Invited Review
Principles of Immunology
Ashley K. Lentz, MD, and Robert J. Feezor, MD
Department of Surgery, University of Florida College of Medicine, Gainesville
ABSTRACT: The immune system, composed of innate
and acquired immunity, allows an organism to fight off
foreign pathogens. Healthy immunity accomplishes four
essential principles: (1) ability to detect and fight off
infection; (2) ability to recognize a hosts own cells as
self, thereby protecting them from attack; (3) a memory
from previous foreign infections; and (4) ability to limit the
response after the pathogen has been removed. In an
unaltered state, the intricate network of immunologic
organs and cells creates an environment for proper host
defense. Without adequate execution of immunologic
mechanisms, a host is rendered defenseless against patho-
gens. Conversely, an unchecked immune response can be
self-destructive. As a result of either of these untoward
sequelae, immune dysfunction can elicit disease states in
the host. The goal of this review is to elucidate the
characteristics of a healthy immune system, focusing on
the principles of immunity and the cells that participate in
host protection. We also briefly discuss the clinical rami-
fications of immune dysfunction.
The concept of immunology originally surfaced
centuries ago, and since then, the field has been the
focus of scientific inquiry and public speculation. In
430 BC, Thucydides wrote about a plague sweeping
through Athens in his work entitled History of the
Peloponnesian War. Historians have speculated that
this plague was in fact an outbreak of smallpox.1
Despite never identifying the agent responsible for
the plague, Thucydides astutely observed that peo-
pleincluding himselfwho survived an attack
never had the plague again. The concept of acquired
protection from disease was lost for centuries, in
part because of the churchs belief that disease was
punishment from God.
Correspondence: Ashley K. Lentz, MD, Department of Surgery,
University of Florida, College of Medicine, PO Box 100286,
Gainesville, FL 32610-0286. Electronic mail may be sent to
lentz@surgery.ufl.edu.
0884-5336/03/1806-0451$03.00/0
Nutrition in Clinical Practice 18:451460, December 2003
Copyright 2003 American Society for Parenteral and Enteral Nutrition
451
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It was not until 1798 that Edward Jenner pub-
lished a landmark discovery that propelled the sci-
ence of immunology into the everyday life of common
man.2 He observed that the incidence of smallpox
was dramatically decreased in milkmaids and
hypothesized that some immunologic mediator,
which was later identified as cowpox, protected
them from succumbing to this deadly illness. To test
his theory, Jenner collected pus from cowpox sores
located on the hands of milkmaids and inoculated an
8-year-old boy.2 He successfully transferred the
milkmaids resistance to the boy and, in doing so,
created the modern vaccination.
To better understand the processes of immunol-
ogy, one must first appreciate the ideals or princi-
ples inherent to a competent immune system. Vio-
lations of these principles often are the basis of
disease states. Additionally, one should acquire an
appreciation of the machinery involved in host
defense, namely, the organs and cells that function
as part of the immune system. The goal of this
review is to provide a solid overview of the funda-
mental concepts of medical immunology. It should
be recognized that immunology, perhaps more than
any other field in the medical sciences, is in rapid
evolution, and many of the facts learned today will
become modified, tailored, or even outright dis-
proved as research evolves. Modulation of the
immune system has been a focus of research in
terms of preventing and fighting infections, elimi-
nating cancers, and limiting inflammation.311
Basic Principles of Immunity
Immunity is the term used to describe the
defenses of the body that offer protection against
foreign pathogens, called antigens. The immune
system allows an organism to respond to noninfec-
tious and inflammatory stimuli while it maintains a
balance of reactive and counteractive responses
between the host and its surroundings. The immune
system may be incompetent either because of a
failure to recognize antigens or a failure to respond
effectively. When either of these inappropriate
responses occurs, the host succumbs to infection. On
the other hand, when the immune system is overac-
tive, the protective mechanisms act in a detrimental
manner, as in the case of autoimmune diseases.
452 LENTZ AND FEEZOR
The immune system is composed of two functional
components: the innate and the acquired immune
systems. The innate system requires no external
stimuli to initiate a response and is believed by some
to have evolved in multicellular organisms as a way
to reduce the sequelae of established infection.12,13
By contrast, the inception of the acquired system
occurs at the time of pathogen detection and is
highly specific for the microbial antigen. A healthy
immune system possesses four key qualities: (1) the
capacity to detect and fight off potential infections;
(2) the ability to recognize the hosts own cells as
self; (3) a retained memory from previous attacks;
and (4) the ability to limit its responses after remov-
ing the offending agent.
