Transcript Document

The Immune System
Chapter 51
Introduction
Vertebrates have three levels of defenses
-1. The Integumentary System
-Skin and mucous membranes provide
first line of defense
-2. Nonspecific (innate) Immune System
-Acts very rapidly after onset of infection
-3. Specific Immune System
-Eliminates microbes that escaped the
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second line of defense
Skin
The skin is the largest organ of the body
-Provides a nearly impenetrable barrier,
reinforced with chemical weapons
-Oil & sweat glands give skin a pH of 3-5
-Lysozyme breaks bacterial cell walls
-Also contains many normal flora
-Non-pathogenic microorganisms that
out-compete pathogenic ones
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Skin
The skin is composed of three layers:
epidermis, dermis, hypodermis
-Epidermis = 10-30 cells thick
-Stratum corneum – Outermost layer;
cells shed continuously
-Stratum spinosum – Middle layer
-Stratum basale – Innermost layer
cells actively dividing
-Contains keratin, which makes
skin tough and water-resistant
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Mucosal Epithelial Surfaces
The digestive, respiratory and urogenital
tracts are lined by mucous membranes
-Cells secrete mucus which traps microbes
Digestive tract
-Salivary lysozyme; acidic stomach
Respiratory tract
-Ciliary action
Urogenital tract
-Acidic urine
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Nonspecific Immunity
The nonspecific or innate immune system
consists of cellular and chemical devices
that respond to any microbial infection
-The response is quite rapid
Among the most important defenses are 3
types of LEUKOCYTES (WHITE BLOOD
CELLS)
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Leukocyte 1 of 3
Macrophages
-Large, irregularly
shaped cells
-Kill microbes by
phagocytosis
-Mature from
monocytes that
enter tissues
from the blood
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Leukocytes 2 and 3
Neutrophils
-The most abundant circulating leukocytes
-First to appear at site of damage/infection
-Kill microbes by phagocytosis
Natural killer (NK) cells
-Destroy pathogen-infected and cancer
cells by programmed cell death or
apoptosis
-Produce perforins and granzymes
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NK Cells and Macrophages
Working Together
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The Inflammatory Response
-Injured cells release chemical alarms, including histamine
and prostaglandins (seen in allergies)
-Cause nearby blood vessels to dilate and increase in
permeability
-Promote phagocyte accumulation
-Hallmark signs = Redness, warmth, swelling, pain, and 10
potential loss of function
The Inflammatory Response
Inflammation is accompanied by an acute
phase response, manifested by fever
-Macrophages release interleukin-1
-Causes hypothalamus to raise body
temperature
-Promotes activity of phagocytes,
while impeding microbial growth
-However, very high fevers are hazardous
as they may denature critical enzymes
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Complement
The complement system consists of about 30
different proteins that circulate in the blood in an
inactive form
-Upon pathogen encounter, a cascade of
activation occurs
-Some proteins aggregate to form a membrane
attack complex (MAC) on surface of pathogen
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Complement
Other functions of complement proteins
-C3b coats surface of invading pathogens,
thereby enhancing their phagocytosis
-Some stimulate the release of histamine
from mast cells and basophils
-Some attract more phagocytes to the area
of infection
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Interferon
Interferons (IFN) are proteins that play a key
role in body defense...they are secreted
ligands
-Three major types: IFN-a, IFN-b, IFN-g
-IFN-a and IFN-b are produced by almost all
body cells in response to viral infection
-Induce degradation of viral RNA
-IFN-g is produced only by T-lymphocytes
and natural killer cells
-Protects from infection and cancer
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The Specific Immune System
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The Specific Immune System
The scientific study of immunity began with
Edward Jenner in 1796
-Observed that milkmaids who had cowpox
rarely experienced smallpox
-Inoculated individuals with fluid from
cowpox vesicles to protect them from
smallpox
-Vaccination
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The Specific Immune System
Two important concepts
Has cellular memory (an ability to remember
antigens)
Does not harm the body’s own cells (when all
is working well).
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ANTIGENS
An antigen is a molecule that provokes a
specific immune response.
A single protein may have many different
antigenic determinants or epitopes
-Each can stimulate a distinct immune
response
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Lymphocytes
Lymphocytes are leukocytes (FROM BONE
MARROW--via hematopoiesis) with surface
receptors for antigenic determinants
-Direct an immune response against either the
antigen or the cell that carries it
When a naïve lymphocyte binds a specific
antigen for the first time, it gets activated by a
process called clonal selection
-Produces a clone of cells: some respond
immediately, others are memory cells
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Examples of 2 Lymphocytes
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or display.
