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Chapter 10
Immunology, Organ Interaction and Homeostasis
Gabi Nindl Waite, Ph.D.
Active Learning Objectives
Upon mastering the material in this chapter you should be able to:
Explain what triggers an immune response and where in the body the immune response occurs
Understand how the immune system handles exogenous and endogenous antigen differently
Define the differences between innate and adaptive immunity and their complementary activities
Discuss how antigen specificity is achieved in the immune system
Understand the different roles of immune cells and their communication
Describe the structure and functions of different antibodies
Outline the functions of acute inflammation and separate them from chronic inflammation
Explain the immune-related requirements for organ transplantation
Present an overview of immune system disorders
Explain the immune system’s role in allergic and immune system disorders
Portray how the immune system interacts with other systems to maintain homeostasis
Talk about some novel immune topics in clinics and research
The immune system is the body’s primary defense system against all harmful agents. Harmful agents
might be living matter such as bacteria, parasites, fungi and viruses, or non-living matter such as toxins,
chemicals, drugs or foreign particles. The immune system is composed of a complex system of organs,
tissues, specialized cells and a circulatory system. It tries to prevent the agents from entering the body,
and if they do enter, attacks them. When the immune system functions optimally, the substances are
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eliminated before the host shows disease symptoms. The immune system is also involved in detecting
aberrant cellular structures such as tumor cells. A body without an immune system would not be able to
survive more than a few days.
Understanding the immune system is of crucial importance to understanding how the body functions,
and hence is an important part of physiology. However, one chapter about the immune system cannot do
justice to such a fascinating aspect of our body. The aim of the current chapter is to place the functioning
of the immune system within the framework of the whole human organism and its homeostasis, and to
provide the foundation on which one can expand in the specialty courses immunology, microbiology and
pathophysiology.
<h1>ACTIVATION AND LOCATION OF THE IMMUNE SYSTEM
The ultimate function of the immune system is to recognize and to destroy foreign substances in the
body. Any substance that provokes the immune system is called an immunogen. Organisms that might
cause diseases are called pathogens. They may enter the body through a cut in the skin, as in the case of
the hepatitis B virus, through membranes of the respiratory tract, as in the case of the measles virus, or
through membranes of the digestive tract, as in the case of salmonella bacteria. Pathogens may further
be transmitted by insect bites, as in the case of malaria, or by sexual encounter, as in the case of the HIV
virus. Antigens are substances that bind to receptors on T and B cells or antibodies. Haptens are similar
to antigens, but are only immunogenic when linked to a carrier molecule. In addition to pathogens, a
large number of other foreign substances can be antigenic. Pesticides, cosmetics and exhaust particles
are examples of such substances, whose number increases with the advancement of technology in our
society.
Exogenous antigens such as bacteria and foreign particles are most accessible to immune elimination.
They first activate the innate immunity (see Innate Immune System below). As part of it, immune cells
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might engulf the antigen or destroy it with enzymes and oxygen radicals. Complement proteins might
lyse the organism and promote inflammation (see Inflammation below). If the pathogen evades the
innate immune system, the adaptive immunity response is triggered, where cells and antibodies work
together to eliminate the antigen (see Adaptive Immune System below).
Endogenous (intracellular) antigens such as viruses, protozoan parasites, and intracellular bacteria are
eliminated together with the infected host cell. Antibodies can bind directly to the infected cell and
activate complement, if some immunogenic parts of the microorganism are present on the plasma
membrane of the host cell (see humoral immunity below). If the antigen cannot immediately be
recognized on the surface of the cell, it is degraded intracellularly into smaller pieces. These are then
incorporated into the host cells’ plasma membranes and together with major histocompatibility complex
(MHC) proteins presented to T cells (see T cell mediated immunity below).
<h2>A Molecule Must Be Recognized as Foreign to Elicit a Physiological Immune Response
Any antigen that is not recognized as being a normal part of the body is marked as being potentially
dangerous to the body. This discrimination of self from non-self is one of the core tasks of the immune
system. Body cells carry molecules that label them as “self” so that the immune system ignores them, a
process called self-tolerance. Foreign molecules also carry distinctive markers, and the immune system
recognizes many millions of them. There are some exemptions. We generally tolerate food-derived
foreign particles; although some foods induce allergic reactions (see Immune Diseases below). A mother
does not reject the fetal molecules that are derived from the father. Identical twins can accept skin grafts
from each other without causing immune reactions (see Organ Transplantation below). On the other
hand, when a body erroneously mounts an immune response against its own tissues, it leads to
autoimmune diseases (see Immune Diseases below).
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Each part of the antigen bound by a unique antibody is called an epitope. Most protein antigens have
several epitopes that are recognized by different B cells and induce a polyclonal antibody response.
Antibodies of a single specificity (monoclonal) are used for immune diagnostic tests and
immunotherapy. Epitopes may be shared by closely related antigens (cross-reactivity). For instance, the
vaccine against tetanus disease contains tetanus toxoid, which makes the body produce antibodies that
also recognize tetanus toxin, the poisonous substances produced by Clostridium tetani bacteria.
Proteins are by far the best immunogens. Polysaccharides, lipids and nucleic acids by themselves
induce either weak or no immune responses, but their antigenicity is greatly improved when attached to
proteins. This principle is used for many vaccines. For instance, the vaccine targeting the carbohydrate
capsule of Streptococcus pneumoniae is conjugated to protein carriers to enhance its effectiveness. The
immunogenicity of substances increases with their complexity. For instance, polymers made of only one
type of nucleotide are poor immunogens regardless of their size, while polymers made of more than one
base are usually good immunogens. Nevertheless, size matters, and typically, only molecules with a
molecular weight of 4000 Dalton or above elicit an immune response. Other factors that increase the
likelihood of being recognized by the immune defenses are protein aggregation, protein charges and
complex three-dimensional conformation.
<h2>Body Defenses After Injury Can Occur With or Without Immune Activation
Immune responses are tied in with other body defenses and reactions. When the body sustains injury,
whether from physical force, cellular breakdown, or biological infection, the decision for immune
activation depends on the severity and type of the injury. If the cells are not too severely injured, cells
may adapt to the event by changing their size, number and functions. For instance, skeletal muscle cells
in a patient on bed rest respond with downsizing to the cellular stress of lack of physiological stimuli, an
event that is usually not associated with immune responses. On the other hand, the replacement of
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glandular epithelium in the lungs of a smoker by a better protecting squamous epithelium goes along
with inflammation of the airway cells, triggered by strongly irritating smoke particles.
If the damage to a cell is too great to cope with, the cell will die by necrosis. The immune system is
activated when the cells collapse and their cellular contents leak into the surrounding tissue. As a result,
various types of immune cells are attracted by chemokines to the injury site and initiate the inflammatory
response, which further activates the immune response. On the other hand, cell death by apoptosis will
not cause immune activation. The cells die without bursting apart, and as a result, no damaging
substances are released from the cells and an inflammatory response is avoided. Apoptosis is the body’s
non-pathological process of removing cells. This is especially important for the role of the immune
system in keeping homeostasis and regulating tolerance. Every day, several millions of B and T cells are
generated and the majority of those dies apoptotically by processes called negative selection, or
activation-induced-cell-death.
<h2>The Immune System Encompasses Distinct Immunological Organs As Well As Cells and
Non-cellular Elements That Are Part of Every Tissue
Thymus and bone marrow are primary (or central) lymphatic organs (Fig. 10.1). These are the
organs where the cells mature to become immunocompetent. All immune cells derive from a common
precursor stem cell in the bone marrow (see Chapter 9). While most immune cells including B
lymphocytes begin a life of patrol once they are released from the bone marrow, T lymphocytes first
undergo further maturation in the thymus. Lymph nodes, tonsils, lymph follicles of mucous membranes
and the spleen belong to the list of secondary (or peripheral) lymphatic organs. These are the organs
where mature immune cells participate in specific immune defense reactions. Figure 10.1 also shows the
different types of immune cells. Their morphology was introduced in chapter 9. Their immune function
is presented as part of the sections on innate and adaptive immunity (see below).
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Lymph nodes are the sites through which blood, lymph and immune cells are filtered. These
encapsulated organs are located throughout the body at junctions of lymphatic vessels and are optimized
for interaction between antigen-presenting cells and T and B lymphocytes. During a bacterial infection,
lymph nodes swell due to proliferation of immune cells. Palpation of lymph nodes to give an indication
of the activity level of the immune system is part of most orderly clinical examinations. The movement
of lymph through lymph vessels and lymph nodes is supported by skeletal muscle movement, but is
otherwise passive. There is no organ similar to the heart to pressurize the lymph flow.
There is an abundance of non-cellular immune elements in blood and lymph. They include, but are not
limited to, antibodies (see Table 10.4), communication molecules (see Table 10.5), and complement.
Additionally, the innate immune system encompasses a variety of fluids and other non-cellular
components with antimicrobial character (see Innate Immunity below).
<h1>THE INNATE IMMUNE SYSTEM:
The ability of cells and tissues to respond to and to get rid of environmental challenges is an ancient
evolutionary development that has persisted through vertebrate development as innate immunity (Table
10.1). It is also called nonspecific or natural immunity. In humans it is present at birth. It is always in
place throughout life, can be rapidly mobilized, and it acts quickly. All antigens are attacked pretty
much equally and there is no long-term change in the quantity or quality of the response.
<h2>Elements of the Innate Immune System Include Anatomic and Physiologic Barriers and
Antibacterial Agents
Our skin is a good anatomical and physiological barrier against microorganisms. The cells of the
epidermal layers are dry and densely packed making it an inhospitable environment to many bacteria.
Salty secretions from sweat glands and oily secretions from the sebaceous glands associated with hair
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follicles create a hyperosmotic and slightly acidic skin environment, which dehydrates bacteria and
discourages those that prefer a neutral pH for colonization. Additionally, the continuous desquamation
of skin cells eliminates bacteria adhering to epithelial cells. Lastly, a large number of non-invasive, nonpathogenic commensal (part of normal flora) microorganisms on the skin prevent growth of harmful
microorganisms in a process called competitive exclusion.
Acidity is also used in other places of the body as an antimicrobial tool. For example, natural
microflora alters the fluids of the vaginal and urinary tract to an acidic pH below 4.5, so that yeast and
other microorganisms cannot grow. Parietal cells of the stomach create highly acidic gastric juice below
pH 3. Other factors such as low oxygen tension and fever are said to contribute to the innate barrier
