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Chapter 15
The immune system contains a diverse group of
structures and cells that are spread throughout the body (Fig.
15.1). These structures include the thymus gland, red
bone marrow, spleen, lymph nodes, lymph
vessels, other structures containing lymphatic tissues
(tonsils, lining of the respiratory system and GI tract), and skin.
These structures promote the development of the cells of this system and,
together with blood and lymph, serve as the main repositories for them. Immune
system cells include macrophages, Langerhans cells,
and several types of lymphocytes. Special protein molecules
called antibodies (see below) are also considered part of the
immune system.
MAIN FUNCTIONS FOR HOMEOSTASIS
The immune system is a main defense mechanism for the body
against harmful agents, including many foreign substances, bacteria, parasites,
viruses, and its own cancer cells. This system uses different defense
strategies against different agents, including blocking their entrance,
abolishing those found in the body, and helping neutralize or eliminate
undesirable substances produced by invading organisms.
Therefore, a person's immune system serves like a
combination of a nation's agencies for customs and immigration, drug
enforcement, and counter-insurgency. Unfortunately, as with such agencies,
immune system activities occasionally injure innocent constituents through
misidentification or overzealous actions such as autoimmunity and allergy.
Three characteristics of the immune system make it unique
among the body's defense mechanisms. First, it shows self-recognition,
which means that the immune system attempts to distinguish between substances
that are normal constituents of a person's body and substances that are foreign
to it. Upon identifying a substance as foreign, the immune system mounts an immune
response against it. It can perform an immune response against some
types of cancer cells because they display molecules identified as foreign. Any
substance that causes an immune response is called an antigen.
The second unique characteristic is specificity,
which means that an immune response will operate only against one antigen.
Therefore, a different immune response must be produced each time a different
antigen is encountered. For example, specificity explains why an immune
response against the virus that causes measles provides no protection against
the virus that causes chickenpox. In contrast to the immune system, other
bodily defense mechanisms against harmful chemicals, microbes, viruses, and
cancer cells are called nonspecific because each mechanism
helps protect the body against a variety of these agents. Some nonspecific
defense mechanisms, such as the skin, mucous membranes, and mucus, prevent
harmful agents from entering the body, while others, such as movements of
cilia, defecation, and urination, help expel them. Other mechanisms, such as
fever, perspiration, sebum, and acidic conditions in the stomach and vagina,
inhibit the growth of harmful microbes. Finally, phagocytic cells (e.g., WBCs)
and natural killer (NK) cells act nonspecifically in killing microbes and
cancer cells.
The third unique characteristic is memory.
When the immune system responds against an antigen, it develops a residual set
of lymphocytes called memory cells and usually develops a group
of long-lasting antibodies. Antibodies are protein molecules that
adhere to antigens and help combat them. Each time a particular antigen is
encountered, the memory cells and antibodies developed for that antigen cause a
quicker and more intense attack and thus eliminate it faster. In contrast, nonspecific
defense mechanisms function with the same speed and intensity each time an
injurious agent presents itself, allowing for the same risk of injury from the
agent before it is eliminated.
DEVELOPMENT OF THE IMMUNE SYSTEM
A burst of development in the immune system occurs over
several weeks before and after birth. At first the prenatal liver and spleen
produce monocytes, which are phagocytic white blood cells, and lymphocytes.
As the time of birth approaches, production of monocytes and lymphocytes shifts
to the red bone marrow, which continues to produce these cells thereafter (Fig.
15.2)
Fig.
15.2 - Development of macrophages, T cells, and B cells. (1) Bone marrow
cells produce monocytes and lymphocytes. (2) Monocytes enter blood vessels and
are transported to capillaries throughout the body. (3a) Some lymphocytes enter
blood vessels and are transported to the thymus. (3b) Some lymphocytes enter
blood vessels and are transported to other areas, such as bone marrow. (4) Some
monocytes leave capillaries and become macrophages (M) among body cells. (5)
Lymphocytes in the thymus reproduce and develop HLA receptors and
antigen-specific receptors and become T cells (T). (6) T cells with
antigen-specific receptors for self-antigens are destroyed (clonal selection).
(7) Remaining T cells are transported to lymphatic tissues such as the lymph
nodes and spleen. (8) T cells in lymph tissues reproduce and mature to form T
cell clones. (9) Lymphocytes in bone marrow reproduce and develop HLA proteins
and antigen-specific receptors to become B cells (B). (10) B cells with
antigen-specific receptors for self-antigens are destroyed (clonal selection).
(11) Remaining B cells enter blood vessels and are transported throughout the
body.)
Macrophages
and Langerhans Cells
Many monocytes pass through capillary walls and enter the
spaces among body cells and within lymph nodes and other lymphatic tissues.
