Chapter 18 - Defense Mechanisms
of the Body - pages 695-738
SECTION A - IMMUNOLOGY: DEFENSES AGAINST FOREIGN MATTER
I.
Chapter 18 - Introduction
A.
Basic concept is "self, not-self"
1.
Immunity - any mechanism that maintains the "self, not-self"
distinction (very broad definition)
2.
Not-self
a)
b)
c)
Bacteria, virus, funguses, protozoa, parasites 
read brief description page 696
Non-microbial foreign substances
Destroy cancerous cells in body  immune
surveillance
B.
II.
Categories
1.
Nonspecific immune defenses - does not require prior
exposure and is nonselective in protection; it is inherited
2.
Specific immune defenses - depends on prior exposure to a
specific foreign material, recognition of it upon subsequent
exposure and reaction to it; it is ACQUIRED and not
inherited (one exception explained later)
Cells mediating immune responses
A.
Introduction, overview
1.
Leukocytes - white blood cells (WBC)
a)
Neutrophils
b)
Eosinophils
c)
Basophils
d)
Monocytes
e)
Lymphocytes
(1)
B cells
(2)
T cells
(a)
Cytotoxic T cells
(b)
Helper T cells
(3)
NK cells
2.
Plasma cells
a)
Derived from peripheral lymphoid tissues and B
lymphocytes
b)
Secrete antibodies
3.
Macrophages
a)
Ubiquitous tissue phagocytes b)
Differentiated from monocytes
4.
Macrophage-lke cells
a)
Cells that are produced in most tissues
b)
Are called microglia in the CNS
5.
Mast cells
a)
Produced in almost all tissues and organs
b)
Differentiate from bone marrow cells
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B.
Table 18-1, page 697 - major functions of cells mediating immune
responses
Cells
Neutrophils
Basophils
Eosinophils
Monocytes
B cells
Cytotoxic T cells
Helper T cells
NK cells
Plasma cells
Macrophages
and
macrophage-like
cells
Mast cells
III.
Functions
1. Phagocytosis
2. Release chemicals involved in inflammation
(vasodilators, chemotaxins, etc.)
Have functions in blood similar to those of mast cells in
tissues (see below)
1. Destroy multicellular parasites
2. Participate in immediate hypersensitivity reactions
1. Have functions in blood similar to those of
macrophages in tissues (see below)
2. Enter tissues and are transformed into macrophages
1. Initiate antibody-mediated immune responses by
binding specific antigens to their plasma membrane
receptors, which are immunoglobulins
2. During activation are transformed into plasma cells,
which secrete antibodies
3. Present antigen to helper T cells
Bind to antigens on plasma membrane of target cells
(virus-infected cells, cancer cells, and tissue transplants)
and directly destroy the cells
Secrete cytokines that help to activate B cells, cytotoxic T
cells, NK cells, and macrophages
1. Bind directly and nonspecifically to virus-infected cells
and cancer cells and kill them
2. Function as killer cells in antibody-dependent cellular
cytotoxicity (ADCC)
Secrete antibodies
1. Phagocytosis and intracellular killing
2. Extracellular killing via secretion of toxic chemicals
3. Process and present antigens to helper T cells
4. Secrete cytokines involved in inflammation, activation
and differentiation of helper T cells, and systemic
responses to infection or injury (the acute phase
response)
Release histamine and other chemicals involved in
inflammation
Cytokines
A.
General term for a large number (over 100) of protein messengers
B.
Regulate host cell growth
C.
Function in both specific and nonspecific immune mechanisms
D.
Complex physiology and a lot not known about function
1.
Secreted by more than one type of cell
a)
Immune system cells
b)
Non-immune system cells (endothelial cells &
fibroblasts for instance)
2.
Often operate with cascade effect
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3.
4.
5.
Broad range of actions
Redundancy in function
Involved in non-immune process such as bone formation
and uterine function
IV.
Non-specific immune responses
A.
Introduction - responses that do not have to recognize specific
identity of "invader"
B.
C.
D.
E.
General “markers”  particular classes of carbohydrates or lipids
that are part of most microbial cell walls
Specific immunity depends primarily on protein markers (later)
Defenses at Body Surfaces
1.
Skin is physical barrier but includes microflora of protective
bacteria
2.
Sweat glands, sebaceous and lacrimal glands secrete
antimicrobial chemicals
3.
Mucus secreted by epithelium of respiratory and G.I. tracts is
antimicrobial and sticky helping cilia to sweep away foreign
material and microbes
4.
