular role is the blood protein transferrin. The normal function of transferrin
is to bind molecules of iron that are absorbed into the bloodstream through the
gut and to deliver the iron to cells, which require the mineral to grow. The
protective benefit transferrin confers results from the fact that bacteria,
like cells, need free iron to grow. When bound to transferrin, however, iron is
unavailable to the invading microbes, and their growth is stemmed.
A number of proteins contribute directly to the body's
nonspecific defense system by helping to destroy invading microorganisms. One
group of such proteins is termed complement
because it works with other defense mechanisms of the body, complementing their
efforts to eradicate invaders. Many microorganisms can activate complement in
ways that do not involve specific immunity. Once activated, complement proteins
work together to lyse, or break apart, harmful infectious organisms that do not
have protective coats. Other microorganisms can evade these mechanisms but fall
prey to scavenger cells, which engulf and destroy infectious agents, and to the
mechanisms of the specific immune response. Complement cooperates with both
nonspecific and specific defense systems and is described more fully under Antibody-mediated immune mechanisms.
Another group of proteins that provide protection are the interferons,
which inhibit the replication of many—but not all—viruses. Cells that have been
infected with a virus produce interferon, which sends a signal to other cells
of the body to resist viral growth. When first discovered in 1957, interferon
was thought to be a single substance, but since then several types have been
discovered, each produced by a different type of cell. Alpha interferon
is produced by white blood cells other than lymphocytes, beta interferon
and gamma interferon
All interferons inhibit viral replication by interfering with the transcription
of viral nucleic acid.
Interferons exert additional inhibitory effects by regulating the extent to
which lymphocytes and other cells express certain important molecules on their
surface membranes and by stimulating the activity of natural killer cells,
which are described below.
Proteins from naturally occurring bacteria
In the small
and large intestines the growth of invading bacteria can be inhibited by
naturally gut-dwelling bacteria that do not cause disease. These gut-dwelling
microorganisms secrete a variety of proteins that enhance their own survival by
inhibiting the growth of the invading bacterial species.
- Time-lapse photography of a
macrophage (the light-coloured, globular structure) consuming bacteria.
If an infectious agent is not successfully repelled by the
chemical and physical barriers described above, it will encounter cells whose function is to eliminate foreign
substances that enter the body. These cells are the nonspecific effector cells
of the innate immune response. They include scavenger cells—i.e., various cells
that attack infectious agents directly—and natural killer cells, which attack
cells of the body that harbour infectious organisms. Some of these cells
destroy infectious agents by engulfing and destroying them through the process
while other cells resort to alternative means. As is true of other components
of innate immunity, these cells interact with components of acquired immunity
to fight infection.
All higher animals and many lower ones have scavenger
(white blood cells)—that destroy infectious agents. Most vertebrates, including
all birds and mammals, possess two main kinds of scavenger cells. Their
importance was first recognized in 1884 by the Russian biologist Élie Metchnikoff, who named them microphages and
macrophages, after Greek words meaning “little eaters” and “big eaters.”
Microphages are now called either granulocytes, because of
the numerous chemical-containing granules found in their cytoplasm, or
polymorphonuclear leukocytes, because of the oddly shaped nucleus these cells
contain. Some granules contain digestive enzymes capable of breaking down
proteins, while others contain bacteriocidal (bacteria-killing) proteins. There
are three classes of granulocytes—neutrophils,
are distinguished according to the shape of the nucleus and the way in which
the granules in the cytoplasm are stained by dye. The differences in staining
characteristics reflect differences in the chemical makeup of the granules. Neutrophils
are the most common type of granulocyte, making up about 60 to 70 percent of
all white blood cells. These granulocytes ingest and destroy microorganisms,
especially bacteria. Less common are the eosinophils, which are particularly
effective at damaging the cells that make up the cuticle (body wall) of larger
parasites. Fewer still are the basophils, which release heparin
(a substance that inhibits blood coagulation), histamine,
and other substances that play a role in some allergic reactions (see immune system disorder: Allergies). Very similar in structure and function to basophils are
the tissue cells called mast cells,
which also contribute to immune responses.
Granulocytes, which have a life span of only a few days, are
continuously produced from stem (i.e., precursor) cells in the bone marrow.