defenses, but their physiologic impact is still under discussion. For instance, the role of fever is thought
to have a direct negative effect on certain microorganisms. It may also be helpful to enhance the
efficiency of phagocytosis.
Various types of cellular secretions destroy and eliminate germs. Mucus prevents microorganisms
from adhering to epithelial cells and contains antibacterial components. The mucus of the gut blocks,
inactivates, or destroys pathogens associated with food before they can enter the body. A thin layer of
mucus covering the airway from the nose to the bronchioles traps inhaled viruses, bacteria, pollens and
other particles and facilitates their removal before they can damage the airway lining cells. The flow of
saliva helps to wash away bacteria attached to food particles, while attacking them with thiocyanates
and lysozymes. Saliva can also contain antibodies that destroy oral bacteria in certain people. Tears and
nasal secretions contain similar antibacterial components.
The list of chemical factors with antimicrobial character is long and includes pepsin in the stomach,
defensins produced by immunological cells, and surfactant proteins of the lung, to name a few.
Interferons are a group of proteins that are produced by cells following viral infection. Complement is a
group of serum proteins that circulate in an inactive state and can be activated by a variety of specific
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and non-specific immunologic mechanisms. It is sometimes called the humoral component of the innate
immune system. Its action is discussed again below. These chemical factors often connect the innate
immune system with the adaptive immune system, the system that comes into play when the innate
system is overwhelmed by the invaders or unable to detect them.
<h2>Cellular Elements of the Innate Immune System Involve Phagocytes, Killer Cells,
Eosinophils, and Mast Cells
Figure 10.1 illustrates the cells of the immune system. Table 10.2 identifies neutrophils, macrophages
and dendritic cells as the main cells capable of phagocytosis, an ongoing process of the innate immunity.
Phagocytes are activated by T cell cytokines, and can directly sense the pathogens through a group of
transmembrane receptors, Toll-like receptors. Upon activation, phagocytes engulf the microorganism,
particle, or cell debris. The engulfed matter is enclosed within vacuoles and enzymatically digested,
after fusion with lysosomes. Some pathogens have been coated with opsonins in a process called
opsonization to render them more attractive to phagocytosis. Examples of opsonins are IgG antibody
and the C3b molecule of the complement system.
Neutrophils (or polymorphonuclear leukocytes) recognize chemicals produced by bacteria in a cut
or scratch and migrate towards them. Once arrived, they ingest bacteria and kill them. For killing,
neutrophils use proteolytic enzymes and reactive oxygen species as part of the respiratory burst (see
Chapter 9).
Macrophages are derived from circulating monocytes. Macrophages, like neutrophils, kill by using
the respiratory burst and proteolytic enzymes. Macrophages secrete various cytokines that attract
leukocytes to the infection site and initiate the acute phase inflammatory response. Finally, macrophages
act as antigen-presenting cells to T cells and are hence an important bridge to the adaptive immune
response.
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Macrophages can circulate in lymph vessels (wandering, non-fixed macrophages), or they can reside
in connective tissue, lymph nodules, along the digestive tract, in the lungs, in the spleen and other places
(mature, fixed macrophages). Fixed macrophages are part of the reticuloendothelial system (RES),
which, in addition to removing pathogens, also remove old cells and cellular debris from the
bloodstream. Some of these macrophages have their own names. For instance, the macrophages along
certain blood vessels in the liver are called Kupffer cells, while the macrophages of the joints are called
synovial A-cells. Microglial cells are macrophages located in the brain.
Dendritic cells are, similar to macrophages, a critical link between the innate and adaptive immune
systems. They exist in an immature form throughout the epithelium of the skin (Langerhans’ cells), the
respiratory tract and the gastrointestinal tract. After phagocytosis of pathogens, the cells mature and
travel to regional lymph nodes, where they activate T cells, which then activate B cells to produce
antibodies against the pathogen.
Natural killer (NK) cells attack aberrant body cells such as virus-infected cells and malignant cells.
They release the cytolytic protein perforin, which forms a pore in the plasma membrane of the target
cell. Proteolytic enzymes such as granzyme enter through the pore and induce apoptosis. Upon
exposure to lymphocyte secretions such as interleukin-2 and interferon-gamma, NK cells become
lymphokine-activated killer (LAK) cells, which are even more efficient in killing than NK cells.
Eosinophils are best known as participants in allergic reactions where they might detoxify some of the
inflammation-inducing substances. But they are also able to secrete factors that punch small holes in
worms and certain other parasites causing them to die.
Mast cells are present in most tissues in the vicinity of blood vessels. They are especially prominent
under coverings, lining the body surfaces such as skin, mouth, nose, lung mucosa and digestive tract.
Although best known for their roles in allergy and anaphylaxis of the adaptive immune system, mast
cells play an important role in the innate system as well. They release factors that increase blood flow
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and vascular permeability bringing components of immunity to the site of infection. In combination with
IgE antibody from B cells, mast cells can also target parasites which are too large to be phagocytosed,
such as intestinal worms.
<h1>THE ADAPTIVE IMMUNE SYSTEM:
Microbes that escape the onslaught of cells and molecules of the innate immune system face attack by
T cells and B cell products of the adaptive immune system (Table 10.1), also called the acquired
immune system. Adaptive immunity is a relatively recent evolutionary development and characteristic
of jawed vertebrates. The adaptive immune system is induced by hundreds of thousands of diverse
antigens, which are presented as glycoproteins on the surface of bacteria, as coat proteins of viruses, as
microbial toxins, or as membranes of infected cells. It responds with the generation of antibodies and
cells that specifically assault the invading pathogen. The adaptive immune response is slow, being fullly
activated about four days after the immunological threat. Adaptive immune responses exhibit
immunological memory, so that repeated exposure to the same infectious agent results in improved
resistance against it (anamnestic response).
Although innate and adaptive immune system are characterized by contrasting functions and timing
(Table 10.1), they work together in ways that obscure their differences. For instance, the initiation and
the adequate functioning of the innate system often depends on the presence of elements of the adaptive
immune system such as small amounts of specific antibody in blood plasma. The reverse is true as well.
Antibodies and other mediators of the adaptive immune system depend on elements that are typically
associated with the innate immune system such as neutrophils. Only when working together can the
innate and adaptive immune system provide a considerable obstacle to the establishment and long-term
survival of infectious agents.
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<h2>The Three Most Important Features of Adaptive Immune Responses Are Specificity,
Diversity and Memory
The specificity of the adaptive immune system is created by antigen-recognition molecules which are
synthesized prior to the exposure to antigen and are then modified during the immune response to make
them more specific to the antigen. Three types of molecules participate in this anticipatory defense
system: Specific receptors on T and B lymphocytes, molecules encoded in the major histocompatibility
complex (MHC), and antibodies. All three types of molecules show an extreme diversity so that each
molecule can specifically detect a particular antigen.
The T cell receptor (TCR) resembles the Fab fragment of an immunoglobulin (Fig. 10. 4). There are
two forms of TCRs known. Over 90 percent of peripheral T cells express one of them, the alpha/beta
form. TCRs are antigen-specific. In an individual, there are about 1018 different TCRs, but each T cell
has only one type of it. The B cell receptor (BCR) is a membrane-bound form of immunoglobulin.
There are about 1014 BCRs, again one type of immunoglobulin per B cell. There is a similarly high
number of antigen-specific MHC molecules per individual. The molecule diversity is achieved by
multiple genes encoding for the molecules (polygeny) as well as variable recombination and mutation of
the molecules during cell differentiation (polymorphy). The MHC genes are known as the most
polymorphic genes of the human genome.
The binding of an antigen to the lymphocyte with the best fitting receptor occurs mainly in the local
lymph node and induces the proliferation of the responsive cell, a process known as clonal selection
(Fig. 10.2). However, in the case of T cells, T cell proliferation is only induced if a co-stimulatory
signal, secondary to TCR binding, occurs. Clonal selection amplifies the number of T or B lymphocytes
that are programmed to specifically respond to the inciting stimulus. While all of the cells that were
generated after a single clone has expanded, are specific for the inducing antigen (and hence have the
same TCR or BCR), they may not all possess the same functional characteristics. For instance, clonal
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proliferation of T cells leads to the generation of more antigen-specific T cells and to the production of
effector T cells, such as T helper (TH) cells and cytotoxic T cells (CTL).
Antigen-binding to the BCR of B cells induces their development into plasma cells, which are capable
of generating antibodies, first IgM antibodies and later IgG, IgA and/or IgE antibodies. The antibody can
be found in a variety of body fluids, including saliva, other secretions, and plasma. Other progeny in the
expanded B cell clone may function as memory cells, which account for one of the primary tenets of
immunity. These cells mimic the reactive specificity of the original lymphocytes that responded to the
antigen and accelerate the responsiveness of the immune system when the antigen is encountered again.
It leads to increased resistance after initial exposure to the infectious agent and is the basis for
vaccination (see Clinical Box 3).
<h2>T Cell Mediated Immunity is One of the Two Fundamental Mechanisms of Adaptive
Immunity
Cell-mediated immunity (or cellular immunity) is accomplished by activated T cells (Fig. 10.3). T
cells continuously patrol the body and check the virulence of antigen in a process called immune
surveillance. T cells are activated by binding of antigen to the specific TCR plus a co-stimulatory event.
Antigen can only bind to the TCR when presented by antigen presenting cells (APC) in combination
with MHC. The complex interaction between the T cell and the APC is called immunological synapse.
Almost every cell in the body can present antigen to the TCR of CD8+ cytotoxic T cells. In this case,
the antigen is a cytosolic pathogen, which was degraded in the cytosol and associated with MHC class I
molecules (Table 10.3). In the case that the antigen stems from intra- or extracellular bacteria or toxins,
it is associated with MHC class II molecules and presented to the TCR of CD4+ T helper cells. Only
macrophages, dendritic cells, and B cells can do that. Macrophages become APCs when they upregulate
their MHC-II molecules in response to infection and stimulation of specific lipopolysaccharide (LPS)
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receptors by bacterial ligand. Dendritic cells are mostly found in peripheral tissue where they ingest,
accumulate and process antigens. B cells are the least efficient APCs. They become activated by ligand
binding to the BCR and ingest soluble proteins by pinocytosis.
The CD4+ and CD8+ cells develop in the thymus. CD stands for Cluster of Differentiation. There are
more than one hundred and sixty clusters that coat the lymphocyte surface. CD4 and CD8 are two that
are used to identify T cell subsets. When the cells coming from the bone marrow reach the thymus they
have neither CD4 nor CD8 (double negative T cells), but they then start expressing both markers
(double positive T cells). During development in the thymus they differentiate into either CD4 or CD8
cells. At the same time, they develop their ability to distinguish self from non-self peptides as explained
in the following.
First, cells that do not bind MHC/antigen complexes within 3-4 days will die. This happens to over 95
