Introduction to the Immune Response and Inflammation

Glossary of Key Terms

 antibodies: immunoglobulins; produced by B cell plasma cells in response to a specific protein;

react with that protein to cause its destruction directly or through activation of the
inflammatory response
 antigen: foreign protein
 arachidonic acid: released from injured cells to stimulate the inflammatory response through
activation of various chemical substances
 autoimmune disease: a disorder that occurs when the body responds to specific self-antigens to
produce antibodies or cell mediated responses against its own cells
 B cells: lymphocytes programmed to recognize specific proteins; when activated, these cells
cause the production of antibodies to react with that protein
 calor: heat, one of the four cardinal signs of inflammation; caused by activation of the
inflammatory response
 chemotaxis: property of drawing neutrophils to an area
 complement proteins: series of cascading proteins that react with the antigen–antibody
complex to destroy the protein or stimulate an inflammatory reaction
 dolor: pain, one of the four cardinal signs of inflammation; caused by activation of the
inflammatory response
 Hageman factor: first factor activated when a blood vessel or cell is injured; starts the cascading
reaction of the clotting factors, activates the conversion of plasminogen to plasmin to dissolve
clots, and activates the kinin system responsible for activation of the inflammatory response
 interferon: tissue hormone that is released in response to viral invasion; blocks viral replication
 interleukins: chemicals released by white blood cells (WBCs) to communicate with other WBCs
and to support the inflammatory and immune reactions
 kinin system: system activated by Hageman factor as part of the infl ammatory response;
includes bradykinin
 leukocytes: white blood cells; can be neutrophils, basophils, or eosinophils
 lymphocytes: white blood cells with large, varied nuclei; can be T cells or B cells
 macrophages: mature leukocytes that are capable of phagocytizing an antigen (foreign protein);
also called monocytes or mononuclear phagocytes
 major histocompatibility complex: the genetic identifi cation code carried on a chromosome;
produces several proteins or antigens that allow the body to recognize cells as being self-cells
 mast cells: fixed basophils found in the respiratory and gastrointestinal tracts and in the skin,
which release chemical mediators of the inflammatory and immune responses when they are
stimulated by local irritation
 myelocytes: leukocyte-producing cells in the bone marrow that can develop into neutrophils,
basophils, eosinophils, monocytes, or macrophages
 phagocytes: neutrophils that are able to engulf and digest foreign material
 phagocytosis: the process of engulfing and digesting foreign pyrogens
 pyrogen: fever-causing substance
  rubor: redness, one of the four cardinal signs of inflammation; caused by activation of the
inflammatory response
 T cells: lymphocytes programmed in the thymus gland to recognize self-cells; may be effector T
cells, helper T cells, or suppressor T cells
 tumor: swelling, one of the four cardinal signs of inflammation; caused by activation of the
inflammatory response

Body has many defense systems to protect it from external stressors, stressors such as bacteria, viruses,
other foreign pathogens or non- self-cells, trauma, and exposure to extremes of environmental
conditions.

BODY DEFENSES

- Including barrier defenses, cellular defenses, the inflammatory response and the immune
response
- Each plays a major role in maintaining homeostasis and preventing disease

A. Barrier Defenses
o Prevent the entry of foreign pathogens and to serve as important lines of defense in
protecting body
o Ex. Skin, Mucous membranes, gastric acid, and the major histocompatibility

1. Skin
- The first line of defense
- Acts as a physical barrier to protect the internal tissues and organs of
the body
- Secrete chemicals that destroy or repel many pathogens
- In addition, normal bacterial flora of the skin help to destroy many
disease-causing pathogens