They enter the bloodstream and circulate for a few hours, after which they
leave the circulation and die. Granulocytes are mobile and are attracted to
foreign materials by chemical signals, some of which are produced by the
invading microorganisms themselves, others by damaged tissues, and still others
by the interaction between microbes and proteins in the blood plasma. Some
microorganisms produce toxins that poison granulocytes and thus escape
phagocytosis; other microbes are indigestible and are not killed when ingested.
By themselves, then, granulocytes are of limited effectiveness and require
reinforcement by the mechanisms of specific immunity.
- The destruction of bacteria by
a macrophage, one of the principal phagocytic (cell-engulfing) …
The other main type of scavenger cell is the macrophage, the
mature form of the monocyte.
Like granulocytes, monocytes are produced by stem cells in the bone marrow
and circulate through the blood, though in lesser numbers. But, unlike
granulocytes, monocytes undergo differentiation, becoming macrophages that
settle in many tissues, especially the lymphoid tissues (e.g., spleen
and lymph nodes)
and the liver,
which serve as filters for trapping microbes and other foreign particles that
arrive through the blood or the lymph. Macrophages live longer than
granulocytes and, although effective as scavengers, basically provide a
different function. Compared with granulocytes, macrophages move relatively
sluggishly. They are attracted by different stimuli and usually arrive at sites
of invasion later than granulocytes. Macrophages recognize and ingest foreign
particles by mechanisms that are basically similar to those of granulocytes,
although the digestive process is slower and not as complete. This aspect is of
great importance for the role that macrophages play in stimulating specific
immune responses—something in which granulocytes play no part (see Activation of T and B lymphocytes).
Natural killer (NK) cells
Natural killer cells do not attack invading organisms
directly but instead destroy the body's own cells that have either become
cancerous or been infected with a virus. NK cells were first recognized in
1975, when researchers observed cells in the blood and lymphoid tissues that
were neither the scavengers described above nor ordinary lymphocytes but which
nevertheless were capable of killing cells. Although similar in outward appearance
to lymphocytes, NK cells contain granules that harbour cytotoxic chemicals. NK
cells recognize dividing cells by a mechanism that does not depend on specific
immunity. They then bind to these dividing cells and insert their granules
through the outer membrane and into the cytoplasm. This causes the dividing
cells to leak and die. It is not certain whether NK cells belong to a distinct
lineage or are a special form of lymphocyte. It is known that they are
stimulated by gamma interferon. Their main biological role may be to regulate
the growth of stem cells in the bone marrow and elsewhere.
Nonspecific responses to infection
The body has a number of nonspecific methods of fighting
infection that are called early induced responses. They include the acute-phase
response and the inflammation response, which can eliminate infection or hold
it in check until specific, acquired immune responses have time to develop.
Nonspecific immune responses occur more rapidly than acquired immune responses
do, but they do not provide lasting immunity to specific pathogens.
Nonadaptive immune responses rely on a number of chemical
signals, collectively called cytokines, to carry out their effects. These
cytokines include members of the family of proteins called interleukins, which induce fever and the
acute-phase response, and tumour necrosis factor-alpha, which initiates the inflammatory
When the body is invaded by a pathogen, macrophages release
the protein signals interleukin-1 (IL-1) and interleukin-6 (IL-6) to help fight
the infection. One of their effects is to raise the temperature of the body,
causing the fever that often accompanies infection. (The
interleukins increase body temperature by acting on the temperature-regulating hypothalamus
in the brain and by affecting energy mobilization by fat and muscle cells.) Fever
is believed to be helpful in eliminating infections because most bacteria grow
optimally at temperatures lower than normal body temperature. But fever is only
part of the more general innate defense mechanism called the acute-phase
response. In addition to raising body temperature, the interleukins stimulate
liver cells to secrete increased amounts of several different proteins into the
bloodstream. These proteins, collectively called acute-phase
proteins, bind to bacteria and, by doing so, activate complement proteins that
destroy the pathogen. The acute-phase proteins act similarly to antibodies but
are more democratic—that is, they do not distinguish between pathogens as
antibodies do but instead attack a wide range of microorganisms equally. Another
effect the interleukins have is to increase the number of circulating
neutrophils and eosinophils, which help fight infection.