Macrophages engulf microbes, etc.
5.
Hair in nose, sneezes, coughs
6.
Harmless microbes on the skin and other surface linings can
suppress the growth of other potentially harmful microbes -How?
Inflammation
1.
Summary Table 18-2, 699 (details below)
a)
Initial entry of bacteria (not-self) into tissue
b)
Vasodilation of the microcirculation in the infected
area, leading to increased blood flow
c)
Marked increase in protein permeability of the
venules in the infected area, with resulting diffusion
of protein and filtration of fluid into the interstitial fluid
d)
Chemotaxis: exit of leukocytes from the venules into
the interstitial fluid of the infected area
e)
Destruction of bacteria in the tissue either through
phagocytosis or by mechanisms not requiring prior
phagocytosis
f)
Tissue repair
2.
Vasodilation and increased permeability to protein
a)
Histamine secreted by mast cells
b)
Promote vasodilation and fluid collection
c)
Local capillaries become more permeable to protein
(1)
Kinins are derived from kininogens
(2)
Promote exudation & vasodilation and can
hurt like hell
d)
Fluid collects in area and swelling occurs
e)
Exudation of neutrophils and monocytes
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f)
3.
4.
Destruction of bacteria by phagocytosis or other
means
Chemotaxis
a)
The neutrophils stick to adhesion molecules on the
endothelium and start increased amoeboid
movement
b)
Neutrophil "squeezes" between endothelial cells neutrophil exudation via "stronger" adhesion
molecules
c)
Entire response is called chemotaxis and is induced
by chemotaxins which cause Ca2+ entry into
neutrophils which promotes movement
d)
Monocytes "show up" later and participate in
carnage on foreign agent
e)
Cytokines that are chemoattractants are called
chemokines
Phagocytosis, Figure 18-1, 701 and Figure 18-2, page 701
a)
Opsonin - a substance that "marks" a foreign
substance for phagocytosis (actually binds it and
holds for phagocyte)
Endocytosis  phagosome  phagolysosome 
degranulation  exocytosis
(1)
Phagolysosome produces H2O2 (hydrogen
peroxide) which destroys foreign agent
(2)
Nitric oxide destroys the microbe
(3)
Phagocyte doesn't necessarily die but can
repeat process
c)
Neutrophils and macrophages also secrete
substances that fight invader
(1)
Help regulate inflammatory response
(2)
Extracellular killing of microbes
(3)
Activation of clotting and anticlotting
pathways
(4)
Hormonal regulation of systemic response to
infection
Complement, Figure 18-3, 702 and Figure 18-4, page 703
a)
Group of at least 20 different proteins that normally
circulate in blood
b)
Another mechanism for extracellular microbe killing
c)
When first protein in chain is activated that triggers a
"cascade" effect which results in the final
complement protein "attacking" the plasma
membrane of the foreign agent
(1)
The last protein is actually the five different
proteins called the membrane attack
complex or MAC
b)
5.
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(2)
The MAC penetrates the membrane and
opens channels through which the microbes
"guts" leak out
(3)
This is the major, nonphagocytic, method of
protection in nonspecific immunity
(4)
As the different products of the complement
pathway are formed they may also mediate
other actions, see Figure 18-3, page 703
(5)
C - release of histamine from mast cells
3a
(6)
C - an opsonin and participates in MAC
3b
complex
d)
Classical complement pathway versus alternate
complement pathway
(1)
Classical pathway - Antibodies from
lymphocytes activate C1
(2)
Antibodies are a result of specific immunity - how then is nonspecific complement
system activated?
(3)
Alternate pathway plugs in at C3b (by passes
C1)and does not involve antibodies but the
microbes must have certain carbohydrates
on their surface
(4)
Not all microbes stimulate complement
attack
6.
Local inflammatory mediators, Table 18-3, page 700
Mediator
Source
Kinins
Plasma proteins
Complement
Plasma proteins
Products of blood clotting
Plasma proteins
Histamine
Mast cells
Eicosanoids;
Many cell types
Platelet-activating factor
Many cell types
Cytokines, including chemokines
Monocytes, macrophages,
Examples are interleukin 1, tumor neutrophils, lymphocytes, and
necrosis factor (TNF), and
several nonimmune cell types,
interleukin 6
including endothelial cells and
fibroblasts
Lysosomal enzymes, nitric oxide,
Neutrophils and macrophages
and other oxygen-derived
substances
7.
Tissue repair
a)
Fibroblast divide and form scar
b)
Abscess - bag of pus walled off by fibroblasts and
collagen
c)
Granuloma - like tuberculosis and may be contained
for years within it
8.