The cells and organs of the immune system are
specifically designed to patrol the host for potential
sources of infection, recognize the challenge, and
mount a counterattack. Not surprisingly, there is a
preponderance of immune cells at the most likely
points of entry of invading organisms: the skin and
gastrointestinal tract. Once a challenge is detected,
cellular signaling enables immune cells to initiate,
coordinate, and govern an appropriate response. All
immune cells have a tremendous capacity to com-
municate with each other through chemical media-
tors called cytokines. Depending on the type of
infection detected by the surveying cells, various
amounts of different cytokines are produced, which
then change the nature of the response. In this
regard, the immune system can tailor its response
according to the infection detected. Once the signals
are relayed, the immune system has immense capac-
ity to attract effector cells to kill the offending agent.
This attack involves release of chemical stressors
placed on the agent, neutralization of its noxious
properties, ingestion of the agent by the immune
cells, or even mechanical disruption of the cellular
integrity of the agent.
Integrated into the ability to fight off infection is
the ability of the competent immune system to
distinguish self from nonself. This attribute pre-
vents the hosts own defenses from attacking the
very body it is designed to protect. Each cell within
the body (with the exception of red blood cells) has a
molecule on its surface known as the major histo-
compatibility complex I (MHC I).14,15 Except for
identical twins, no two humans have exactly the
same MHC I molecules. Immune cells recognize the
specific MHC I molecules as self and do not attack
it. This fact not only keeps cells of the immune
system from attacking the hosts own tissue but also
explains the biologic phenomenon of rejection of
transplanted organs, which have different MHC
molecules.
The memory of the immune system enables an
organism to mount an attack against pathogens
years after primary exposure, a trait that is
exploited with vaccinations. Without this, each new
exposure would need the generation and prolifera-
tion of a completely new response tailored to the
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Vol. 18, No. 6
stimulus. Instead, the body stores its responders in
small quantities, and when an antigen is reencoun-
tered, that specific antibody is called back and mul-
tiplied. Often, the reactivation or secondary response
is more intense than the initial one.
Last, the immune system needs to be self-limited
and should be extinguished after the offending agent
is cleared. This aspect of immunology has recently
been explored, and it is now thought that a sus-
tained overactive response to an inflammatory chal-
lenge results in the multiorgan failure and even
death that is seen following severe trauma, infec-
tion, or burn injury.16,17 In fact, it may be that the
bodys ability to limit the infection response is as
important as the ability to mount the attack in the
first place.
Organs and Cells of the Immune System
Biologic structure dictates that cells work
together to form tissue, tissues work together to
form an organ, and organs work together to form a
system. For example, several types of alveolar epi-
thelial cells work together to form alveoli (the air-
exchanging portions of the lung). Alveoli coordinate
to form a functioning lung, and the lungs, together
with the trachea and pharynx, form the respiratory
system. By contrast, the immune system is not
physically distinct. Most of the pathogen-fighting
function of the immune system is accomplished by
specific types of white blood cells known as lympho-
cytes, either as individual cells or as aggregates of
immune system tissue known as lymphoid tissue.
Although many lymphocytes circulate throughout
the body, others are kept separate from circulating
blood or have translocated outside of the blood
vessels. Several organs and other aggregates of
lymphoid tissue are needed for the genesis, develop-
ment, and preservation of these circulating effector
cells.
Tissues and Organs of the Immune System
Lymphoid tissue can broadly be classified into
generative and peripheral organs. The generative or
primary lymphoid organs, in which lymphocytes
develop, are the bone marrow and thymus. Within
the bone marrow, a progenitor stem cell differenti-
ates into separate lineages, which will in turn pro-
duce differing cell types.18 Stem cells have the
potential to become an erythrocyte, platelet, granu-
locyte, lymphoid progenitor cell (which then can
become a T cell or a B cell), or monocyte. Cytokines
signal the cell to respond in a certain way, thereby
enabling the proliferative process and maturation of
cells into effector cells. Depending on the concentra-
tion and types of cytokines present, the stem cell will
become any one of a number of other cells, a process
known as hematopoiesis (Fig. 1).18 In this way, the
production of these effector cells is governed by the
extracellular signals within the generating organ.
December 2003 PRINCIPLES OF IMMUNOLOGY 453

Figure 1. In adult life, hematopoiesis takes place within the bone marrow. Stem cells are pluripotent cells that are
capable of differentiating into any other cell type. The functional mature immune cells arise from stem cells that
differentiate into one of two cell lines: myeloid or lymphoid. Lymphoid cells give rise to T or B cells and memory cells and
plasma cells. Myeloid cells give rise to erythrocytes, platelets, monocytes, and granulocytes. CTL, cytotoxic T cell; TH, T
helper cell; Tc, T cytotoxic cell.

Before their release from generative organs, lym-
phocytes are checked for the ability to detect self
from nonself. As discussed earlier, if this safeguard
fails, an autoimmune phenomenon arises, aptly
described by Paul Ehrlich as the horror intoxi-
cus.19 By nature, all humans have the potential to
manifest autoimmune diseases unless there is inac-
tivation and destruction of self-reactive lymphocytes
at this early stage.