These migrating monocytes are then called macrophages. Similar
cells called Langerhans cells develop in the epidermis. Lifelong
monocyte production by red bone marrow helps sustain the population of
macrophages, and the epidermis attempts to maintain adequate numbers of active
Langerhans cells.
As macrophage formation begins, the blood transports a
portion of the new lymphocytes into the thymus which lies above
the heart and behind the sternum (breastbone) (Fig.
15.1 ,
Fig.
15.2). The thymus converts these lymphocytes into a special type of cell
called T lymphocytes (T cells).
HLA Receptor Formation One process that occurs during T-cell
development involves varying T cells so that they produce cell surface receptor
molecules called human leukocyte-associated (HLA) receptors.
These receptors bind to molecules of HLA protein, which are found
on virtually every cell in the body.
Each person has certain types of HLA proteins on his or her
cells, and these proteins differ from the proteins in every other person.
Therefore, each person's HLA protein identifies each cell as belonging only to
that person's body. Exceptions occur with genetically identical people (e.g.,
identical twins), whose cells have identical HLA proteins.
Antigen-Specific Receptor Formation A second process
during T-cell development results in each T cell producing a second type of
surface receptor, an antigen-specific receptor. All the
antigen-specific receptors on each T cell can bind to only one substance, and
each T cell develops a different type of antigen-specific receptor. There may
be 100 million types of antigen-specific receptors and therefore an equal
number of different types of T cells.
Clonal Selection and Suppression Many scientists
believe that during the formation of antigen-specific receptors samples of all
surface materials on body cells are carried into the thymus. Once these
materials enter the thymus, that gland selectively destroys T cells with
antigen-specific receptors that bind to any of those materials. Surface
materials that bind to antigen-specific receptors are called self-antigens
because they are native body materials that could start an immune response. T
cells that are incapable of binding to self-antigens that enter the thymus
during this period survive and begin to reproduce. Therefore, in each person,
each surviving T cell forms a clone of identical cells. Each cell has HLA
receptors for that person's HLA protein plus one type of antigen-specific
receptor for one substance that is not a self-antigen.
The entire process of T-cell development is called clonal
selection. Members from each clone are carried throughout the body by
the circulatory system, with many of them deposited in the spleen, lymph nodes,
and other lymphatic tissues. Thymic hormones continue to cause the dispersed T
cells to reproduce and mature. Once mature, the T cells can use their HLA
receptors to distinguish the individual's cells from any other cells. The T
cells will be activated to participate in an immune response whenever both
their HLA receptors and their antigen-specific receptors are bound to the
surface of a cell. They are therefore said to be immunocompetent
and have also developed both self-recognition and specificity. Almost all
clonal selection is believed to occur in the thymus within 1 month after birth.
Furthermore, at least some members of each clone probably
survive outside the thymus for many years. Therefore, each clone represents a
widespread reserve of T cells that can attack one antigen each. However, as
long as the thymus secretes ample thymic hormones, these hormones may be able to
stimulate additional conversion of lymphocytes, clonal selection, and
maturation of T cells outside the thymus. These processes could form T-cell
clones for additional antigens and bolster or reestablish some older clones
that had dwindled or vanished through gradual T-cell death.
Many scientists believe that during clonal selection some T
cells actually form T-cell clones against self-antigens. These clones lack
self-recognition and therefore could begin immune responses against the body's
own cells. They are prevented from doing this by mechanisms that suppress their
participation in an immune response. At least part of the suppression may be
performed by special T cells called suppressor T cells (sT
cells).
Recall that only some lymphocytes produced by the red bone
marrow are converted into T cells by the thymus and thymic hormones. Other new
lymphocytes are converted into B lymphocytes (B cells).
B-cell formation does not depend on the thymus. Though its site is unknown,
this process seems to be very similar to the clonal selection that produces
T-cells (Fig.
15.2). However, there are two important differences. First, B cells do not
develop HLA receptors and therefore need have only their antigen-specific
receptors bound to an antigen to begin participation in an immune response.
Second, B cells develop HLA protein, which allows them to bind to HLA receptors
on T cells.
Once macrophages, Langerhans cells, T cells, and B cells
have developed, the immune system is ready to initiate immune responses. The
system begins to monitor substances in the body in an attempt to detect foreign
materials.
Immune responses and other immune system activities are
regulated by signaling substances from the nervous system and endocrine system,
and from the immune system cells themselves. Some regulating substances act at
great distances from their sites of production, and others affect cells close
to their sources. Like hormones, these signaling substances contact many cell
types, yet they affect only certain cells and organs. Usually, the affected
cells respond because they contain receptor molecules to which the signaling
molecules bind.
Different cells exposed to the same amount of a signal
respond to different degrees because they have fewer or more receptors or
because their receptors bind weakly or strongly to the signal molecules. The
strength of each target's response can be changed by modifying the number or
binding strength of its receptors. The effectiveness of a signal can be
influenced by conditions in the target cells. Finally, as with hormones, signal
effectiveness can be influenced by rates of formation and elimination.