percent of the cells. The rest of the cells undergo positive selection. This means that T cells that bind
antigen (self or non-self) complexed with MHC, class I or II, proliferate. This happens in the cortex of
the thymus. At this time, cells with TCRs specific for MHC II retain CD4 and lose CD8 and become T
helper cells. T cells that are specific for MHC I retain CD8 and lose CD4 and become cytotoxic T cells.
After positive selection, cells undergo negative selection in the medulla of the thymus. During this
process cells that bind with high affinity to MHC/self antigen complexes will die by apoptosis. This is
important since these cells would later react with self peptides and cause autoimmune diseases. Cells
that bind with low affinity to MHC/ self antigen are allowed to leave the thymus. They will later only be
activated by high affinity binding to MHC/ foreign antigen complex, the adequate signal for immune
activation.
Cytotoxic CD8+ T cells release lymphotoxins which cause cell apoptosis of virus-infected cells (Fig.
10.3). Suppressor T cells inhibit the production of cytotoxic T cells when they are no longer needed.
Helper CD4+ T cells direct the immune response by secreting lymphokines. They stimulate
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proliferation of cytotoxic T cells and B cells, attract neutrophils, and activate macrophages. The
differentiation of CD4+ T helper cells into helper 1 and helper 2 cells occurs only after they have been
activated during an immune response in the peripheral lymphoid system. Each type of effector T cell
produces a distinct set of effector molecules. For instance, T helper 1 cells release the macrophageactivating effector molecules interferon-gamma and tumor necrosis factor-alpha, while T helper 2 cells
produce B cell activating effector molecules such as interleukin 4, 5, and 15, among numerous other
cytokines. Research shows that the dual T helper cell model, although still widely be used, is too simple
and might soon need to be expanded. For instance, many T cells express cytokines from both profiles.
They are often named T helper zero cells. Additionally, many T cell cytokines are expressed by other
immune cells as well. Lastly, memory T cells recognize a previously encountered pathogen.
T cells and their products may act directly or exert their effects in concert with other effector cells,
such as neutrophils and macrophages. The secretion of T cell factors that recruit and activate other cells
takes time, and thus, the consequences of T cell activation are not noticeable until 24 to 48 hours after
antigen challenge. An example illustrating this time delay is the delayed-type hypersensitivity reaction
(see also Immune Diseases below) to purified protein derivative (PPD), a response used to assess prior
exposure to the bacteria that cause tuberculosis. Injected under the skin of sensitive individuals, PPD
elicits the familiar inflammatory reaction characterized by local erythema and edema 1 to 2 days later.
Cell-mediated immune responses, while slow to develop, are potent and versatile. These delayed
responses provide the main defense against many pathogens. T cells are also responsible for the
rejection of transplanted tissue grafts (see Organ Transplantation below) and containment of the growth
of neoplastic cells (see Immune Disorders below). A deficiency in T cell immunity, such as that
associated with AIDS, predisposes the affected patient to a wide array of serious, life-threatening
infections.
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<h2>Humoral Immunity is the Second Fundamental Mechanism of Adaptive Immunity
Humoral immunity consists of defense mechanisms carried out by soluble mediators in the blood
plasma (Fig. 10.3). Binding of antigen to the BCR activates B lymphocytes, which then start
proliferating and maturing in the presence of T helper cytokines. Most new cells become plasma cells
which produce antibodies for four to five days, resulting in a high level of antibodies in plasma and
other body fluids. These antibodies can specifically bind to the antigenic determinant that induced their
secretion. Other B cell clones become long-lived memory B cells. In general, antibodies are known to
induce immediate responses to antigens and, thereby, provoke immediate hypersensitivity reactions (see
Immune Disorders below).
<h2>Antibodies Consist of Four Protein Chains Arranged Like the Letter Y
Antibodies, also called immunoglobulins or Igs, constitute the gamma globulin part of the blood
proteins. The primary structure of an antibody is illustrated in Figure 10.4. Each antibody molecule
consists of four polypeptide chains (two heavy chains and two light chains) held together as a Yshaped molecule by one or more disulfide bridges. There are two classes (isotypes) of the light chain
called kappa and lambda. Heavy chains have five different isotypes (gamma, alpha, mu, epsilon and
delta), which consitute five different classes of antibody, each with different effector functions (see
below). Each polypeptide chain possesses both a conserved constant region and a variable region,
where considerable amino acid sequence heterogeneity is found.
The amino terminal portions of the variable regions are known as the Fab regions. The hypervariable
regions at the end of the Fab region, known as antibody idiotypes, are the antigen-binding regions. Each
antibody unit possesses two identical antigen-binding sites, one at each end of the “Y.” The carboxy
terminal end of the heavy chain is termed the Fc region. Fc fragments can bind to cells such as
neutrophils, monocytes, and mast cells through their Fc receptors, which amplifies the biological
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activity of antigen-bound antibody. Antibodies are flexible in that the Fab arm can wave, bend and rotate
and even the Fc region has some degree of freedom. This freedom of movement allows it to more easily
conform to the shape of the antigen.
<h2>Antibodies Work in Three Ways to Destroy the Antigen
1. Neutralization. Antibodies can bind to toxins forming easily recognizable antibody-antigen
complexes, which are removed by phagocytosis. Antibodies can also immobilize and agglutinate
infectious agents with the effect that a virus cannot penetrate the host cell or a microbe cannot colonize
mucosal tissue. In some cases the complexes may also settle out of solution and precipitate.
2. Opsonization. IgG antibodies bind to bacteria or virus-infected cells via the Fab region. That way,
the pathogen is ‘tagged’ or ‘opsonized’ for phagocytosis or destruction by free radicals and enzymes.
Some complement components can also act as opsonins.
3. Complement Fixation. Complement is a group of at least nine distinct proteins that circulate in
plasma (Fig. 10.5). A cascade of events occurs when the first protein recognizes preformed immune
complexes of antigen molecules bound to antibodies (classical pathway). These events include the
recruitment of inflammatory cells. In addition, complement can be activated when one of the proteins is
exposed to the cell wall of certain bacteria. Initiation of this system (alternate pathway) results in the
lysis of the target by formation of the membrane attack complex (MAC). Because of its tubular
structure and hydrophobic nature, the MAC inserts into the membrane of the cell and allows free
passage of small molecules, ions and water resulting in the cell’s death. Complement fixation is the basis
for various diagnostic tests to detect a specific antibody or a specific antigen in a patient’s serum
<h2>There Are Five Major Antibody Classes With Different Primary Functions
Figure 10.4 and Table 10.4 summarize the shape and functions of the five major classes of antibodies.
Figure 10.4 additionally shows the similarities of the TCR and the BCR with immunoglobulin.
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IgG is the major antibody produced in response to secondary and higher order antigen encounters.
Secondary immune responses are faster and longer, and produce more antibody with higher affinity to
the antigen compared to primary responses. Hence, IgG is the most prevalent antibody in serum and is
responsible for adaptive immunity to bacteria and other microorganisms. It has a half-life of 23 days, the
longest amongst the antibody classes. When bound to antigen, IgG can activate serum complement and
cause opsonization. IgG exists in serum as a monomer. It can cross the placenta and is secreted into
colostrum, protecting the fetus as well as the newborn from infection.
IgA usually exist as polymers of the fundamental Y-shaped antibody unit. In most IgA molecules, two
antibody units are held together by a secretory piece (J chain), a protein synthesized by epithelial cells.
In this conformation, IgA is actively secreted into saliva, tears, colostrum, and mucus and hence is
known as secretory immunoglobulin. IgA has a half-life of about 6 days.
IgM consists of five Y units. Its size and large number of antigen-binding sites provide the molecule
with an excellent capacity for agglutination of bacteria and blood cells. Such agglutinated antigens are
efficiently and quickly removed by fixed macrophages of the RES system. IgM is the first antibody
secreted after an initial immune challenge and provides resistance early in the course of infection. It has
a half-life of about 5 days.
IgE is a monomeric antibody that is slightly larger than IgG, but has a relatively short half-life of
about 3 days. IgE avidly binds via its Fc region to cells such as mast cells and basophils, which are
involved in allergic reactions (see Immune Diseases below).
IgD is found in plasma and on the surface of some immature B cells. It has a half-life of 3 days. An
exact function is not known. It is expressed early during B-cell differentiation and has been postulated to
be involved in the induction of immune tolerance. IgD serum concentration does increase during chronic
infection, but is not associated with any particular disease.
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<h1>INFLAMMATION
Inflammation is the initial response of the body to infection or trauma. Although microbial infection is
probably the most common cause for inflammation, many types of tissue injury can evoke inflammatory
reactions. These include mechanical injury, radiation, burns, frostbites, chemical irritants, and tissue
necrosis resulting from lack of oxygen or nutrients. The body instigates a non-specific cascade of
physiological processes involving elements of the innate immune system, with the goal to repair cellular
damage in vascularized tissues and to restore the tissue to its normal function.
Inflammation is the response of a complex system that mobilizes immune, endocrine, and neurological
mediators (see Neuroendoimmunology below). In a normal response, it is self-initiating, temporally selfpropagating, and self-terminating. Inflammation is a necessary response to tissue injury, and human life
without inflammation is unthinkable. On the other hand, inflammation often overshoots in its reactions,
which leads to a vicious circle of repeated injury and persistent inflammation. In this respect,
inflammation is closely connected with all kinds of illnesses so that anti-inflammatory therapy is at the
heart of a wide variety of therapies.
<h2>Inflamed Tissue is Swollen, Red, Hot and Painful, Resembling an “Internal Fire”
The clinical aspects of inflammation have been known for over two thousand years and gave
inflammation its name as resembling an internal fire. These include four signs: first, rubor (redness),
generated by increased blood flow due to dilation of small blood vessels, and second, calor (heat)
generated by the metabolism of leukocytes and macrophages recruited to the site of damage. While the
increased blood flow contributes to a small temperature increase in the skin, systemic fever occurs as a
result of the chemical mediators of inflammation, especially IL-1 acting at hypothalamic neurons. The
third and fourth signs are tumor (swelling) due to edema, and dolor (pain) caused by the production of
prostaglandins, bradykinin, and serotonin. With increasing knowledge of the complexity of
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inflammation, many models have been put forward to expand on and to categorize the great variety of
inflammatory responses. However, they are not yet commonly used in clinics beyond the addition of a
fifth sign, functio laesa (the loss of function), which is a common, well-known consequence of
inflammation.
Laboratory investigation of inflammation usually reveals an increased number of neutrophils in
peripheral blood, an increased erythrocyte sedimentation rate (see Chapter 9), and increased
concentration of acute-phase blood proteins. The latter are produced by the liver in response to
circulating pro-inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha (TNF-). An
important member of the blood protein profile is C-reactive protein, a pro-inflammatory marker which
is used to monitor the severity and progression of some cardiovascular diseases. A high serum level of
the amino acid homocysteine has been associated with increased risk of atherosclerosis and other