Infection often results in tissue damage, which may trigger
an inflammatory response. The signs of inflammation include pain, swelling, redness, and
fever, which are induced by chemicals released by macrophages. These substances
promote blood flow to the area, increase the permeability of capillaries,
and induce coagulation.
The increased blood flow is responsible for redness, and the leakiness of the
capillaries allows cells and fluids to enter tissues, causing pain and
swelling. These effects bring more phagocytic cells to the area to help
eliminate the pathogens. The first cells to arrive, usually within an hour, are
neutrophils and eosinophils, followed a few hours later by macrophages.
Macrophages not only engulf pathogens but also help the healing process by
disposing of cellular debris which accumulates from destroyed tissue cells and
neutrophils that self-destruct after ingesting microorganisms. If infection
persists, components of specific immunity—antibodies and T cells—arrive at the
site to fight the infection.
Specific, acquired immunity
It has been known for centuries that persons who have
contracted certain diseases and survived generally do not catch
those illnesses again. The Greek historian Thucydides
recorded that, when the plague
was raging in Athens during the 5th century BC, the sick and dying would have received no nursing at all
had it not been for the devotion of those who had already recovered from the
disease; it was known that no one ever caught the plague a second time. The
same applies, with rare exceptions, to many other diseases, such as smallpox,
Yet having had measles does not prevent a child from contracting chicken pox,
or vice versa. The protection acquired by experiencing one of these infections is specific for that infection; in
other words, it is due to specific, acquired immunity, also called adaptive
There are other infectious conditions, such as the common cold,
diseases, that can be caught again and again; these seem to contradict the
notion of specific immunity. But the reason such illnesses can recur is that
many different infectious agents produce similar symptoms (and thus the same
disease). For example, more than 100 viruses can cause the cluster of symptoms
known as the common cold. Consequently, even though infection with a particular
agent does protect against reinfection by that same pathogen, it does not
confer protection from other pathogens that have not been encountered.
Acquired immunity is dependent on the specialized white
blood cells known as lymphocytes. This section describes the various ways in
which lymphocytes operate to confer specific immunity. Although pioneer studies
were begun in the late 19th century, most of the knowledge of specific immunity
has been gained since the 1960s, and new insights are continually being
The nature of lymphocytes
Location in the lymphatic system
- The human lymphatic system, showing
the lymphatic vessels and lymphoid organs.
are the cells responsible for the body's ability to distinguish and react to an
almost infinite number of different foreign substances, including those of
which microbes are composed. Lymphocytes are mainly a dormant population,
awaiting the appropriate signals to be stirred to action. The inactive
lymphocytes are small, round cells filled largely by a nucleus.
Although they have only a small amount of cytoplasm compared with other cells,
each lymphocyte has sufficient cytoplasmic organelles (small functional units
such as mitochondria, the endoplasmic reticulum, and a Golgi apparatus) to keep the cell alive. Lymphocytes
move only sluggishly on their own, but they can travel swiftly around the body
when carried along in the blood
At any one time an adult human has approximately 2 × 1012
lymphocytes, about 1 percent of which are in the bloodstream. The majority are
concentrated in various tissues scattered throughout the body, particularly the
and lining of the intestines, which make up the lymphatic system (see illustration).
Organs or tissues containing such concentrations of lymphocytes are termed
lymphoid. The lymphocytes in lymphoid structures are free to move, although
they are not lying loose; rather, they are confined within a delicate network
of lymph capillaries located in connective tissues that channel the lymphocytes
so that they come into contact with other cells, especially macrophages, that
line the meshes of the network. This ensures that the lymphocytes interact with
each other and with foreign materials trapped by the macrophages in an ordered
T and B cells
Lymphocytes originate from stem cells in the bone marrow;
these stem cells divide continuously, releasing immature lymphocytes into the
bloodstream. Some of these cells travel to the thymus,
where they multiply and differentiate into T lymphocytes, or T cells.
The T stands for thymus-derived, referring to the fact that these
cells mature in the thymus. Once they have left the thymus, T cells enter the
bloodstream and circulate to and within the rest of the lymphoid organs, where
they can multiply further in response to appropriate stimulation. About half of
all lymphocytes are T cells.
