Chapter
22: The Lymphatic System and Immunity
An
Overview of the Lymphatic System and Immunity
The lymphatic system includes the cells, tissues,
and organs responsible for defending the body against both environmental
hazards, such as various pathogens, and internal threats, such as cancer cells.
Lymphocytes are
said to provide a specific defense , known as the immune
response . The ability to resist infection and disease through the
activation of specific defenses constitutes immunity .
Organization
of the Lymphatic System
The lymphatic system consists of (1) lymph , a
fluid that resembles plasma, but contains a much lower concentration of
suspended proteins; (2) a network of lymphatic vessels , often
called lymphatics , which begin in peripheral tissues and end
at connections to veins; (3) an array of lymphoid tissues and lymphoid
organs scattered throughout the body; and (4) lymphocytes and smaller
numbers of supporting and phagocytic cells.
Functions
of the Lymphatic System
Most of the body's lymphocytes are produced and stored within
lymphoid tissues, such as the tonsils, and lymphoid organs,
such as the spleen and thymus. However, lymphocytes are also produced in areas
of red bone marrow, along with various supporting cells, such as monocytes and macrophages.
Lymphatic
Vessels
Lymphatic vessels carry lymph from peripheral tissues to the
venous system. The smallest lymphatic vessels are called lymphatic
capillaries .
Lymphatic Capillaries.
(a) The
interwoven network formed by blood capillaries and lymphatic capillaries.
Arrows show the movement of fluid out of blood vessels and the
net flow of interstitial fluid and lymph. (b) A
sectional view showing movement of fluid from the plasma through the
interstitial fluid and into the lymphatic system.
The
Relationship between the Lymphatic Ducts and the Venous System.
(a) The thoracic
duct carries lymph originating in tissues inferior to the
diaphragm and from the left side of the upper body. The smaller right
lymphatic duct services the rest of the body.
(b) The thoracic duct empties
into the left subclavian vein. The right lymphatic duct drains into
the right subclavian vein. (c) The lymphatic vessels of
the trunk
Lymphedema
Blockage
of the lymphatic drainage from a limb produces lymphedema, a
condition in which interstitial fluids accumulate and the limb gradually
becomes swollen and grossly distended. If the condition persists, the
connective tissues lose their elasticity and the swelling becomes permanent.
In filariasis,
larvae of a parasitic roundworm, generally Wuchereria bancrofti ,
are transmitted by mosquitoes or black flies. The adult worms form massive
colonies within lymphatic vessels and lymph nodes. Repeated scarring of the
passageways eventually blocks lymphatic drainage and produces extreme
lymphedema with permanent distension of tissues. The limbs or external
genitalia typically become grossly distended; this parasite–induced edema is
called elephantiasis.
Lymphocytes account for 20–30 percent of the
circulating white blood cell population. However, circulating lymphocytes are
only a small fraction of the total lymphocyte population..
Types of
Lymphocytes
Three
classes of lymphocytes are in blood: (1) T ( t hymus–dependent) cells ,
(2) B ( b one marrow–derived) cells ,
and (3) NK ( n atural k iller) cells .
Each type has distinctive biochemical and functional characteristics.
Approximately
80 percent of circulating lymphocytes are classified as T cells. There are many
types of T cells, including the following:
Cytotoxic
T cells ,
which attack foreign cells or body cells infected by viruses. Their attack
commonly involves direct contact. These lymphocytes are the primary cells
involved in the production of cell–mediated immunity ,
or cellular immunity .
Helper
T cells ,
which stimulate the activation and function of both T cells and B cells.
Suppressor
T cells ,
which inhibit the activation and function of both T cells and B cells.
B
cells account
for 10–15 percent of circulating lymphocytes. When stimulated, B cells can
differentiate into plasma cells , which are responsible for
the production and secretion of antibodies –soluble proteins
also known as immunoglobulins . These proteins bind to
specific chemical targets called antigens
The remaining
5–10 percent of circulating lymphocytes are NK cells, also known as large
granular lymphocytes . These lymphocytes attack foreign cells, normal
cells infected with viruses, and cancer cells that appear in normal tissues.
Their continuous policing of peripheral tissues has been called immunological
surveillance .
Life Span and
Circulation of Lymphocytes
. All
types of lymphocytes move throughout the body, wandering through tissues and
then entering blood vessels or lymphatic vessels for transport.
T cells move relatively
quickly. For example, a wandering T cell may spend about 30 minutes in the
blood, 5–6 hours in the spleen, and 15–20 hours in a lymph node. B cells, which
are responsible for antibody production, move more slowly. A typical B cell
spends about 30 hours in a lymph node before moving on.
Lymphocytes
have relatively long life spans. Roughly 80 percent survive for 4 years, and
some last 20 years or more.
Lymphocyte
Production
lymphocyte production, or lymphopoiesis, involves the
bone marrow, thymus, and peripheral lymphoid tissues.
The Derivation and
Distribution of Lymphocytes.
Hemocytoblast
divisions produce stem cells with two fates. (a) One group
remains in the bone marrow, producing daughter cells that mature into B cells
or NK cells. (b) The other group migrates to the thymus, where
subsequent divisions produce daughter cells that mature into T cells. The
mature B cells, NK cells, and T cells circulate throughout the body in the
bloodstream and then (c) temporarily reside in peripheral
tissues.
Lymphoid
tissues are
connective tissues dominated by lymphocytes. In a lymphoid nodule ,
or lymphatic nodule , the lymphocytes are densely packed in an
area of areolar tissue
Lymphoid
nodules occur in the connective tissue deep to the epithelia lining the
respiratory, digestive, and urinary tracts.