conditions involving inflammation.
<h2>Acute Inflammation Involves Vasodilation, Vascular Leakage and Leukocyte Emigration
The immediate response of acute inflammation includes local dilation of blood vessels, which
increases blood flow to the injured area, sometimes up to ten-fold. The vessel walls become leaky, on the
one hand due to the injury-related necrosis of endothelial cells, and on the other hand due to chemically
directed retraction of endothelial cells. Next, water, salts and small proteins, such as fibrinogen, exit
from the plasma into the damaged area in a process called exudation. The leaking fluid is called
exudate, or pus in the case of an infected wound. Fibrinogen forms fibrin, which impedes the
movement of microorganisms and makes them easier to phagocytose. Acute inflammation is initially
mediated by histamine, followed by factors derived from local cells (e.g. bradykinin), and recruited
neutrophils (Table 10.5).
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Recruited neutrophils adhere to the endothelial cells via selectins. Loose bridges are established
between P-selectin and E-selectin on endothelial cells and L-selectins on neutrophils (margination).
Thus slowed down, the neutrophils move along the endothelium like tumbleweed (rolling). A more firm
connection is built between integrins on neutrophils, and Intracellular and Vascular Adhesion Molecules
(ICAM, VCAM) on the endothelial side. This allows neutrophils to actively migrate through the blood
vessel basement membranes into the tissue (transmigration or diapedesis) without damaging the
endothelial cells. Eventually, monocytes are attracted and differentiate into macrophages when leaving
the blood. Lymphocytes follow as well. The appearance of these non-granular cells marks the entry into
chronic inflammation.
<h2>Inflammatory Mediators Are Small Secreted Substances Which Regulate Inflammation
Inflammatory mediators are soluble molecules that act locally at the site of damage and coordinate the
development of inflammatory responses. Exogenous mediators include endotoxin, bacterial toxin
associated with the LPS complex of gram-negative bacteria. It is released when bacteria are lysed and
binds to receptors on monocytes and macrophages thus activating them. Endogenous mediators are
released from injured or activated cells at the inflammation site. There is a long list of substances that
are known to regulate inflammation, many of them with seemingly redundant functions. Table 10.5 lists
a few of them.
An important class of mediators is cytokines, which are cell products synthesized de novo in response
to immune stimuli. They generally act over short distances and short time spans. They include
lymphokines (cytokines made by lymphocytes), monokines (made by monocytes), chemokines
(chemoattractants made by various cells), and interleukins (made by one leukocyte and acting on other
leukocytes). Many mediators can interact with multiple receptors, often exerting very diverse functions.
For instance, histamine interacts with three receptors. The H1 receptors mediate acute pro-inflammatory
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vascular effects, while activation of H2 receptors results in anti-inflammatory actions. H3 receptors are
involved in the control of histamine release.
From a structural standpoint, inflammatory mediators belong to many different categories, such as
proteins (e.g. complement, antibodies, acute phase reactants), lipids (e.g. prostaglandins, plateletactivating factor), amines (e.g. histamine), gases (e.g. NO, O2-), kinins (e.g. bradykinin) and
neuropeptides (e.g. substance P). Many plasma-derived mediators are present as precursors and need
enzymatic cleavage to become active. Cell-derived mediators can be preformed (e.g. histamine) or
synthesized as needed (e.g. prostaglandin).
<h2>Acute Inflammation Is Considered to Be a Stereotypic but Highly Complex Process That Self
Terminates
Modern molecular biology superimposes many additional layers of complexity onto the presented
model of inflammation, and our current understanding of acute inflammation as a stereotypic response
might soon need to be revised. For instance, it has been shown that aspects of both inflammation and
repair can be triggered and modulated by factors independent of the vasculature. Vibration and hypoxia
can lead to degranulation of mast cells and release of histamine, hence initiating inflammatory events.
Similarly, increased mechanical load on tendon fibroblasts can modulate their inflammatory response.
In addition, pro-inflammatory molecules can be upregulated without any stimulation by inflammatory
cell invasions.
Under normal circumstances acute inflammation terminates itself. Chemical mediators disappear due
to a short half-life or are enzymatically inactivated (e.g. kininases inactivate kinins). Substrates are
consumed, and the lymph flow carries the mediators away faster than they can be produced. Repair of
damaged tissue is induced by anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth
factor beta (TGF-). Pools of lymph fluid (blisters) may form in response to burns, infections, or
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irritating agents. If an infected area is further liquefied and shielded from surrounding tissue as a
response of the body, it is called an abscess. Some abscesses are acutely cleared (e.g. pimples), but other
lesions might become chronic and then require natural or surgical drainage for healing. Following
inflammation, tissue that is capable of regeneration will be almost completely restored, while, otherwise,
scar formation occurs.
<h2>Chronic Inflammation Is the Failure to Resolve Inflammation and Usually Causes Serious
Body Harm
Chronic inflammation develops when neither agent nor host is strong enough to overwhelm the other
(e.g in the case of osteomyelitis, the staphylococcus infection of bone), when there is prolonged
exposure to the toxic agent (e.g. silicosis from inhalation of crystalline silica dust), or as part of
autoimmune diseases (e.g. rheumatoid arthritis). It can also develop without being preceded by acute
inflammation (e.g. in tuberculosis). Chronic inflammation may last weeks, months, or years and leads to
chronic wounds. They are composed of loosely arranged connective tissue (granulation tissue),
infiltrated fibroblast, and inflammatory cells. The vastly dominant inflammatory cell type, and the only
cell type present in the case of chronic inflammation due to a non-antigenic agent (e.g. suture thread), is
monocytes/ macrophages. In the case that the injurious agents are also antigenic, other cell types appear
such as lymphocytes, plasma cells, and eosinophils.
Chronic inflammation leads to ongoing tissue damage and clinical symptoms found in typical
inflammatory diseases such as rheumatoid arthritis, atherosclerosis, or psoriasis. Inflammatory cells
secrete products such as reactive oxygen species and proteases that cause additional cell damage. Other
products, such as arachidonic acid and pro-inflammatory cytokines, amplify, as well as propagate, the
responses. This is a vicious cycle that weakens the body and makes it more susceptible to infection.
Overwhelming inflammation combined with immune suppression can lead to Systemic Inflammatory
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Response Syndrome (SIRS), which is called sepsis when the inflammation is due to infection. This can
lead in the worst case to organ failure and death.
Inflammation can happen everywhere in the body. Inflammatory conditions are usually indicated by
adding the suffix “itis”. Myocarditis is the inflammation of the heart, nephritis is the inflammation of the
kidney. Some inflammatory conditions don’t follow the conventional terminology. The most common
one is Asthma (see Clinical Focus Box 1). Another example is pneumonia, which is more commonly
used than pneumonitis to name chronic infection of the lung, characterized by inflamed and fluid-filled
alveoli.
<h2>Novel Solutions to Resolve Chronic Inflammation Are a Core Topic of 21st Century Medical
Research
In recent years, the role of inflammation in diseases that were traditionally not recognized as
inflammatory diseases is viewed with considerable interest. In fact, inflammation is now recognized to
be a critical pathologic component underlying a wide variety of diseases ranging from Alzheimer’s and
Parkinson’s disease to diabetes and certain types of cancer (e.g. colon cancer). While the association
between inflammation and disease has been recognized for a long time, inflammation was mainly
considered as being a result of the illness, instead of being a cause of it. Recent studies clearly show that
the destructive self-promoting cycle between oxidative stress and resulting inflammation that causes
more oxidative stress, contributes to the development of chronic illnesses. These chain of events may
initially occur at a low, unnoticeable level, which leads to the speculation that subacute chronic
inflammation is part of, and may be even the source of, all illnesses. This is a provocative, but
interesting thought that is worth pursuing in light of the increasing occurrence of chronic diseases in our
aging population.
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Glucocorticoid steroid hormones are the most powerful anti-inflammatory drugs currently available.
Corticosteroids inhibit the accumulation of neutrophils at sites of inflammation, (see
Neuroendoimmunology below) but also have widespread effects on other inflammatory cells and
processes. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (Cox) involved in
prostaglandin production. There are at least two isoforms of the enzyme. Cox-1 is found in platelets, and
catalyzes the production of thromboxane A2. Cox-1 inhibition leads to diminished blood clotting, thus
drugs that block Cox-1 can be used as blood thinners. Cox-2 is expressed in blood vessels and
macrophages in response to inflammation, and leads to production of prostaglandin I2. Drugs that
specifically block Cox-2 can decrease inflammatory pain. However, both Cox-1 and Cox-2 are present
at many more sites, a reason for the abundant pharmacological side effects of the drugs. Alternative
medical therapies include nutrients (e.g. vitamin E), herbs (e.g. chamomile) and supplements (e.g.
glucosamines) with anti-oxidative and anti-inflammatory abilities.
Since the side effects of many available anti-inflammatory drugs outweigh their benefits, a main focus
of 21st century medical research is to develop novel anti-inflammatory strategies. New drugs generally
aim to target specific pathways instead of general inflammatory processes. For instance, leukotriene
modifiers are a relatively new class of anti-inflammatory medications for asthma patients (see Clinical
Focus Box 1) that specifically block the products of arachidonic acid metabolism to prevent an asthma
episode before it even starts. Another example is the use of molecularly engineered antibodies that are
directed against specific inflammatory cytokines or cytokine receptors by using gene recombinant
techniques. Novel non-pharmacological anti-inflammatory therapies may be developed from research
that shows that vibration or low energy radiation suppresses inflammation.
<h1>ORGAN TRANSPLANTATION
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Organ transplantation is indicated when irreversible damage has occurred and alternative treatments
are not applicable. The first human kidney was transplanted in the early 1950’s to the donor’s identical
twin brother. Such a transplant is called an isograft since donor and recipient are genetically identical.
Today, over 10,000 kidneys and many other organs are transplanted in the US per year, most often as
allografts between genetically different, but immunogenically matched people. Kidneys, lungs and
livers come from living donors since a person can live with one kidney and one lung and since liver
tissue regenerates. Transplants of heart, whole lung, pancreas, or cornea come from deceased donors.
So-called non-vital transplants of body parts such as hands, knees, uterus, trachea and the larynx have
also been achieved. Tissue that is transplanted in the same individual from one place to another place is
called an autograft. Skin and blood vessels are common tissue for such transplantation.
While transplantation is nowadays a viable therapeutic option, it is mainly limited by the immensely
larger demand for transplantation organs compared to their availability (see Clinical Box 2). An attempt
to overcome the donor organ shortage is xenograft transplantation, where animal tissue is used to
replace human organs. Two other avenues for replacement of necrotic tissue are the development of
artificial organs and the transplantation of stem cells that may be able to regenerate full functioning
organs. The latter is the holy grail of organ replacement since the new tissue would not be recognized as
foreign, if the stem cells come from the recipient. However, as of today, these alternatives don’t work
nearly as well as allografted organs. Additionally, there are major ethical problems involved.