Therefore, determining secretion rates or measuring concentrations of signaling
substances provides only a small portion of the information needed to evaluate
immune system performance. In this section, only a few of the signaling
substances will be mentioned and only some of their main effects will be
described.
The macrophages perform this surveillance by phagocytizing
microbes, viruses, and unusual molecules (Fig.
15.3).
Fig.
15.3 Processing and presentation of antigens and the formation of
specialized T cells. (1)
Macrophages (M) ingest antigen. (2)
Macrophages digest antigen and present antigen fragments. (3) T cells (T) with antigen-specific
receptors for the antigen join to the presenting macrophage, using HLA
receptors and antigen-specific receptors. IL-1 from macrophages stimulates the
joined T cells. (4) T cells reproduce
and form specialized T cells (hT, cT, dT, sT). (5) Specialized T cells
reproduce.
As a macrophage or Langerhans cell digests and destroys
these items, it transports fragments of each one through its cell membrane.
Then the cell presents the fragments, together with its own HLA protein, to
neighboring T cells. If a fragment and the HLA protein bind to a T cell, the
fragment and the item from which it came (microbe, virus, or molecule) are considered
antigens. Both the macrophage and the T cell are activated to initiate an
immune response against these antigens.
T-Cell Specialization The activated macrophage secretes interleukin-1
(IL-1), which stimulates the T cell to produce more identical T
cells. The new T cells specialize into any combination of four different types,
depending on the source of the antigen fragment and the type of HLA used: helper
T cells (hT cells), cytotoxic T cells (cT
cells), delayed-hypersensitivity T cells (dT cells),
and suppressor T cells (sT cells). Some of these
cells have other names: hT cells are CD4+ cells; cT cells are CD8+ cells.
Langerhans cells act like macrophages except that they do
not produce IL-1. However, neighboring keratinocytes produce IL-1, and so
similar immune activities occur in the skin. Besides stimulating T cells, IL-1
evokes inflammation and fever, two nonspecific defense mechanisms.
In the rest of this section, note that IL-1 and several
specialized T-cell secretions (IL-2, lymphokines) cause positive feedback
effects that amplify the immune response until sT cells come into play.
Helper T-Cell (hT-Cell) Activities There are two main
types of hT cells. TH-1 hT cells produce signaling substances that stimulate cT
cells and that promote inflammation. These substances from TH-1 hT cells
include IL-2, interferon-γ (IFN-γ), and tumor necrosis factor (TNF).
Macrophages also produce TNF and stimulate inflammation. TH-2 hT cells produce
signaling substances that stimulate B cells. Examples include IL-4, IL-5, IL-6,
and IL-10. Many cell types including monocytes, macrophages, endothelial cells,
mast cells, keratinocytes, and osteoblasts produce IL-6. IL-6 promotes
inflammation, bone matrix removal, and other body activities. The signaling
substances from hT-cells and from other cells regulate the hT-cells and other
immune response cells so immune system activities remain balanced.
The hT cells that are produced bind to the original
presenting macrophage or to any other macrophage that presents the same
antigen. Then the hT cells then secrete interleukin-2 (IL-2).
IL-2 initially enhances the developing immune response in several ways (Fig.
15.4).
Fig.
15.4 Activation and activities of hT cells. (1) Macrophages
(M) ingest antigen. (2) Macrophages
digest and present the antigen. (3)
hT cells with specific receptors for the antigen join the presenting
macrophage, using HLA receptors and antigen-specific receptors. (4) hT cells produce IL-2, which stimulates
macrophages, hT cells, cT cells, and B cells that are joined to the antigen. (5) hT cells produce lymphokines.
First, it stimulates macrophages to phagocytize more
antigen, leading to the digestion and presentation of more antigen and the
activation of more T cells specific for that antigen. Second, it stimulates the
production of more hT cells and cT cells. Third, it stimulates the
proliferation and activity of any B cells that have bound to the original
undigested antigen.
While the hT cells are producing IL-2, they also secrete
other helpful defense substances called lymphokines. These
substances increase macrophage phagocytosis in several ways and protect normal
body cells from viruses.
Cytotoxic T-Cell (cT-Cell) Activities Unlike hT cells,
which bind to antigen and HLA protein on macrophages and Langerhans cells, cT
cells bind to antigen and HLA protein on other body cells (Fig.
15.5).
Fig.