In contrast to generative organs of the immune
system, peripheral (secondary) lymphoid tissue is
positioned throughout the body, which allows lym-
phocytes to interact with antigens closer to the point
of their invasion of the host. The peripheral immune
organs include the lymph nodes, spleen, mucosa-
associated lymphoid tissue, and the cutaneous
immune system. These aggregates of tissue respond
when effector cells detect a foreign antigen and
present or show it to cells within a lymphoid
organ. It is then that the body can mount a very
specialized and specific response to that pathogen.
Lymph nodes are small nodules composed of lym-
phoid tissue scattered throughout the body along
lymphatic chains. There is an abundance of lymph
nodes in the groins, axillae, and neck, which are
often enlarged during infections of the legs, arms,
and throat, respectively. Lymph nodes are con-
nected by microscopic channels that assist with the
drainage and collection of lymphatic fluid from the
skin, gastrointestinal (GI) tract, mucosa, and respi-
ratory tract. Each lymph node has three regions, the
cortex, paracortex, and medulla, and each maintains
a role in lymphocyte maturation.
The spleen is located within the left upper quad-
rant of the abdomen and protected by the lower
portion of rib cage. Antigens are presented to it by
way of the splenic artery, one of the bodys major
blood vessels. The spleen has two compartments: red
pulp and white pulp. Old red blood cells, no longer
functional for carrying oxygen, are destroyed within
the red pulp, whereas the white pulp consists mostly
of lymphocytes that are poised to have an antigen
presented to them.
Mucosa-associated lymphoid tissue (MALT) con-
sists of clusters of lymphoid tissue found just
beneath the lining of the intestine, tonsils, and
appendix. It is also found in globular aggregates
within the walls of the small intestine, a histologic
configuration known as a Peyers patch. This tissue
provides defense against mucosal-invading antigens
commonly found in the diet. Specialized cells, called
M cells, are present within mucous membranes and
assist in recognizing antigens and mounting a
defense within the mucosal surface. Much like the
intestinal epithelium, the skin provides a physical

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454 LENTZ AND FEEZOR
barrier to the environment and therefore plays an
active role in host defense.
Cells of the Immune System
As stated earlier, the immune system is not a
physically distinct group of organs, but rather, the
cells of the immune system circulate through the
body from the lymphatic spaces and the skin to the
blood and lymphoid organs. This pervasive anatomic
organization allows the effector cells to interact with
antigens on any front and mount an immune
response rapidly.
However, no rapid response could exist without
the effector cells, the lymphocytes. There normally
are 5000 to 10,000 white blood cells per milliliter of
circulating whole blood, and lymphocytes normally
constitute 20% to 40% of the total white blood cell
population. They may be divided into three groups:
B cells, T cells, and null cells. B cells mature within
the bone marrow and, when presented with a foreign
antigen, express a binding receptor on the surface
that is specific for a particular region of this antigen.
These receptors, called antibodies (Fig. 2), are mem-
brane-bound glycoproteins that recognize and bind
antigens. Once antigen-antibody binding occurs, the
B cell proliferates into memory cells and plasma
cells. Memory cells circulate for years, carrying the
same specificity for the particular antigen as the
parent B cell. On the other hand, plasma cells
produce antibody to be released into circulation.
Plasma cells have a much shorter life span than the
memory cell, yet each plasma cell is capable of
producing enormous quantities of antibodies.
In contradistinction to B lymphocytes, T lympho-
cytes exit the bone marrow and travel to the thymus,
where they subsequently mature. T cells express
surface receptors that recognize antigens presented
Figure 2. Immunoglobulins are composed of 2 light chains
and 2 heavy chains. The constant portion (Fc) anchors the
antibody, whereas the variable portion (Fab) is comple-
mentary to the offending antigen.
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Vol. 18, No. 6
by other immune cells. The antigens recognized by T
cells are bound to a MHC molecule. T cells prolifer-
ate into memory T cells and effector T cells. Effector
T cells exist as either T helper cells (TH) or T
cytotoxic cells (TC), each distinguished by specific
proteins on their surfaces. TH cells express the
surface protein CD4, whereas TC cells express CD8.
Stimulation with an antigen causes TH cells to
secrete cytokines to drive the differentiation and
proliferation of progenitor cells within the marrow.
In this way, the immune system is a self-propelling
phenomenon, and the host does not need repeated
stimulation with a pathogen to mount a successful
response.