Some lymphocytes remain in the bone marrow, where they
differentiate and then pass directly to the lymphoid organs. They are termed B
lymphocytes, or B cells, and they, like T cells, can mature and
multiply further in the lymphoid organs when suitably stimulated. Although it
is appropriate to refer to them as B cells in humans and other mammals, because
they are bone-marrow derived, the B actually stands for the bursa
a lymphoid organ found only in birds, the organisms in which B cells were first
B and T cells both recognize and help eliminate foreign
such as those that are part of invading organisms, but they do so in different
ways. B cells secrete antibodies,
proteins that bind to antigens. Since antibodies circulate through the humours
(i.e., body fluids), the protection afforded by B cells is called humoral immunity.
T cells, in contrast, do not produce antibodies but instead directly attack
invaders. Because this second type of acquired immunity depends on the direct
involvement of cells rather than antibodies, it is called cell-mediated
immunity. T cells recognize only infectious
agents that have entered into cells of the body, whereas B cells and antibodies
interact with invaders that remain outside the body's cells. These two types of
specific, acquired immunity, however, are not as distinct as might be inferred
from this description, since T cells also play a major role in regulating the
function of B cells. In many cases an immune response involves both humoral and
cell-mediated assaults on the foreign substance. Furthermore, both classes of lymphocytes
can activate or enhance a variety of nonspecific immune responses.
Ability to recognize foreign
Lymphocytes are distinguished from other cells by their
capacity to recognize foreign molecules. Recognition is accomplished by means
of receptor molecules. A receptor
molecule is a special protein whose shape is complementary to a portion of a
foreign molecule. This complementarity of shape allows the receptor and the
foreign molecule to conform to each other in a fashion roughly analogous to the
way a key fits into a lock.
Receptor molecules are either attached to the surface of the
lymphocyte or secreted into fluids of the body. B and T lymphocytes both have
receptor molecules on their cell surfaces, but only B cells manufacture and
secrete large numbers of unattached receptor molecules, called antibodies. Antibodies correspond in structure to
the receptor molecules on the surface of the B cell.
Any foreign material—usually of a complex nature and often a
protein—that binds specifically to a receptor molecule made by lymphocytes is
called an antigen.
Antigens include molecules found on invading microorganisms, such as viruses,
as well as molecules located on the surface of foreign substances, such as pollen,
dust, or transplanted tissue. When an antigen binds to a receptor molecule, it may
or may not evoke an immune response. Antigens that induce such a response are
Thus, it can be said that all immunogens are antigens, but not all antigens are
immunogens. For example, a simple chemical group that can combine with a
lymphocyte receptor (i.e., is an antigen) but does not induce an immune
response (i.e., is not an immunogen) is called a hapten. Although haptens cannot evoke an immune
response by themselves, they can become immunogenic when joined to a larger,
more complex molecule such as a protein, a feature that is useful in the study
of immune responses.
Many antigens have a variety of distinct three-dimensional
patterns on different areas of their surfaces. Each pattern is called an
antigenic determinant, or epitope,
and each epitope is capable of reacting with a different lymphocyte receptor.
Complex antigens present an “antigenic mosaic” and can evoke responses from a
variety of specific lymphocytes. Some antigenic determinants are better than
others at effecting an immune response, presumably because a greater number of
responsive lymphocytes are present. It is possible for two or more different
substances to have an epitope in common. In these cases, immune components
induced by one antigen are able to react with all other antigens carrying the
same epitope. Such antigens are known as cross-reacting antigens.
T cells and B cells differ in the form of the antigen they
recognize, and this affects which antigens they can detect. B cells bind to
antigen on invaders that are found in circulation outside the cells of the
body, while T cells detect only invaders that have somehow entered the cells of
the body. Thus foreign materials that have been ingested by cells of the body
or microorganisms such as viruses that penetrate cells and multiply within them
are out of reach of antibodies but can be eliminated by T cells.
Diversity of lymphocytes
The specific immune system (in other words, the sum total of
all the lymphocytes) can recognize virtually any complex molecule that nature
or science has devised. This remarkable ability results from the trillions of
different antigen receptors
that are produced by the B and T lymphocytes. Each lymphocyte produces its own
specific receptor, which is structurally organized so that it responds to a
different antigen. After a cell encounters an antigen that it recognizes, it is
stimulated to multiply, and the population of lymphocytes bearing that
particular receptor increases.