The
collection of lymphoid tissues linked with the digestive system is called
the mucosa–associated lymphoid tissue (MALT) . Clusters of
lymphoid nodules deep to the epithelial lining of the intestine are known
as aggregated lymphoid nodules , orPeyer's patches. In
addition, the walls of the appendix , or vermiform ("worm–shaped") appendix ,
a blind pouch that originates near the junction between the small and large
intestines, contain a mass of fused lymphoid nodules.
Tonsils are large nodules in the walls of
the pharynx. Most people have five tonsils. Left and right palatine
tonsils are located at the posterior, inferior margin of the oral
cavity, along the boundary with the pharynx. A single pharyngeal
tonsil , often called the adenoids , lies in the
posterior superior wall of the nasopharynx, and a pair of lingual
tonsils lie deep to the mucous epithelium covering the base
(pharyngeal portion) of the tongue. Because of their location, the latter are
usually not visible unless they become infected and swollen.
The lymphocytes in a lymphoid nodule are not always
able to destroy bacterial or viral invaders that have crossed the adjacent
epithelium. If pathogens become established in a lymphoid nodule, an infection
develops. Two examples are probably familiar to you: tonsillitis ,
an infection of one of the tonsils (generally the pharyngeal or palatine),
and appendicitis , an infection of the appendix that begins in
the lymphoid nodules.
Lymphoid
Organs
A fibrous connective–tissue capsule separates the lymphoid
organs–the lymph nodes , the thymus , and
the spleen –from surrounding tissues.
Lymph nodes are small, oval lymphoid organs ranging in diameter from 1
to 25 mm (to about 1 in.). Figure 22–1 , p. 780, shows the general pattern of
lymph node distribution in the body. Each lymph node is covered by a capsule of
dense connective tissue
Lymph Flow Lymph delivered by the afferent
lymphatics flows through the lymph node within a network of sinuses, open
passageways with incomplete walls
Lymph Node
Function- A
lymph node functions like a kitchen water filter, purifying lymph before it
reaches the venous circulation. As lymph flows through a lymph node, at least 99
percent of the antigens in the lymph are removed. Fixed macrophages in the
walls of the lymphatic sinuses engulf debris or pathogens in lymph as it flows
past. Antigens removed in this way are then processed by the macrophages and
"presented" to nearby lymphocytes.
A
minor injury commonly produces a slight enlargement of the nodes along the
lymphatic vessels draining the region. This symptom, often called "swollen
glands," typically indicates inflammation or infection of peripheral
structures. The enlargement generally results from an increase in the number of
lymphocytes and phagocytes in the node in response to a minor, localized
infection. Chronic or excessive enlargement of lymph nodes constitutes lymphadenopathy,
a condition that may occur in response to bacterial or viral infections,
endocrine disorders, or cancer.
Lymphatic
vessels are located in almost all portions of the body except the central
nervous system, and lymphatic capillaries offer little resistance to the
passage of cancer cells. As a result, metastasizing cancer cells commonly spread
along lymphatic vessels. Under these circumstances, the lymph nodes serve as
way stations for migrating cancer cells. Thus, an analysis of lymph nodes can
provide information on the spread of the cancer cells, and such information
helps determine the appropriate therapies.
The Thymus is located in the mediastinum,
generally just posterior to the sternum. It is pink and has a grainy
consistency. In newborn infants and young children, the thymus is relatively
large, commonly extending from the base of the neck to the superior border of
the heart. The thymus reaches its greatest size (relative to body size) in the
first year or two after birth. Although the organ continues to increase in size
throughout childhood, the body as a whole grows even faster, so the size of the
thymus relative to that of the other organs in the mediastinum gradually
decreases. The thymus reaches its maximum absolute size, at a weight of about
40 g (1.4 oz), just before puberty. After puberty, it gradually diminishes in
size and becomes increasingly fibrous, a process called involution .
By the time an individual reaches age 50, the thymus may weigh less than 12 g
(0.3 oz). It has been suggested that the gradual decrease in the size and
secretory abilities of the thymus may make the elderly more susceptible to
disease.
The capsule that covers the thymus divides it into
two thymic lobes.
Hormones of the Thymus The thymus produces several
hormones that are important to the development and maintenance of normal
immunological defenses. Thymosin is the name originally
given to an extract from the thymus that promotes the development and
maturation of lymphocytes.
The Spleen contains the largest collection of lymphoid tissue in the
body. In essence, the spleen performs the same functions for blood that lymph
nodes perform for lymph. Functions of the spleen can be summarized as (1) the
removal of abnormal blood cells and other blood components by phagocytosis, (2)
the storage of iron from recycled red blood cells, and (3) the initiation of
immune responses by B cells and T cells in response to antigens in circulating
blood.
Anatomy of the
Spleen The
spleen is about 12 cm (5 in.) long and weighs, on average, nearly 160 g (5.6
oz). In gross dissection, the spleen is deep red, owing to the blood it
contains. The spleen lies along the curving lateral border of the stomach,
extending between the 9th and 11th ribs on the left side.
The
Spleen. (a) A
transverse section through the trunk, showing the typical position of the
spleen within the abdominopelvic cavity. The shape of the spleen roughly
conforms to the shapes of adjacent organs. (b) The external
appearance of the intact spleen, showing major anatomical landmarks. Compare
this view with that of part (a). (c) The histological
appearance of the spleen. White pulp is dominated by lymphocytes; it appears
blue because the nuclei of lymphocytes stain very darkly. Red pulp contains a
preponderance of red blood cells.
The
spleen has a soft consistency, so its shape primarily reflects its association
with the structures around it. The cellular components within
constitute the pulp of the spleen. Red pulp contains
large quantities of red blood cells, whereas white pulpresembles
lymphoid nodules.
This
circulatory arrangement gives the phagocytes of the spleen an opportunity to
identify and engulf any damaged or infected cells in circulating blood.