TC lymphocytes eliminate cells that produce anti-
gens and cells infected with viruses, microbes, or
tumor. These cells predominantly recognize cells
that have been infected with an intracellular patho-
gen, bind to the infected cell, and then kill it either
by secreting a noxious chemical directly into the
infected cell or by activating enzymes within the
infected cell that cause it to ingest its own DNA.19
The null cell is the third class of lymphocyte and
typically called a natural killer cell (NK cells). This
subtype represents a minority of circulating lympho-
cytes and of splenic lymphocytes and is rarely found
in the lymph node. This cell has the ability to lyse
infected cells without the presence of a specific
receptor because it recognizes cells without a MHC
molecule. NK cells kill target cells via a process
called antibody-dependent cell-mediated cytotoxicity.
The mononuclear phagocytic system consists of
circulating monocytes and macrophages. Monocytes
are released from the bone marrow into the circula-
tion and have the capacity to differentiate into a
macrophage. The macrophage, in turn, usually
edges out of the circulation through pores in the
blood vessel wall (translocates) and is deposited into
different tissues. Different macrophage populations
reside in specific bodily locations: for example,
Kupffer cells are macrophages of the liver and his-
tiocytes are macrophages within connective tissue.
A macrophage has a vast potential to become acti-
vated with the onset of an immune response, which
triggers the release of inflammatory mediators and
other chemicals that serve to attract even more
inflammation-inducing cells and chemicals. Ulti-
mately, the protective actions of the macrophage
assist in the release of inflammatory mediators,
activation of the TH cell, and elimination of patho-
gens by phagocytosis (the ingestion and digestion of
an antigen).
Granulocytic cells, so named because histologi-
cally they seem to contain granules within their
cytoplasm, include polymorphonuclear cells (neutro-
phils), eosinophils, and basophils. Despite histologic
and functional differences, each of these cell types is
still classified as a leukocyte. Neutrophils increase
in number in response to an acute bacterial infec-
tion. Clinically, patients manifest with a leukocyto-
sis, or increase in total leukocyte count, with a left
December 2003 PRINCIPLES OF IMMUNOLOGY
shift, indicating a predominance of neutrophils and
their immature forms. Neutrophils participate in
phagocytosis and typically are among the first
responders to an immune challenge. Eosinophils
also phagocytize particles, yet they are most appre-
ciated for their role in parasitic infection and imme-
diate hypersensitivity (allergic) reactions. Basophils
do not participate in phagocytosis; rather, they
release chemical mediators from their cytoplasmic
granules, and they, too, play a major role in allergic
responses.
An accessory cell important in the induction of
immune response is the dendritic cell. Two types of
dendritic cells exist: interdigitating dendritic cells
and follicular dendritic cells. Interdigitating den-
dritic cells are found in the lymph nodes and in
many organs, including the liver, heart, lungs, GI
tract, spleen, and throughout the epidermis of the
skin. Just as special nomenclature exists for macro-
phages within certain body organs, dendritic cells
found in the skin are called Langerhans cells. Den-
dritic cells are among the best cells in the body at
trapping antigen and taking it to regional lymph
nodes for destruction and presentation to B cells.
Innate Immunity
Innate or nonspecific immunity offers basic pro-
tection to disease and is composed of anatomic,
chemical, mechanical, and cellular barriers. It is not
stimulated through exposure to a foreign antigen
but rather is always present and functioning. Innate
immunity begins with the anatomic barrier that
includes skin and mucous membranes. In addition
to offering physical protection, the skin has an
increased acidity in which most organisms cannot
survive. On the other hand, mucus traps organisms
and dispels them from the host with the help of the
hairlike cilia present on many mucosal surfaces. The
best example of the protection afforded by cilia is the
sneeze, which occurs when particulate matter irri-
tates the nasopharyngeal cilia, triggering coordi-
nated muscular propulsions of the particles back out
of the nose and mouth.
In addition to physical barriers, the innate
immune system has chemical protection. Bodily
secretions including sweat, saliva, mucus, and tears
carry a hydrolytic enzyme called lysozyme that
destroys bacteria by breaking down their cell walls.
Penetration of a foreign body into the skin will result
in an inflammatory response. This response includes
the influx of phagocytic cells and chemical mediators
to the site of tissue damage.
Monocytes, macrophages, and neutrophils are all
capable of ingesting pathogens through phagocyto-
sis. Once the antigens are ingested, phagocytes
release chemical factors that recruit additional
pathogen-fighting cells.
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455
Acquired Immunity
Acquired immunity differs from innate immunity
because these cells mount a specific attack and later
remember antigen exposure. The cells in specific
immunity assist the innate immune system through
up-regulation of its immune mechanisms. Lympho-
cytes and antigen presenting cells are required for
effective specific immunity. The subsystems within
specific immunity are the humoral immunity and
cell-mediated immunity. Humoral immunity
depends on B lymphocytes for their recognition of
antigen and their proliferation into memory and
plasma cells. Once B cells recognize antigens, they
are programmed to produce and release antibodies.
Antibodies, or immunoglobulins, consist of two heavy
chains and two light chains in the shape of a Y (Fig.