2. Mucous Membranes
- Line the areas of the body that are exposed to external influences but
do not have benefit of skin protect
- Areas include: respiratory tract, which is exposed to air; the
gastrointestinal (GI) tract, which is exposed to anything ingested by
mouth; and the genitourinary (GU) tract, which is exposed to many
pathogens from the perineal and rectal area.
- Like skin, it acts as a physical barrier to invasion
- Secrete a sticky mucus capable of trapping invaders and inactivating
them for later destruction and removal by the body.
Respiratory tract: Cilia – mucous membrane is lined with tiny,
hair-like processes. The cilia sweep any captured pathogens or
 foreign materials upward toward the mouth, where they will be
swallowed. The cilia also can move the captured material to an
area causing irritation, which leads to removal by coughing or
sneezing.
GI tract: the mucous membrane serves as a protective coating,
preventing erosion of GI cells by the acidic environment of the
stomach, the digestive enzymes of the small intestine, and the
waste products that accumulate in the large intestine. The
mucous membrane also secretes mucus that serves as a
lubricant throughout the GI tract to facilitate movement of the
food bolus and of waste products. The mucous membrane acts
as a thick barrier to prevent foreign pathogens from penetrating
the GI tract and entering the body
GU tract: the mucous membrane provides direct protection
against injury and trauma and traps any pathogens in the area
for destruction by the body.

3. Gastric Acid
- The stomach secretes acid in response to many stimuli.
- The acidity of the stomach not only aids digestion, but also destroys
many would-be pathogens that are either ingested or swallowed after
removal from the respiratory tract.

4. Major Histocompatibility Complex

- Last barrier, ability to distinguish between self- cells and foreign
- No two people have exactly the same code. In humans, the genetic
identification code is carried on a chromosome and is called the major
histocompatibility complex.
- The MHC produces several proteins called histocompatibility antigens,
or human leukocyte antigens (HLAs).
- These antigens (proteins) are located on the cell membrane and allow
the body to recognize cells as being self-cells.
- Cells that do not have these proteins are identified as foreign and are
targeted for destruction by the body.

B. Cellular Defenses
o Any foreign pathogen that manages to get past the barrier defenses will encounter
the human inflammatory and immune systems, or mononuclear phagocyte system
(MPS).
o Previously called the reticuloendothelial system, the MPS is composed primarily of
leukocytes, lymphocytes, lymphoid tissues, and numerous chemical mediators.
o Stem cells in bone marrow produces 2 types WBC or leukocytes: (1) Lymphocytes -
key components of the immune system and consist of T cells, B cells, and natural
killer cells (2) Myelocytes - can develop into a number of different cell types that are
important in both the basic inflammatory response and the immune response.
Myelocytes include neutrophils, basophils, eosinophils, and monocytes, or
macrophages.

Myelocytic Cells:

1. Neutrophils
- Are polymorphonuclear leukocytes that are capable of moving outside
of the blood stream (diapedesis) and engulfing and digesting foreign
material (phagocytosis).
- When the body is injured or invaded by a pathogen, neutrophils are
rapidly produced and move to the site of the insult to attack the foreign
substance. Because neutrophils are able to engulf and digest foreign
material, they are called phagocytes.
- Phagocytes are able to identify non–selfcells by use of the MHC, and
they can engulf these cells or mark them for destruction by cytotoxic T
lymphocytes.

2. Basophils
- Are myelocytic leukocytes that are not capable of phagocytosis.
- They contain chemical substances or mediators that are important for
initiating and maintaining an immune or inflammatory response.
- These substances include histamine, heparin, and other chemicals used
in the inflammatory response
- Are fixed and do not circulate are called mast cells.
- They are found in the respiratory and GI tracts and in the skin.
- They release many of the chemical mediators of the inflammatory and
immune responses when they are stimulated by local irritation.
 3. Eosinophils
- Are circulating myelocytic leukocytes whose exact function is not
understood.
- They are often found at the site of allergic reactions and may be
responsible for removing the proteins and active components of the
immune reaction from the site of an allergic response.

4. Monocytes/Macrophages
- Are also called macrophages
- They are mature leukocytes that are capable of phagocytizing an
antigen.
- Macrophages help to remove foreign material from the body, including
pathogens, debris from dead cells, and necrotic tissue from injury sites,
so that the body can heal. They also can process antigens and present
them to active lymphocytes for destruction.
- Macrophages can circulate in the blood stream or they can be fi xed in
specific tissues, such as the Kupffer cells in the liver, the cells in the
alveoli of the respiratory tract, and the microglia in the central nervous
system (CNS), GI, circulatory, and lymph tissues.
- As active phagocytes, macrophages release chemicals that are
necessary to elicit a strong inflammatory reaction. These cells also
respond to chemical mediators released by other cells that are active in
the inflammatory and immune responses to increase the intensity of a
response and to facilitate the body’s reaction.