15.5 Activation and activities of cT cells. (1a) Antigen
invades body cells (bc). (2a) cT
cells (cT) with specific receptors for the antigen join to the infected body
cell, using HLA receptors and antigen-specific receptors. (3a) cT cells produce lymphokines (jagged
arrow) against infected cells. (4a) Infected
cells and enclosed antigen are destroyed. (5a)
cT cells produce more identical cT cells to attack other body cells that are
infected with the antigen. (1b) Body
cells become cancer cells (cc) and produce antigens. (2b) cT cells with specific receptors for the antigen join
to the cancer cells, using HLA receptors and antigen-specific receptors. (3b) cT cells produce lymphokines against the
cancer cells. (4b) Cancer cells are
destroyed. (5b) cT cells produce more
identical cT cells to attack other identical cancer cells.
Such combinations occur on cells infected with viruses,
fungi, or bacteria; certain types of cancer cells; and cells transplanted into
the body from a person with different HLA protein or from an animal. When a cT
cell binds to an antigen-bearing cell, it is activated and proliferates,
producing a clone of cT cells that bind to other cells with the same antigen.
With the assistance of IL-1 and IL-2, each cT cell destroys the cell to which
it binds, using secretions that damage the cell membrane. This type of immune
response is called a cell-mediated response because the cT cells
make direct contact with each antigen-bearing cell they attack. It contrasts
with the humoral response by B cells, which secrete antibodies
that attack antigens at a distance (see below).
Every cT cell can move from cell to cell, selectively
destroying each antigen-bearing cell that binds to both of its types of
receptors. The cT cells also release lymphokines, which activate macrophages
and other types of T cells while protecting normal cells from viruses. Certain
cT-cell lymphokines also stimulate natural killer cells (NK
cells), nonspecific lymphocytes that destroy cancer cells.
Delayed-hypersensitivity T-cell (dT cell) Activities
Delayed-hypersensitivity T cells are similar to cT cells in the way in
which they identify abnormal cells. However, these cells do not kill cells
directly. Rather, the lymphokines produced by these cells stimulate other
immune system cells (e.g., macrophages) to destroy cells with surface antigens.
These lymphokines also cause inflammation, which increases the defense of the
affected area (Chap. 3). The inflammation is evident during excessive dT-cell
reactions, such as those resulting from poison ivy or positive skin tests for
tuberculosis (e.g., tine tests). Delayed-hypersensitivity cells received their
name because at least 1 day is required for them to cause significant
inflammation. By contrast, allergic reactions caused by B cells are called immediate-hypersensitivity
reactions because they produce significant effects within minutes or
hours. Examples of immediate-hypersensitivity reactions include forms of asthma
and allergic reactions to penicillin, bee stings, and foods.
Suppressor T-Cell (sT-Cell) Activities We have seen that
IL-2 stimulates immune activity by acting on hT cells, cT cells, and dT cells.
However, IL-2 also stimulates the proliferation of sT cells. Since this occurs
slowly, it takes approximately 1 week to develop a large number of sT cells
specific for the antigen being attacked. When enough sT cells have developed,
their secretions overpower and quell the immune activities of the attacking
immune system cells and the immune response to that antigen subsides. By this
time the antigen usually is being reduced or has been eliminated.
Suppression of the immune response helps prevent the adverse
effects that may accompany excessive or prolonged immune activity. Examples
include discomfort and damage from accidental immune injury to normal body
components and from inflammation. Therefore, sT cells help maintain homeostasis
by providing timely negative feedback that reverses the positive feedback effects
of other immune system cells.
Though some sT cells are antigen-specific and therefore
suppress specific immune responses, others suppress immune responses to many
different antigens simultaneously. This provides ongoing regulation of the
entire immune system. One benefit is a reduction in autoimmune reactions,
which are immune responses against normal parts of the body, such as rheumatoid
arthritis and insulin-dependent diabetes mellitus. Another benefit is a
reduction in allergic responses, which are excessive immune
responses against foreign antigens, such as hay fever, asthma, and food and
drug allergies.
Most aspects of the immune response mentioned up to this
point result in nonspecific defense reactions against an antigen (e.g.,
phagocytosis, inflammation, fever). Only the portion of the antigen bound to
cells bearing HLA protein is specifically attacked. To understand how unbound
antigen, such as antigen suspended in body fluids, is attacked, we must examine
the operations of B cells and the antibodies they produce.
B-Cell Activation Since antigen-specific receptors on B cells
are more complete than antigen-specific receptors on T cells, B cells can bind
to an antigen even when HLA protein is not present (Fig.
15.6).
Fig.
15.6 Activation and activities of B cells. (1) Antigen binds to B cells (B) that have specific receptors
for the antigen. (2) B cells with
bound antigen join hT cells (hT) that have specific receptors for the antigen,
using HLA receptors and antigen-specific receptors. (3)
hT cells release IL-2 which stimulates B cells to reproduce. (4) Stimulated B cells produce mB cells (mB)
and plasma cells (p). (5) Plasma
cells produce antibodies that have specific bonding sites for the antigen. (6) Antibodies bind to the antigen.