2). The two light chains are each bound to a heavy
chain, and this pairing creates a Fab fragment that
is responsible for the interaction with the circulating
antigen. The FC portion of the immunoglobulin
structure refers to the location of the immunoglob-
ulin molecule in which the 2 heavy chains pair
together. The FC region is distinct from the Fab
fragments, and it binds in order to activate the
immune cells. Immunoglobulins are capable of sur-
rounding the antigen and in essence, flagging it for
easier recognition by phagocytic cells. Antibodies
can also surround antigens in such as way so as to
render them inactive by preventing adherence to
additional host cells.
Once antibodies have bound to the offending
antigen, these antigen-antibody complexes activate
the classic pathway of the complement cascade. The
complement system plays a large role in humoral
immunity as it destroys cells, viruses, and bacteria
once activated by antigen-antibody complexes.
Five types of immunoglobulin (Ig) classes exist:
IgG, IgD, IgE, IgA, and IgM. They are distinguished
from each other via their individual heavy chain
amino acid sequences. IgG is released from B cells
and functions as the predominant immunoglobulin
found in serum. It circulates in the vessels, yet is
capable of crossing into the tissues and coating
antigens. Additionally, a distinct property includes
the ability to cross the placental barrier, allowing
immunologic protection from a mother to her unborn
fetus.20 IgD differs from IgG in that its FC portion
remains bound to the B cell. This membrane bound
molecule plays a role in activation of the B cell,
although the exact mechanism is not completely
understood. IgE mediates the hypersensitivity aller-
gic reaction. Again, the FC portion binds to receptors
on basophils, eosinophils, and mast cells, thereby
causing spillage of their cellular contents. This pro-
cess is known as degranulation because these cells
appear granulated microscopically, and when the FC
portion binds, the contents of these granules (eg,
histamine) are released. The release of histamine
can trigger a variable clinical response, from a mild
reaction consisting of skin redness and slight itching
456 LENTZ AND FEEZOR Vol. 18, No. 6

to full-blown anaphylaxis with airway obstruction
and complete circulatory collapse. Among the factors
that influence the strength of the IgE-mediated
response are genetic predispositions, history of expo-
sure, and nature of the antigen.19 Genetic predispo-
sitions in certain individuals manifest as high con-
centrations of IgE, causing an abnormally high
familial prevalence of such disorders as hay fever,
asthma, and eczema.19
The two final immunoglobulins do not exist alone;
rather, they bind to other similar immunoglobulins.
IgA exists as a dimer or tetramer in the MALT and
other secretory regions. This immunoglobulin plays
a large role in defense against organisms that invade
the mucosal surfaces. Importantly, breast milk con-
tains IgA to assist the immunodeficient infant. Chil-
dren who are breast-fed are known to have a
reduced incidence of respiratory tract infections, ear
infections, and infection-induced wheezing com-
pared with non breast-fed cohorts.21 This immune
protection attributed to IgA appears to extend
beyond the breast-feeding period22 and may even be
responsible for a decrease in the number of allergies
experienced once the child gets older.21 Finally, IgM
can be found alone on the surface of B cells or in
pentameric form in the serum. The pentamer allows
the molecule to bind numerous antigens simulta-
neously.
In contrast to humoral immunity, which relies on
the production of antibodies specific for the offend-
ing antigen, cell-mediated immunity depends on T
lymphocyte activity. T cells differ from B cells in
that they are only capable of recognizing antigens
that are presented by antigen presenting cells. Mac-
rophages, dendritic cells, and B cells all are capable
of presenting antigen to T cells. They internalize
antigens and then display portions of those antigens
on their surfaces together with an MHC molecule.
Recall that there are two types of major histocom-
patibility complex molecules: types I and II. Type I
molecules are glycoproteins found on all nucleated
cells, and antigens presented by MHC I molecules
are recognized by cytotoxic T lymphocytes only. In
comparison, class II MHC molecules are recognized
by helper T lymphocytes. Once activated, a T lym-
phocyte secretes cytokines that activate phagocytic
systems. T helper cell activation is required for both
humoral and cell-mediated immunity.
Cytokines
It should be clear that if the immune system is to
function properly, the ability of immune cells to
communicate with each other is paramount. They do
this largely through the use of chemical messages
called cytokines (Table 1). Both innate and acquired
immunity function through the use of cytokines.
