INNATE IMMUNITY
24.1 All animals have innate immunity
Nearly everything in the environment teems with pathogens , . Yet we do not constantly
become ill, thanks to the immune system , the body’s system of defenses against agents that cause disease. The
immune systems of all animals include innate immunity , a set of defenses that are active immediately upon
infection and are the same whether or not the pathogen has been encountered previously (Figure 24.1A).
Invertebrate Innate Immunity Invertebrates rely solely on innate immunity. For example, insects have an
exoskeleton, which is a tough, dry barrier that keeps out bacteria and viruses. Pathogens that breach these external
defenses confront a set of internal
defenses. Additional physical barriers, a
low pH, and the secretion of lysozyme,
an enzyme that breaks down bacterial
cell walls, protect the insect digestive
system. Circulating insect immune cells
are capable of phagocytos is , cellular
ingestion and digestion of foreign
substances (see Module 5.9). The insect
innate immune system also includes
recognition proteins that bind to
molecules found only on pathogens.
Recognition of an invading microbe
triggers the production of antimicrobial
pep‐tides that bring about the
destruction of the invaders.
Vertebrate Innate Immunity In
vertebrates, innate immunity coexists
with the more recently evolved system of adaptive immunity (discussed later in this chapter). In mammals, innate
defenses include barriers such as skin and mucous membranes that protect organ systems open to the external
environment, such as the digestive, respiratory, reproductive, and urinary systems. Nostril hairs filter incoming air, and
mucus in the respiratory tract traps most microbes and dirt that get past the nasal filter. Cilia on cells lining the
respiratory tract then sweep the mucus and any trapped microbes upward and out, helping to prevent lung infections.
Microbes that breach a mammal’s external barriers, such as those that enter through a cut in the skin, are confronted by
innate immune cells. These are all classified as white blood cells, although they are found in interstitial fluid as well as in
the blood. Most, such as abundant neutrophi l s , are phagocytes (phagocytic cells). Macrophages (“big eaters”) are
large phagocytic cells that wander through the interstitial fluid, “eating” any bacteria and virus‐ infected cells they
encounter. Natura l k i l ler (NK) cells attack cancer cells and virus‐infected cells by releasing chemicals that lead to cell
death.
Figure 24.1A An overview of animal immune systems (along with the module number where each topic is covered)
Other components of vertebrate innate
immunity include proteins that either
attack microbes directly or impede their
reproduction. Inter ferons are proteins,
produced by virus‐ infected cells that help
to limit the cell‐ to‐ cell spread of viruses
(Figure 24.1B). The virus infects a cell,
which causes interferon genes in the
cell’s nucleus to be turned on. The cell
synthesizes interferon. The infected cell
then dies, but its interferon molecules
may diffuse to neighboring healthy cells,
stimulating them to produce other
proteins that inhibit viral reproduction.
Additional innate immunity in vertebrates
is provided by the complement
system , a group of about 30 different
kinds of proteins that circulate in an
inactive form in the blood. As you’ll see later in the chapter, these proteins can act together (in complement) with other
defense mechanisms. Substances on the surfaces of many microbes activate the complement system, resulting in a
cascade of steps that may lead to the lysis, or bursting, of the invaders. Certain complement proteins also help trigger
the inflammatory response, the subject of the next module.
Figure 24.1B The interferon mechanism against viruses
Which components of innate immunity described here actually help prevent infection? Which come
into play only after infection has occurred?
Answer
24.2 Inflammation mobilizes the innate immune response
The in f lammatory response is a major component of our innate immunity. Any damage to tissue, whether
caused by micro‐organisms or by physical injury— even just a scratch or an insect bite— triggers this response. You may
see signs of the inflammatory response when your skin is cut. The area becomes red, warm, and swollen. This reaction is
inflammation, which literally means “setting on fire.”
Figure 24.2 shows the chain of events when a pin has broken the skin, allowing infection by bacteria. The
damaged cells soon release chemical alarm signals, such as his tamine . The chemicals spark the mobilization of
various defenses. Histamine, for instance, induces neighboring blood vessels to dilate and become leaky. Blood flow to
the damaged area in‐creases, and blood plasma passes out of the leaky vessels into the interstitial fluid of the affected
tissues. Other chemicals, some that are part of the complement system, attract phagocytes to the area. Squeezing
between the cells of the blood vessel wall, these phagocytic white blood cells (yellow in the figure) migrate out of the
blood into the tissue spaces. The local increase in blood flow, fluid, and cells produces the red‐ness, heat, and swelling
characteristic of inflammation.
The major function of the inflammatory response is to dis‐infect and clean injured tissues. The white blood cells that
migrate into the area engulf bacteria and the remains of any body cells killed by them or by the physical injury. Many of
the white cells die in the process, and their remains are also engulfed and digested. The pus that often accumulates at
the site of an infection consists mainly of dead white cells, fluid that has leaked from capillaries, and other tissue debris.