Xenotransplantation may introduce new diseases to humans and disrespectfully treat animals. The use of
animal and artificial organs may raise problems of self esteem, and stem cell therapy may require the
destruction of human embryos.
<h2>Histocompatibility is the Most Important Criterion for Match in Organ Donation
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The major reason for the donor organ shortage is that the blood and tissue of the donor and recipient
need to have similar immunogenic markers to avoid rejection. For instance, virtually all kidneys with
unmatched ABO blood group between donor and recipient will be rejected within minutes. It is critical
that the recipient does not have, or develop, antibodies against the donor’s human leukocyte antigen
(HLA). HLA are the human antigens of the MHC complex (see T Cell Mediated Immunity above).
These antigens are present on the surface of most body cells, but were first discovered on leukocytes.
For minimum requirements, transplant doctors look at only six of the many HLA antigens (two A, two
B, and two DRB1 antigens) for matching donors to patients. However, research has shown that a match
in more HLA antigens and additional factors such as race, age and sex, improves the patient’s chances
for success.
Although tissue typing decreases the risk of transplant rejection, the match between donor and
recipient is never perfect (except for identical twins). The reality of clinical practice results in organ
transfer from less well-matched donors. So, clinical symptoms resulting from immune attacks on the
transplant are fairly common. Table 10.6 summarizes the different types of rejections.
Immunosuppressive drugs greatly decrease the risk of rejection. There are a wide variety of drugs
available that inhibit different immune processes. Many of them aim to downregulate the unwanted T
cell responses. Total destruction of T cells and other leukocytes by whole body irradiation is used before
bone marrow transplanation (see Clinical Focus Box 2).
<h1>IMMUNE SYSTEM DISORDERS
Many things can go wrong in the complex world of the immune system. First, the immune system may
overreact. It is important for proper functioning that the immune system be very sensitive to pathogens
and use enough power to definitely defeat the pathogen since even small numbers of residual
microorganisms may soon endanger the body again. But this principle comes at the risk of overdoing it.
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Asthma, familial Mediterranean fever (recurrent episodes of peritonitis, pleuritis and arthritis) and
Crohn's disease (inflammatory bowel disease) are examples of an over-reacting immune system.
The most common overreactions of the immune system are known as allergies, or anaphylaxis in the
case of severe forms. Allergies are categorized into four classes (see Table 10.7). Dependent on the
sensitivity of the affected person, they can cause localized or systemic symptoms. Localized reactions
are usually biphasic, with an immediate response mainly due to histamine (erythema, wheal and flare)
and a delayed response that may last several hours. Systemic reactions might be life-threatening due to
the sudden loss of blood pressure as a result of general vasodilation and due to airway obstruction as a
result of smooth muscle contraction.
Second, the immune system may not respond. Immunodeficiencies occur when a part of the immune
system is not present or not working properly. A large variety of disorders falls into this category,
although the number of patients with congenital immunodeficiency diseases is low. The study of these
diseases reveal important insights into cellular and molecular immunology. For instance, Severe
Combined Immuno Deficiency (SCID), commonly known as “bubble boy disease”, represents a group
of congenital disorders characterized by little or no immune response. Research showed that in the xlinked form of SCID, T cells are disfunctioning due to a mutation of the IL-2 receptor gamma chain. The
immunological consequences are severe and may lead to the patient’s death within the first year of life.
Third, the immune system may respond inappropriately. Autoimmune disorders are the attack on the
body’s own cells, with minimal to devastating consequences. What triggers autoimmune reactions is still
poorly understood and involves genetic, hormonal, and environmental factors. An example is Systemic
lupus erythematosus (SLE), a chronic autoimmune disease with largely unknown etiology that affects
multiple organs, possibly as a result of unregulated apoptosis. Autoimmune phenomena may also occur
secondarily to another disease.
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The examples presented in Table 10.7 are not intended to be comprehensive, but to provide a
framework, which can be expanded in pathology courses. Many diseases involve mechanisms that fit
into several of the categories. Rheumatoid arthritis (RA) is a good example. It is thought to be initiated
by an unknown antigen that stimulates antibody formation, characteristic of type III hypersensitivity.
This leads to joint damage, and as a result, auto-antigens are released, which perpetuate the disease in
the typical fashion of an autoimmune disease. T cells are recruited and activate macrophages which
leads to chronic inflammation. The disease is maintained by immune responses dominated by T helper 1
cells, characteristic of type IV hypersensitivity reactions.
<h2>The Adaptive Immune System Can Cause Malignant Tumors, But Also Recognize Tumors
From Other Tissues
Like any cell, cells of the immune system can grow out of control. Leukemia, the abnormal growth of
leukocytes, is the most common childhood cancer. Lymphomas encompass a diverse group of cancers
which present as solid masses specific to the lymphatic system. At least two viral infections have been
associated with immune system malignancies. The human T cell leukemia virus type 1 (HTLV-1) can
cause acute T cell leukemia and lymphoma (ATLL), and the Epstein-Barr virus of the herpes family is
linked to Burkitt’s lymphoma and possibly Hodgkin’s lymphoma. In both cases, most people remain
healthy when infected. However, people who are immuno-compromised due to previous infections,
other diseases, or age, may develop cancer. For instance, Burkitt’s lymphoma is the most common
childhood cancer in central Africa, where malaria and malnutrition lead to immune weakness.
Some leukemias and lymphomas are easy to differentiate histologically from healthy tissue, others are
not. For instance, lymphoblasts in acute lymphoblastic leukemia (ALL) look very different from normal
lymphocytes. However, the cells in chronic lymphocytic leukemia (CLL) are hard to distinguish from
normal cells and the disease might resemble a physiological high lymphocyte count. In this case,
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identification of specific cell markers, which are not present in healthy cells, will aid the diagnosis. If
these tumor markers are antigenic, the immune system might recognize them as well. The resulting
combat of the immune system against cancer that has already developed is not well understood. It has
led, however, to the rapidly advancing field of cancer immunotherapy, which aims to enhance the
body’s natural defense against malignant tumors.
<h1>NEURO-ENDO-IMMUNOLOGY:
The actions of the immune system are interconnected with the actions of the endocrine and the
neuronal systems (Fig. 10.6). For instance, it is well known that the physiological stress response
downregulates the immune system. As a consequence, individuals, stressed from losing a relative, or
stressed by examinations, become sick more easily. From the fast growing knowledge of the
mechanisms that underlie such phenomena the picture emerges that there is far more information
exchange among the three systems through hormones, neurotransmitters and cytokines than previously
thought. Immune, endocrine, and neuronal systems share a number of the same receptors and synthesize
and secrete some of the same molecules. Accordingly, the strength of a person’s immune response
depends not only on the type of antigen or the person’s age and genetic makeup, but also on the
individual’s lifestyle choices, emotional character, and ability to cope with stress.
<h2>Neuronal Components of the Central and Autonomic Nervous System Modulate Immune
Functions
During an immune response cytokines such as IL-1 stimulate the activity of paraventricular
hypothalamic neurons to release corticotropin-releasing factor (CRF). This starts the physiological stress
response aimed at bringing an individual back to physiological homeostasis. In the pituitary gland CRF
stimulates the expression of POMC, which is converted to beta-endorphin and ACTH. ACTH stimulates
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the release of corticosteroids from the adrenal gland. All these molecules can bind directly to receptors
on immune cells. The resulting actions are generally inhibitory to the immune system, but can also be
immunosupportive, especially during acute stress.
Activating the stress response via CRF also leads to activation of the sympathetic nervous system and
the release of its neurotransmitter norepinephrine. This autonomic path of the stress response can also be
activated by cytokines that are released by immune cells, or by cells of the central nervous system
(CNS) such as microglia and astrocytes. A network of autonomic nerve fibers send information from the
CNS to the spleen and lymph nodes, where the fibers end in close proximity to T lymphocytes and
macrophages. These immune cells, as well as B cells, express beta-adrenergic receptors of the beta 2
subtype and their activation generally leads to inhibition of cell function. For instance, adrenergic
activation of T cells decreases their expression of integrins, so that they cannot migrate out of the blood
vessel into the tissue, which explains the high T cell counts seen soon after a stressful event.
Sympathetic nerve endings and the adrenal medulla also release endorphins and enkephalins. These
opioid peptides oppose the body’s stress response and help maintain homeostasis during times of
physical and psychological stress. The immune responses to opioids vary, dependent on the subtype and
concentration of the neuropeptide. Melatonin, a hormone of the pineal gland, seems to regulate the
opioid network and consequently the immune system. Melatonin therapy is under consideration to
support the immune system of aged people to avoid immunosenescence.
<h2>Immune Cells and Their Secretions Affect the Central Nervous System, Modulated by
Hormones
The information flow from the peripheral immune system to the CNS is carried by lymphokines and
and thymokines (produced by the thymus). For instance, IL-1 is a potent mitogen for astroglial cells. In
addition, it acts at hypothalamic cells causing fever. IL-2 promotes the division and maturation of
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oligodendrocytes, and IL-3 supports the survival of cholinergic neurons. Additionally, CD4+ T cells and
macrophages manufacture neuropeptides such as Vasoactive Intestinal Peptide (VIP) and Pituitary
Adenylate Cyclase Activating Polypeptide (PACAP) which was previously thought to be products solely
of non-immunological cells.
Until recently, it was also believed that the brain is devoid of peripheral immune cells. It is now
known that immune cells can pass the blood brain barrier and enter the central nervous system, where
they may trigger autoimmune disorders. For instance, autoimmune T cells that recognize myelin basic
protein of myelin sheaths might be associated with the development of the demyelinating disease
multiple sclerosis. However, it seems that neuronal autoimmune cells are present in the CNS in the first
place to regulate physiological neuronal events. For instance, it is discussed that they contribute to
maintaining the brain’s ability for cognitive functions.
A large number of hormones have been linked to immune functions. For instance, thyroid stimulating
hormone (TSH), best known as a regulator of metabolic functions, is also produced and used by cells of
the immune system. Growth hormone, prolactin, female and male sex hormones, and leptin are
additional examples of hormones that unequivocally modulate the immune system. In the typical fashion
of hormones, they exert multiple actions in a variety of target cells, dependent on the hormone
concentration, the target tissue, and the environment. This makes hormones optimal regulators of the
body’s homeostasis, but usually causes unwanted side effects when used clinically.
Currently available immune therapies using hormones or neuropeptides are still limited. The adrenal
hormone epinephrine is given to reverse some effects of allergy, and immunocompromised people are
counseled to find ways for dealing with stress. However, many new applications are being developed
and it is safe to say that in the near future distinct enhancement or suppression of immune cell functions
will play a more important role in our approaches to help the body to maintain homeostasis.
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CHAPTER SUMMARY