No macrophages or other cells are needed to process or
present the antigen to B cells, and B cells specific for the antigen bind to it
wherever they meet it. This stimulates the attached B cells to proliferate and
produce two special types of B cells-memory B-cells (mB
cells) and plasma cells-both of which continue to
reproduce. All the mB cells and plasma cells have the same antigen specificity
as the B cells from which they were derived. Memory B cells are described below
in connection with memory. The plasma cells manufacture and secrete antibodies
(immunoglobulins), which combat the antigen in several ways (see
below). However, the original antigen-bound B cells and their progeny usually
function inadequately unless they are stimulated by IL-2. The hT cells provide
a concentrated application of IL-2 to the antigen-bound B cells, plasma cells,
and mB cells by binding to them. This cell-to-cell binding is similar to other
types employed by various T cells. That is, the two types of hT-cell receptors
bind simultaneously to their corresponding HLA proteins and antigens on the
surfaces of the B cells and their progeny.
Several days after the antigen is detected by the T cells
and B cells, many fully activated plasma cells are produced and secrete
antibodies profusely. Each plasma cell may continue antibody production for up
to 1 week, after which it dies. Exhausted plasma cells may be replaced by new
ones.
Antibodies All antibodies from a plasma cell have the
same antigen specificity as did the B cell that first bound to the antigen.
Therefore, these antibodies also bind to the antigen wherever the two meet.
However, different classes of antibodies are produced and concentrated in
different places in the body.
The different antibody classes are designated by different
letters. IgA antibodies are concentrated in the secretions from mucous
membranes lining body systems (e.g., respiratory system, digestive system).
When they bind to antigens, they help block the entry of the antigens into the
body. Most antibodies in the IgM and IgG classes are found in blood and lymph.
IgM and IgG prevent injury from antigens in several ways. For example, they
cause some antigens to become more easily phagocytized by clumping them
together and coating them with phagocyte-stimulating substances. IgM and IgG
chemically neutralize other antigens. They also lead to the destruction of
other antigens by activating a group of substances in the blood called the complement
system. Complement substances can kill antigenic cells such as bacteria
directly and intensify defense activities by promoting phagocytosis and
inflammation. IgE antibodies bind to mast cells. When antigen later binds to
this IgE, the mast cells release histamine and cause inflammation. Antibodies
assist only in fighting antigens; they do not destroy antigens.
We have seen that an antigen causes the production of a
large number of specialized T cells, plasma cells, and antibodies that have
specificity. It takes several days to produce enough of these cells and
antibodies to combat a large dose of antigen the first time it is encountered.
This is called a primary immune response. (Fig.
15.7)
Secondary Immune Response Many specialized T cells and plasma cells
produced during the primary immune response are eliminated once the antigen has
been reduced. The remaining specialized T cells constitute a cadre of memory
T cells (mT cells). The mB cells and much of the antibody
produced during the primary immune response also remain, though the amount of
antibody declines over a period of weeks. Since memory cells are abundant and
specialized, they swiftly produce many specialized T cells and plasma cells if
the antigen is detected again. Furthermore, the antibody level rises
precipitously, reaching a valve far above the peak level attained during the
primary immune response. Therefore, the old antibody, along with the new
specialized T cells and the antibody from new plasma cells, produces a more rapid
and intense attack on the antigen if it appears in the body again. An immune
response to an antigen encountered a second or subsequent time is called a secondary
immune response. This response may effectively eliminate an antigen
within 1 day of its detection by the immune system (Fig.
15.8).
With each subsequent secondary immune response to an
antigen, additional memory cells and antibody for that antigen may accumulate
and the antibody level may decline more slowly. When this happens, each
subsequent secondary immune response is faster and more effective than the
previous one. This further decreases the risk of sustaining injury from the
antigen each time it is present. It can also cause allergic responses to become
worse with repeated exposure to certain antigens (e.g., penicillin, bee
stings).
Acquired Active Immunity sometimes the formation of memory is so
effective that only one exposure to an antigen prompts complete and permanent
resistance. For example, most people have measles or chickenpox only once. Once
the secondary immune response is strong enough to prevent significant adverse
effects from the next encounter with an antigen, the person has an acquired
active immunity against that antigen. Such immunity may result when the
first dose of antigen is sufficient to cause serious illness, as occurs with
full-blown measles. However, this immunity is sometimes acquired after a person
receives an antigen in one or more doses that are not strong enough to cause
significant illness. Acquired active immunity against antigens such as polio,
tetanus, diphtheria, and influenza can be intentionally induced in this way,
using vaccines that contain the antigen.
