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43
The Immune System: Internal Defense
Lecture Outline
I.
Nonspecific and specific immunity: an overview
A. Overview
1. An immune response is the process of recognizing foreign macromolecules
and responding to eliminate them
2. Nonspecific responses provide general protection against pathogens,
parasites, some toxins and drugs, and cancer cells
a) The cuticle or skin is a barrier
b) Phagocytosis destroys bacteria
c) Various molecules are involved as well
3. Specific immune responses are highly specific
a) The immune system recognizes foreign antigens
b) Antibodies are proteins that recognize and bind specific antigens
c) Immunological memory is an important characteristic
B. Invertebrates make mainly nonspecific immune responses
1. All invertebrates studied to date can distinguish between self and nonself
2. Nonspecific defense mechanisms include phagocytes and the inflammatory
response
3. Antimicrobial peptides inactivate or kill pathogens
4. Animal cells have signaling receptors, the Toll group, which recognize
molecular features of pathogens called pathogen-associated molecular
patterns (PAMPs)
5. Some invertebrates have demonstrated immunological memory
C. Vertebrates launch both nonspecific and specific immune responses
1. A specialized lymphatic system allows more complicated immunological
responses
2. Only vertebrates have true lymphocytes
II.
Nonspecific defense responses involve a variety of molecules and cells
A. The skin is the first defense against pathogens
1. Sweat and sebum contain antibacterial chemicals
2. Lysozyme in tears and other fluids is a defense against gram-positive
bacteria
3. Enzymes and stomach acid destroy ingested pathogens
4. Nose hairs and respiratory mucous trap inhaled pathogens that are then
phagocytized
B.
Soluble molecules destroy pathogens
1. Cytokines, regulatory proteins, act in a variety of ways
a) Interferons are produced by macrophages in response to infection by
intracellular parasites like viruses
(1) Neighboring cells then produce proteins that interfere with viral
replication
(2) Recombinant interferon has been used to treat hepatitis B and C,
genital warts, and other diseases
b) Interleukins are secreted by macrophages and lymphocytes and are
named in order of their discovery
(1) IL-1 induces fever by acting on the hypothalamus
c) Chemokines attract, activate, and direct the movement of various cells
of the immune system
d) Tumor necrosis factors (TNF) are cytokines that are important in the
inflammatory response
(1) TNFs also kill tumor cells, but may also be involved in some
potentially harmful immune responses
2. Complement leads to the destruction of pathogens
a) Complement is a set of plasma proteins that complements the action of
other defense mechanisms
b) Complement is typically inactive until exposed to antigens
c) Complement action is a non-specific defense mechanism, and acts in a
variety of ways
C. Phagocytes and natural killer cells destroy pathogens
1. Inflammation leads to phagocytosis, particularly by neutrophils and
macrophages, which can engulf large numbers of bacteria before being
inactivated
2. Vertebrate macrophages have Toll-like receptors that recognize certain
PAMPs
3. Natural killer (NK) cells account for about 15% of circulating lymphocytes
a) NK cells are large, granular lymphocytes closely related to T cells
b) NK cells attack a wide variety of infected cells and tumor cells
c) NK cells function without prior exposure and do not require
presentation of antigens
d) NK cells produce cytokines, perforins, and various enzymes
D. Inflammation is a protective response
1. Injured cells and basophils release histamines that dilate blood vessels
2. Increased blood flow increases the temperature of the affected area, brings
increased numbers of phagocytes, and causes redness
3. Histamines make the capillaries more permeable, and phagocytes leave the
blood vessels
4. The leaky blood vessels also release plasma, causing edema and
accompanying pain
5.
III.
Inflammation is often simply a local response, but fever is a widespread
inflammatory response
a) Fever interferes with the growth of some bacteria and increases the
activity of certain lymphocytes
Specific immune responses include antibody-mediated and cell-mediated immunity
E. Lymphocytes are the principal warriors in specific immune responses
1. The three types of lymphocytes are T lymphocytes (T cells), B lymphocytes
(B cells), and natural killer (NK) cells
2. T cells are responsible for cell-mediated immunity
3. B cells are responsible for antibody-mediated immunity
a) B cells mature into plasma cells that produce antibodies, which bind
specific antigens and either neutralize them or mark them for
destruction
4. All lymphocytes are produced in the bone marrow
a) B cells complete their development in the bone marrow
b) T cells mature in the thymus gland
5. Each B cell has a specific glycoprotein receptor
a) Binding of a specific B cell with a specific antigen activates the B cell
b) The activated B cell divides, forming plasma cells that produce soluble
antibodies
c) The antibodies bind to the antigen that originally activated the B cell
d) Some B cells become long-living memory cells that continue to
produce small amounts of antibodies
6. T cells are responsible for cellular immunity, originate from stem cells in
the bone marrow, and become immunocompetent in the thymus gland
a) Only T cells that possess particular receptors are selected to divide,
hence this is an example of positive selection
b) T cells that react to self-antigens undergo apoptosis, which is a form of
negative selection
c) They may be identified by their T cell antigen receptor (TCR)
d) CD8 cells include cytotoxic T and suppressor T cells
(1) Cytotoxic T cells (Tc), also called killer T cells, recognize and
destroy cells with foreign antibodies
(a) Their targets are virus-infected cells, tumor cells, and
foreign tissue
(b) Their action is via release of cytokines and various
enzymes
e) T helper cells are called CD4 cells because of CD4 marker molecules
(1) T helper cells are regulatory cells
F. Antigen-presenting cells activate T helper cells
1. Macrophages, dendritic cells, and B cells function as antigen-presenting
cells (APCs)
2.