Lymphocytes are scattered throughout the red pulp, and the area surrounding the
white pulp has a high concentration of macrophages and dendritic cells. Thus,
any microorganism or other antigen in the blood will quickly come to the
attention of the splenic lymphocytes.
Because
the spleen is relatively fragile, it is very difficult to repair surgically.
(Sutures typically tear out before they have been tensed enough to stop the
bleeding.) A severely ruptured spleen is removed, a process called a splenectomy.
A person without a spleen survives, but has a greater risk of bacterial
infection, particularly involving pneumococcal bacteria than do individuals
with a functional spleen.
The
Lymphatic System and Body Defenses
The human body has multiple defense mechanisms, which
can be sorted into two general categories:
Nonspecific
defenses do
not distinguish one type of threat from another. Their response is the same,
regardless of the type of invading agent. These defenses, which are present at
birth, include physical barriers , phagocytic
cells , immunological surveillance , interferons , complement , inflammation ,
and fever . They provide a defensive capability known as nonspecific
resistance .
Specific
defenses protect
against particular threats. For example, a specific defense may protect against
infection by one type of bacterium, but be ineffective against other bacteria
and viruses. Many specific defenses develop after birth as a result of
accidental or deliberate exposure to environmental hazards. Specific
defenses depend on the activities of lymphocytes . The body's specific
defenses produce a state of protection known as immunity, or specific
resistance
22–3
Nonspecific Defenses
Nonspecific defenses prevent the approach, deny the entrance, or
limit the spread of microorganisms or other environmental
hazards. Nonspecific defenses deny pathogens access to the
body or destroy them without distinguishing among specific types.
Physical
barriers keep hazardous organisms and materials outside the
body. For example, a mosquito that lands on your head may be unable to reach
the surface of the scalp if you have a full head of hair.
Phagocytes are cells that engulf pathogens
and cell debris. Examples of phagocytes are the macrophages of peripheral
tissues and the microphages of blood.
Immunological
surveillance is the destruction of abnormal
cells by NK cells in peripheral tissues.
Interferons are chemical messengers that
coordinate the defenses against viral infection.
Complement is a system of circulating
proteins that assist antibodies in the destruction of pathogens.
The inflammatory
response is a local response to injury or infection that is
directed at the tissue level. Inflammation tends to restrict the spread of an
injury as well as combat an infection.
Fever is an elevation of body
temperature that accelerates tissue metabolism and defenses
Phagocytes perform janitorial and police
services in peripheral tissues, removing cellular debris and responding to
invasion by foreign compounds or pathogens.
Microphages are the neutrophils and
eosinophils that normally circulate in the blood. These phagocytic cells leave
the bloodstream and enter peripheral tissues that have been subjected to injury
or infection.
Macrophages are large, actively phagocytic
cells. Your body contains several types of macrophages, and most are derived
from the monocytes of the circulating blood. Macrophages either are fixed
permanently or move freely. Although no organs or tissues are purely
phagocytic, almost every tissue in the body shelters resident or visiting
macrophages. This relatively diffuse collection of phagocytic cells has been
called the monocyte–macrophage system , or the reticuloendothelial
system .
It
may engulf a pathogen or other foreign object and destroy it with lysosomal
enzymes.
It
may bind to or remove a pathogen from the interstitial fluid, but be unable to
destroy the invader until assisted by other cells.
It
may destroy its target by releasing toxic chemicals, such as tumor
necrosis factor , nitric oxide, or hydrogen peroxide, into the
interstitial fluid.
Fixed
macrophages ,
or histiocytes , are permanent residents of
specific tissues and organs. These cells are normally incapable of movement, so
the objects of their phagocytic attention must diffuse or otherwise move
through the surrounding tissue until they are within range. Fixed macrophages
are scattered among connective tissues, usually in close association with
collagen or reticular fibers. Their presence has been noted in the papillary
and reticular layers of the dermis, in the subarachnoid space of the meninges,
and in bone marrow. In some organs, the fixed macrophages have special names:
Microglia are macrophages in the central
nervous system, and Kupffer cells are macrophages located in
and around the liver sinusoids.
Free
Macrophages Free macrophages , or mobile
macrophages , travel throughout the body, arriving at the site of an
injury by migration through adjacent tissues or by recruitment from the
circulating blood. Some tissues contain free macrophages with distinctive
characteristics; for example, the exchange surfaces of the lungs are patrolled
by alveolar macrophages , also known as phagocytic
dust cells
Movement and
Phagocytosis
Free macrophages and microphages share a number of
functional characteristics:
Both
can move through capillary walls by squeezing between adjacent endothelial
cells, a process known as emigration , or diapedesis .
The endothelial cells in an injured area develop membrane "markers"
that let passing blood cells know that something is wrong. The cells then
attach to the endothelial lining and migrate into the surrounding tissues.
Both
may be attracted to or repelled by chemicals in the surrounding fluids, a
phenomenon called chemotaxis . They are particularly sensitive
to cytokines released by other body cells and to the chemicals released by
pathogens.
For
both, phagocytosis begins with adhesion , the attachment of
the phagocyte to its target. In adhesion, receptors on the cell membrane of the
phagocyte bind to the surface of the target. Adhesion is followed by the formation
of a vesicle containing the bound target, as detailed in Figure 3–25 , p. 97.
The contents of the vesicle are then digested when the vesicle fuses with
lysosomes or peroxisomes.
Immunological
Surveillance
The immune system generally ignores the body's own
cells unless they become abnormal in some way. Natural killer (NK) cells are
responsible for recognizing and destroying abnormal cells when they appear in
peripheral tissues. The constant monitoring of normal tissues by NK cells is
called immunological surveillance .