The immune system encompasses key immunological organs such as thymus, spleen, bone marrow,
lymph system. It additionally includes cells and non-cellular elements that are part of every tissue
throughout the body.

Leukocytes traffick between lymphoid organs, lymphatics and blood vessels.

A substance that elicits an immune response is called immunogen. Haptens and antigens are
substances that bind to T cells or antibodies, but only antigens elicit an immune response.

The overall goal of the immune system is to distinguish between self and foreign molecules inside
our body tolerating normal body substances and eliminating any invasion by foreign substances.

To battle foreign invaders, the immune system has two systems: the innate system as the immediate
response to common immunogens, and the adaptive system, which changes throughout life and
which has memory to respond to an encounter more strongly the second time compared to the first
time.

Innate immunity includes physical, chemical, and mechanical barriers to entry of pathogens. It also
includes phagocytes, killer cells, eosinophils and mast cells.

Phagocytes encompass neutrophils, macrophages, and dendritic cells. They have receptors for
pathogens and for complement-coated and antibody-coated antigens. They can engulf and destroy
pathogens, influence immune responses via immune mediators. Macrophages and dendritic cells can
act as antigen-presenting cells to T cells.

Acute inflammation is the body’s initial response to infectious microorganisms and injuries. It is
characterized by the dilation and leaking of blood vessels and subsequent attraction of circulating
leukocytes to the inflammatory site, where innate immune responses occur.

Adaptive immunity is a delayed, but highly effective, immune response against specific antigens.
The adaptive immune system is divided into cell-mediated immunity, which targets infected cells
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and is managed by T cells, and humoral immunity, which deals with infectious agents in blood and
tissues, and is mediated by B cells and their antibodies.

B and T cells have antigen-specific receptors, which bind pure antigen in the case of B cells, or
antigen presented on MHC in the case of T cells.

Stimulation by antigen plus other signals causes T lymphocytes to proliferate into clones of effector
cells and memory cells.

Cytotoxic CD8+ T cells recognize and kill cells that are infected with endogenous pathogen
presented on class I MHC. CD4+ T helper 1 cells activate macrophages that present antigen on class
II MHC. CD4+ T helper 2 cells activate B cells that present exogenous antigen on Class II MHC.

Activated B cells become antibody-producing plasma cells and memory cells.

Antibodies are antigen-specific binding proteins that neutralize and opsonize antigen and activate
complement to promote various immune reactions. Antibodies occur in five isotpyes with special
functions.

Graft rejection is the major complication of organ transplantation and mainly depends on the
allogeneic differences in the human leukocyte antigens (HLAs) between organ donor and recipient.

Every acute illness evokes an immunological response, and nearly every prolonged serious illness
interferes with the immune system.

Chronic inflammation leads to tissue damage and clinical symptoms. It is associated with the
predisposition to a multitude of diseases.

Immune system diseases are caused by abnormal or absent immunologic mechanisms, whether
humoral, cell-mediated, or both.