The inflammatory response also helps prevent the spread of infection to surrounding tissues. Clotting proteins (see
Module 23.14) present in blood plasma pass into the interstitial fluid during inflammation. Along with platelets, these
substances form local clots that help seal off the infected region and allow healing to begin.
Inflammation may be localized, as we have just described, or widespread (systemic). Sometimes microorganisms
such as bacteria or protozoans get into the blood or release toxins that are carried throughout the body in the
bloodstream. The body may react with several inflammatory weapons. For instance, the number of white blood cells
Tissue injury; signaling molecules,
such as histamine, are released.
Dilation and increased leakiness of
local blood vessels; phagocytes migrate to the area.
Phagocytes ( macrophages and
neutrophils) consume bacteria and cellular debris; the tissue heals.
circulating in the blood may increase several fold within just a few hours; an elevated “white cell count” is one way to
diagnose certain infections. Another response to systemic infection is fever, an abnormally high body temperature.
Toxins themselves may trigger the fever, or macrophages may release compounds that cause the body’s thermostat to
be set at a higher temperature. A very high fever is dangerous, but a moderate one may stimulate phagocytosis and
hasten tissue repair. (How a moderate fever aids immune defenses is a subject of active debate within the medical com‐
munity.) Anti‐ inflammatory drugs, such as aspirin and ibuprofen, dampen the normal inflammatory response and thus
help reduce swelling and fever.
Sometimes bacterial infections bring about an overwhelming systemic inflammatory response leading to a condition
called septic shock. Characterized by very high fever and low blood pressure, septic shock is a common cause of death in
hospital intensive care units. Clearly, while local inflammation is an essential step toward healing, widespread
inflammation can be devastating.
Why is the inflammatory response considered a form of innate immunity?
Answer
24.3 The lymphatic system becomes a crucial battleground during infection
The l ymphat ic system , which is involved in both innate and adaptive immunity, consists of a branching network
of vessels, numerous l ymph nodes— little round organs packed with macrophages and white blood cells called
lymphocytes— the bone marrow, and several organs ( Figure 24.3). The lymphatic vessels carry a fluid called l ymph ,
which is similar to the interstitial fluid that surrounds body cells but contains less oxygen and fewer nutrients. The
lymphatic system is closely associated with the circulatory system. If an infectious agent gets inside the body, it usually
winds up in the circulatory system. From there, it is carried into the lymphatic system, which can usually filter it out. The
filtered fluid can then be recycled into the circulatory system. The lymphatic system thus has two main functions: to
return tissue fluid back to the circulatory system and to fight infection. As we noted in Module 23.11, a small amount of
the fluid that enters the tissue spaces from the blood in a capillary bed does not reenter the blood capillaries. Instead,
this fluid is re‐turned to the blood via lymphatic vessels. The enlargement in Figure 24.3 (bottom right) shows a
branched lymphatic vessel in the process of taking up fluid from tissue spaces in the skin. As shown here, fluid enters the
lymphatic system by diffusing into tiny, dead‐ end lymphatic capillaries that are intermingled among the blood
capillaries. Lymph drains from the lymphatic capillaries into larger and larger lymphatic vessels. Eventually, the fluid
reenters the circulatory system via two large lymphatic vessels that fuse with veins in the chest. As the close‐ up
indicates, the lymphatic vessels resemble veins in having valves that prevent the back‐flow of fluid toward the capillaries
(see Figure 23.7C). Also, like veins, lymphatic vessels depend mainly on the movement of skeletal muscles to squeeze
their fluid along. The green arrows in the close‐ ups indicate the flow of lymph. When your body is fighting an infection,
the organs of the lymphatic system become a major battleground. As lymph circulates through the lymphatic organs—
such as the lymph node shown in Figure 24.3, top right— it carries microbes, parts of microbes, and their toxins picked
up from infection sites anywhere in the body. Once inside lymphatic organs, macrophages that reside there permanently
may engulf the invaders as part of the innate immune response. Lymph nodes fill with huge numbers of defensive cells,
causing the tender “swollen glands” in your neck and armpits that your doctor looks for as a sign of infection. In addition
to the functioning of macrophages and other components of the innate immune response, cells of the adaptive immune
response, called lymphocytes, may be activated against specific invaders. We examine adaptive immunity next.
What are the two main functions of the lymphatic system?
Answer
ADAPTIVE IMMUNITY
24.4 The adaptive immune response counters specific invaders
All the defenses you’ve learned about so far are called innate because they’re ready “off the rack”; that is, innate
defenses are always standing by, ready to be used in their current form. When the innate immune response fails to ward
off a pathogen, a set of adaptive defenses, ones that are “custom‐ tailored” to each specific invader, provides a second
line of defense. Adapt ive immunity— also called acquired immunity— is a set of defenses, found only in
vertebrates, that is activated only after exposure to specific pathogens. Thus, unlike innate immunity, adaptive immunity
differs from individual to individual,
depending on wha t pathogens they have
been previously exposed to. Once activated,
the adaptive immune response provides a
strong defense against pathogens that is
highly specific; that is, it acts against one
infectious agent but not another. Moreover,
adaptive immunity can amplify certain
innate responses, such as inflammation and
the complement system.