The
cell membrane of an abnormal cell generally contains antigens that are not
found on the membranes of normal cells. NK cells recognize an abnormal cell by
detecting the presence of those antigens. The recognition mechanism differs
from that used by T cells or B cells, which are activated only by exposure to
a specific antigen at a specific site on a
cell membrane. An NK cell responds to a variety of abnormal antigens that may
appear anywhere on a cell membrane. NK cells are therefore much less selective
about their targets than are other lymphocytes; if a membrane contains abnormal
antigens, it will be attacked. As a result, NK cells are highly versatile: A
single NK cell can attack bacteria in the interstitial fluid, body cells infected
with virus, or cancer cells.
NK
cells attack
cancer cells and cells infected with viruses. Cancer cells probably appear
throughout life, but their cell membranes generally contain unusual proteins
called tumor–specific antigens , which NK cells recognize as
abnormal. The affected cells are then destroyed, preserving tissue integrity.
Unfortunately,
some cancer cells avoid detection, perhaps because they lack tumor–specific
antigens or because these antigens are covered in some way. Other cancer cells
are able to destroy the NK cells that detect them. This process of avoiding
detection or neutralizing body defenses is called immunological
escape . Once immunological escape has occurred, cancer cells can
multiply and spread without interference by NK cells
NK
cells are also important in fighting viral infections. Viruses reproduce inside
cells, beyond the reach of circulating antibodies. However, infected cells
incorporate viral antigens into their cell membranes, and NK cells recognize
these infected cells as abnormal. By destroying them, NK cells can slow or
prevent the spread of a viral infection.
Interferons are small proteins released
by activated lymphocytes and macrophages and by tissue cells infected with
viruses. On reaching the membrane of a normal cell, an interferon binds to
surface receptors on the cell and, via second messengers, triggers the
production of antiviral proteins in the cytoplasm. Antiviral
proteins do not interfere with the entry of viruses, but they do interfere with
viral replication inside the cell.
Complement
Your plasma contains 11 special complement
proteins (C) , which form the complement system . The
term complement refers to the fact that this system
complements the action of antibodies.
The complement proteins interact with one another in
chain reactions, or cascades , comparable to those of the
clotting system.
The Destruction
of Target Cell Membranes. Five of the
interacting complement proteins bind to the cell membrane, forming a functional
unit called the membrane attack complex (MAC) . The MACs
create pores in the membrane that are comparable to those produced by perforin,
and that have the same effect: The target cell is soon destroyed.
The Stimulation
of Inflammation. Activated complement proteins
enhance the release of histamine by mast cells and basophils. Histamine
increases the degree of local inflammation and accelerates blood flow to the
region.
The Attraction of
Phagocytes. Activated complement proteins
attract neutrophils and macrophages to the area, improving the chances that
phagocytic cells will be able to cope with the injury or infection.
The Enhancement
of Phagocytosis. A coating of complement
proteins and antibodies both attracts phagocytes and makes the target easier to
engulf. Macrophage membranes contain receptors that can detect and bind to
complement proteins and bound antibodies. After binding, the pathogens are
easily engulfed. The antibodies involved are called opsonins ,
and the effect is called opsonization
Inflammation
The inflammatory
response , is a localized tissue response to injury. Inflammation
produces local sensations of swelling, redness, heat, and pain.
The changes in the
interstitial environment trigger the complex process of inflammation.
Inflammation
has a number of effects:
The
injury is temporarily repaired, and additional pathogens are prevented from
entering the wound.
The
spread of pathogens away from the injury is slowed.
Local,
regional, and systemic defenses are mobilized to overcome the pathogens and
facilitate permanent repairs. This repair process is called regeneration .
The Response to Injury
Mast cells play a pivotal role in the inflammatory
response. When stimulated by mechanical stress or chemical changes in the local
environment, these cells release histamine, heparin, prostaglandins, and other
chemicals into interstitial fluid. Events then proceed in a series of
integrated steps:
The
histamine that is released increases capillary permeability and accelerates
blood flow through the area. The increased blood flow brings more cellular
defenders to the site and carries away toxins and debris, diluting them and
reducing their local impact.
Clotting
factors and complement proteins leave the bloodstream and enter the injured or
infected area. Clotting does not occur at the actual site of injury, due to the
presence of heparin. However, a clot soon forms around the damaged area, and
this clot both isolates the region and slows the spread of the chemical or
pathogen into healthy tissues. Meanwhile, complement activation through the
alternative pathway breaks down bacterial cell walls and attracts phagocytes.
The
increased blood flow elevates the local temperature, increasing the rate of
enzymatic reactions and accelerating the activity of phagocytes. The rise in
temperature may also denature foreign proteins or vital enzymes of invading
microorganisms.
Debris
and bacteria are attacked by neutrophils drawn to the area by chemotaxis. As
they circulate through a blood vessel in an injured area, neutrophils
undergo activation , a process in which (1) they stick to the
side of the vessel and move into the tissue by diapedesis; (2) their metabolic
rate goes up dramatically, and while this respiratory burst continues,
they generate reactive compounds, such as nitric oxide and hydrogen peroxide,
that can destroy engulfed pathogens; and (3) they secrete cytokines that
attract other neutrophils and macrophages to the area.
Fixed
and free macrophages engulf pathogens and cell debris. At first, these cells
are outnumbered by neutrophils, but as the macrophages and neutrophils continue
to secrete cytokines, the number of macrophages increases rapidly. Eosinophils
may get involved if the foreign materials become coated with antibodies.
Other
cytokines released by active phagocytes stimulate fibroblasts to begin
barricading the area with scar tissue, reinforcing the clot and further slowing
the invasion of adjacent tissues.
The
combination of abnormal tissue conditions and chemicals released by mast cells
stimulates local sensory neurons, producing sensations of pain. The individual
becomes consciously aware of these sensations and may take steps to limit the
damage they signal, such as removing a splinter or cleaning a wound.
As
inflammation is under way, the foreign proteins, toxins, microorganisms, and
active phagocytes in the area activate the body's specific defenses.