Once an APC is activated, it ingests a pathogen and displays fragments of
the foreign antigen on its surface
3. The APC then presents these antigens to T cells
4. Dendritic cells develop from monocytes and are specialized to process,
transport, and present antigens to T cells
G. The major histocompatibility complex permits recognition of self
1. The MHC is a complex of membrane proteins; in humans the MHC is
called the HLA (human leukocyte antigen) group
2. A group of polymorphic genes codes for the HLA group; there may be
over 40 alleles for a given gene
a) Therefore, it is unlikely that any two persons, except identical twins,
would ever have identical MHC proteins
3. MHC class I antigens are on most nucleated cells and aid in differentiating
between self and nonself
a) These antigens bind to foreign antigens, and this complex is
recognized by cytotoxic T cells
b) MHC class II antigens are only found on certain cells of the immune
system and interact with T, B, and antigen-presenting cells
c) MHC class III proteins include components of the complement system
IV.
Cell mediated immunity
H. The T cells and APCs are responsible for cell-mediated immunity
1. When a virus infects a cell, viral antigens are displayed on class I MHC
molecules
2. The binding of a specific cytotoxic T cell with this complex activates the T
cell and causes it to divide into a clone
3. Cytotoxic T cells leave the lymph nodes and move to the site of infection
4. Cytotoxic T cells secrete proteins that destroy the target cell
V.
Antibody-mediated immunity
I. B cells produce a specific antibody that can combine with a specific antigen
1. The binding activates the B cell in a complex process that involves
macrophages (presenting antigens), helper T cells, or dendritic cells
2. A macrophage displaying a foreign antigen-MHC complex secretes
interleukins, which activates helper T cells
3. The B cell binds with the complementary antigen and displays it with a
class II MHC protein
4. The B cell grows, divides and forms a clone, known as clonal selection
5. Some of the clone mature into plasma cells, which produce an antibody
specific to that antigen
6. The B cells remain in the lymph nodes, but the antibodies pass out into the
lymph and ultimately the blood
7.
Some activated B cells become memory cells and avoid the programmed
death
a) These memory cells produce small amounts of antibody, which
becomes part of the gamma globulin fraction of the blood
b) Memory cells can become effective plasma cells if re-exposed to the
same antigen at a later time
J. A typical antibody consists of four polypeptide chains
1. Antigenic determinants, or epitopes, are specific sequences of amino acids
2. Antibodies are typically Y shaped proteins
3. The portion of the antibody that binds to the antigen is the Fab section
4. The portion of the antibody that interacts with other cells of the immune
system is the Fc section
5. The four polypeptide chains consist of two identical heavy chains and two
identical short chains
a) Each chain has a constant segment (C region) that is the same among
any class of immunoglobulin
b) Each chain has a junctional segment (J region) that is somewhat
variable
c) Each chain has a variable segment (V region) that is unique
(1) The V region is like the lock for a specific antigen, as it folds 3dimensionally
K. Antibodies are grouped in five classes
1. Antibodies are immunoglobulins (IG)
2. IgG makes up about 75% of human immunoglobulins, and is part of the
gamma globulin fraction of the blood
a) IgG and IgM interact with macrophages and activate the complement
system
b) IgA is present in other body fluids, such as mucus, tears, saliva, and
milk and prevents pathogens from attaching to epithelia
c) IgD is present in low concentrations, and with IgM is important in the
function of B cells
d) IgE is important in immunity to parasitic worms and release of
histamines
L. Antigen-antibody binding activates other defenses
1. The antigen-antibody complex may inactivate the pathogen or its toxin
2. The antigen-antibody complex stimulates phagocytic cells to ingest the
pathogen
3. Antibodies of IgG and IgM work through the complement system to more
easily destroy the pathogen
M. The immune system responds to millions of different antigens
1. Although each human cell has a large amount of DNA, it is not enough to
provide a different gene to code for each of the possible antibodies
2.
An immunoglobin has three regions (V, C, and C), each encoded by
separate families of genes
3. During development of the B cell, rearrangement of these DNA segments
produces an enormous number of potential combinations
N. Monoclonal antibodies are highly specific
1. Monoclonal antibodies were developed in the 1970s
2. They are produced by injecting mice with an antigen followed by
harvesting B cells; The B cells are fused with a culture of cancerous interest,
cells, allowing the resulting hybridomas to live indefinitely
3. Monoclonal antibodies are pure and specific and have a myriad of uses in
medicine and therapies
VI.