5. Lymphoid Tissues
- Play an important part in the cellular defense system include the lymph
nodes, spleen, thymus gland (a bipolar gland located in the middle of
the chest, which becomes smaller with age), bone marrow, and
lymphoid tissue throughout the respiratory and GI tracts.

C. Inflammatory Response
o Is the local reaction of the body to invasion or injury. Any insult to the body that
injures cells or tissues sets off a series of events and chemical reactions.
o Cell injury causes the activation of a chemical in the plasma called factor XII or
Hageman factor.
o Hageman factor is responsible for activating at least three systems in the body: the
kinin system, which is discussed here; the clotting cascade, which initiates blood
clotting; and the plasminogen system, which initiates the dissolution of blood clots.

1. Kinin System
- Hageman factor activates kallikrein, a substance found in the local
tissues, which causes the precursor substance kininogen to be
converted to bradykinin and other kinins.
Bradykinin
 Was the first kinin identified and remains the one that is
best understood.
 Causes local vasodilation, which brings more blood to
the injured area and allows white blood cells to escape
into the tissues.
 It also stimulates nerve endings to cause pain, which
alerts the body to the injury
 Also causes the release of arachidonic acid from the cell
membrane.
 Arachidonic acid causes the release of other substances
called autacoids. These substances act like local
hormones—they are released from cells, cause an effect
in the immediate area, and then are broken down.
These autacoids include the following:
• Prostaglandins, some of which augment the
inflammatory reaction and some of which block it.
• Leukotrienes, some of which can cause vasodilation
and increased capillary permeability, and some of which
can block the reactions.
• Thromboxanes, which cause local vasoconstriction
and facilitate platelet aggregation and blood
coagulation.

2. Histamine Release
- Injury to a cell membrane causes the local release of histamine.
- Histamine causes vasodilation, which brings more blood and blood
components to the area.
- It also alters capillary permeability, making it easier for neutrophils and
blood chemicals to leave the bloodstream and enter the injured area.
- In addition, histamine stimulates pain perception.
- The vasodilation and changes in capillary permeability bring neutrophils
to the area to engulf and get rid of the invader or to remove the cell
that has been injured
3. Chemotaxis
- Ability to attract neutrophils and to stimulate them and other
macrophages in the area to be very aggressive.
- Activation of the neutrophils and release of other chemicals into the
area can lead to cell injury and destruction. When destroyed, the cell
releases various lysosomal enzymes that dissolve or destroy cell
membranes and cellular proteins
- The lysosomal enzymes are an important part of biological recycling and
the breakdown of once-living tissues after death.

4. Clinical Presentation
- Activation of the inflammatory response produces a characteristic
clinical picture.
- The Latin words calor, tumor, rubor, and dolor describe a typical
inflammatory reaction.
 Calor, or heat, occurs because of the increased blood flow to
the area.
 Tumor, or swelling, occurs because of the fluid that leaks into
the tissues as a result of the change in capillary permeability.
 Rubor, or redness, is related again to the increase in blood flow
caused by the vasodilation.
 Dolor, or pain, comes from the activation of pain fibers by
histamine and the kinin system.
For example, if you scratch the top of your hand and wait for
about a minute, the direct line of the scratch will be red (rubor)
and raised (tumor). If you feel it gently, it will be warmer than
the surrounding area (calor). You should also experience a
burning sensation or discomfort at the site of the scratch
(dolor).
- Once the inflammatory response is under way and neutrophils become
active, engulfing and digesting injured cells or the invader, they release
a chemical that is a natural pyrogen, or fever-causing substance. This
pyrogen resets specific neurons in the hypothalamus to maintain a
higher body temperature, seen clinically as a fever. The higher
temperature acts as a catalyst to many of the body’s chemical reactions,
making the inflammatory and immune responses more effective.
Treating fevers remains a controversial subject because lowering a fever
decreases the efficiency of the immune and inflammatory responses.
- The leukotrienes (autocoids activated through the kinin system) affect
the brain to induce slow-wave sleep, which is believed to be an
important energy conservation measure for fighting the invader. They
 also cause myalgia and arthralgia (muscle and joint pain)—common
signs and symptoms of various inflammatory diseases—which also
cause reduced activity and save energy. All of these chemical responses
make up the total clinical picture of an inflammatory reaction.