Lymphocyte Receptor Proteins
B Cell
T Cell
Antigen-binding Antigen-binding
site
site
Antigen
B-cell
receptor
Antigen
Plasma membraneT-cell
receptor
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Examples of 2 Lymphocytes
B lymphocytes (B cells)
-Respond to antigens by secreting antibodies or
immunoglobulins (Ig)
-Participate in HUMORAL IMMUNITY
T lymphocytes (T cells)
-Regulate other immune cells or directly attack
cells that carry specific antigens
-Participate in CELL-MEDIATED IMMUNITY
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Organs of the Immune System
-Primary lymphoid organs
-Bone marrow and thymus
-Secondary lymphoid organs
-Lymph nodes, spleen, and
mucosal-associated lymphoid
tissue (MALT)
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B cells come from the Bone Marrow
The bone marrow is site of B cell maturation
-Each B cell has about 105 Ig molecules on
its surface, all with the same specificity
-However, different B cells will have
different specificities
-B cells recognize epitopes directly
-Any lymphocytes that are likely to bind to
self-antigens undergo apoptosis
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T cells come from the Bone Marrow
The thymus is the site of T cell maturation
-Each T cell has about 105 identical T-cell
receptors on its surface
-Recognize epitopes only if they are
combined with major
histocompatibility
complex (MHC)
peptides
-Lymphocytes that cannot bind MHCs, or
that bind self-MHC/self-peptide too
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Not All B cells leave the Bone Marrow
Not all T cells leave the Thymus
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Bone marrow
stromal cell
Ig on B cell
surface binds,
inducing
apoptosis
Igs
Ig does not
bind; B cell
leaves bone
marrow
MHC–
peptide
complex
Dendritic cell
TCR binds
TCRs
tightly, inducing
apoptosis
TCR binds
weakly;
T cell leaves
thymus
Cells that cannot
bind MHC are
also eliminated
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Secondary Lymphoid Organs
The locations of these organs promote the
filtering of antigens that enter any part of
an individual’s body
-Mature but naïve B and T cells become
activated in the lymph nodes
-The spleen is site of immune responses to
antigens found mainly in the blood
-Mucosal-associated lymphoid tissue
(MALT) include the tonsils and appendix
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2 types of T Cells
-Cytotoxic T cells (Tc)
-CD8+ cells, recognize MHC class I
(found on all nucleated cells)
-Helper T cells (TH)
-CD4+ cells, recognize MHC class II
(found only on antigen-presenting cells)
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Cytotoxic T cells
-Naïve TC cells are activated
upon TCR recognition of
foreign peptide displayed on
self-MHC class I
protein on dendritic cells
-Clonal expansion and
differentiation into activated
cells and memory cells
-Activated cells induce apoptosis
in cells with same specificity as
first cell
-Likely a viral-infected or cancer cell
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Helper T cells Working with B cells and
Macrophages
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Helper T cells Working with B cells and
Macrophages...CONTINUED
-TH cells respond to exogenous antigen that is
taken up by an antigen presenting cell
-Antigen is partially digested, then complexed with
MHC class II proteins
-Complex is transported to and displayed on the
cell surface
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Helper T cells Working with B cells and
Macrophages...CONTINUED
-Activated TH cell gives rise
to a clone of TH cells
including both effector
cells and memory cells
-Most effector TH cells leave
the lymphoid organs and
circulate around the body
-Secrete proteins
called cytokines
-Promote humoral and
cell-mediated immune
responses
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Helper T cells Working with B cells and
Macrophages...CONTINUED
-Humoral immunity begins when naïve B cells in
secondary lymph organs meet antigens
-B cells are activated when their surface Igs
bind to a specific epitope on an antigen
-TH cytokines may also
be required
-Activation results in
clonal expansion and
differentiation into
plasma and memory cells
-Plasma cells produce
soluble antibodies
against the same epitope
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Helper T cells Working with B cells and
Macrophages...CONTINUED
Plasma cells produce
soluble antibodies
against the same epitope
Macrophage or
Neutrophil
binds the antibody epitope
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Immunoglobulins
An immunoglobulin consists of two identical short
polypeptides, light chains, and two identical
longer polypeptides, heavy chains
-Four chains are held by disulfide bonds, forming a
Y-shaped molecule
-Fab regions = Two “arms”
-Fc region = “Stem”
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Immunoglobulins
Each chain has a variable region (amino acid
sequence differs between Igs) and a constant
region
-The variable regions fold together to form a cleft,
the antigen-binding site
Each Ig can bind two identical epitopes
-Allows formation of antigen-antibody complexes
-Indeed, Igs can agglutinate, precipitate or
neutralize antigens
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Immunoglobulin Diversity
Human B cells can generate antibodies
with over 1010 different antigen-binding
sites
-This diversity is generated through a
process called DNA rearrangement
An Ig protein is encoded by different
segments of DNA
-V (variable), D (diversity), J (joining)
-Plus a constant region
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Immunoglobulin Diversity
These segments are joined during maturation in the bone
marrow in B-cells
-First, a D and a J segment are joined
-Then, DJ is combined with a V segment
-Transcription and RNA processing follow, linking variable
region to a constant region
-Translation occurs in the rough ER, where heavy and light
chains are joined together
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The regional genes (V, D, J) are flanked by Recombination
Signal Sequences (RSSs) that are recognized by a group of
enzymes known collectively as the VDJ recombinase.