Any molecule that elicits an adaptive
immune response is called an ant igen .
Antigens may be molecules that protrude
from pathogens or other particles, such as viruses, bacteria, mold spores, pollen, house dust, or the cell surfaces of
trans‐planted organs. Antigens may also be substances released into the extracellular fluid, such as toxins secreted by
bacteria. When the immune system detects an antigen, it responds with an increase in the number of cells that either
attack the invader directly or produce immune proteins called ant ibodies . An antibody is a protein found in blood
plasma that attaches to one particular kind of antigen and helps counter its effects. (The word antigen is a contraction of
“antibody‐ generating,” a reference to the fact that the foreign agent provokes an adaptive immune response.) The
defensive cells and antibodies produced against a particular antigen are usually specific to that antigen; they are
ineffective against any other foreign substance.
Adaptive immunity has a remarkable “memory”; it can “remember” antigens it has encountered before and react
against them more quickly and vigorously on subsequent exposures. For example, if a person is infected by the varicella
zoster virus and then contracts chicken pox, the immune system “remembers” certain molecules on the virus. Should
the virus enter the body again, the adaptive immune response mounts a quick and decisive attack that usually destroys
the virus before symptoms appear. Thus, in the adaptive immune response, unlike innate immunity, exposure to a
foreign agent enhances future responses to that same agent.
Adaptive immunity is usually obtained by natural exposure to antigens (that is, by being infected), but it can also be
achieved by vacc inat ion , also known as immunization. In this procedure, the immune system is confronted with a
vacc ine composed of a harmless variant or part of a disease‐ causing microbe, such as an inactivated bacterial toxin, a
dead or weakened microbe, or a piece of a microbe. The vaccine stimulates the immune system to mount defenses
against this harmless antigen, defenses that will also be effective against the actual pathogen because it has similar
antigens. Once you have been successfully vaccinated, your immune system will respond quickly if it is exposed to the
actual microbe. Such protection may last for life.
In industrialized nations, routine childhood vaccination has virtually eliminated many viral diseases. In the United States,
most children receive a series of shots starting soon after birth, including vaccinations against diphtheria/ pertussis/
tetanus (DPT, or “diptet”), polio, hepatitis, chicken pox, and measles/ mumps/ rubella (MMR). One of the major success
stories of modern vaccination involves smallpox, a potentially fatal viral infection that affected over 50 million people
per year worldwide in the 1950s. A massive vaccination effort has been so effective that there have been no cases of
smallpox since 1977. Since 2001, however, the U. S. government has stockpiled hundreds of millions of doses of
smallpox vaccine and has begun to vaccinate high‐ risk health‐ care and military workers in case the smallpox virus is
used in a bioterrorist attack (Figure 24.4).
Whether antigens enter the body naturally (if you catch the flu) or artificially (if you get a flu shot), the resulting
immunity is called act ive immunity because the person’s own immune sys‐tem actively produces antibodies. It is
also possible to acquire pass ive immunity by receiving premade antibodies. For example, a fetus obtains antibodies
from its mother’s bloodstream; a baby receives antibodies in breast milk that protect the digestive tract (although these
antibodies are broken down there and do not enter the bloodstream); and travelers sometimes get a shot containing
antibodies to pathogens they are likely to encounter. In yet another example, the effects of a poisonous snakebite may
be counteracted by injecting the victim with antibodies extracted from animals previously immunized against the
venom. Passive immunity is temporary because the recipient’s immune system is not stimulated by antigens. Immunity
lasts only as long as the antibodies do; after a few weeks or months, these proteins break down and are recycled by the
body.
Why is protection resulting from a vaccination considered active immunity rather than passive
immunity?
Answer
24.5 Lymphocytes mount a dual defense
Lymphocytes , white blood cells that spend most of their time in the tissues and organs of the lymphatic system,
are responsible for adaptive immunity. Like all blood cells, lymphocytes originate from stem cells in the bone marrow. As
shown in Figure 24.5A, some immature lymphocytes continue developing in the bone marrow; these become
specialized as B lymphocytes, or B ce l l s . Other immature lymphocytes migrate to the thymus, a gland above the heart.
There, the lymphocytes become specialized as T
lymphocytes, or T ce l l s . Both B cells and T cells
eventually make their way via the blood to the
lymph nodes, spleen, and other lymphatic organs.
