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Chapter 17
Immunity
Dr. Bruce Forciea
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Immunity
Our immune systems offer us protection against a world full of pathogens. Our immune systems work by
providing two types of immunity. In non-specific immunity our bodies present the same kinds of defense
systems regardless of the type of pathogens. Non-specific immunity works much like a fence around
your property. The fence does not differentiate between friend or foe. It keeps everyone out. The other
type of immunity is known as specific immunity (defense). Specific defense produces an attack against a
specific pathogen. This is much like having an attendant at the gate of the fence around your house. The
attendant can identify potential foes and keep them out.
Before birth the body inventories all of the cells and tissues of the body and classifies them as “self”
cells. The presentation of non-self cells can then trigger the immune system.
Non-Specific Defense
Non-specific defense (innate immunity) consists of mechanisms that either keep pathogens out or
destroy them regardless of their type. Non-specific defense includes mechanical barriers, chemical
substances, cells and inflammation.
Mechanical barriers include the skin and mucous membranes. Besides presenting a physical barrier that
stops pathogens they also work to remove substances from the surface of membranes. Examples
include the movement of mucous moving substances toward the digestive tract and tears washing
substances from the eyes.
Chemical substances work to destroy pathogens. These include enzymes, cytokines, and the
complement system. For example, mucous from the respiratory tract moves toward the pharynx and
esophagus where it is swallowed. Upon reaching the digestive tract pathogens are destroyed by
powerful digestive enzymes.
Cytokines are a series of protein substances secreted by cells that work to destroy pathogens.
Interferons are cytokines that bind to cells causing them to produce substances that inhibit viral
replication. One type of interferon can affect many types of viruses. Interferons can also activate other
immune cells such as macrophages and natural killer cells.
Some cytokines produce fever. Interleukin I (endogenous pyrogen) is a cytokine that acts as a pyrogen
(raises body temperature). This cytokine is released in response to toxins or pathogens and causes an
increase in body temperature.
The compliment system is a series of about 20 plasma proteins (fig. 17.1). They include proteins that are
named C1-C9 and factors B, D, P. They act much like the clotting cascade (see blood chapter) in that
activation of the first compliment protein causes the others to activate. There are two pathways in
which to activate the compliment system.
The alternative pathway is activated by the presentation of a pathogen to the body. The C3 protein is
normally inactivated by the body’s cells, however presentation of a non-self cell can cause it to remain
active triggering a response.
Complement system responses include inflammation, phagocytosis from white blood cells attracted to
the area, and attacking non-self cells.
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Inflammation is produced by facilitating the release of histamine from white blood cells called mast
cells. Histamine promotes local vasodilation increasing capillary permeability and bringing more blood to
the area.
Neutrophils and macrophages are attracted to activated complement proteins for phagocytosis of
pathogens. Certain antibodies (we will cover antibodies later) called opsonins work with complement
proteins to facilitate phagocytosis. This process is called opsonization.
Some complement proteins (C5-C9) bind to cell membranes to form a membrane attack complex (MAC)
that drill holes in cells allowing substances to rush in and burst the cell.
The classical pathway is part of specific defense which will be covered later in this chapter.
Inflammation is characterized by swelling, redness, heat and pain (tumor, rubor, calor, dolor).
Inflammation is produced by tissue destruction from trauma, cuts, temperature and chemicals.
Inflammation causes an increased blood flow to the damaged area. Blood brings substances for repair
and the stasis of blood in the area prevents further spread of pathogens.
Inflammation is primarily caused by the release of histamine and heparin from mast cells (similar to
basophils). Histamine promotes local vasodilation and capillary permeability while heparin inhibits
clotting. Phagocytes are also attracted to the area and remove debris. Neutrophils release substances
that activate fibroblasts to begin to repair the area. Substances released by cells stimulate pain
receptors in the tissue causing the sensation of pain.
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Figure 17.1. Complement System
http://commons.wikimedia.org/wiki/File:Complement_pathway.png
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Specific Defense
Specific defense (sometimes called adaptive immunity) recognizes and coordinates attacks against
specific pathogens. The system can also remember pathogens and produce a powerful response the
next time a pathogen enters the body.
There are two types of specific defense. These include cell-mediated immunity and antibody-mediated
immunity. Cell-mediated immunity occurs when T-lymphocytes (T-cells) become activated by exposure
to pathogens. Activated T-cells then attack pathogens directly.