The
tissue degeneration that occurs after cells have been injured or destroyed is
called necrosis . The process begins several hours after the
initial event, and the damage is caused by lysosomal enzymes. Lysosomes break
down by autolysis, releasing digestive enzymes that first destroy the injured
cells and then attack surrounding tissues.
As
local inflammation continues, debris, fluid, dead and dying cells, and necrotic
tissue components accumulate at the injury site. This viscous fluid mixture is
known as pus . An accumulation of pus in an enclosed tissue
space is called an abscess .
Fever is
the maintenance of a body temperature greater than 37.28C (998F). In Chapter 14
, we noted the presence of a temperature–regulating center in the preoptic area
of the hypothalamus. Circulating proteins called pyrogens can
reset this thermostat and raise body temperature. A variety of stimuli,
including pathogens, bacterial toxins, and antigen– antibody complexes, either
act as pyrogens themselves or stimulate the release of pyrogens by macrophages.
Within
limits, a fever can be beneficial. High body temperatures may inhibit some
viruses and bacteria, but the most likely beneficial effect is on body
metabolism. For each rise in temperature, your metabolic rate jumps by 10
percent.
22–4
Specific Defenses:
Specific resistance, or immunity, is provided by the coordinated
activities of T cells and B cells, which respond to the presence of specific
antigens. The basic functional relationship can be summarized as follows:
T
cells are responsible for cell–mediated
immunity (or cellular immunity ), our defense against
abnormal cells and pathogens inside cells.
B
cells provide antibody–mediated
immunity (or humoral immunity ), our defense against
antigens and pathogens in body fluids.
Forms
of Immunity
Immunity is either innate or acquired
Types
of Immunity
Innate immunity is genetically determined; it is
present at birth and has no relationship to previous exposure to the antigen
involved. For example, people do not get the same diseases that goldfish do.
Innate immunity breaks down only in the case ofAIDS or other
conditions that depress all aspects of specific resistance.
Acquired
immunity is
not present at birth; you acquire immunity to a specific antigen only when you
have been exposed to that antigen. Acquired immunity can be active or passive .
Active immunity appears after exposure to an antigen, as a consequence of the
immune response. The immune system is capable of defending
against a large number of antigens. However, the appropriate defenses are
mobilized only after you encounter a particular antigen. Active acquired immunity
can develop as a result of natural exposure to an antigen in the environment
( naturally acquired immunity ) or from deliberate exposure to
an antigen ( induced active immunity ).
Passive
immunity is
produced by the transfer of antibodies from another source.
Natural
passive immunity results
when a mother's antibodies protect her baby against infections during gestation
(across the placenta) or in early infancy (through breast milk).
In induced
passive immunity , antibodies are administered to fight infection or
prevent disease. For example, antibodies that attack the rabies virus are
injected into a person bitten by a rabid animal.
An
Introduction to the Immune Response
T Cells and
Cell–Mediated Immunity
T cells play a key role in the initiation, maintenance, and
control of the immune response. We have already introduced three major types of
T cells:
Cytotoxic
T cells which
are responsible for cell–mediated immunity. These cells enter peripheral
tissues and directly attack antigens physically and chemically.
Helper
T cells which
stimulate the responses of both T cells and B cells. Helper T cells are
absolutely vital to the immune response, because B cells must be activated by
helper T cells before the B cells can produce antibodies. The reduction in the
helper T cell population that occurs in AIDS is largely responsible for the
loss of immunity.
Suppressor
T cells which
inhibit T cell and B cell activities and moderate the immune response.
Antigen
presentation occurs
when an antigen–glycoprotein combination capable of activating T cells appears
in a cell membrane. The structure of these glycoproteins is genetically
determined. The genes controlling their synthesis are located along one portion
of chromosome 6, in a region called the major histocompatibility
complex (MHC) . These membrane glycoproteins are called MHC
proteins , or human leukocyte antigens (HLAs) .
Antigen
Recognition
Inactive T cells have receptors that recognize Class I or Class II
MHC proteins. The receptors also have binding sites that detect the presence of
specific bound antigens. If an MHC protein contains any antigen other than the
specific target of a particular kind of T cell, the T cell remains inactive. If
the MHC protein contains the antigen that the T cell is programmed to detect,
binding will occur. This process is called antigen recognition ,
because the T cell recognizes that it has found an appropriate target.
Cytotoxic
T cells ,
also called cells or killer T cells , seek
out and destroy abnormal and infected cells. Killer T cells are highly mobile
cells that roam throughout injured tissues. When a cytotoxic T cell encounters
its target antigens bound to Class I MHC proteins of another cell, it
immediately destroys that cell. Three different methods may be used to destroy
the target cell
Antigen
Recognition and the Activation of Cytotoxic T Cells.
An inactive cytotoxic T cell not only must encounter
an appropriate antigen bound to Class I MHC proteins, but also must receive
costimulation from the membrane it contacts. It is then activated and undergoes
divisions that produce memory cells and active cells. When one of the active
cells encounters a membrane displaying the target antigen, it will use one of
several methods to destroy the cell
The T
cell may (1) destroy the antigenic cell membrane through the release of
perforin, (2) kill the target cell by secreting a poisonous lymphotoxin,
or (3) activate genes in the target cell's nucleus that tell that cell to die
Memory
Tc cells are
produced by the same cell divisions that produce cytotoxic T cells. Memory Tc
cells ensure that there will be no delay in the response if the antigen
reappears. These cells do not differentiate further the first time the antigen
triggers an immune response, although thousands of them are produced. Instead,
they remain in reserve. If the same antigen appears a second time, memory T
cells will immediately differentiate into cytotoxic T cells,
producing a swift, effective cellular response that can overwhelm an invading organism
before it becomes well established in the tissues.
Suppressor
T cells suppress
the responses of other T cells and of B cells by secreting suppression
factors.