The B cells and T cells of the adaptive immune
response together provide a dual defense. The first
type of defense is called the humoral immune
response . The humoral immune response
involves the secretion of free‐ floating antibodies
by B cells ( Figure 24.5B, left) into the blood and
lymph. (The humoral response is so named
because blood and lymph were long ago called
body “ humors.”) The humoral system defends
primarily against bacteria and viruses present in
body fluids. As discussed in the last paragraph of
Module 24.4, the humoral immune response can
be passively transferred by injecting antibody‐
containing blood plasma from an immune
individual into a nonimmune individual. As you will
see in Module 24.9, antibodies mark invaders by
binding to them. The resulting antigen‐ antibody
complexes are easily recognized for destruction
and disposal by phagocytic cells.
The second type of adaptive immunity,
produced by T cells (Figure 24.5B, right), is called
the ce l l ‐mediated immune response . As its
name implies, this defensive system results from
the action of defensive cells, in contrast to the
action of free‐ floating defensive antibody proteins
of the humoral response. Certain T cells attack
body cells infected with bacteria or viruses. Other T
cells function indirectly by promoting phagocytosis
by other white blood cells and by stimulating B
cells to produce antibodies. Thus, T cells play a part
in both the cell‐ mediated and humoral immune
responses.
When a B cell develops in bone marrow or a T
cell develops in the thymus, certain genes in the
Humoral immune response
Cell‐ mediated immune response
cell are turned on. This causes the cell to synthesize molecules of a specific protein, which are then incorporated into the
plasma membrane. As indicated in Figure 24.5A, these protein molecules stick out from the cell’s surface. The molecules
are ant igen receptors , capable of binding one specific type of antigen. Each B or T cell has about 100,000 antigen
receptors, and all the receptors on a single cell are identical— they all recognize the same antigen. In the case of a B cell,
the receptors are almost identical to the particular antibody that the B cell will secrete. Once a B cell or T cell has its
surface proteins in place, it can recognize a specific antigen and mount an immune response against it. One cell may
recognize an antigen on the mumps virus, for in‐stance, while another detects a particular antigen on a tetanus‐causing
bacterium. In Figure 24.5A, you can see that after the B cells and T cells have developed their antigen receptors, these
lymphocytes leave the bone marrow and thymus and move via the blood‐stream to the lymph nodes, spleen, and other
parts of the lymphatic system. In these organs, many B and T cells take up residence and encounter infectious agents
that have penetrated the body’s outer defenses. Because lymphatic capillaries extend into virtually all the body’s tissues,
bacteria or viruses infecting nearly any part of the body eventually enter the lymph and are carried to the lymphatic
organs. As we will describe in Module 24.7, when a B or T cell within a lymphatic organ first con‐fronts the specific
antigen that it is programmed to recognize, it differentiates further and becomes a fully mature component.
An enormous diversity of B cells and T cells develops in each individual. Researchers estimate that each of us has mil‐
lions of different kinds— enough to recognize and bind to virtually every possible antigen. A small population of each
kind of lymphocyte lies in wait in our body, genetically programmed to recognize and respond to a specific antigen. Only
a tiny fraction of the immune system’s lymphocytes will ever be used, but they are all available if needed. It is as if the
immune system maintains a huge standing army of soldiers, each made to recognize one particular kind of invader. The
majority of soldiers never encounter their target and remain idle. But when an invader does appear, chances are good
that some lymphocytes will be able to recognize it, bind to it, and call in reinforcements. We’ll take a closer look at the
different types of T cells in Modules 24.11 and 24.12.
Contrast the targets of the humoral immune response with those of the cell‐ mediated immune
response.
Answer
24.6 Antigens have specific regions where antibodies bind to them
As molecules that elicit the adaptive immune response, anti‐gens usually do not belong to the host animal. Most
antigens are proteins or large polysaccharides that protrude from the surfaces of viruses or foreign cells. Common
examples are protein‐ coat molecules of viruses, parts of the capsules and cell walls of bacteria, and macromolecules on
the surface cells of other kinds of organisms, such as protozoans and parasitic worms. (Sometimes a particular microbe
is called an antigen, but this usage is misleading because the microbe will almost always have several kinds of antigenic
molecules.) Other sources of antigenic molecules include blood cells or tissue cells from other individuals, of the same
species or of a different species. Antigenic molecules are also found dissolved in body fluids; foreign molecules of this
type include bacterial toxins and bee venom.
As shown in Figure 24.6, an antibody usually
recognizes and binds to a small surface‐ exposed region
of an antigen called an ant igenic determinant , also
known as an epitope. An antigen‐ binding site, a specific
region on the antibody molecule, recognizes an antigenic
determinant by the fact that the binding site and
antigenic determinant have complementary shapes, like
an enzyme and substrate or a lock and key. An antigen
usually has several different determinants (there are
three in the diagram here), so different antibodies (two,
in this case) can bind to the same antigen. A single kind of antigen molecule may thus stimulate the immune system to
make several distinct antibodies against it. Notice that each antibody molecule has two identical antigen‐ binding sites.