Long-term immunity depends on immunological memory
O. A secondary immune response is more rapid than a primary response
1. The primary response results in antibodies produced within 3-14 days of
exposure
a) IgM is the primary antibody produced during the primary response,
peaking during the logarithmic phase
b) The antibody production declines after the infection is suppressed
2. The secondary response occurs after the second exposure to the same
antigen, as memory cells may last throughout the entire life of a person
a) The secondary response is a rapid, effective response
b) Developing a second cold or flu is due to exposure to a slightly
different strain of the bacterium or virus to which there are no specific
memory cells or antibodies
P. Active immunity can be induced with immunization
1. A vaccination causes production of the appropriate antibodies and
memory cells
a) Viruses may be attenuated so that they do not cause diseases after
administration of a vaccine
b) Some vaccines are killed pathogens or are derived from bacterial
toxins
c) DNA vaccines are in clinical trials
Q. Passive immunity is borrowed immunity
1. Passive immunity is the acquisition of antibodies produced by the immune
system of another organism
2. The effects are less long lasting, but include injections of gamma globulin
and the immunity conferred to babies in the uterus (primarily IgG) or via
nursing (primarily IgA)
VII.
Many factors compromise the immune system, leading to disease
R. Cancer is a failure in immunosurveillance
1.
Dendritic cells, NK cells, and cytotoxic T cells are central in defending
against cancer cells
2. The immune system must make varied responses to the hundreds of types
of cancer
3. Monoclonal antibodies and vaccines are promising new treatments for
cancer
4. DNA microarrays are used to detect gene expression in cancer cells
S. Immunodeficiency disease can be inherited or acquired
1. Absence or failure of some component of the immune system can result in
immunodeficiency disease and increase susceptibility to infection
2. In DiGeorge syndrome the thymus is reduced or absent and results in a
deficiency of T cells
3. Severe combined immunodeficiency syndromes (SCIDs) are sex-linked and
autosomal disorders that result in multiple infections
T. HIV Is the major cause of acquired immunodeficiency
1. HIV was first isolated in 1983
2. More than 38.6 million adults and 3.2 million children are infected
worldwide
3. AIDS is caused by HIV
4. Immunosuppression is caused by HIV destruction of helper T cells
5. AIDS is transmitted by semen, blood, or other bodily fluids
6. AIDS begins with various unusual opportunistic diseases, and may end
with AIDS dementia
7. HIV enters a helper T cell by attaching to the CD4 membrane protein
8. AZT is a drug that is used to treat AIDS, and acts by blocking reverse
transcriptase, necessary for viral replication
9. Protease inhibitors are a more promising, recently developed treatment
VIII. Immune responses are sometimes inconvenient or harmful
U. Hypersensitivity is an exaggerated allergic reaction
V. Graft rejection is an immune response against transplanted tissue
1. Tissues and organs from a donor have different MHC antigens, which
provoke graft rejection by the T cells
2. Tissue typing allows close matches of MHC antigens
3. If close matching is not possible, immunosuppressive drugs are
administered
4. Certain sites in the body are immunologically privileged
a) The brain and cornea, for example, lack circulatory vessels and so have
little or no access to lymphocytes
W. Rh incompatibility can result in hypersensitivity
1. Rh incompatibility is probably the most important maternal-fetal blood
type incompatibility
a)
If a woman is Rh-negative and the father of the fetus is Rh-positive the
fetus may be Rh-positive
b) The fetus's red blood cells activate the mother's white blood cells,
stimulating them to produce anti-D antibodies
c) This may can the disease erythroblastosis fetalis, which results in the
destruction of many fetal red blood cells and death of the fetus
X. Allergic reactions are directed against ordinary environmental antigens
1. Allergens are mild antigens that only trigger immune responses in some
individuals
2. Allergic asthma or hay fever is seen in about 20% of the population of the
United States
3. The first step is sensitization; macrophages degrade the allergen and
display it to the T cells
4. T cells become activated and stimulate B cells to become plasma cells and
produce IgE
5. Mast cells are activated by the allergen binding to the IgE on the mast cells
a) Mast cells release histamine and seratonin that result in inflammation
6. The mast cells attract white blood cells to the inflamed area, which further
damage tissue and promote the allergic response
7. Systemic anaphylaxis, which results in widespread vasodilation and may
lead to death, occurs after development of an allergy
8. Allergic reactions are often treated with antihistamines, which block
histamines
Y. In an autoimmune disease the body attacks its own tissues
1. Autoimmune diseases are hypersensitivities to antigens of self
2. Autoimmune diseases include rheumatoid arthritis, multiple sclerosis, a
form of lupus, insulin-dependent diabetes, psoriasis, and others
3. Autoimmune diseases seem to have a genetic link, and perhaps are
triggered by a viral or bacterial infection
Research and Discussion Topics

Investigate a particular autoimmune disease. Describe the disease symptoms,
treatments, and suggested causes. Subjects on which students should find sufficient
research material: insulin-dependent diabetes, multiple sclerosis, lupus, psoriasis.

Discuss what is known on the activity of the complement system. How do these
proteins aid in suppression of pathogens?
Take a look at the most recent statistics for diseases, including autoimmune disorders
including AIDS. Look at the Centers for Disease Control (CDC) site, particularly their
MMR information (Morbidity and Mortality Rate).