Because innate immunity is mostly mediated by
mononuclear phagocytic cells, the cytokines
involved in innate immunity are collectively known
as monokines. By contrast, activated T lymphocytes
produce the majority of cytokines involved in

Table 1
Cytokines: chemical messages that enable cells of the immune system to communicate with each other to coordinate the hosts
response to immune challenge*

Name (abbreviation) Cell(s) of origin Principal function

Tumor necrosis factor- Macrophage Proinflammatory; stimulates the innate immune

response
IL-1 Activated mononuclear phagocytes Mediator of local inflammation; promotes
coagulation
IL-2 T cells Stimulates growth, activation, and cytokine
production
IL-6 Mononuclear phagocytes, vascular Stimulates acute phase response by activating
endothelial cells, fibroblasts hepatocytes; acts as a growth factor of B
cells
IL-10 T helper cells Inhibits cytokine production by macrophages,
thereby inhibiting T cellmediated immune
reaction
IFN- Monocytes, macrophages Antiviral; inhibits B cell and monocyte
proliferation
IFN- Fibroblasts Increases host response to viruses
IFN- Activated TH cells Activates monocytes and macrophages
Transforming growth factor- T cells, mononuclear phagocytes Inhibits activation and proliferation of T cells
and mononuclear phagocytes
Granulocyte-macrophage Activated mononuclear phagocytes, vascular Stimulates hematopoiesis of all cell lines
colony-stimulating factor endothelial cells, fibroblasts
Macrophage colony- Mononuclear phagocytes, endothelial cells, Stimulates proliferation of macrophages;
stimulating factor fibroblasts activates mature macrophages

*Listed are several of the more well-described cytokines; this list is not meant to be complete.
IFN, interferon; IL, interleukin.

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December 2003
acquired immunity, and therefore these cytokines
are referred to as lymphokines.19
Cytokines can be either proinflammatory or anti-
inflammatory, and each cytokine has specific recep-
tors on cells they are designed to influence. Much
medical research has focused on quelling the produc-
tion of pro-inflammatory cytokines, or blocking the
ability of the cytokines to bind, but these efforts
have been largely unsuccessful.23 Part of the failure
has been attributed to the improper timing of the
attempted therapy, the heterogeneity of the patient
population being studied, and the redundancy of the
cytokine-mediated inflammatory pathways.24
It was originally thought that cytokines were
released into the bloodstream and therefore could be
detected throughout the body. It is now believed that
some cytokines are released near the site they are
needed, and hence their systemic levels are essen-
tially zero.12 Nevertheless, their main functions are
to attract effector cells, activate them, and then to
further recruit cells to assist in the defense and
subsequent reparation phase.
The innate immune response is regulated by the
cytokines tumor necrosis factor-, interleukin
(IL)-1, IL-4, IL-6, IL-12, and interferon-.12 How-
ever, these same cytokines are involved in the initi-
ation and propagation of the acquired immune
response, demonstrating the unequivocal overlap in
Table 2
Selected clinical syndromes resulting from dysfunctions in immunity*
Name
Loss of defense abilities
AIDS
Severe combined immune deficiency syndrome
DiGeorges syndrome
Loss of self-tolerance
Systemic lupus erythmatosus
Hashimotos thyroiditis
Rheumatoid arthritis
Uncontrolled, exaggerated immune response
Poststreptococcal glomerulonephritis
Polyarteritis nodosa
*Predominantly, immune-mediated diseases are either deficiencies in protecting the host against foreign pathogens or losses in the ability to
maintain self-tolerance.
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PRINCIPLES OF IMMUNOLOGY 457
the two systems.12 The end result of the activation of
the innate immune response by these cytokines is
widespread and includes neurologic, endocrine,
hematopoietic, metabolic, and hepatic alterations.
Although the innate immune system uses cyto-
kines to activate and sustain its response, the
acquired immune system requires cytokines for the
fine-tuning of the specific response.12 As mentioned
above, the balance of the different cytokines influ-
ences the maturation process of progenitor cells.
Diseases of the Immune System
The disorders of the immune system, as expected,
can range from the mild and almost undetectable to
the uniformly fatal. These dysfunctions can be
inherited or acquired (naturally or iatrogenically)
and can be evident at birth or may manifest later in
life. However, not all of the disorders of regulation of
the immune system are a dysfunctional or incompe-
tent system: patients can also be affected by an
overactive immune system with deleterious effects.
For reference, Table 2 contains some of the named
disorders of the immune system.
The most common type of immune hyperactivity
is the simple allergy. As described above, IgE anti-
body corresponding to the offending antigen binds
via an Fc receptor to a granulated cell, which
Immune dysfunction Clinical manifestation
T cell dysfunction Cachexia, malignancy,
opportunistic infection
Deficient lymphocytes Early onset of infections that are
resistant to treatment
Depressed T cell immunity Abnormal faces, lowset ears,
hypothyroidism, congenital
heart disease, recurrent chronic
infection
Auto-antibodies against DNA and Nephritis, arthritis, vasculitis
nuclear proteins
Auto-antibody to thyroglobulin and Enlarged thyroid, decreased heart
thyroid peroxidase rate, fatigue, forgetfulness,
depression, dry skin
Auto-antibody to the Fc portion of Stiffness and joint pain, deformity
IgG in serum and synovial fluid of multiple joints
Immune complexes of Glomerulonephritis
streptococcal antigen and
corresponding antibodies
deposited in the kidneys
Ig and complement deposits in the Fever, fatigue, myalgia, weight
walls of blood vessels cause loss
vasculitis of medium-sized
arteries
458 LENTZ AND FEEZOR
becomes activated and releases histamine, produc-
ing an allergic reaction. The basis of the antiallergy
pharmaceutical industry is in decreasing the hyper-
response without suppressing the requisite immune
function of the host.