Interferon, Figure 18-6, page 704
a)
Different sites of production and ranges of biological
activity
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b)
V.
A family of proteins that fight viral infections in
particular
c)
Inhibits viral replication in host cells by the following
mechanism
(1)
Virus enters a cell that can make interferon
(2)
Interferon leaves that cell and binds to
surface membranes of neighboring cells
(3)
That binding induces synthesis of antiviral
enzymes in that cell that block the synthesis
of proteins that the viruses need for
replication
(4)
The antiviral proteins are not activated until
the virus actually enters the cell (viral RNA
activates)
d)
Interferon stimulates lymphocytes into action to
attack and kill virus-infected cells and cancer cells
(possible treatment!)
Specific Immune Responses
A.
Lymphocytes mediate specific immune responses, See Table 18-1,
page 697
B.
Overview of typical immune response
1.
2.
Antigen  defined as any foreign molecule that can trigger a
specific immune response against itself or the cell bearing it
a)
Specific foreign matter
(1)
Any foreign matter that can trigger a specific
immune response and it can appear from
within or from without
(2)
It is a functional term
(3)
Normally protein or complex carbohydrate
(4)
Can part of a smaller molecule or part of a
large object such as pollen
b)
Antigen processing must occur in the body before
lymphocytes can interact with it
(1)
Macrophages play this role - the general
term is antigen-presenting cell (APC)
(2)
The foreign substance or thing is
phagocytized and unfolded or otherwise
"dismembered" - the unfolding, etc.,
exposes internal amino acids for recognition
(3)
The macrophages "shuttle" the processed
molecules to the cell surface where they
may be accessible by lymphocytes
Three stage process - 1) antigen encounter and recognition,
2) lymphocyte activation, 3) the attack
a)
Antigen Encounter And Recognition: During its
development each lymphocyte synthesizes and
inserts into its plasma membrane receptors that are
able to bind to a specific antigen.
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(1)
b)
c)
If the lymphocyte encounters that antigen
later, the antigen binds to the receptor. This
binding is termed "recognition" in
immunology.
(2)
Lymphocytes are able to distinguish one
antigen from another by the nature of their
plasma-membrane receptors.
(3)
Each lymphocyte is specific for just one type
of antigen
(a)
Estimated that the lymphocyte
population expresses more than 100
million distinct antigen receptors.
(b)
A single type of antigen receptor
may be expressed by a small
number of lymphocytes, termed a
clone.
(c)
That is, there are more than 100
million distinct small clones of
lymphocytes in the body.
(d)
Called the Clonal Selection Theory
Of Immunity
Lymphocyte Activation: The binding of antigen to
receptor is the trigger for lymphocyte activation.
(1)
The lymphocyte undergoes multiple mitotic
divisions
(2)
Only one still has the antigen combined with
it.
(3)
Many lymphocytes are formed that are
identical to the one that started the cycles
and can recognize the antigen; this is
termed clonal expansion
(4)
Lymphocyte Activation: lymphocytes
undergo a differentiation process, depending
upon the lymphocyte type.
(5)
After activation, types-B cells and cytotoxic
T cells-then function as "effector lymphocytes," which are actors in the attack
phase.
(6)
Helper T cells, after activation, secrete
cytokines that enhance the function of B
cells and cytotoxic T cells.
The Attack: The activated effector lymphocytes
launch an attack against all antigens of the kind that
initiated the immune response.
(1)
It takes only one or two antigen molecules to
initiate the specific immune response - an
attack on all of the other antigens of that
specific kind in the body.
(2)
B cells differentiate into cells termed plasma
cells, which secrete antibodies into the
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C.
blood, and these antibodies then recruit and
guide other molecules and cells to perform
the actual attack.
(3)
Cytotoxic T cells directly attack and kill the
cells bearing the antigens.
Lymphoid organs and lymphocyte origins
1.
Lymphocytes circulate in the blood but most are in lymphoid
organs
a)
Primary lymphoid organs
(1)
Bone marrow and thymus
(2)
Supply peripheral lymphoid organs with
mature lymphocytes ready to do the job
b)
Secondary lymphoid organs (a.k.a. peripheral
lymphoid organs)
(1)
Lymph nodes, spleen, tonsils, and
lymphocytes found in the intestinal,
respiratory, genital and urinary tracts
(2)
Lymphocytes in the secondary organs can
undergo mitosis and form clones
(3)
It is in these locations that lymphocytes do
their thing
2.