The actions of the immune system are closely interrelated with the actions of the endocrine and the
neuronal systems to keep body homeostasis.
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REVIEW QUESTIONS
1. After the nurse covers a patient’s wound with an adhesive bandage, he rapidly develops a red rash
with small blisters. The called clinician diagnoses acute dermatitis. He explains to the nurse that the
patient’s T lymphocytes are overreacting, while in most other acute inflammatory conditions another
cell type dominates. To which other cells is the doctor referring?
A. B cells
B. Dendritic cells
C. Eosinophils
D. Mast cells
E. Neutrophils
2. Penicillin is a small antibiotic molecule with a molecular weight of 300 Dalton. It binds to an enzyme
in the wall of many bacteria, which leads to the weakening of the cell wall. As an unwanted side effect,
penicillin can also bind to serum or tissue proteins, and the resulting complexes can cause allergic
reactions mediated through IgE antibodies. Which of the following describes the parent penicillin
molecule?
A. Antigen
B. Hapten
C. Immunogen
D. Opsonin
E. Pathogen
3. A 40-year old woman is determined to run a marathon once in her life. For the last 4 months, she
trained almost every day, ate high protein meals, and lost 10 kg, while still keeping up with her job and
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motherly duties. Her husband recognizes that she more frequently blows her nose, rubs her eyes and
clears her throat in the evening. Which of the following best characterizes her condition?
A.
Acquired immunodeficiency
B.
Anaphylaxis
C.
Atopic disease
D.
Food allergy
E.
Non-allergic asthma
4. A scientific article announces a breakthrough for organ transplantation in an article entitled “Specific
suppression of CD4+ T cell alloreactivity by allo-MHC class I- restricted CD8+ T cells.” Which of the
following bests describes the finding?
A.
Cytotoxic T cells were suppressed by MHC antigen-presenting cells
B.
Cytotoxic T cells were suppressed by T helper cells
C.
MHC antigen-presenting cells were suppressed by T helper cells
D.
T helper cells were suppressed by cytotoxic T cells
E.
T helper cells were suppressed by MHC antigen-presenting cells
5. Herpes simplex viruses tend to infect cells of skin or mucous membranes. As part of the immune
response against the infection, the virus is presented by a host cell (1), with antigen-presenting
molecules (2), to target cells (3). Which of the following are correct for 1, 2 and 3?
A. 1: Any cell
2: MHC class I
3: Cytotoxic T cell
B. 1: Any cell
2: MHC class II
3: T helper cell
C. 1: Any cell
2: MHC class I
3: T helper 1 cell
D. 1: B cell
2: MHC class II
3: Cytotoxic T cell
E. 1: Dendritic cell
3: MHC class II
3: Cytotoxic T cell
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ANSWERS AND RATIONALES
1. The answer is E. Neutrophils are the main cells to mediate the effects of acute inflammation. They
remove the irritating agents by phagocytosis and destroy microorganisms by lysosomal enzymes and
reactive oxygen radicals. The presence of lymphocytes and monocytes/macrophages is usually an
indication that the inflammation has reached the chronic state. However, in most inflammatory disorders
of the skin, such as dermatitis, lymphocytes are the common reacting cells. This is even the case, with
rare exceptions, for immune-mediated skin reactions.
2. The answer is B. Penicillin is a chemical hapten that needs to bind to a macromolecule, usually a
protein, to become immunogenic.
3. The answer is E. Non-allergic asthma can be triggered by strenuous exercise or stress. It leads to the
same symptoms as allergic asthma, also called atopic asthma. Anaphylaxis, or severe allergy, is not the
best answer since her husband is the one that recognizes the symptoms. Food allergy is a possibility due
to the altered diet, but there is no mentioning of any relation between the symptoms and meals. Acquired
immunodeficiencies may develop after a disease or due to malnutrition.
4. The answer is D. CD4+ cells are T helper cells. CD8+ cells are cytotoxic T cells. Cytotoxic T cells
were raised that could recognize MHC class I antigens on target antigen-presenting cells and
consequently suppress the response of T helper cells to MHC class II antigen of the same antigen
presenting cell. This would support the goal to suppress the host’s immune response to donor MHC
antigens for organ transplantation.
5. The answer is A. Endogenous antigens such as viruses replicating within a host cell are digested by
enzymes of the host cell and presented, coupled to MHC class I molecules, to CD8+ cytotoxic T cells,
which destroy the infected cell. Class I MHC is expressed by almost all host cells.
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CLINICAL FOCUS BOXES
<box>10.1 Allergies and Asthma
Epidemiological data confirm what many parents suspected. Allergies amongst children are more
common compared to the incidence rate during their childhood. In the past 30 years, the prevalence of
allergies has been greatly increasing in the US and in the world, proportionally more so in wealthy
countries compared to poorer countries and more so in urban areas compared to rural areas. One
hypothesis to explain this phenomenon proposes that the children that are not exposed to enough
antigens or innocuous microorganisms from soil or water early in their childhood don’t adequately
develop their T helper 1 cell response. This leads to an imbalance towards T helper 2 cell responses
which are present since birth. Even though this hypothesis is disputed as being desperately
oversimplified, it is undisputed that the various manifestations of allergic inflammation are the result of
wrongly activated T helper 2 cells.
Asthma is one common allergic disorder, which affects about 5% of the US population. It belongs to the
category of type I hypersensitivity reaction, and is characterized by airways that narrow excessively in
response to a wide variety of provoking stimuli. Typical allergens causing atopic (also called extrinsic or
allergic) asthma are animal dander, dust mites, grass pollen and cockroach antigen. Non-atopic asthma
might be triggered by strenuous exercise or worry. The symptoms of both asthma types are similar and
include wheezing, breathlessness, chest tightness, and coughing. They are caused by chronic
inflammation of the airways which leads to their swelling. The restriction of the airflow to and from the
lungs is further exacerbated by bronchoconstriction, excess production of mucus, and increased collagen
deposition.
The development of asthmatic symptoms ultimately depends on the presence of T helper 2 cells, which
secrete a characteristic cytokine repertoire. Interleukin-4 activates B cells to produce IgE antibodies,
which bind to mast cells, eosinophils and other airway cells via receptors that are specific for the Fc
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portions of IgE antibodies. Upon subsequent encounter with the antigen, IgE-crosslinking on mast cells
and eosinophils occurs and leads to the cells’ activation and their release of histamine and leukotrienes.
These and other inflammatory factors recruit inflammatory cells including additional T helper 2 cells to
the lung resulting in a damaging immunological positive feedback cycle. IL-4, together with IL-9, is also
necessary for mast cell maturation, and along with IL-5, for eosinophil recruitment.
Several treatments are available that interfere with the different allergic processes. Antihistamine drugs
for treatment of atopic asthma are targeting H1 receptors or prevent the release of histamine from mast
cells. Epinephrine and beta-2 selective agonists for treatment of systemic anaphylaxis modulate the
sympathetic nervous system (see Neuroendoimmunology). Corticosteroids and leukotriene receptor
antagonists aim at suppression of inflammation. Immunotherapy (also called hypo- or desensitization)
involves subcutaneous injections that contain gradually increasing doses of an allergen extract. The
immune system responds with gradually increasing levels of IgG antibodies, which seems to avoid
dramatic reactions when the allergen is then encountered naturally.
<box>10.2 Bone Marrow Transplantation
When a patient has a terminal bone marrow disease, such as leukemia or aplastic anemia, often the only
possibility for a cure is a bone marrow transplant. In this procedure, healthy bone marrow cells are
used to replace the patient’s diseased hematopoietic system. To identify a suitable donor, blood
leukocytes of prospective donors, usually a close relative, are screened to determine whether their
antigenic pattern matches that of the patient. The antigenic composition of leukocytes in bone marrow
and peripheral blood are identical, so analysis of blood leukocytes usually provides enough information
to determine whether the transplanted cells will engraft successfully. If significantly different from the
recipient’s tissue type, transplanted leukocytes may be recognized as foreign by the patient’s immune
system and, therefore, be rejected, a phenomenon called host-versus-graft response.
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More commonly, sufficient differences between the engrafted cells and the host’s own tissue lead to
debilitating consequences as a result of graft-versus-host disease (GVHD). In GVHD, functional T
cells in the proliferating graft recognize host tissue as foreign and mount an immune response. The
disease often begins with a skin rash, as transplanted lymphocytes invade the dermis, and ends in death
as lymphocytes destroy every organ system in the marrow recipient.
Recent advances have decreased the morbidity of marrow transplants and have substantially increased
the potential pool of bone marrow donors for a given patient. Immunosuppressive agents, including
steroids, cyclosporine, and anti-T cell antiserum, effectively decrease the immune function of the
transplanted lymphocytes. Another useful approach involves “purging”—the physical removal of T cells
from bone marrow prior to transplantation. T cell-depleted bone marrow is much less capable of causing
acute GVHD than untreated marrow. These techniques have enabled the successful transplantation of
bone marrow obtained from unrelated donors.
Many problems remain, however. One of the most serious is donor identification. An unrelated
transplant is successful only if the donor’s human leukocyte antigens (HLA) closely match those of the
recipient. Since there are several antigenic determinants and each can be occupied by any one of several
genes, there are thousands of possible combinations of leukocyte antigens. The chance that any
individual’s cells will randomly match those of another is less than one in a million. Finding a suitable
donor is a formidable problem that often generates intense frustration. In conjunction with continued
development of methods to reduce or eliminate GVHD, the expanding bone marrow transplant registries
may someday allow identification of a donor for anyone who needs a bone marrow transplant.
<box>10.3 Vaccination and DNA vaccines against AIDS (From Bench to Bedside)
According to a 2006 estimate, about 1.2 million people in the US and over 60 million worldwide are
infected with HIV, the human immunodeficiency virus causing acquired immunodeficiency syndrome
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(AIDS). Since its first diagnosis in 1981, more than 20 million people have died of AIDS. One
preventative measure against the spreading of pandemic infectious diseases such as AIDS is
vaccination. For instance, vaccination has eradicated the polio virus from the Western hemisphere.
Great effort is currently being undertaken to develop an AIDS vaccine.
The principle of vaccination, also called immunization, is to stimulate the acquired immune system of
the body to fight diseases. Passive immunization refers to the administration of antibodies and
lymphocytes. These last only a few days and hence provide only transient protection. Nevertheless, it
might be a life saving measure in emergencies as in the case of a person bitten by an animal with the
rabies virus. Active immunization is necessary to provide long-term protection, because it generates
immunological memory. To immunize against viral diseases, the vaccine generally contains an
attenuated (weakened) or killed virus. The vaccine for immunization against bacterial diseases often
contains only a portion of the bacteria. These vaccines might be generated by recombinant technology,
where the gene coding for the pathogenic epitope of the bacteria is isolated and expressed in an
appropriate host cell.
In the fight against AIDS, several clinical trials are underway using another type of vaccine, DNA
plasmid vaccine. In this case, genes that encode proteins of pathogens are injected into a person, rather
than the pathogens themselves. The gene of interest is grown in bacteria and hence called plasmid DNA.
When injected in humans, it is taken up by mainly antigen-presenting cells, which then produce the
encoded protein. This antigenic protein elicits an immune response just like a conventional vaccine.
DNA vaccines are attractive for protection against HIV, where inoculation with a dead or attenuated
virus is very risky. It has been proven, at least in animal models, that DNA vaccines activate both
cellular and humoral immune responses. This is advantageous since live viral vaccines only induce the
cellular response, while vaccines containing killed microorganisms, or subunits of them, only induce the
humoral response. Another advantage is the stability of DNA vaccines at ambient temperatures, which
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makes them useable in areas where constant refrigeration of the vaccine is not possible. Finally, DNA
vaccines are cheaper and easier to produce than conventional vaccines and can be manipulated by the
tools of recombinant technology.
The potential that the vaccine plasmid DNA might become integrated into human chromosomal DNA
raises concern. This could induce cancer due to the disruption of a cell division gene or the activation of
an oncogene. Another problem of DNA vaccines includes the question of how to terminate their actions.
Continuous antigenic stimulation may lead to immune tolerance or autoimmunity. Another safety
consideration involves the potential induction of antibodies against the plasmid DNA, which again
might lead to autoimmune diseases. These concerns are currently being addressed, for instance, by
improving the delivery of the plasmid DNA only to antigen-presenting cells, and at the correct time for
immune cells to respond. While the ultimate clinical effectiveness of DNA vaccines is unclear, they