The most common type of immune deficiency is the
selective immunoglobulin deficiency.25 These patients
may have mild reactions from occasional respiratory
infections to permanent airway or gastrointestinal
damage from overwhelming infections. Replacement
therapy has become a mainstay of therapy for these
patients.25 Other inherited immunodeficiencies
include congenital T-cell deficiency (DiGeorges syn-
drome), combined immunodeficiency (severe com-
bined immunodeficiency disease), and others.
The best-know acquired immunodeficiency is
acquired immunodeficiency syndrome (AIDS). AIDS
primarily affects TH cells, macrophages, and dendritic
cells in lymph nodes19 and renders patients suscepti-
ble to opportunistic infections (ones against which a
competent immune system could defend) and even
specific forms of cancer (Kaposis sarcoma). Besides
AIDS, however, there are other more common
acquired immunodeficiencies, including malnutrition,
cancer, and even infection per se. Increasingly more
common are patients who are iatrogenically immuno-
suppressed through drugs such as corticosteroids,
cyclosporine, tacrolimus, or chemotherapies.
Because many malignancies produce antigens
distinct from those recognized as self by normally
functioning immune systems, many scientists have
been attempting to develop vaccines against these
antigens. Several hundred have been identified, but
the ability to activate and sustain specific T cell
responses has escaped researchers.26 Once achieved,
this will represent a major breakthrough in oncol-
ogy, allowing intense chemotherapy to the target
malignant cells without the systemic toxicities of
current drugs. In this regard, Jenners idea of a
vaccination has been expanded, and the vaccine
would be used to treat existing disease instead of
being a mere prevention.
Because one of the key features of a competent
immune system is to recognize nonself, by very
definition, transplantation of an organ from one
individual to another violates the ideals of immunol-
ogy. Physicians purposely place transplant recipi-
ents on immunosuppressant drugs (eg, prednisone,
cyclosporine, or tacrolimus) to keep the body from
rejecting its new organ. There is a balance between
level of immunosuppression to prevent transplant
rejection and still having enough defense capabili-
ties for the host to fight off environmental infec-
tions. Interestingly, identical twins have a distinct
advantage because they possess the same genetic
constitution, and the immune system from one
twin will view the organ received from the other as
self.
Asthma and allergies (whether food, seasonal,
insects, etc) are predicated upon a hyperresponsive-
ness to an environmental pathogen. The reactions
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Vol. 18, No. 6
can be as variable as the inciting agents. Because
proteins have particularly immunogenic antigens,
the reactions seen with peanut allergies can be
impressive. Similarly, asthma is primarily an air-
way inflammatory disease with secondary bronchio-
lar constriction. For most allergic reactions, the
treatment of choice is avoidance of the offending
agent. Once a reaction ensues, the mainstays of
therapy are blocking the mediators of the immuno-
logic response, global immunosuppression, and sup-
portive care. Histamine blockers (eg, diphenhydra-
mine) help prevent some of the effectors of the
reaction and may be the only agent needed in milder
reactions. Full-blown allergic reactions can be char-
acterized by circulatory collapse and intense airway
edema, requiring vasopressors and intubation.
Not all clinical sequelae of immune dysfunction
are due to related external antigenic stimulation.
The immune system plays a role in the bodys
response to injury, and in fact, some theorists now
propose that the immune system responds to inter-
nal danger signals as opposed to external stimu-
li.27 Severe trauma with associated soft tissue injury
is associated with an intense inflammatory and
subsequently an anti-inflammatory reaction.16,17 If
the response is exaggerated, the immune system
originally designed to defend the body becomes
harmful, and patients develop multiorgan failure,
including pulmonary, neurologic, renal, hepatic, and
cardiac damage. For decades, scientists have been
trying to modulate the immune response to severe
infection and injury in hopes of decreasing late
mortality. Despite successes in animal models of
systemic infection, little advances have been made
in human studies.28 31
As technologies have evolved, immune-modulat-
ing research has shifted from attempts to block or
add a single cytokine to a global assessment of
genetic responses and predispositions. Different
groups have noted that there is individual variation
in levels of cytokines generated in response to sim-
ilar inciting events, and these variations may be
genetic. For example, the part of the gene encoding
a particular cytokine may be altered in a minority of
the population, rendering them more susceptible to
morbidity and mortality after injury or sepsis,3237
or have a worsened clinical course in the cases of
rheumatoid or juvenile arthritis,38,39 renal trans-
plantation,40 ulcerative colitis,41 psoriasis,42 menin-
gococcal disease,43 or even coronary artery dis-
ease.44 Clearly, these studies are at present
associative and not causative, but they collectively
tend to suggest that inherent variation in genes
causes different people to respond to immune-stim-
ulating challenges in divergent ways.