As a
result, suppressor T cells act after the initial immune
response. In effect, these cells put on the brakes and limit the degree of
immune system activation from a single stimulus.
Activation
of CD4 T Cells
Upon activation, CD4 T cells undergo a series of
divisions that produce helper T cells and memory
Antigen
Recognition and Activation of Helper T Cells.
Inactive CD4 T cells ( cells) must be exposed to
appropriate antigens bound to Class II MHC proteins. The cells then undergo
activation, dividing to produce active cells and memory cells. Active cells
secrete cytokines that stimulate cell–mediated and antibody–mediated
immunities. They also interact with sensitized B cells, as Figure 22–20 shows.
The
memory cells remain in reserve, whereas the helper T cells secrete a variety of
cytokines that coordinate specific and nonspecific defenses and stimulate
cell–mediated and antibody–mediated immunities. For example, activated helper T
cells secrete cytokines that:
Stimulate
the T cell divisions that produce memory T cells and accelerate the maturation
of cytotoxic T cells.
Enhance
nonspecific defenses by attracting macrophages to the affected area, preventing
their departure, and stimulating their phagocytic activity and effectiveness;
Attract
and stimulate the activity of NK cells, providing another mechanism for the
destruction of abnormal cells and pathogens; and
Promote
the activation of B cells, leading to B cell division, plasma cell maturation,
and antibody production.
A Summary of the Pathways of T Cell
Activation
B Cells and
Antibody–Mediated Immunity
B cell membranes contain Class II MHC proteins. During
sensitization, antigens are brought into the cell by endocytosis. The antigens
subsequently appear on the surface of the B cell, bound to Class II MHC
proteins. (The mechanism is comparable to that shown in Figure 22–16b , p.
802). Once this happens, the sensitized B cell is ready to go, but it generally
will not undergo activation unless it receives the "OK" from a helper
T cell
Next, a sensitized B cell
encounters a helper T cell already activated by antigen presentation. The
helper T cell binds to the MHC complex, recognizes the presence of an antigen,
and begins secreting cytokines that promote B cell activation. After activation
has occurred, these same cytokines stimulate B cell division, accelerate plasma
cell formation, and enhance antibody production.
The
Sensitization and Activation of B Cells.
A B cell is sensitized by exposure to antigens that
bind to antibodies in the B cell membrane. The B cell then displays those
antigens in its cell membrane. Activated helper T cells encountering the
antigens release cytokines that trigger the activation of the B cell. The
activated B cell then divides, producing memory B cells and plasma cells that
secrete antibodies
When stimulated by
cytokines from helper T cells, a plasma cell can secrete up to 100 million
antibody molecules each hour.
Memory
B cells perform
the same role for antibody–mediated immunity that memory T cells perform for
cell–mediated immunity. Memory B cells do not respond to a threat on first
exposure. Instead, they remain in reserve to deal with subsequent injuries or
infections that involve the same antigens. On subsequent exposure, the memory B
cells respond by dividing and differentiating into plasma cells that secrete
antibodies in massive quantities.
Antibody
Structure.
(a) A
diagrammatic view of the structure of an antibody. (b) A
computer–generated image of a typical antibody. (c) Antigen–antibody
binding. (d) A hapten, or partial antigen, can become a
complete antigen by binding to a carrier molecule.
An
antibody consists of two parallel pairs of polypeptide chains: one pair
of heavy
chains and
one pair of light
chains .
Each chain contains both constant segments and variable
segments .
B
cells produce only five types of constant segments. These form the basis of a
classification scheme that identifies antibodies as IgG, IgE, IgD,
IgM , or IgA
Classes and
Actions of Antibodies
Body fluids have five classes of antibodies, or immunoglobulins
(Igs) : IgG, IgE, IgD, IgM ,
and IgA
The
formation of an antigen–antibody complex may cause the elimination of the
antigen in seven ways:
Neutralization. Both
viruses and bacterial toxins have specific sites that must bind to target
regions on body cells in order to enter or injure those cells. Antibodies may
bind to those sites, making the virus or toxin incapable of attaching itself to
a cell. This mechanism is known as neutralization .
Agglutination
and Precipitation.
The
three–dimensional structure created by such binding is known as an immune complex . When the antigen is a soluble
molecule, such as a toxin, this process may create complexes that are too large
to remain in solution. The formation of insoluble immune complexes is
called precipitation . When the target antigen is on
the surface of a cell or virus, the formation of large complexes is
called agglutination . The clumping of red blood cells
that occurs when incompatible blood types are mixed is an agglutination
reaction.
The
Activation of Complement. On binding to an antigen, portions of the
antibody molecule change shape, exposing areas that bind complement proteins.
The bound complement molecules then activate the complement system, destroying
the antigen (as discussed previously).
The
Attraction of Phagocytes. Antigens covered with antibodies attract
eosinophils, neutrophils, and macrophages–cells that phagocytize pathogens and
destroy foreign or abnormal cell membranes.
Opsonization. A
coating of antibodies and complement proteins increases the effectiveness of
phagocytosis.
The
Stimulation of Inflammation. Antibodies may promote inflammation through
the stimulation of basophils and mast cells.
The
Prevention of Bacterial and Viral Adhesion. Antibodies dissolved in
saliva, mucus, and perspiration coat epithelia and provide them with an
additional layer of defense. A covering of antibodies makes it difficult for
pathogens to attach to body surfaces and penetrate their defenses.
Primary
and Secondary Responses to Antigen Exposure
The initial response to exposure to an antigen is called the primary
response . When the antigen appears again, it triggers a more
extensive and prolonged secondary response .
The Primary
Response
Because the antigen must activate the appropriate B
cells, which must then differentiate into plasma cells, the primary response
does not appear immediately
The
Primary and Secondary Immune Responses.