Lymphoid organs versus lymphatic system
a)
Lymphatic system is a conducting system
b)
Only the lymph nodes are part of the lymphoid
"organs"
3.
Thymus
a)
Lies in upper chest and is large in infant and
gradually gets smaller
b)
Secretes thymosin (thymopoietin) which is a group
of hormones that is largely not understood
4.
Lymph nodes, Figure 18-7, page 705
a)
Lined with macrophages
b)
Have large clusters of lymphocytes
5.
Spleen
a)
Largest lymphoid organ (lies in abdomen)
b)
Blood percolates through
(1)
Large collection of lymphocytes and
macrophages
(2)
Also phagocytize aging and dead
erythrocytes
c)
In adult only lymphocytes are formed in spleen, in
fetus all types of blood cells are formed there
6.
Tonsils
a)
In pharynx
b)
Filled with lymphocytes and macrophages
7.
Recirculation of lymphocytes goes on constantly all over the
body
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D.
Lymphocyte origins  B and T cells
1.
B cells  mature in blood marrow and are carried to
lymphoid organs (first called B cells because they pass
through the bursa of the chicken and that is where they were
first discovered)
2.
T cells  leave bone marrow in an immature state during
fetal and neonatal life and are carried to the thymus
a)
That is why they are called T cells
Subsets of T cells  cytotoxic, helper and
suppressor
3.
Natural killer cells (NK cells)
a)
Arise in bone marrow but exact origin is unclear
b)
Are not dependent on specific antigens (more later)
Functions of B cells and T cells
1.
Figure 18-8, page 707 – derivation of B and T cells
2.
B-cells, "humoral", antibody mediated
a)
B cells differentiate into plasma cells following
activation
b)
Antibodies are proteins in group called
immunoglobulins (more detail later)
(1)
Figure 18-9, page 708
(2)
Present in plasma membranes of B cells
(3)
Are produced by plasma cells after
activation
(4)
The secreted antibodies travel via the blood
stream all over the body
(5)
Defend against bacteria, viruses, other
microbes in extracellular fluid and against
toxins
3.
T-Cells (cytotoxic and helper) and natural killer cells - known
as cell mediated immunity
a)
Will not discuss hypothesized suppressor T
b)
Cytotoxic T cells travel everywhere but attack cells
with antigens that initiated the original immune
response
b)
E.
4.
5.
(1)
Cytotoxic T cells  CD8 proteins in plasma
membrane, a.k.a. CD8+ cells
(2)
Helper T cells  CD 4 proteins in plasma
membrane, a.k.a. CD4+ cells
Helper T cells  CD4+ cells
a)
Undergo activation but do not attack antigen
b)
Secrete messenger substances that facilitate the
activation and function of B cells and cytotoxic T
cells
Generalizations
a)
Antibody mediated responses are more varied than
cell mediated
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b)
F.
Cell mediated attacks are limited, in particular,
cancerous or cells infected with viruses
6.
Figure 18-9, page 708 – summary of roles of B and T cells
Lymphocyte receptors
1.
B-cell receptors
a)
Has copies of "its" antibodies on cell surface and
acts as the receptor - technically it's not an antibody
but a glycoprotein
b)
There are millions of different kinds B cells
(1)
There are more kinds of B cells than there
are genes (200) to make them
(2)
Clonal selection
(3)
Different kind of DNA and enzymes to create
such a large variety of B cells
c)
Structure, Figure 18-10, page 709
(1)
Four interlinked polypeptides
(2)
Two heavy or long chains and two short or
light chains
(3)
Five classes of immunoglobulins, A, D, E, G
and M
(4)
Fv for variable and contains the antigenbinding site - there are many kinds of these
- millions!
(5)
B cell receptors can bind either freely
circulating antigens or antigens on surface
of a foreign cell -- the B cell can be attached
to the foreign cell via the connection
2.
T-cell receptors
a)
T cells do not produce immunoglobulins
b)
Have two-chained proteins that differ in one region
from T cell to T cell
c)
T cells mature in the thymus
d)
The antigen in question must form a complex with
certain of the body's own plasma-membrane
proteins in order to combine with the T cell receptor
(1)
Major histocompatibility complex (MHC) MHC proteins - two classes, I and II
(2)
Except for identical twins, no two people
have the same MHC proteins
(3)
With the exception of erythrocytes, Class I
MHC proteins are found on the surface of all
the cells in the body
(4)
Class II proteins are found primarily on the
surfaces of macrophages and a few other
cell types including B cells
(5)
Restriction elements is a termed used to
describe MHC proteins since the different T
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G.
cells have different requirements for
recognition, Table 18-4, page 710
Cell type
MHC restriction
B
None (do not interact with
MHC proteins)
Helper T
Class II, found only on
macrophages, macrophagelike cells and B cells
Cytotoxic T
Class I, found on all nucleated
cells of the body
NK
No MHC interaction for
activation
3.