Conclusion
A competent immune system functions to defend
the host against foreign antigens and respond to
December 2003 PRINCIPLES OF IMMUNOLOGY
inflammatory stimuli in such a manner as to main-
tain homeostasis. The innate immune system is a
generalized, nonspecific response to external stim-
uli, whereas the acquired system uses specialized
cells and lymphocytes that are poised for pathogen
detection and destruction. The systems are inte-
grated in their responses and depend on cytokines in
order to communicate with each other. Without this
complex interwoven system of checks and balances,
organisms are susceptible to infection, cancer, and
autoimmune dysfunction.
Glossary
Acquired immunity. Also called specific immunity,
this type of immunity is responsible for the develop-
ment of cells in response to an antigen. It may be
divided into two separate systems, humoral and
cell-mediated immunity.
Antibody. A protein found in circulation or
attached to cells that binds to antigens and assists
in humoral immunity. This is also referred to as an
immunoglobulin.
Antibody-dependent cell-mediated cytotoxicity. A
form of cellular lysis, performed by natural killer
cells, that is dependent of the presence of IgG
antibodies.
Antigen. A foreign protein marker on a cell that
induces specific immunity.
Basophil. A type of granulocytic cell that releases
its cellular contents and plays a role in allergic
responses.
B lymphocyte. A cell that is derived from a stem
cell within the bone marrow. This cell may differen-
tiate into memory cells and plasma cells, and ulti-
mately it is responsible for the production of anti-
bodies.
Bone marrow. Organ responsible for the produc-
tion and maturation of immune cells.
Cell-mediated immunity. A form of specific immu-
nity dependent on T lymphocyte recognition of anti-
gens in the context of a major histocompatibility
complex molecule.
Complement. A system that helps to destroy cells,
viruses, and bacteria once it is activated.
Cytokine. Chemical signals released by cells that
trigger the proliferation and maturation of immune
cells.
Dendritic cell. A cell that traps antigens and
presents them to B cells for destruction or presents
antigen to T-helper cells.
Eosinophil. A cell that phagocytizes foreign parti-
cles and plays a role in allergic reactions and para-
sitic infection.
Erythrocyte. Also called a red blood cell, this cell is
responsible for carrying oxygen within the circula-
tory system.
Fab fragment. A portion of the antibody/immuno-
globulin molecule that noncovalently binds to an
antigen.
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459
Granulocyte. A cell that contains immunologically
active granules within its cytoplasm. These include
neutrophils, basophils, and eosinophils.
Humoral immunity. This portion of the immune
system is responsible for B lymphocyte recognition
of antigen and proliferation of the lymphocyte into
memory and plasma cells.
Innate immunity. A defense mechanism that
offers basic protection to disease, including skin and
mucous membranes.
Lymph node. An accumulation of lymphoid tissue
that allows interaction between antigens and cells of
the immune system.
Lymphoid progenitor cell. A cell that can prolifer-
ate into a B lymphocyte or T lymphocyte.
Macrophage. A cell that functions as an antigen-
presenting cell, plays a major role in activation of
the T lymphocytes, and functions as a phagocyte.
Memory cell. A type of T or B lymphocyte that has
the ability to remember foreign antigens and
mounts an immune response against them.
Monocyte. A cell released from the bone marrow
that differentiates into a macrophage.
Mucosal associated lymphoid tissue (MALT). Tis-
sue found in the intestine, tonsils, and appendix
that offers defense against mucosal invading
organisms.
Neutrophil. A type of granulocyte that is one of the
first cells present during a bacterial infection that
assists in phagocytosis of foreign material.
Null cell/natural killer cell. A type of lymphocyte
with the ability to lyse infected cells.
Plasma cell. A type of B lymphocyte that releases
antibodies into circulation.
Spleen. An organ responsible for destruction of
erythrocytes, whereas it also offers a location for
antigen-lymphocyte interaction.
Thymus. A gland that allows the maturation of T
lymphocytes.
T lymphocyte. A cell that is derived from the bone
marrow and matures in the thymus. It is responsible
for the recognition of antigens and mounting an
immune response.
T-cytotoxic cell. A type of T lymphocyte that elim-
inates cells infected with virus, microbe, or tumor.
T-helper cell. A type of T lymphocyte that secretes
cytokines and helps to stimulate an immune
response.
Translocation. Movement of particles across a
membrane.
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