(a) The
primary response takes about two weeks to develop peak antibody titers, and IgM
and IgG antibody concentrations do not remain elevated. (b) The
secondary response is characterized by a very rapid increase in IgG antibody
titer, to levels much higher than those of the primary response. Antibody
activity remains elevated for an extended period after the second exposure to
the antigen.
As
the plasma cells differentiate and begin secreting, the concentration of
circulating antibodies undergoes a gradual, sustained rise.
During the primary response, the antibody
titer ("standard"), or level of antibody activity, in the
plasma does not peak until one to two weeks after the initial exposure.
Two
types of antibodies are involved in the primary response. Molecules of immunoglobulin
M , or IgM , are the first to appear in the
bloodstream. IgM is secreted by the plasma cells that form immediately after B
cell activation. These lymphocytes do not pause to produce memory cells. Levels
of immunoglobulin G, or IgG , rise more slowly,
because the stimulated lymphocytes undergo repeated cell divisions and generate
large numbers of memory cells as well as plasma cells. In effect, IgM provides
an immediate but limited defense that fights the infection until massive
quantities of IgG can be produced.
The Secondary
Response
Unless they are exposed to the same antigen a second
time, memory B cells do not differentiate into plasma cells. If and when that
exposure occurs, the memory B cells respond immediately–faster than the B cells
stimulated during the initial exposure
The
effectiveness of the secondary response is one of the basic principles behind
the use of immunization to prevent disease.
Summary:
The Immune Response
We have now described the basic chemical and cellular
interactions that follow the appearance of a foreign antigen in the body.
An
Integrated Summary of the Immune Response
The
Course of the Body's Response to Bacterial Infection.
An outline of the basic sequence of events that
begins with the appearance of bacteria in peripheral tissues
In the early stages of bacterial infection, before antigen processing
has occurred, neutrophils and NK cells migrate into the threatened area and
destroy bacteria. Over time, cytokines draw increasing numbers of phagocytes to
the region. Cytotoxic T cells appear as arriving T cells are activated by antigen
presentation. Last of all, the population of plasma cells rises as activated B
cells differentiate. This rise is followed by a gradual, sustained increase in
the level of circulating antibodies.
The basic sequence of events is similar when a viral infection
occurs. The initial steps are different, however, because cytotoxic T cells and
NK cells can be activated by contact with infected cells.
Defenses
against Bacterial and Viral Pathogens.
(a) Defenses
against bacteria are usually initiated by active macrophages. (b) Defenses
against viruses are usually activated after the infection of normal cells.
Hormones of the Immune System
One
example of physical interaction is antigen presentation by activated
macrophages and helper T cells. An example of the release of chemical
messengers is the secretion of cytokines by many of the cells involved in the
immune response.
Cytokines
are classified according to their origins: Lymphokines are
produced by lymphocytes, monokines by active macrophages and
other antigen–presenting cells.
Interleukins may be the most diverse and
important chemical messengers in the immune system. Nearly 20 types of
interleukins have been identified;. Lymphocytes and macrophages are the primary
sources of interleukins, but specific interleukins, such as interleukin–1
(IL–1), are also produced by endothelial cells, fibroblasts, and astrocytes.
Interleukins have the following general functions:
Increasing
T Cell Sensitivity to Antigens Exposed on Macrophage Membranes .
Stimulating
B Cell Activity, Plasma Cell Formation, and Antibody production
Enhancing
Nonspecific Defenses .
Known effects of interleukin production include (1) the stimulation of
inflammation, (2) the formation of scar tissue by fibroblasts, (3) the
elevation of body temperature via the preoptic nucleus of the central nervous
system, (4) the stimulation of mast cell formation, and (5) the promotion of
adrenocorticotropic hormone (ACTH) secretion by the anterior lobe of the
pituitary gland.
Moderating
the Immune Response .
Some interleukins help suppress immune function and shorten the duration of an
immune response.
If
the regulatory process sometimes breaks down, and massive production of
interleukins can cause problems at least as severe as those of the primary
infection. For example, in Lyme disease the release of IL–1 by
activated macrophages in response to a localized bacterial infection produces
symptoms of fever, pain, skin rash, and arthritis that affect the entire body.
Interferons stimulate NK cell activity,
interferons can be used to fight some cancers. For example, alpha–interferons
have been used in the treatment of malignant melanoma, bladder cancer, ovarian
cancer, and two forms of leukemia, while alpha– or gamma–interferons may be
used to treat Kaposi's sarcoma, a cancer that typically develops in individuals
with AIDS.
Tumor
necrosis factors (TNFs) slow the growth of a tumor and kill sensitive tumor cells.
Activated macrophages secrete one type of TNF and carry the molecules in their
cell membranes. Cytotoxic T cells produce a different type of TNF. In addition
to their effects on tumor cells, tumor necrosis factors stimulate granular
leukocyte production, promote eosinophil activity, cause fever, and increase T
cell sensitivity to interleukins
Chemicals
Regulating Phagocytic Activities
Several cytokines coordinate immune defenses by
adjusting the activities of phagocytic cells. These cytokines include factors
that attract free macrophages and microphages and prevent their premature
departure from the site of an injury.
Colony–Stimulating
Factors
We introduced colony–stimulating factors
(CSFs) in Chapter 19 . These factors are produced by active T cells,
cells of the monocyte–macrophage group, endothelial cells, and fibroblasts.
CSFs stimulate the production of blood cells in bone marrow and lymphocytes in
lymphoid tissues and organs.
Normal and
Abnormal Resistance
The ability to produce an immune response after exposure to an
antigen is called immunological competence . Cell–mediated
immunity can be demonstrated as early as the third month of fetal development,
but active antibody–mediated immunity appears later.
The
Development of Immunological Competence
The
natural immunity provided by maternal IgG may not be enough to protect the
fetus if the maternal defenses are overrun by a bacterial or viral infection.