NK-cell receptors
a)
These cells may have no MHC restriction
b)
Less specific than cytotoxic T cells
c)
NK cell receptors are not understood
Antigen presentation to T cells - APC (antigen-presenting cells)
1.
T cells can bind antigen only when the antigen appears
on the plasma membrane of a host cell that is
complexed with the cell’s MHC proteins.
2.
Presentation to helper T cells
a)
Helper T cells require class II MHC
b)
Class II MHC is found only on macrophages, B cells
and macrophage-like cells
c)
Only the cells above can act as APCs for helper T
cells
d)
Antigen processing and recognition, Figure 18-11a,
page 711
e)
An antigenic determinant is known as an epitope
f)
Macrophage may process and present antigen at
the site of entry
g)
Macrophage may enter lymphatic vessel and travel
to lymph node
h)
Bacteria may enter lymph vessels or blood
untouched and be processed in lymph nodes or by
spleen in the blood
3.
B-cell activation: The role of helper T cells - Figure 18-11b,
711
a)
B cells can not, on their own, inactivate an antigen,
helper T cells must secrete lymphokines
b)
B cell binds antigen, T cell binds Class II MHC on
surface of macrophage (or other antigen presenting
cell) - the macrophage is being bound by B cells and
helper T cells
c)
T cell "costimulus" activation, Figure 18-12,page 711
(1)
Non-receptor plasma membrane proteins
(non-antigenic matching proteins)
(2)
APC secretes interleukin 1 (IL-1) and TNF in
response to binding
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d)
4.
Activated helper T cell secretes cytokines that act as
paracrines, autocrines
Presentation to cytotoxic T cells, Figure 18-13, page 712
a)
Any cell with class I MHC can act as APS for a
cytotoxic T cell
b)
Antigens that complex with class I MHC arise within
the body's cells - they are endogenous
(1)
Virus infected cells (virus can not trigger
immune response since it is in a cell)
(a)
The resident virus causes foreign
protein to end up in the cell
membrane of the host
(b)
The foreign protein is complexed
with the Class I MHC
(c)
This complex can then be bound by
antigen-specific cytotoxic T cells
(2)
Cancer cells
(a)
Cancer cells also produce "foreign"
protein and it complexes with the
Class I MHC in the plasma
membrane
(b)
This complex can then be bound by
antigen-specific cytotoxic T cells
(c)
Oncogenes  genes that have
been altered and generate
cancerous tissue
5.
H.
Natural killer cells
a)
Distinct class of lymphocytes
b)
Functions
(1)
Target virus infected cells and cancer cells
(2)
Attack and kill target cells directly
c)
Not antigen specific - require no prior exposure and
no antigen presentation
d)
Not known if there is an MHC restriction,
e)
Why not cover under non-specific immunity? (too
complex)
Development of immune tolerance: Self versus Not-Self or how
does body recognize its own proteins?
1.
Clonal deletion
a)
T cells are exposed to variety of self proteins in
utero and postnatal  by unknown mechanism the
thymus cells destroy the cells that “recognize” these
proteins and they are destroyed via apoptosis
b)
Thus the cells which would destroy self proteins are
themselves destroyed early in life
2.
Clonal inactivation
a)
Some proteins do not pass through thymus
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b)
I.
By unknown mechanism self-reactive T cells are
inactivated
3.
Mechanisms?
a)
Costimulus is not provided in early development so
T cell is not activated
b)
This can occur later in life also
Antibody-mediated immune responses: defenses against bacteria,
extracellular viruses and toxins; Table 18-5, page 713 and Figure
18-14, page 714
1.
In peripheral lymphoid organs, bacterial antigen binds to
specific receptors on the plasma membrane of B cells.
2.
Simultaneously, antigen-presenting cells (for example,
macrophages) (APCs) present to helper T cells processed
antigen complexed to MHC Class II proteins on the APCs
and secrete IL-1 & TNF, which acts on the helper T cells.
3.
In response, the helper T cells secrete IL-2, which activates
the helper T cells to proliferate and secrete IL-2 and other
cytokines. These activate the antigen bound B cells to
proliferate and differentiate into plasma cells. Some of the B
cells differentiate into memory cells rather than plasma cells.