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T Cell Receptors
The structure of a TCR
-Unlike Igs, TCRs are
not secreted
-TCR diversity is also
caused by DNA
rearrangements
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Immune Responses
The first encounter with a foreign antigen is
called the primary immune response
-Only few B or T cells can recognize
antigen
The second encounter is called the
secondary immune response
-This time there is a large clone of
memory cells that can recognize the
antigen
-Immune response is more effective
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Autoimmunity
The acceptance of self cells is known as
immune tolerance
Autoimmune diseases are caused by the
failure of immune tolerance
-Result in activation of autoreactive T
cells, and production of autoantibodies
by B cells
-Cause inflammation and organ damage
-Alleviated by corticosteroids and
NSAIDs, including aspirin
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Allergy
Allergy refers to a greatly
heightened response to a
foreign antigen, or allergen
-The most common type is
known as immediate
hypersensitivity
-Results from excessive
IgE production
-Seasonal hay fever
-Provoked by ragweed or
other pollen
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Allergy
On initial exposure to allergen, B cells are activated
to secrete IgE antibodies
-Bind to FC receptors on mast cells or basophils
On subsequent exposure to allergen, allergen
cross-links bound IgEs
-Cells are induced to release histamine and other
inflammatory mediators
-Produce symptoms of allergy
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Allergy
In systemic anaphylaxis, the allergic reaction
is severe and potentially life-threatening
-Anaphylactic shock = Blood pressure
drop, and bronchial constriction
-Death within 20-30 minutes
Most people, however, experience local
anaphylaxis
-Hives or mild asthma
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Allergy
-Contact dermatitis
-Caused by varied materials, such as
poison ivy, nickel in jewelry and
cosmetics
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Antibodies in Medicine
A person’s blood type is determined by
antigens found on surface of red blood cells
-ABO blood types = Types A, B, AB and O
-Rh factor = Rh positive and Rh negative
The immune system is tolerant of its own
RBC antigens, but makes antibodies that
bind to those that differ
-For example, people with type A blood
make antibodies against the B antigen 48
Antibodies in Medicine
In blood transfusions, the antigens of the
donor can’t trigger the antibodies of the
recipient
-For instance, a type A person cannot
donate to a type B or type O
-These would have anti-A antibodies
Blood is typed by agglutination reactions,
using circulating IgM antibodies
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Antibodies in Medicine
A mismatched blood transfusion may be
deadly
-Within 5-8 hours, tremendous hemolysis of
the transfused RBCs is detected
-Due to formation of complement MACs
-The released hemoglobin is converted to
bilirubin
-Can cause severe organ damage,
especially to kidneys
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Evading the Immune System
Some pathogens can alter their surface antigens to
avoid immune system detection
Influenza virus expresses 2 surface proteins:
hemaglutinin (HA) and neuraminidase (NA)
-Antigenic drift = Point mutations to the HA and
NA genes
-Antigenic shift = Appearance of a new virus
subtype where HA and/or NA proteins are a mix of
surface antigens from two original strains
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Evading the Immune System
Salmonella typhimurium
-Can alternate between
expression of two different
flagellar proteins
Mycobacterium tuberculosis
-Once phagocytosed, inhibits
fusion of the phagosome with
lysosomes
Neisseria gonorrhoeae
-Secrete proteases that
degrade IgA antibodies
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Evading the Immune System
HIV, human immunodeficiency virus,
mounts a direct attack on TH cells
-Binds to CD4 proteins, and is endocytosed
An individual is considered to have AIDS
when their TH cell level has dropped
significantly
-Immunosuppression results in an increase
in opportunistic infections and cancers
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Evading the Immune System
HIV in red TH cells in green
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