How is it that the body has such an incredible diversity of
receptors that are always ready to respond to invading molecules? To understand
this, a quick review of genes and proteins will be helpful. Antigen
receptor molecules are proteins,
which are composed of a few polypeptide chains (i.e., chains of amino acids
linked together by chemical bonds known as peptide bonds). The sequence in
which the amino acids are assembled to form a particular polypeptide chain is
specified by a discrete region of DNA,
called a gene.
But, if every polypeptide region of every antigen receptor were encoded by a
different gene, the human genome (all the genetic information encoded in the
DNA that is carried on the chromosomes of cells) would need to devote trillions
of genes to code just for these immune system proteins. Since the entire human
genome contains approximately 30,000 genes, individuals cannot inherit a gene
for each particular antigen receptor component. Instead, a mechanism exists
that generates an enormous variety of receptors from a limited number of genes.
What is inherited is a pool of gene segments for each type
of polypeptide chain. As each lymphocyte matures, these gene segments are
pieced together to form one gene for each polypeptide that makes up a specific
antigen receptor. This rearrangement of alternative gene segments occurs
predominantly, though not entirely, at random, so that an enormous number of
combinations can result. Additional diversity is generated from the imprecise
recombination of gene segments—a process called junctional
diversification—through which the ends of the gene segments can be shortened or
lengthened. The genetic rearrangement takes place at the stage when the
lymphocytes generated from stem cells first become functional, so that each
mature lymphocyte is able to make only one type of receptor. Thus, from a pool
of only hundreds of genes, an unlimited variety of diverse antigen receptors
can be created.
Still other mechanisms contribute to receptor diversity.
Superimposed on the mechanism outlined in simplified terms above is another
process, called somatic mutation.
is the spontaneous occurrence of small changes in the DNA during the process of
cell division. It is called somatic when it takes place in body cells (Greek soma
means “body”) rather than in germ-line cells (eggs and sperm). Although somatic
mutation can be a chance event in any body cell, it occurs regularly in the DNA
that codes for antigen receptors in lymphocytes. Thus, when a lymphocyte is
stimulated by an antigen to divide, new variants of its antigen receptor can be
present on its descendant cells, and some of these variants may provide an even
better fit for the antigen that was responsible for the original stimulation.
B-cell antigen receptors and antibodies
The antigen receptors on B lymphocytes are identical to the
binding sites of antibodies that these lymphocytes manufacture once stimulated,
except that the receptor molecules have an extra tail that penetrates the cell
membrane and anchors them to the cell surface. Thus, a description of the
structure and properties of antibodies, which are well studied, will suffice
Basic structure of the
- The four-chain structure of an
antibody, or immunoglobulin, molecule
Antibodies belong to the class of proteins called globulins,
so named for their globular structure. Collectively, antibodies are known as
immunoglobulins (abbreviated Ig). All immunoglobulins have the same basic
molecular structure, consisting of four polypeptide
chains. Two of the chains, which are identical in any given immunoglobulin
molecule, are heavy (H) chains; the other two are identical light (L) chains.
The terms heavy and light simply mean larger and smaller. Each
chain is manufactured separately and is encoded by different genes. The four
chains are joined in the final immunoglobulin molecule to form a flexible Y
shape, which is the simplest form an antibody can take.
At the tip of each arm of the Y-shaped molecule is an area
called the antigen-binding, or antibody-combining,
site, which is formed by a portion of the heavy and light chains. Every
immunoglobulin molecule has at least two of these sites, which are identical to
one another. The antigen-binding site is what allows the antibody to recognize
a specific part of the antigen (the epitope,
or antigenic determinant). If the shape of the epitope corresponds to the shape
of the antigen-binding site, it can fit into the site—that is, be “recognized”
by the antibody. Chemical bonds called weak bonds then form to hold the antigen
within the binding site.
The heavy and light chains that make up each arm of the
antibody are composed of two regions, called constant
(C) and variable (V). These regions are distinguished
on the basis of amino acid similarity—that is, constant regions have
essentially the same amino acid sequence in all antibody molecules of the same
class (IgG, IgM, IgA, IgD, or IgE), but the amino acid sequences of the
variable regions differ quite a lot from antibody to antibody. This makes
sense, because the variable regions determine the unique shape of the
antibody-binding site. The tail of the molecule, which does not bind to
antigens, is composed entirely of the constant regions of heavy chains.
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