4.
The plasma cells secrete antibodies specific for the antigen
that initiated the response, and the antibodies circulate all
over the body via the blood.
5.
Antibodies combine with antigen on the surface of the
bacteria anywhere in the body.
6.
Presence of antibody bound to antigen facilitates
phagocytosis of the bacteria by neutrophils and
macrophages. It also activates the complement system,
which further enhances phagocytosis and can directly kill the
bacteria by the membrane attack complex. It may also
induce antibody-dependent cellular cytotoxicity mediated by
NK cells that bind to the antibody's Fc portion.
7.
B cells undergo great cytoplasmic expansion, especially
granular endoplasmic reticulum as they become plasma
cells (plasma cells belly up in a day or two after producing
millions of antibodies)
a)
Memory cells - some plasma cells become memory
cells which can respond later in a rapid fashion
b)
The antibodies travel everywhere in the extracellular
fluid and "attack" their specific antigen
c)
Antibodies play two roles in immune response
(1)
Initial recognition on B cells
(2)
Circulating antibodies bind to bacteria
bearing the same antigen, marking them as
targets to be attacked
8.
Antibody secretion
a)
Plasma cells produce thousands of antibodies until
they die within a day or two
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b)
9.
10.
IgG (gamma globulin) - most abundant plasma
antibody
c)
IgM - provide bulk of antibodies against bacteria and
viruses
d)
IgE - mediate allergic responses
e)
IgA - secreted by gastrointestinal, respiratory,
genitourinary tracts and breast milk
f)
IgD - unknown function
g)
ALL ANTIGEN-ANTIBODY COMPLEXES
ENHANCE THE INFLAMMATION RESPONSE
The attack: effects of antibodies
a)
Direct enhancement of phagocytosis
(1)
The presence of an IgG antibody-antigen
complex enhances phagocytosis
(2)
Acts as an opsonin - Figure 18-14, page 708
(3)
Phagocyte has Fc receptors
b)
Activation of complement system – Figure 18-15,
page 716
(1)
The most important mechanism for antigenantibody complex enhancing inflammation is
the via the complement system
(2)
Classical complement pathway
(a)
C1 binds to complement receptors
on the Fc portions of the antibody
(IgG and IgM) that is combined with
antigen
(b)
This activates the enzymatic portion
of the complement pathway
(c)
The C1 will attach to all classes of
immunoglobins and that is why it is
such a powerful enhancer of the
inflammatory response.
c)
Antibody-dependent cellular cytotoxicity (ADCC)
(1)
Complement (C1) and a phagocyte can bind
nonspecifically to Fc
(2)
NK cells can do the same
(3)
The NK cells secrete cytotoxins but there
must be antibody present (ADCC)
d)
Direct neutralization of bacterial toxins and viruses
(1)
Toxins can trigger immune response via
antibodies
(2)
The antibody-antigen complex can form
chains which can then be phagocytized
(3)
The toxin or viruses can not then enter or do
damage to the body or cells
Active and passive humoral immunity
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a)
Time for immune response? - First challenge takes
several days to produce antibodies, Figure 18-17,
page 717
Vaccine  may consist of attenuated microbes,
toxins are harmless antigens
c)
Subsequent challenges have almost immediate
effect
d)
Active immunity is what has been discussed thus far
e)
Passive immunity is through mother's breast milk
and through injection of antibodies such as in pooled
gamma globulin
Defenses against virus-infected and cancer cells, Figure 18-18,
page 718
1.
Introduction
a)
Previous immune response was about “exogenous
antigens”
b)
This section deals with how cells infected with
viruses or are cancerous are dealt with by cytotoxic
T cells, NK cells and activated macrophages
c)
How the body's own cells are killed
2.
Role of cytotoxic T cells
b)
J.
a)
b)
Similar to antibody-mediated immunity 
macrophages process and present antigens in
association with the macrophage's Class II MHC
proteins to helper T cells
Helper cells respond to stimulation by TNF & IL-1
and release IL-2
(1)
Acts as autocrine to stimulate helper T cell
proliferation
(2)
The IL-2 also activates cytotoxic T cells and
NK cells to proliferate and attack the target
cells
Gamma interferon (a lymphokine) 
secreted by helper T cells and by NK cells
where it acts as an autocrine for cytotoxic T
cells
c)
Cytotoxic T cells release cytoplasmic secretory
vesicles by exocytosis into extracellular space
between itself and target cell
d)
The vesicles contain pore-forming protein that insert
into the target cell's membrane  perforin
e)
The target cell becomes leaky and loses cytoplasm,
etc.