have shown promising results in preclinical trials against diseases such as AIDS.
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Table 10.1 Characteristics of the Innate and Adaptive Immune Systems
System
Stimulation
Specificity
Response
Memory
Soluble factors
Cells
Innate
Adaptive
Old, present in all
animals
Present at birth
Highly reliable
Not required
Minimal
Evolved in early vertebrates
Within minutes
No change in quality and
quantity over time
No
Lysozyme, complement,
acute phase proteins,
interferon, cytokines
Phagocytic leukocytes,
NK Cells
Transferable to other individuals
Frequently malfunctioning
Required
Highly specific
Self vs non-self discrimination
Receptor mediated
Develops over days
Improved by previous infection
Yes
Antibodies
T cells, B cells
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Table 10.2 Cellular Elements of the Innate Immune System
Effector Cells
Main function
Phagocytosis
Neutrophils
Kill microorganisms
intracellularly
+
Macrophages
Kill microorganisms intraand extracellularly
+
Dendritic cells
Destroy microorganisms
+
NK and LAK
cells
Destroy virus infected and
tumor cells
-
Eosinophils
Secrete factors that kill
certain parasites and
worms
-
Mast Cells
Release factors which
increase blood flow and
vascular permeability
-
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Table 10.3 T cell mediated immunity response
Source of antigen
:
Viruses, some bacteria
Bacteria, phagocytosed or
living in phagosomes
Extracellular proteins
(vaccines, toxins)
Location of antigen
:
Cytosol
Phagosomes
Endosomes
Antigen Presenting Cell (APC)
:
Any cell
Macrophages, dendritic
cells
B cells
Location of APC
:
Anywhere
Lymphoid and
Connective tissue, Body
cavities, Epithelium
Lymphoid tissues, Blood
Molecules of display
:
MHC class I
MHC class II
MHC class II
Antigen recognition cells
:
CD8+
CD4+
CD4+ TH2 cells
Response
:
Release of cytotoxic
effector molecules
Release of macrophageactivating effector
molecules
B cell activation
Effect
:
Death of infected cell
Killing of bacteria and
parasites
Secretion of antibody to
eliminate bacteria and
toxins
CTL cells
TH1 cells
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Table 10.4 Characteristics of Different Antibody Classes
10-3
Molecular weight (x
Daltons)
Y units/molecule
Serum concentration (mg/dL)
Serum concentration (% of Ig)
Crosses placenta
Enters secretions
Agglutinates particles
Allergic reactions
Complement fixation
Fc receptor binding to monocytes and
neutrophils
Dominant in secondary immune response
Main antibody in external secretions
Dominant in primary immune responses
Responsible for hypersensitivity
IgG
IgA
IgM
IgD
IgE
150
1
600–1500
~76
+
+
+
+
+
++
150, 400
1–2
85–300
~15
++
+
-
900
5
50–400
8
+++
++
+
180
1
<15
1
-
190
1
0.01–0.03
0.002
++++
-
+
+
+
+
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Table 10.5 Endogenous Inflammatory Mediators
Chemical
mediators
Histamine
Lysosomal compounds
Eicosanoids
Prostaglandins
Thromboxanes
Leukotrienes
Platelet activating factor
Serotonin
Cytokines
Chemokines
Gases
Nitric oxide
Neuropeptides
Tachykinins
Kinins
Plasma
factors
Complement
(most important C5a,
C3a, but others also
involved)
Kinins
Coagulation Factors
Fibrinolytic system
Released By
Mast cells, basophils,
eosinophils, leukocytes,
platelets
Neutrophils,
macrophages
Some Actions
Vasodilation
Vascular permeability
Many cells
Neutrophils
Vasoactive properties, platelet
aggregation, prolong edema
Neutrophils,
monocytes, mast cells,
eosinophils
Mast cells, platelets
Lymphocytes,
monocytes
Tissues cells,
endothelial cells,
leukocytes
Endothelial cells,
macrophages
Vascular permeability
Neutrophil migration
Bronchoconstriction
Vasoconstriction
Vasoactive and chemotactic
properties
Chemotaxis of inflammatory effector
cells
Mainly sensory neurons
Activated By
Enzymes from dying
cells; antigen-antibody
complexes (classical
pathway); endotoxins
(alternate pathway);
products of kinin,
coagulation and
fibrinolytic system
Coagulation factor XII
Coagulation factor XII
Vascular permeability
Complement activation
Vascular smooth muscle relaxation
and vasodilation, kills microbes,
counteracts platelet actions
Vasodilation, vascular permeability,
smooth muscle contraction, mucus
secretion, pain
Chemotaxis, phagocyte, mast cell and
platelet degranulation, cytolytic
activity, opsonization of bacteria
(facilitates phagocytosis)
Vascular permeability
Mediators of pain
Non-vascular smooth muscle
contraction
Conversion of fibrinogen to fibrin
Plasmin lyses fibrin
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Table 10.6 Types of Graft Rejection
Type
Time
Reasons
Hyperacute
Acute
Minutes - hours
Chronic
Months - years
Pre-formed anti-donor antibodies trigger
type II hypersensitivity reactions
HLA incompatibility or inappropriate
connection to blood supply trigger T cell
activation and type IV hypersensitivity
reactions. Complicated by antibodymediated rejection.
Unclear. Cellular and humoral
mechanisms involved. Reoccurance of
disease possible.
Days – weeks
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Table 10.7 Immune Disorders
Names
Mechanisms
Examples (common names of diseases)
Hypersensitivity Disorders: Damaging immune responses elicited by allergens
Immediate Hypersensitivity:
Type I
(Immediate hypersensitivity)
Allergens cause cross-linking of IgE bound to mast
cells, which release vasoactive mediators (e.g.
histamine). Symptoms within minutes.
 Atopic diseases: Hives, Asthma, Hay fever
 Food allergy
 Systemic anaphylaxis
Type II
(Ag-Ab cytotoxicity)
Cytotoxicity mediated by antibody (primarily IgG)
directed against epitopes on surface membrane of
host cells. Symptoms within hours.
 Newborn hemolytic anemia
 Autoimmune hemolytic anemia
 Blood transfusion reactions
Type III
(Ag-Ab immune complex
disease)
Circulating immune complexes (primarily IgG)
escape phagocytosis and cause deposits in tissues or
blood vessels. Symptoms within hours.
 Serum sickness
 Glomerulonephritis
 Farmer's lung (allergic pneumonitis)
Memory TH1 cells cause cell-mediated immunity
resulting in tissue damage by macrophages.
Symptoms within day(s).
 Contact dermatitis (e.g. poison ivy)
 Photoallergic dermatitis (e.g. sunscreen)
 Celiac disease (gluten)
Delayed-type hypersensitivity:
Type IV
(Cell-mediated
hypersensitivity)
Immunodeficiency Disorders: Diseases caused by deficiencies (primary) or being the result of it (secondary)
B cell
Deficiency in antibody-mediated immunity
 Bruton’s agammaglobulinemia
 IgA deficiency
T cell
Deficiency in cell-mediated immunity
 DiGeorge syndrome (thymic hypoplasia)
Combined
Combined deficiency of cellular and humoral
immunity
 SCIDs
Non specific
Mediated by deficient phagocytic and/or natural killer  Leukocyte adhesion deficiency
cells
 Chronic granulomatous disease
Complement
Defects of individual components or control proteins  C1, C4, C2, C3, C5-9 deficiencies
 Hereditary angioedema (lack of C1 inhibitor)
Acquired
Human immunodeficiency virus (HIV) infects and
kills CD4+ T helper cells, which leads to massive
immunosuppression and increased risk of cancer.
 AIDS
 Prolonged serious disorders (cancers, kidney
failure, diabetes, liver problems, etc)
Autoimmune Disorders: Immune responses against the body’s own tissue
Antibody mediated
A specific antibody targets a particular antigen, which  Autoimmune hemolytic anemia (erythrocytes)
leads to its destruction and the signs of the disease
 Myasthenia gravis (neuromuscular receptors)
 Graves’s disease (adrenal gland cells)
Immune complex mediated
Antibodies complex with autoantigen into large
 Systemic lupus erythematosus
molecules which circulate around the body and cause  Rheumatoid arthritis
destruction
T cell mediated
T cells recognize autoantigen, which leads to tissue
destruction without requiring the production of
autoantibody
Mediated by complement
deficiency
Deficiencies in complement components often lead  Systemic lupus erythematosus
to, or predispose to the development of autoimmunity
 Multiple sclerosis
 Type 1 Diabetes
 Hashimoto’s thyroiditis
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Figure Legends
FIGURE 10.1
Organs and cells of the immune system. Thymus and bone marrow are primary lymphatic organs.
Lymph nodes, tonsils, spleen, and the lymphatic tissue of the gut are secondary lymphatic organs.
Leukocytes are immune cells which circulate in blood. Macrophages, dendritic cells and mast cells are
primarily found in tissues.
FIGURE 10.2
Clonal selection of lymphocytes. Only the clone of lymphocytes that has the unique ability to recognize
the antigen of interest proliferates and generates progenitor cells. These cells are specific to the inducing
antigen, but may have different functions. In the case of B cells, plasma cell clones produce antibodies,
and memory cell clones enhance subsequent immune responses to the specific antigen.
FIGURE 10.3
Cellular and humoral immune responses of the adaptive immune system. Cellular immune
responses are accomplished by activated T cells, humoral immune responses are mediated by B cells and
antibodies. Exogenous antigen activates B cells by binding to the B cell receptor (BCR) and T cells by
binding to the T cell receptor (TCR). However, TCR binding only occurs when antigen peptide is
presented by antigen-presenting cells (APC) in association with major histocompatibility complex
(MHC). The TCR is either associated with CD4 or CD8, dependent on the T cell type. Endogenous
antigens are presented via MHC to cytotoxic T cells, which destroy the host cell together with the
intracellular pathogen.
FIGURE 10.4
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Antibodies and antigen receptors. Antibodies are immunoglobulins (Ig) with five isotypes (IgA, IgD,
IgE, IgG, IgM). The basic unit of each isotype is a monomer that consists of two heavy chains and two
light chains held together in a Y configuration by disulfide bonds. The heavy chains differ in the various
isotypes. IgG and IgD consist of one monomer, IgA of two, and IgM of five monomers. Each end of the
“Y” is called Fab since it is the fragment that contains the antigen-binding site. A second, crystablizable
fragment is called Fc. The B cell receptor resembles a membrane-associated Ig monomer. The T cell
receptor contains a Fab-like structure.
FIGURE 10.5
Complement. Complement (C) proteins “complement” antibody activity in a cascade of events to
eliminate pathogens. The endpoint is formation of a membrane attack complex (MAC), which inserts
into membranes of cells and causes their lysis. The classical pathway is activated by antigen-antibody
complexes. The alternate pathway is activated by pathogen surface molecules. The lectin pathway is in
response to inflammation. Most proteins exist in an inactive form. Two important activation enzymes,
C3 convertase and C5 convertase, are shown.
FIGURE 10.6
Integration of the immune system with the nervous and endocrine systems. Immune, endocrine, and
neuronal systems synthesize some of the same hormones, neuropeptides, thymosins and lymphokines,
which act as communication molecules and regulate body homeostasis.
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GLOSSARY TERMS
(For blood cells, see chapter 9)
Active immunity: Immunity due to activation of lymphocytes (natural), or immunity due to vaccination
(artificially)
Acute phase blood proteins: Serum proteins elevated during acute inflammation
Adaptive immune system: Antigen-specific immune response
AIDS: Acquired immunodeficiency syndrome caused by the human immunodeficiency virus (HIV)
Allergy: Type I immediate hypersensitivity disorder
Allo: greek: other
Allograft: Transplant between genetically different people
Anamnestic response: Increased immune response to repeated antigen exposure
Antibody: Secreted proteins that can bind antigen
Antigen: Substance that binds to antigen receptors and antibody
APC: Antigen-presenting cell. Cell displaying antigen on its surface together with MHC class II
Antigen-recognition molecules: TCR, BCR, MHC
Apoptosis: Non-immunogenic cell death
Atopy: Predisposition to becoming allergic
Auto: Greek: self
Autograft: Transplant grafted into a new position on the same person
BCR: B cell receptor. Antigen-specific receptor on B cells
Calor: Heat associated with inflammation
Cancer immunotherapy: Therapeutic use of natural immune system to fight cancer
CD: Cluster of differentiation. Distinct plasma membrane molecules used as cell markers
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Cellular immunity: Immunity mediated by activated T cells
Chemokine: Cytokine that attract and activate leukocytes
Clonal selection: Proliferation of specific lymphocytes (positive selection) or inhibition of growth
(negative selection)
Complement: Serum proteins that can be activated as part of a cascade of events that may lead to cell
lysis, formation of opsonins and regulation of inflammation
Cross-reactivity: Antibody that react with antigen closely related to the one that induced its formation
Cytokine: Communication molecules synthesized in response to immune stimuli
Dendritic cell: APC of epithelia and blood
Diapedesis
DNA vaccine
Dolor
Effector cell
Endotoxin
Epitope
Exudate
Functio laesa
Gamma globulin
Graft versus host disease
Graft:
Granzyme: enzymes present in the granules of cytotoxic T cells and NK cells which induce apoptosis in
the target cells. now called fragmentins.
Hapten small molecule which is immunogenic only when covalently linked to a carrier molecule.
Histamine
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HLA
Host versus graft disease
Humoral immunity
Hypersensitivity
Idiotype: the antigenic specificity of the variable (antigen-binding) region of an antibody or TCR
molecule.
Immune deficiency
Immune surveillance
Immune tolerance
Immunogen
Immunoglobulin
Immunological synapse
Inflammation
Innate immune system: Nonspecific defense mechanisms.
Interleukin: Cytokine made by one leukocyte and acting on another
Leukemia
LPS
Lymph node
Lymphatic organs: primary and secondary
Lymphocyte
Lymphokine: Cytokine made by lymphocytes
Lymphokine-activated killer cells
Lymphoma
MAC
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Macrophages
Margination
Mast cells
Memory cell
MHC: Major histocompatibility complex
Monokine: Cytokine made by monocytes
Necrosis
Opsonin:
Passive immunity: Immunity passed from mother to child (natural), and immunity obtained by injection
of foreign antibodies (artificially)
Pathogen
Perforin molecule used by NK cells and cytotoxic T cells (CTL) to make pores in the membranes of
target cells.
Phagocyte
Rh: Rhesus antigen.
Rolling
Rubor
Self-tolerance
Sepsis
TCR: T cell receptor
Thymus
Toll-like receptor
Toxoid inactivated toxin, often used as a vaccine against the toxin.
Vaccine: include attenuated
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