We’ll return to antibody structure in Module 24.8. But first let’s see how the body produces large quantities of
antibodies and defensive cells in response to specific infections.
Why is it inaccurate to refer to a pathogen, such as a virus, as an antigen?
Answer
24.7 Clonal selection musters defensive forces against specific antigens
The immune system’s ability to defend against a wide variety of antigens depends on a process known as clonal
selection. Once inside the body, an antigen encounters a diverse pool of B and T lymphocytes. However, one particular
antigen inter‐acts only with the tiny fraction of lymphocytes bearing receptors specific to that antigen. Once activated by
the antigen, these few “selected” cells proliferate, forming a clone— a genetically identical population— of thousands of
cells all specific for the stimulating antigen. This antigen‐ driven cloning of lymphocytes— clonal selection— is a vital
step in the adaptive immune response against infection.
The Steps of Clonal Selection Figure 24.7A indicates how clonal selection of B cells works in the humoral immune
response. (A similar mechanism activates clonal selection for T cells in the cell‐ mediated immune response.) The row
of three cells at the top of the figure represents a vast repertoire of B cells in a lymph node. Notice that each lymphocyte
has its own specific type of antigen receptor embedded in its surface (represented by different colors in the figure). The
cells’ receptors are in place before they ever encounter an antigen. The first time an antigen enters the body and is
swept into a lymph node, antigenic determinants on its surface bind to the few B cells that happen to have
complementary receptors. Other lymphocytes, without the appropriate binding sites (in the figure, the ones with the
green and blue receptors), are not affected.
Primed by the interaction with the antigen,the selected cell is activated: It grows, divides, and differentiates into
two genetically identical yet physically distinct types of cells. Both newly produced types of cells are specialized for
defending against the very antigen that triggered the response.
One group of newly cloned cells is short‐ lived but fast‐ acting ef fector ce l l s , which combat the antigen.
Because the example in the figure involves B cells, the effector cells produced are plasma ce l l s . Each plasma cell
secretes antibody molecules into the blood and lymph, all of the same type. Each plasma cell makes as many as 2,000
copies of its antibody per second and thus requires large amounts of endoplasmic reticulum, a characteristic of cells
actively synthesizing and secreting proteins. The secreted antibodies circulate in the blood and lymphatic fluid,
contributing to the humoral immune response. Although highly effective at combating infection, each effector cell lasts
only 4 or 5 days before dying off.
A second group of cells produced by the activated B cells is a smaller number of memory cells, which differ from
effector cells in both appearance and function. In contrast to short‐lived effector cells, memory ce l l s may last for
decades. They remain in the lymph nodes, poised to be activated by a second exposure to the antigen. In fact, in some
cases, memory cells confer lifetime immunity, as they may after vaccination against such childhood diseases as mumps
and measles. Steps 1– 5 show the initial phase of adaptive immunity, called the pr imary immune response . This
phase occurs when lymphocytes are exposed to an antigen for the first time.
When memory cells produced during the primary
response are activated by a second exposure to the
same antigen— which may occur soon or long after the
primary immune response— they initiate the
secondary immune response . This response is
faster and stronger than the first. Another round of
clonal selection ensues. The selected memory cells
multiply quickly, producing a large second clone of
lymphocytes that mount the secondary response. Like
the first clone, the second clone includes effector cells
that produce antibodies and memory cells capable of
responding to future exposures to the antigen. In our
example here with B cells, the secondary response
produces very high levels of antibodies that, though
they are short‐ lived, are often more effective against
the antigen than those produced during the primary
response.
The concept of clonal selection is so fundamental to
under‐standing adaptive immunity that it is worth
restating: Each antigen, by binding to specific receptors, selectively activates a tiny fraction of lymphocytes; these few
selected cells then give rise to a clone of many cells, all specific for and dedicated to eliminating the antigen that started
the response. Thus, we see that the versatility of
the adaptive immune response depends on a great
diversity of preexisting lymphocytes with different
antigen receptors.
Primary versus Secondary Immune
Responses Now that we have seen how clonal
selection works, let’s take a look at the two phases
of the adaptive immune response in an individual.
The blue curve in Figure 24.7B illustrates the
difference between the two phases, triggered by
two exposures to the same antigen. On the far left
of the graph, you can see that the primary
response does not start right away; it usually takes several days for the lymphocytes to become activated by an antigen (
called X here) and form clones of effector cells. When the effector cell clone forms, antibodies start showing up in the
blood, as the graph shows. During this delay, a stricken individual may become ill. The antibody level reaches its peak 2–
3 weeks after initial expo‐sure. As the antibody levels in the blood and lymph rise, the symptoms of the illness typically
diminish and disappear. The primary response subsides as the effector cells die out.