Role of NK cells and “activated macrophages”, Figure 18-19,
page 719
a)
These two destroy virus-infected and cancer cells
also
b)
Major signal is IL-2 and interferon-gamma secreted
by helper T Cells
(3)
3.
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c)
4.
5.
6.
NK cell response is non-specific but requires a
specific response by helper T Cells to trigger
response  secrete cytotoxins
d)
Macrophages can be activated also by this
mechanism an are called activated macrophages 
secrete tumor necrosis factor (TNF)
Interleukin 1 (IL-1), TNF and IL-6 (Interleukin 6) - secreted
by macrophages and is required by lymphocytes for
activation
Table 18-6, page 720, summary of host responses to viruses
Role of macrophages in immune response,
MAIN CELLS
INVOLVED
Nonspecific defenses
Anatomical barriers
Inflammation
Interferon
COMMENT ON ACTION
Body surface linings
Tissue macrophages
Most cell types after
viruses enter them
Physical barrier; antiviral chemicals
Phagocytosis of extracellular virus
Interferon nonspecifically prevents viral
replication inside host cells
Antibody-mediated
Plasma cells derived
from B cells secrete
antibodies
Direct cell killing
Cytotoxic T cells, NK
cells, and activated
macrophages
Antibodies neutralize virus and thus
prevent viral entry into cell
Antibodies activate complement, virus
Antibodies recruit NK cells via
cytotoxicity
Via secreted chemicals, destroy host
cell and thus induce release
Activity is stimulated by IL-2 and
interferon-gamma.
Specific defenses
VI.
Systemic manifestations of infection, Figure 18-20, page 721
A.
Acute phase response
B.
Most significant is the secretion of endogenous pyrogens which
reset the hypothalamus thermoregulatory center and cause "fever"
(up to a certain point an elevated temperature is probably beneficial
to the organism)
1.
Plasma concentration of iron and zinc decrease and are thus
unavailable for bacteria to reproduce
2.
Loss of appetite deprives microbes of nutrients
3.
Acute phase proteins - liver secretes these during stress and
they effect inflammatory process, immune cell function and
tissue repair
4.
Bone marrow releases neutrophils and other granulocytes
(granulopoiesis)
5.
Release of amino acids from muscle for synthesis of proteins
to fight infection and for tissue repair
C.
Colony-stimulating factors - stimulate bone marrow to produce more
neutrophils and monocytes
D.
Role of macrophages in immune response, Table 18-7, page 722
1.
In nonspecific inflammation phagocytize particulate matter,
including microbes. Also secrete antimicrobial chemicals
and protein messengers (cytokines) that function as local
inflammatory mediators. The inflammatory cytokines
include IL-1 and TNF
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2.
3.
Process and present antigen to helper T cells.
Secrete IL-1, which stimulates helper T cells to secrete IL-2
and to express the receptor for IL-2.
4.
During specific immune responses, perform same killing and
inflammation inducing functions as in (1) but are more
efficient because antibodies act as opsonins and because
the cells are transformed into activated macrophages by IL-2
and gamma interferon, both secreted by helper T cells.
5.
Secrete IL-1, TNF, and IL-6, which mediate many of the
systemic responses to infection or injury,
VII.
Factors that alter the body's resistance to infection
A.
The term resistance is difficult because so many factors come into
play - generally it is all the immune factors working in concert to
protect the body and it can either be optimal or below optimal
B.
Examples that lower resistance
1.
Protein-calorie malnutrition (PCM) - poor nutrition is directly
linked to lowered immune response
2.
Preexisting disease - e.g., diabetes, or an injury
3.
Congenital defects - boy in a bubble
4.
Acquired immune deficiency syndrome (AIDS) - no cure
5.
Prolonged stress - more later
C.
Antibiotics - drugs that can selectively kill pathogens (especially
bacteria but not viruses) and not harm the host too much
VIII.
Harmful Immune Response
A.
Graft rejection
1.
Cytotoxic T cells are mainly responsible
2.
Half of the genetic make up of the placenta is foreign tissue
to mother
a)
Why doesn't mother reject?
b)
Trophoblasts may not present adult MHC class I
proteins but rather an "acceptable" form
c)
Much more to learn about this
B.
The Fetus as a graft
C.
Transfusion reactions and blood types
1.