D. Immune Response
1. T Cells
- Programmed in the thymus gland and provide what is called cell-
mediated immunity

a. Effector or cytotoxic T cells

 are found throughout the body.
 These T cells are aggressive against non– self-cells, releasing
cytokines, or chemicals, that can either directly destroy a
foreign cell or mark it for aggressive destruction by
phagocytes in the area via an inflammatory response.
  These non–self-cells have membrane-identifying antigens
that are different from those established by the person’s
MHC.
 They may be the body’s own cells that have been invaded
by a virus, which changes the cell membrane; neoplastic
cancer cells; or transplanted foreign cells.

b. Helper T cells
 respond to the chemical indicators of immune activity and
stimulate other lymphocytes, including B cells, to be more
aggressive and responsive.

c. Suppressor T cells
 respond to rising levels of chemicals associated with an
immune response to suppress or slow the reaction.

2. B Cells
- found throughout the MPS in groups called clones. B cells are
programmed to identify specific proteins, or antigens.
- They provide what is called humoral immunity
- When a B cell reacts with its specific antigen, it changes to become a
plasma cell. Plasma cells produce antibodies, or immunoglobulins,
which circulate in the body and react with this specific antigen when it is
encountered. This is a direct chemical reaction. When the antigen and
antibody react, they form an antigen–antibody complex. This new
structure reveals a new receptor site on the antibody that activates a
series of plasma proteins in the body called complement proteins.
3. Complement Proteins
- react in a cascade fashion to form a ring around the antigen–antibody
complex.
- The complement can destroy the antigen by altering the membrane,
allowing an osmotic inflow of fluid that causes the cell to burst.
- They also induce chemotaxis (attraction of phagocytic cells to the area),
increase the activity of phagocytes, and release histamine.
- Histamine release causes vasodilation, which increases blood fl ow to
the area and brings in all of the components of the inflammatory
reaction to destroy the antigen. The antigen–antibody–complement
complex precipitates out of the circulatory system and deposits in
various sites, including end arteries in joints, the eyes, the kidneys, and
the skin. The signs and symptoms of the inflammatory response can be
seen where the antigen–antibody complexes are deposited. Chickenpox
eruptions are an example of an antigen–antibody– complement
 complex that deposits in the skin and causes a local inflammatory
reaction.

4. Antibody Formation
- The initial formation of antibodies, or primary response, takes several
days. Once activated, the B cells form memory cells that will produce
antibodies for immediate release in the future if the antigen is
encountered. The antibodies are released in the form of
immunoglobulins. Five different types of immunoglobulins have been
identified:
• The first immunoglobulin released is M (IgM), which contains the
antibodies produced at the first exposure to the antigen.
• IgG, another form of immunoglobulin, contains antibodies made by
the memory cells that circulate and enter the tissue; most of the
immunoglobulin found in the serum is IgG.
• IgA is found in tears, saliva, sweat, mucus, and bile. It is secreted by
plasma cells in the GI and respiratory tracts and in epithelial cells. These
antibodies react with specific pathogens that are encountered in
exposed areas of the body.
• IgE is present in small amounts and seems to be related to allergic
responses and to the activation of mast cells.
• IgD is another identified immunoglobulin whose role has not been
determined.