T-cells become activated when exposed to antigens on pathogens. T-cells react with portions of antigens
called antigenic determinants (epitopes). T-cells contain antigen receptors on their surface that combine
with antigenic determinants on pathogens. The antigen receptors are polypeptide chains that contain
variable and constant regions. The variable region binds to the antigenic determinant. This is known as
direct activation of T-cells.
Major Histocompatibility Complexes
Specific glycoproteins can activate T-cells. These glycoproteins are called major histocompatibility
complex molecules (MHC molecules). MHC molecules reside on cell membranes and contain a variable
region. The variable region is the portion of the molecule that allows for binding to antigens.
MHC class I molecules display antigens on the surface of cells. The antigens are produced inside cells.
One example is a cell infected with a virus. The virus replicates inside the cell producing proteins. These
proteins combine with MHC class I molecules that move to the outer cell membrane for display. Once
displayed on the surface of the cell the immune system can attack and destroy the cell.
MHC class II molecules are found on cells that present antigens. Antigens enter cells via endocytosis and
combine with MHC class II molecules in vesicles. The antigen-MHC complex combination is then
transported to the cell membrane and displayed on the surface. The response to MHC class II complexes
differs from MHC class I in that the MHC class II presenting cells are not directly attacked. The MHC II
complex acts more like a signal to other immune system cells to mobilize against the antigen.
Types of T-cells
Types of T-cells include cytotoxic , helper, and suppressor cells. These cells differ in the presence of
certain proteins known as cluster of differentiation (CD) markers. Cytotoxic T-cells contain the CD8
protein in their cell membranes. Cytotoxic T-cells respond to MCH class I molecules. Helper T-cells have
CD4 markers and respond to MCH class II molecules.
T-cell activation typically requires costimulation in order to fully activate the cell. Costimulation involves
a secondary binding to an antigen. Costimulation helps to ensure that the appropriate cell is attacked
(fig. 17.3).
Activated cytotoxic T-cells destroy pathogenic cells by either phagocytosis, release of a substance that
drills holes in the infected cell called perforin, secreting a substance that is toxic to the cell called a
lymphotoxin, or activating genes in the infected cell that tell it to destroy itself. The latter is known as
apoptosis.
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Suppressor T-cells also develop from CD8 T-cells. Suppressor T-cells secrete substances known as
suppression factors that suppress the action of T-cells and B-cells. These cells require a longer period of
time for activation and help to protect against over-activation of the immune system.
Helper T-cells contain the CD4 protein. Helper T-cells facilitate rapid mitosis of other T-cells, cause
chemotaxis of macrophages to the infected area, help to activate B-cells, and stimulate natural killer
cells.
B-cells
The other major type of lymphocyte is the B-cell (B for bursa of fabricus of the chicken after where they
were discovered). There are millions of B-cells in the body and each contains a specific set of antibodies.
Some antibodies are present on the surface of the B-cell. Antigen containing pathogens bind to
antibodies causing sensitization of the B-cells. Antigens are then displayed on MHC class II proteins on
the surface of the B-cells. Helper T-cells complete the activation of B-cells by binding to the MHC class II
proteins and secreting cytokines that stimulate the B-cells. Activated B-cells undergo rapid mitosis with
some of the cells remaining immature memory cells. Activated B-cells produce and secrete antibodies
(fig. 17.4).
Antibodies consist of a pair of polypeptide chains called light chains connected to another pair of
polypeptide chains called heavy chains. The chains are connected by disulfide bonds and contain both
constant and variable segments. The base of the antibodies is formed by the constant segments of the
heavy chains that help to identify the antibody. This region can also activate the complement system.
The other end of the antibody contains the variable region. The antigen binding sites are located on this
variable region. These sites can connect with antigens on pathogens to form antibody-antigen
complexes.
Haptens are incomplete antigens and do not activate B-cells unless they combine with carrier molecules
that act as complete antigens.
A number of different effects result from antibody-antigen complexes. Antibodies can bind to cellular
receptors and neutralize cells so they cannot enter other cells. Antibodies can cause agglutination or
clumping of cells that attract phagocytes (opsonization). Antibodies can produce inflammation by
stimulating basophils and activate the complement system.
The activation of the complement system by antibody-antigen complexes is known as the classical
pathway.