Though acquired active immunity against antigens such as
polio usually lasts indefinitely, the memory cells and antibodies for other
antigens may diminish substantially if the cells do not encounter the antigen
again for months or years (e.g., tetanus). Then the antigen may cause
approximately the same degree of injury that it did when it was first
encountered because several days may be required to produce enough of an immune
response to eliminate it. This sometimes can be prevented by receiving a
vaccine again (a booster dose) at appropriate intervals.
Distinguishing age changes from other changes in the immune
system is difficult for various reasons. Reasons include limited understanding
of this complex system; confounding influences from changes in nonspecific
defense mechanisms; diverse and rapidly changing methods of research;
controversy over the interpretation of results; and diversity in the factors
affecting it. Examples of such factors include chronic exposure to sunlight;
cirrhosis; malnutrition; diabetes mellitus; cancer; chemotherapy; radiation
therapy; anesthesia; surgery; and stress. Common age-related increases in most
of these factors reduce immune system effectiveness. Finally, comparing immune
systems between individuals reveals an age-related increase in heterogeneity.
Therefore, unless otherwise noted, the immune system changes described below
represent average age-related changes that may be due in part to aging of the
system.
Trends
As the age of a population increases, the proportion of
people with a declining immune function increases and the level of immune
function within the individual decreases. Decreases in immune function include
reductions in the speed, strength, and duration of immune responses and in the
regulation of the immune system. These age changes are a major reason for the
higher susceptibility of elders to Coronavirus COVID-19, which spread as a
national and worldwide pandemic starting in early 2020.
Most developmental changes in the immune system occur before
the end of puberty and result in the formation of a mature immune system. The
few developmental changes after this period may be considered age changes, most
of which result in declining immune system functioning.
Macrophages and Langerhans Cells Age changes and
age-related changes in macrophage production and numbers have not been well
studied, suggesting that these changes are small. However, the rate of
production of Langerhans cells falls below the rate of destruction, leading to
significant decreases in cell numbers. Areas of skin chronically exposed to
sunlight have much greater reductions than do unexposed areas. These reductions
lead to decreases in the processing and presentation of antigens in the
epidermis, causing increasing risks of skin infection and cancer and decreasing
delayed-hypersensitivity reactions, including allergic reactions. The latter
change causes a reduction in signs and symptoms (e.g., local swelling, itching,
rash) that warn of the presence of potentially harmful substances (e.g.,
topical medications) and are used in skin tests to detect previous exposure to
tuberculosis (e.g., tine test).
Thymus and T Cells The thymus begins to shrink during or
shortly after puberty and continues to do so until about age 50, when it may be
only 5 percent of the original size. Thymic hormone production declines in a
parallel fashion, and circulating levels of these hormones reach zero by age
60. These changes cause a precipitous decline soon after puberty in the
conversion of unspecialized lymphocytes to T cells and the clonal selection of
T cells. Lymphocyte conversion and clonal selection for T cells finally cease,
ending the development of immune response capabilities against additional
antigens.
Though changes in T cells in human lymph tissues have not
been well studied, healthy people seem to retain a steady rate of production of
antigen-specific T cells in lymphoid tissue since the total number of T cells
in the blood remains stable. However, declining thymic hormone causes reduced
maturation of T cells, resulting in a decrease in the ratio of mature to
immature T cells in the blood. This change decreases the number of circulating
T cells that can respond to and combat each antigen. The degree of change
varies considerably between individuals because of differences in aging,
abnormal conditions, diseases, and other factors. Up to 25 percent of older
people may show no decrease in T-cell functioning, while approximately 50
percent have moderate declines. The remaining 25 percent experience major
decreases in T cell responses to an antigen.
B Cells As with T cells, B-cell production from
B-cell clones that were established early in life seems to remain steady in
many people since the total number of these cells in the blood usually remains
stable. However, the number of circulating B cells decreases in some
individuals. Ordinary changes in B-cell numbers are not important since
limitations in B-cell functioning derive from decreases in T-cell stimulation
of B cells rather than from changes in B cells themselves.
Decreases in immune system function result not only from
developmental changes in the immune system but also from age-related changes in
immune responses.
Processing and Presentation Aging seems to have
little or no effect on the functioning of macrophages and Langerhans cells
during the initial processing and presentation stage of an immune response.
However, the effectiveness of macrophages and Langerhans cells during an immune
response decreases with aging because they receive less IL-2 stimulation from
hT cells that bind to them. The effectiveness of Langerhans cells also declines
because their total number decreases with age.
T-Cell Participation Age-related changes
in the ability of macrophages and Langerhans cells to convert T cells into
specialized T cells (hT cells, etc.) are unclear. However, when T cells from
older people are experimentally stimulated to reproduce, fewer T cells can
reproduce and those which reproduce do so fewer times. These decreases seem to
be caused by a combination of declining production of IL-2 and declining T-cell
responsiveness to IL-2. Since the progeny from T cells control all subsequent
aspects of the immune response, age-related reductions in T-cell proliferation lead
to reductions in all the subsequent parts of an immune response. Part of the
decline in cell reproduction may result from loss of telomeres.