- This process of antibody formation, called acquired or active immunity

is a lifelong reaction. For example, a person exposed to chicken pox will
have a mild respiratory reaction when the virus (varicella) fi rst enters
the respiratory tract. There will then be a 2- to 3-week incubation
period as the body is forming IgM antibodies and preparing to attack
any chicken pox virus that appears.
- The chicken pox virus enters a cell and multiplies. The cell eventually
ruptures and ejects more viruses into the system. When this happens,
the body responds with the immediate release of antibodies, and a full-
scale antigen– antibody response is seen throughout the body. Fever,
myalgia, arthralgia, and skin lesions are all part of the immune response
to the virus. Once all of the invading chicken pox viruses have been
destroyed or have entered the CNS to safely hibernate away from the
antibodies, the clinical signs and symptoms resolve. (Varicella can enter
the CNS and stay dormant for many years. The antibodies are not able
to cross into the CNS, and the virus remains unaffected while it stays
there.)
5. Other Mediators
- Interferons are chemicals that are secreted by cells that have been
invaded by viruses and possibly by other stimuli. The interferons
prevent viral replication and also suppress malignant cell replication and
tumor growth.
- Interleukins are chemicals secreted by active leukocytes to infl uence
other leukocytes. Interleukin 1 (IL-1) stimulates T and B cells to initiate
an immune response. IL-2 is released from active T cells to stimulate the
production of more T cells and to increase the activity of B cells,
cytotoxic cells, and natural killer cells. Interleukins also cause fever,
arthralgia, myalgia, and slow-wave sleep induction—all things that help
the body to conserve energy for use in fighting off the invader
- The thymus gland also releases a number of hormones that aid in the
maturation of T cells and that circulate in the body to stimulate and
communicate with T cells. Thymosin, a thymus hormone that has been
replicated, is important in the maturation of T cells and cell mediated
immunity. Research is ongoing on the use of thymosin in certain
leukemias and melanomas to stimulate the immune response.
- Tumor necrosis factor (TNF), a cytokine, is a chemical released by
macrophages that inhibits tumor growth and can actually cause tumor
regression. It also works with other chemicals to make the inflammatory
and immune responses more aggressive and efficient.

a. Interrelationship of the Immune and Inflammatory Responses

 Work together to protect the body and to maintain a level
of homeostasis within the body. Helper T cells stimulate the
activity of B cells and effector T cells. Suppressor T cells
monitor the chemical activity in the body and act to
suppress B-cell and T-cell activity when the foreign antigen
is under control. Both B cells and T cells ultimately depend
on an effective inflammatory reaction to achieve the end
goal of destruction of the foreign protein or cell
Pathophysiology Involving the immune System

 Drugs that Stimulate or Suppress the Immune System

1. Neoplasms
o Occur when mutant cells escape the normal surveillance of the immune system and
begin to grow and multiply.
o For example, aging causes a decreased efficiency of the immune system, allowing
some cells to escape detection.
o Location of the mutant cells can make it difficult for lymphocytes to get to an area
to respond. Mutant cells in breast tissue, for example, are not well perfused with
blood and may escape detection until they are quite abundant.
o Sometimes cells are able to avoid detection by the T cells until the growing mass of
cells is so large that the immune system cannot deal with it. Tumors also can
produce blocking antibodies that cover the antigen receptor sites on the tumor and
prevent recognition by cytotoxic T cells.
o In addition, a weakly antigenic tumor may develop; such a tumor elicits a mild
response from the immune system and somehow tricks the T cells into allowing it to
survive.

2. Viral Invasion of Cells

o Viruses are parasites that can survive only by invading a host cell that provides the
nourishment necessary for viral replication.
o Invasion of a cell alters the cell membrane and the antigenic presentation of the cell
(the MHC). This change can activate cellular immunity, or it can be so subtle that the
immune system’s response to the cell is mild or absent.
o In some cases, the response activates a cellular immune reaction to normal cells
similar to the one that was invaded. This is one theory for the development of
autoimmune disease.

3. Autoimmune Disease
o occurs when the body responds to specific self-antigens to produce antibodies or
cell mediated immune responses against its own cells.
o The cause of autoimmune disease is not known, but theories speculate that (1) it
could be a result of response to a cell that was invaded by a virus, leading to
antibody production to similar cells; (2) production of autoantibodies is a normal
process that goes on all the time, but in a state of immunosuppression, the
suppressor T cells do not suppress autoantibody production; or (3) there is a genetic
predisposition to develop autoantibodies.

4. Transplant Rejection
o With the growing field of organ transplantation, more is being learned about the
reaction to foreign cells that are introduced into the body.
o Typically, self-transplantation, or autotransplantation, results in no immune
response.
o All other transplants produce an immune reaction. Therefore, matching a donor’s
HLA markers as closely as possible to those of the recipient for histocompatibility is
essential. The more closely the foreign cells can be matched, the less aggressive will
the immune reaction be to the donated tissue.