The second exposure to antigen X (at day 28 in the graph) triggers the secondary immune response. Notice that
this secondary response starts faster than the primary response, typically in 2– 7 days, versus 10– 17 days. As
mentioned, the secondary response is also of greater magnitude, producing higher levels of antibodies, and is more
prolonged. This is why vaccination is so effective: The vaccine induces a primary immune response that produces
memory cells; an encounter with the actual pathogen then elicits a rapid and strong secondary immune response.
The red curve in Figure 24.7B illustrates the specificity of the immune response. If the body is exposed to a
different antigen (Y), even after it has already responded to antigen X, it responds with another primary response, this
one directed against antigen Y. The response to Y is not enhanced by the response to X; that is, adaptive immunity is
specific.
Although we have focused on the humoral immune response (produced by B cells) in this module, clonal selection,
effector cells, and memory cells are features of the cell‐ mediated immune response (produced by T cells) as well. In the
next several modules, we discuss the humoral immune response further. After that, we focus on how the cell‐ mediated
arm of the immune system helps defend the body against pathogens.
What is the immunological basis for referring to certain diseases, such as mumps, as childhood
diseases?
Answer
24.8 Antibodies are the weapons of the humoral immune response
B cells are the “frontline warriors” of the humoral immune response. Plasma cells— the effector cells produced during
clonal selection of B cells (as shown in Figure 24.7A)— make and secrete antibodies, proteins that serve as molecular
weapons of defense.
We have been using Y‐ shaped symbols to represent antibodies, and their shape actually does resemble a Y, as the
computer‐ generated rendering of an anti‐body molecule in Figure 24.8A illustrates. Figure 24.8B is a simplified diagram
explaining antibody structure. Each antibody molecule is made up of four polypeptide chains, two identical “heavy”
chains and two identical “light” chains. In both figures,
the parts colored in shades of pink represent the fairly
long heavy chains of amino acids that give the molecule
its Y shape. Bonds (the black lines in Figure 24.8B) at
the fork of the Y hold these chains together. The two
green regions in each figure are shorter chains of amino
acids, the light chains. Each of the light chains is bonded
to one of the heavy chains. As Figure 24.8A indicates,
the bonded chains actually intertwine.
An antibody molecule has two related functions in
the humoral immune response: to recognize and bind
to a certain antigen and to assist in neutralizing the
antigen it recognizes. The structure of an antibody
allows it to perform both of these functions. Notice in
Figure 24.8B that each of the four chains of the
molecule has a C ( constant) region, where amino acid
sequences vary little among different antibodies, and a
V ( variable) region, where the
amino acid sequence varies
extensively among
antibodies. At the tip of
each arm of the Y, a pair of
V regions forms an
ant igen ‐ binding s i te , a
region of the molecule
responsible for the antibody’s
recognition‐ and‐ binding
function. A huge variety in
the three‐ dimensional
shapes of the binding sites
of different antibody
molecules arises from a
similarly large variety in the
amino acid sequences in the V
regions; hence the term
variable. The top left of Figure 24.8B illustrates such a fit, with the recognized antigen colored gold. The great structural
variety of antigen‐ binding sites accounts for the diversity of lymphocytes and gives the humoral immune system the
ability to react to virtually any kind of antigen.
The tail of the antibody molecule, formed by the constant regions of the heavy chains, helps mediate the disposal of
the bound antigen. Antibodies with different kinds of heavy‐ chain C regions are grouped into different classes. Humans
and other mammals have five major classes of antibodies, called IgA, IgD, IgE, IgG, and IgM ( Ig stands for
immunoglobulin, another name for antibody). Each of the five classes differs in where it’s found in the body and how it
works. However, all five classes of antibodies perform the same basic function: to mark invaders for elimination. We
take a closer look at this process next.
How is the specificity of an antibody molecule for an antigen analogous to an enzyme’s specificity for
its substrate?
Answer
24.9 Antibodies mark antigens for elimination
Antibodies do not kill pathogens. Instead, antibodies mark a pathogen by combining with it to form an antigen‐ antibody
complex. Weak chemical bonds between antigen molecules and the antigen‐ binding sites on antibody molecules hold
the complex together. Once marked in this manner, other immune system components bring about the destruction of
the antigen.
As Figure 24.9 illustrates, the binding of antibodies to antigens can trigger several mechanisms that disable or
destroy an invader. In neutralization, antibodies bind to sur‐face proteins on a virus or bacterium, thereby blocking its
ability to infect a host cell and presenting an easily recognized structure to macrophages. This increases the likelihood
that the foreign cell will be engulfed by phagocytosis. Another an‐tibody mechanism is the agglutination ( clumping
together) of viruses, bacteria, or foreign eukaryotic cells. Because each antibody molecule has at least two binding sites,
antibodies can hold a clump of invading cells together. Agglutination makes the cells easy for phagocytes to capture. A
third mech‐anism, precipitation, is similar to agglutination, except that the antibody molecules link dissolved antigen
molecules to‐gether. This makes the antigen molecules precipitate; that is, they separate, in solid form, from the
surrounding liquid. Precipitation, like the other effector mechanisms discussed so far, enhances engulfment by
phagocytes.