Regardless of reductions in the proliferation of T cells or
specialized T cells, there is an age-related decline in both the production and
effectiveness of IL-2 from hT cells. This decline stems from a decrease in IL-2
receptors on T cells and specialized T cells. By reducing the positive feedback
effects of IL-2, these changes diminish the intensity of both the cell-mediated
and humoral parts of an immune response, reducing all its defensive
capabilities. Delayed-hypersensitivity responses also decline, reducing their
roles in defense and as warning mechanisms.
Since aging decreases the ratio between TH-1 hT cells and
TH-2 hT cells, immune responses become unbalanced. This loss of balance causes
reductions in certain aspects of the response while producing excesses in other
aspects including IL-6 production and autoimmune responses. The extra IL-6
contributes to loss of bone matrix and unwanted inflammation. The excess
inflammation contributes to increased damage from free radicals and age-related
diseases (e.g., atherosclerosis, arthritis, Alzheimer's disease, kidney
disease). These and other adverse effects from weaker, unbalanced, and poorly
regulated immune responses form the basis for the immune theory of aging (see
Chapter 2).
The average activity level of NK cells, which receive
stimulation from cT cells, does not change. However, total NK-cell activity
becomes more heterogeneous between individuals. Additional NK-cell
heterogeneity develops because of individualized increases and decreases in NK
cells for different types of cancer. People with a reduction in NK-cell
activity may have an increased risk of developing cancer.
Finally, age-related decreases in IL-2 may contribute to a
decline in sT-cell numbers or effectiveness, which may be a main factor in the
age-related reduction in the regulation of the immune system. This reduction is
evident as an increase in the production of autoantibodies, which
are antibodies against self-antigens. No significant consequences from
autoantibodies resulting from aging have been discovered. However, while they
are suspected of contributing to age-related detrimental changes such as
seminiferous tubule degeneration, they may be beneficial by helping rid the
body of abnormally altered proteins. Autoantibodies resulting from processes
other than aging may contribute to abnormal or disease conditions such as
rheumatoid arthritis.
B-cell Participation and Antibodies Aging seems to have
little or no direct effect on the ability of B cells to bind to antigen, be
activated, or perform their other functions during a primary immune response.
As mentioned previously, however, all aspects of B-cell participation decline
with aging because B cells receive less IL-2 stimulation from hT cells.
Consequently, more antigen is needed to prompt antibody production, antibody
production is slower, antibody production ends sooner, a lower peak antibody
concentration is achieved, and the antibody level declines faster. Furthermore,
the effectiveness of antibodies against certain antigens declines because some
antibodies bind less well to their antigens and because of the increased variability
in the proportions of the different classes of antibodies. Of note is a decline
in IgE. Finally, there is an increase in autoantibody production.
The first six changes contribute to the age-related decline
in the effectiveness of primary immune responses. The decline in IgE
contributes to the age-related decline in allergic reactions. All changes in B
cells and antibodies develop slowly until approximately age 60, after which
they occur more rapidly.
Memory As primary immune responses diminish with
aging, they leave the body with fewer memory cells and less residual antibody
for memory. Furthermore, residual antibody dissipates faster. As immune memory
declines with aging, the speed and strength of the initial secondary immune
response against an antigen also decline. Therefore, the higher the age at
which an antigen is first encountered, the greater injury caused by a second
encounter with that antigen. The antigen also may cause injury many times
because additional secondary responses may be needed before acquired active
immunity develops. Because of these changes, aging is accompanied by a decline
in the effectiveness of initial vaccinations.
Though memory produced from primary immune responses
declines substantially with aging, there is much less of a decline in the
ability to maintain memory produced during youth or young adulthood. Therefore,
secondary immune responses resulting from such early memory remain effective,
especially if the antigen is encountered occasionally, as occurs with booster
doses of vaccines.
Furthermore, since the decline in establishing memory
becomes particularly evident after age 60 and advances more rapidly afterward,
vaccinations should be received well before age 60. However, vaccines can be
beneficial at any age, especially for those who are weakened by other factors
and are at high risk for exposure to certain bacterial pneumonias (e.g.,
pneumococcal pneumonia) or strains of influenza virus.
In conclusion, age changes in the immune system contribute
to a decline in the ability to maintain homeostasis because they decrease
resistance to harmful foreign materials and lead to an increase in the
incidence and severity of infections and cancer. The risks increase with the
age at which antigens or carcinogenic factors are first encountered. The risks
also increase, though less so, with the number of years between encounters with
an antigen. The effects on the immune system of many other age-related factors
magnify these consequences, as do many age-related changes in nonspecific
defense mechanisms. By contrast, the undesirable effects of allergic reactions
decrease with aging.