For example, the microorganisms responsible for syphilis and rubella
("German measles") can cross from the maternal to the fetal
bloodstream, producing a congenital infection that leads to the production of
fetal antibodies. IgM provides only a partial defense, and these infections can
result in severe developmental problems for the fetus.
Delivery eliminates the maternal supply of IgG. Although the
mother provides IgA antibodies in her breast milk, the infant gradually loses
its passive immunity. The amount of maternal IgG in the infant's bloodstream
declines rapidly over the first two months after birth. During this period, the
infant becomes vulnerable to infection by bacteria or viruses that were
previously overcome by maternal antibodies. The infant also begins producing
its own IgG, as its immune system begins to respond to infections,
environmental antigens, and vaccinations. It has been estimated that, from birth
to age 12, children encounter a "new" antigen every six weeks. (This
fact explains why most parents, exposed to the same antigens when they were
children, remain healthy, while their children develop runny noses and colds.)
Over this period, the concentration of circulating antibodies gradually rises
toward normal adult levels, and the populations of memory B cells and T cells
continue to increase.
Autoimmune
disorders develop
when the immune response mistakenly targets normal body cells and tissues. In
an immunodeficiency disease , either the immune system fails
to develop normally or the immune response is blocked in some way. Autoimmune
disorders and immunodeficiency diseases are relatively rare–clear evidence of
the effectiveness of the immune system's control mechanisms. A far more common,
and generally far less dangerous, class of immune disorders is the allergies.
The recognition system can
malfunction, however. When it does, the activated B cells make antibodies
against other body cells and tissues. These misguided antibodies are
called autoantibodies . The trigger may be a reduction in
suppressor T cell activity, the excessive stimulation of helper T cells, tissue
damage that releases large quantities of antigenic fragments, haptens bound to
compounds normally ignored, viral or bacterial toxins, or a combination of
factors.
The
symptoms produced depend on the specific antigen attacked by autoantibodies.
For example,
The
inflammation of thyroiditis results from the release of
autoantibodies against thyroglobulin;
Rheumatoid
arthritis occurs
when autoantibodies form immune complexes within connective tissues, especially
around the joints; and
Insulin–dependent
diabetes mellitus (IDDM) is generally caused by autoantibodies that attack cells in the
pancreatic islets.
Many
autoimmune disorders appear to be cases of mistaken identity. For example,
proteins associated with the measles, Epstein–Barr, influenza, and other
viruses contain amino acid sequences that are similar to those of myelin proteins.
As a result, antibodies that target these viruses may also attack myelin
sheaths. This mechanism accounts for the neurological complications that
sometimes follow a vaccination or a viral infection. It is also the mechanism
that is likely responsible for multiple sclerosis .
Immunodeficiency Diseases
Immunodeficiency diseases result from (1) problems
with the embryological development of lymphoid organs and tissues; (2) an
infection with a virus, such as HIV, that depresses the immune function; or (3)
treatment with, or exposure to, immunosuppressive agents, such as radiation or
drugs.
Individuals born with severe combined
immunodeficiency disease (SCID) fail to develop either cellular or
antibody–mediated immunity. Their lymphocyte populations are low, and normal B
and T cells are absent. Such infants cannot produce an immune response, and
even a mild infection can prove fatal. Total isolation offers protection at
great cost, with severe restrictions on lifestyle. Bone marrow transplants from
compatible donors, normally a close relative, have been used to colonize
lymphoid tissues with functional lymphocytes. Gene–splicing techniques have led
to therapies that can treat at least one form of SCID.
AIDS, an immunodeficiency
disease that we consider on page 820, is the result of a viral infection that
targets primarily helper T cells. As the number of T cells declines, the normal
immune control mechanism breaks down. When an infection occurs, suppressor
factors released by suppressor T cells inhibit an immune response before the
few surviving helper T cells can stimulate the formation of cytotoxic T cells
or plasma cells in adequate numbers.
Immunosuppressive drugs
have been used for many years to prevent graft rejection after transplant
surgery. But immunosuppressive agents can destroy stem cells and lymphocytes,
leading to a complete immunological failure. This outcome is one of the
potentially fatal consequences of radiation exposure.
Allergies are inappropriate or excessive
immune responses to antigens. The sudden increase in cellular activity or
antibody titers can have a number of unpleasant side effects. For example,
neutrophils or cytotoxic T cells may destroy normal cells while attacking the
antigen, or the antigen–antibody complex may trigger a massive inflammatory
response. Antigens that trigger allergic reactions are often called allergens .
There
are several types of allergies. A complete classification recognizes four
categories: immediate hypersensitivity (Type I), cytotoxic reactions
(Type II), immune complex disorders (Type III) , and delayed
hypersensitivity (Type IV) . Here we will consider only immediate
hypersensitivity, probably the most common form of allergy. One form, allergic
rhinitis , includes hay fever and environmental allergies that may
affect 15 percent of the U.S. population.
In anaphylaxis,
a circulating allergen affects mast cells throughout the body .
The
Mechanism of Anaphylaxis
The
entire range of symptoms can develop within minutes. Changes in capillary
permeabilities produce swelling and edema in the dermis, and raised welts,
or hives , appear on the surface of the skin. Smooth muscles
along the respiratory passageways contract; the narrowed passages make
breathing extremely difficult. In severe cases, an extensive peripheral
vasodilation occurs, producing a fall in blood pressure that can lead to a
circulatory collapse. This response is anaphylactic shock
Many
of the symptoms of immediate hypersensitivity can be prevented by the prompt
administration of antihistamines –drugs that block the action
of histamine. (diphenhydramine hydrochloride) is a popular
antihistamine that is available over the counter. The treatment of severe
anaphylaxis involves antihistamine, corticosteroid, and epinephrine injections