There are a number of different types of antibodies (fig. 17.2). Antibodies are also known as
immunogloblulins and can be organized into five categories. These include IgE (immunoglobulin E), IgG,
IgM, IgD, and IgA. IgG is the largest category and accounts for 80% of all antibodies. IgG antibodies
attack viruses and bacteria. IgE antibodies function in allergic reactions. They facilitate the release of
histamine and heparin from basophils. IgD antibodies bind to antigens on the surface of B-cells and help
in activation of B-cells. IgM antibodies work with IgG antibodies to form immune complexes. IgM
antibodies are also resident in plasma as anti-A and anti-B antibodies. IgA is found in secretions such as
tears, mucous and saliva and attack pathogens.
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Figure 17.2. Antibody structure
http://commons.wikimedia.org/wiki/File:Anti
body.jpg
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Figure 17.3. T-cell activation
http://commons.wikimedia.org/wiki/File:T_cell_activation.png
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Figure 17.4. B-cell activation
http://commons.wikimedia.org/wiki/File:B_cell_activation.png
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Dendritic Cells
Dendritic cells are antigen presenting cells found in mucous membranes, lymphatic organs and the
epidermis of the skin. These cells have a branched appearance and can engulf pathogens by way of
endocytosis. Dendritic cells contain receptors that recognize non-self antigens that trigger endocytosis
when activated.
Reticular Cells
Reticular cells (sometimes called fibroblastic reticular cells) are antigen presenting cells located in
lymphatic organs. These cells are known to help regulate T-cell function.
Macrophages
Macrophages develop from monocytes that have moved out of the blood. They ingest pathogens by
phagocytosis. They also clean up cellular debri including dead neutrophils. Macrophages can display
pathogenic antigens on their surface.
Primary and Secondary Immune Response
The first exposure to an antigen with activation of the immune system is known as the primary
response. The immune system produces memory cells so that the next time the antigen is presented the
system is ready to respond. The second presentation of the same antigen to the immune system is
known as the secondary response.
The primary response takes longer to develop (from one to two weeks). During this time B-cells are
producing antibodies resulting in a gradual increase in antibodies. The immune system is also producing
clones and memory cells that will be ready for the next presentation of the antigen. These memory cells
can last for as long as 20 years.
The secondary response is much faster. The second exposure to an antigen results in maturation of the
memory cells and production of antibodies. Vaccinations primarily rely on the secondary response (fig.
17.5).
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Figure 17.5. Immune response
http://commons.wikimedia.org/wiki/File:Immune_response.jpg
Allergies
Allergies are immune responses to non-pathological or inert substances. Allergic responses produce a
large number of antibodies that can produce a number of adverse effects. Types of allergic responses
include Type I anaphylactic, Type II cytotoxic reactions, Type III immune complex disorders, Type IV
delayed hypersensitivity (fig. 17.6).
The type I reaction is also known as an immediate hypersensitivity reaction and can be life threatening.
It is caused by an inherited tendency to overproduce the IgE antibodies in response to a specific antigen.
The first exposure generally does not produce symptoms due to the time it takes for B-cell activation.
However the second exposure can be quite severe producing large amounts of inflammation. The most
severe reaction is known as anaphylaxis and produces a number of adverse effects within a very brief
time period. These include hives, constriction of bronchioles, and peripheral vasodilation that can cause
shock.
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Figure 17.6. Allergic response
http://commons.wikimedia.org/wiki/File:Mast_cells.jpg
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Autoimmune Disorders
In some cases the immune system reacts to self cells and tissues and produces an immune response to
them. B-cells produce antibodies known as autoantibodies. Examples of autoimmune disorders include
rheumatoid arthritis, systemic Lupus erythematosis, insulin dependent diabetes, and thyroidosis.
Types of Immunity
Immunity is either innate or acquired by exposure to a pathogen. Active immunity is developed after
exposure to a pathogen and production of antibodies. Passive immunity results from the presentation of
antibodies from other sources.
Naturally acquired active immunity results from exposure to a pathogen. The immune system is
activated and produces antibodies and memory cells.
Artificially acquired active immunity results from exposure to pathogens given to the body in the form of
vaccines. Vaccines contain inactive or attenuated pathogens that are just strong enough to produce an
immune response.
Naturally acquired passive immunity occurs in utero with the passing of antibodies to the fetus from the
mother. Antibodies are also passed to the infant through breast milk after birth.
Artificially acquired passive immunity occurs when antibodies are given to a person who has a damaged
immune system. Antibodies must be injected periodically because of their short life span.
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