There is an increased incidence of renewed injury from the
bacteria causing tuberculosis (TB) and the virus causing chickenpox. In both
cases the disease-causing agent may reside within body cells indefinitely,
where it is hidden from immune cells after the disease seems to have
disappeared. As immune memory against these diseases fades and age-related
changes and factors such as stress weaken the immune system, the bacteria or
virus is no longer held in check. TB bacteria, which reside in lung cells, may
then cause a reactivated infection and additional lung damage. The chickenpox
virus, which resides close to the spinal cord in sensory neurons, will be
transported down sensory neurons to the areas of the skin they serve. Once
there, the virus can cause excruciating pain and severe skin eruptions known as
herpes zoster or shingles.
Finally, age changes in the immune system increase the
progress and the severity of effects from HIV infection.
Since the consequences of declining immune system
effectiveness often lead to a reduced quality of life and lower life
expectancy, researchers are seeking ways to prevent, reduce, or delay the
deterioration of the immune system caused by aging. Though some success has
been achieved in animals (e.g., diet regulation), no practical and effective
methods for humans are available. Other research is aimed at restoring immune
system effectiveness lost because of age changes. Studies with animals
involving supplements (e.g., thymic hormones, sex hormones) and other drugs
have been somewhat successful, but safe and effective methods for aging humans
have not been developed. A potential hazard from stimulating immune functioning
is the activation of harmful immune activities (e.g., autoimmunity, allergic
reactions) along with beneficial ones.
Though there are no practical methods for controlling aging
of the human immune system, steps can be taken to help minimize other
undesirable changes in this system, including avoiding or reducing factors
known to suppress immune system functioning. Other actions may reduce the risks
of developing the adverse consequences of decreases in immune functioning.
These actions include receiving vaccinations in a timely fashion and minimizing
exposure to potentially harmful agents such as bacteria, viruses, and
carcinogens. Finally, risks can be reduced by preventing or treating abnormal
conditions and diseases that promote infections and cancer.
ABNORMAL AND DISEASE CONDITIONS
Recall that aging is accompanied by a decrease in the
balanced regulation of the immune system and an increase in the production of
new autoantibodies. The autoantibodies produced as part of aging are of little-known
importance. In addition, there is only a small increase in the incidence of
new-onset autoimmune diseases among the elderly. However, the damage that seems
to result from excess inflammation and autoimmune response activities that are
part of abnormal or disease conditions often become more serious with age. This
occurs largely because chronic inflammation and many autoimmune responses
initiated during childhood or young adulthood continue to injure or destroy
body components for many years. Some age-related diseases associated with
chronic inflammation and autoimmune responses are atherosclerosis, valvular
heart disease, chronic obstructive pulmonary diseases, Alzheimer's disease, and
chronic renal diseases.
Some abnormal autoimmune responses follow a steady course
and cause unremitting progressive damage (e.g., atrophic gastritis). Other
autoimmune diseases occur as periodic or occasional flare-ups separated by
periods of remission (e.g., rheumatoid arthritis). In these disorders the
affected individual's condition worsens in a stepwise manner. However, in all
autoimmune disorders there is great variability among individuals regarding the
rate at which deleterious effects develop.
A few abnormal autoimmune conditions important in the
elderly have been described in Chaps. 9 and 10 (e.g., atrophic gastritis,
rheumatoid arthritis). Other abnormal and disease conditions important to older
people that seem to involve autoimmune responses and are serious and relatively
common will be mentioned briefly here.
Bullous pemphigoid
causes blistering of the skin and accompanying itching and discomfort. Rheumatic
heart disease results when rheumatic fever leads to autoimmune damage
to valves in the heart. Common outcomes include the failure of one or more
chambers of the heart and respiratory problems from pulmonary edema. Multiple
sclerosis involves patchy deterioration of myelin in the CNS and can
result in diverse deficits depending on the portions of the CNS affected. This
disorder is characterized by flare-ups and remissions of varying duration. Myasthenia
gravis involves autoimmune damage to receptors for acetylcholine at
neuromuscular junctions and leads to progressive muscle weakness and paralysis,
including the muscles for respiration. Regional enteritis (Crohn's
disease), which often involves flare-ups and remissions, causes
inflammation of the small intestine and large intestine and often results in
decreased absorption of nutrients, pain, and diarrhea. Ulcerative colitis
is similar to regional enteritis; though it affects only the large intestine,
it often causes intestinal bleeding and increases the risk of developing
colorectal cancer. Graves' disease results in abnormally high
blood levels of thyroid hormone which increase the metabolic rate and cause
bulging and deterioration of the eyes.
©
Copyright 2020: Augustine G. DiGiovanna, Ph.D.,
Salisbury University, Maryland
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