One of the most important steps in the humoral immune response is the activation of the complement system ( see
Module 24.1) by antigen‐ antibody complexes. Activated complement system proteins ( right side of the figure) can
attach to a foreign cell. Once there, several activated proteins may form a complex that pokes a hole in the plasma
mem‐brance of the foreign cell,
causing cell lysis, or rupture.
Taken as a whole, this figure
illustrates a fundamental concept
of adaptive immunity: All
antibody mechanisms involve a
specific recognition‐ and‐ attack
phase followed by a nonspecific
destruction phase. Thus, the
antibodies of the humoral
immune response, which identify
and bind to foreign invaders,
work with the components of
innate immunity, such as
phagocytes and complement, to
form a complete defense system.
How does adaptive humoral immunity interact with the body’s innate immune system?
Answer
24.11 Helper T cells stimulate the humoral and cell- mediated immune responses
The antibody‐ producing B cells of the humoral immune response make up one army of the adaptive immune response
network. The humoral defense system identifies and helps destroy invaders that are in our blood, lymph, or interstitial
fluid— in other words, outside our body cells. But many invaders, including all viruses, enter cells and reproduce there. It
is the cell‐ mediated immune response produced by T cells that battles pathogens that have already entered body cells.
Whereas B cells respond to free antigens present in body fluids, T cells respond only to antigens present on the
surfaces of the body’s own cells. Recall from Module 24.7 that effector cells act quickly against an antigen. There are
two main kinds of effector T cells. Cytotox ic T ce l l s attack body cells that are infected with pathogens; we’ll discuss
these T cells in Module 24.12. Helper T ce l l s play a role in many aspects of immunity. They help activate cytotoxic T
cells and macrophages and even help stimulate B cells to produce antibodies. Other types of T cells include memory T
cells, analogous to memory B cells.
Helper T cells interact with other white blood cells— including macrophages and B cells—
that function as ant igen ‐present ing ce l l s (APCs) . All of the cell‐ mediated immune
response and much of the humoral immune response depend on the precise interaction of antigen‐ presenting cells and
helper T cells. This interaction activates the helper T cells, which can then go on to activate other cells of the immune
system. As its name implies, an antigen‐ presenting cell presents a foreign antigen to a helper T cell. Consider a typical
antigen‐presenting cell, a macrophage. As shown in Figure 24.11, the macrophage ingests a microbe or other foreign
particle and breaks it into fragments— foreign antigens . Then molecules of a special protein belonging to the
macro‐phage, which we will call a se l f prote in (because it belongs to the body), bind the foreign antigens—
nonsel f molecules— and display them on the cell’s surface. (Each of us has a unique set of self proteins, which
serve as identity markers for our body cells.) Helper T cells recognize and bind to the combination of a self protein and
a foreign antigen— called a self‐nonself complex — displayed on an antigen‐ presenting cell. This double‐
recognition system is like the system banks use for safe‐ deposit boxes: Opening your box requires the banker’s key
along with your specific key.
The ability of a helper T cell to specifically recognize a unique self‐ nonself complex on an antigen‐ presenting cell
depends on the receptors (purple) embedded in the T cell’s plasma membrane. A T cell receptor actually has two binding
sites: one for antigen and one for self protein. The two binding sites enable a T cell receptor to recognize the overall
shape of a self‐ nonself complex on an antigen‐ presenting cell. The immune response is specific because the receptors
on each helper T cell bind only one kind of self‐ nonself complex on an antigen‐ presenting cell.
The binding of a T cell receptor to a self‐ nonself complex activates the helper T cell. Several other kinds of signals can
enhance this activation. For example, certain proteins secreted by the antigen‐ presenting cell, such as interleukin‐ 1 (
green arrow), diffuse to the helper T cell and stimulate it.
Activated helper T cells promote the immune response in several ways, with a major mechanism being the secretion
of additional stimulatory proteins. One such protein, interleukin‐ 2 ( blue arrows), has three major effects. First, it
makes the helper T cell itself grow and divide, producing both memory cells and additional active helper T cells. This
positive‐ feedback loop amplifies the cell‐ mediated defenses against the antigen at hand. Second, interleukin‐ 2 helps
activate B cells, thus stimulating the humoral immune response. And third, it stimulates the activity of cytotoxic T
cells, our next topic.
How can one helper T cell stimulate both humoral and cell‐mediated immunity?
Answer
24.12 Cytotoxic T cells destroy infected body cells
As you have just learned, two types of T cells participate in the cell‐ mediated immune response: helper T cells and
cytotoxic T cells. Helper T cells activate many kinds of cells, including cytotoxic T cells, the only T cells that actually kill
infected cells.
Once activated, cytotoxic T cells identify infected cells in the same way that helper T cells identify antigen‐ presenting
cells. An infected cell has foreign antigens— molecules belonging to the viruses or bacteria infecting it— attached to self
proteins on its surface (Figure 24.12). Like a helper T cell, a cytotoxic T cell carries receptors that can bind with a self‐
nonself complex on the infected cell.
Cytotoxic T cells also play a role in protecting the body against the spread of some cancers. About 20% of human
cancers are caused by viruses. Examples include the hepatitis B virus, which can trigger liver cancer, and the human
papillomavirus ( HPV), which can trig‐ger cervical cancer. When a human cancer cell harbors such a virus, viral proteins
may end up on the surface
of the infected cell. If they
do, they may be recognized
by a cytotoxic T cell, which
can then destroy the
infected cell, halting the
proliferation of that
cancerous cell.
The self‐ nonself
complex on an infected
body cell is like a red flag to
cytotoxic T cells that have
matching receptors. As
shown in the figure, a cytotoxic T cell binds to the infected cell. The binding activates the T cell, which then
synthesizes several toxic proteins that act on the bound cell, including one called perforin ( ). Perforin is discharged
from the cytotoxic T cell and attaches to the infected cell’s plasma membrane, making holes in it. T cell enzymes ( ) then
enter the infected cell and promote its death by apoptosis, programmed cell death. The infected cell is destroyed, and
the cytotoxic T cell may move on to destroy other cells infected with the same pathogen.
Compare and contrast the T cell receptor with the antigen receptor on the surface of a B cell.
Answer
24.16 Malfunction or failure of the immune system causes disease
Our immune system is highly effective, protecting us against most potentially harmful invaders. But when the system
fails to function properly, serious disease can result.
Autoimmune diseases result when the immune system goes awry and turns against some of the body’s own
molecules. In systemic lupus erythematosus (lupus), for example, B cells produce antibodies against a wide range of self
molecules, such as histones and DNA released by the normal breakdown of body cells. Lupus is characterized by skin
rashes, fever, arthritis, and kidney malfunction. Rheumatoid arthritis is another antibody‐ mediated autoimmune
disease; it leads to damage and painful inflammation of the cartilage and bone of joints (Figure 24.16). In type 1 (insulin‐
dependent) diabetes mellitus, the insulin‐ producing cells of the pancreas are
attacked by cytotoxic T cells. In multiple sclerosis ( MS), T cells react against the
myelin sheath that surrounds parts of many neurons ( see Figure 28.2), causing
progressive muscle paralysis. Recent re‐search suggests that Crohn’s disease, a
chronic inflammation of the digestive tract, may be caused by an autoimmune
reaction against normal flora (bacteria) that inhabit the intestinal tract.
Gender, genetics, and environment all influence susceptibility to autoimmune
disorders. For example, many autoimmune diseases afflict females more than
males; women are two to three times more likely to suffer from MS and
rheumatoid arthritis and nine times more likely to develop lupus. The cause of this
sex bias is an area of active research and debate.
Most medicines for treating autoimmune diseases either suppress immunity in general or are limited to the
alleviation of specific symptoms. However, as research scientists learn more about these diseases and about the normal
operation of the immune system, they hope to develop more effective therapies.
In contrast to autoimmune diseases are a variety of defects called immunodef ic iency diseases in which an
immune response is defective or absent. People born immunodeficient are thus susceptible to frequent and recurrent
infections. In the rare congenital disease severe combined immunodeficiency (SCID), both T cells and B cells are absent
or inactive. People with SCID are extremely vulnerable to even minor infections. Until recently, their only hope for
survival was to live behind protective barriers (providing inspiration for “bubble boy” stories in the popular media) or to
receive a successful bone marrow transplant that would continue to supply functional lymphocytes. Since the early
1990s, medical researchers have been testing a gene therapy for this disease, with some success (see Module 12.10).
Immunodeficiency is not always an inborn condition; it may be acquired later in life. In addition to AIDS, another
example is Hodgkin’s disease, a type of cancer that damages the lymphatic system and can depress the immune system.
Radiation therapy and the drug treatments used against many cancers can also disrupt the immune system. There is
growing evidence that physical and emotional stress can harm immunity. Hormones secreted by the adrenal glands
during stress affect the numbers of white blood cells and may suppress the immune system in other ways. The
association be‐tween emotional stress and immune function also involves the nervous system. Some neurotransmitters
secreted when we are relaxed and happy may enhance immunity. In one study, college students were examined just
after a vacation and again during final exams. Their immune systems were impaired in various ways during exam week;
for example, interferon levels were lower. These and other observations indicate that general health and state of mind
affect immunity.
What is a probable side effect of autoimmune disease treatments that suppress the immune system?
Answer