ABO system, Table 18-8, page 725
a)
This is an atypical system in that the individual can
have antibodies for an antigen without prior
exposure - called natural antibodies (may be
induced from intestinal bacteria)
(1)
A person has B antibodies, B person has A
antibodies, AB has neither and O has both A
and B antibodies
(2)
No one has anti-O antibodies
b)
Natural antibody production is unknown (antibodies
without prior exposure) otherwise
c)
No such thing, in practice, of universal donor or
recipient, must do direct cross matching
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d)
Rh factor - requires prior exposure
Rh incompatibility  Rh-negative mother
bearing Rh-positive child
(2)
Antigens cross placental barrier and mother
synthesizes antibodies - for first child it
happens at parturition so not dangerous,
subsequent births may be jeopardized
(3)
Give mother rhogam, antibodies that bind to
antigens of RBCs that might have entered
mother's circulation and prevent them from
inducing antibody production (a clinical
"blocking antibody" so to speak)
Allergy (Hypersensitivity Reactions), Table 18-9, page 726
a)
Some people show immune responses to
environmental factors such as dust, ragweed
etceteras, called allergy or hypersensitivity
(1)
Can be very debilitating to fatal
(2)
The phenomenon is paradoxical since the
response is not warranted by the antigen
(3)
There is immediate responses and delayed
hypersensitivity like poison oak
(4)
(Discuss misuse of the word allergy)
b)
Immediate hypersensitivity, Figure 18-21, page 727
(1)
The antibodies involved here are of the IgE
class
(2)
Attach to mast cells and stimulate the
release of histamine, chemotaxins for
eosinophils and the synthesis of
prostaglandins in the mast cells
(3)
All this leads to a local inflammatory
response which in the respiratory system
can be severe
(4)
If inflammatory response goes beyond local
that can lead to anaphylactic shock which
can be fatal, as in a bee sting
(5)
Treatment is with antihistamines and/or
cortisols in extreme situations
(6)
The normal role of this response and IgE
antibodies and eosinophils is in the body's
defense against parasitic worms
Autoimmune disease
a)
Recognized as autoimmune in origin
(1)
Multiple sclerosis
(2)
Myasthenia gravis
(3)
Rheumatoid arthritis
(4)
Insulin-dependent diabetes mellitus
b)
Normally the lymphocytes that would attack self are
destroyed or suppressed in fetus and early infancy
(1)
2.
3.
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(1)
4.
5.
6.
This is an unanswered question. It is not
known how the immune system determines
self and not-self
(2)
See Scientific American, December, 1990,
page 106, Trends in Immunology: The Body
Against Itself by John Rennie
c)
Possible causes of autoimmune attack, Table 18-10,
page 728
(1)
There may be failure of clonal deletion in the
thymus or of clonal inactivation in the
periphery
(2)
Normal body proteins may be altered by
combination with drugs or environmental
chemicals. This leads to an attack on the
cells bearing the now--foreign" protein.
(3)
In immune attacks on virus-infected bodily
cells, so many cells may be destroyed that
disease results.
(4)
Genetic mutations in the body's cells may
yield new proteins that serve as antigens.
(5)
The body may encounter microbes whose
antigens are so close in structure to certain
of the body's own proteins that the
antibodies or cytotoxic T lymphocytes
produced against these microbial antigens
also attack cells bearing the self proteins.
(6)
Proteins normally never encountered by
lymphocytes may become exposed as a
result of some other disease.
Excessive inflammatory responses to microbes
a)
In systemic immune response the mediators can
cause harmful responses such as IL-1 and TNF
b)
Septic shock can result
c)
Excessive inflammation caused by HIV which
causes microglia to produce large amounts of
inflammatory cytokines that are toxic to neurons
d)
This same mechanism may be implicated in
Alzheimer's disease
Chronic inflammatory diseases – asthma, rheumatoid
arthritis and inflammatory bowel disease
Immune-privileged sites and tissues (NOT IN TEXT)
a)
Immune-privileged sites are regions of the body
where grafts of foreign tissue survive for extended
periods (even indefinitely), compared to
conventional (nonprivileged) sites.
b)
Sites and tissues
(1)
Anterior chamber of the eye
(2)
Cornea
(3)
Retina
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IX.
(4)
Brain
(5)
Hair follicles
(6)
Cartilages
(7)
Liver
(8)
Adrenal cortex
(9)
Pregnant uterus
(10)
Placenta
(11)
Ovary
(12)
Testis
(13)
Prostate
(14)
Tumors
(15)
Hamster cheek pouch
SUMMARY AND GLOSSARY, TABLE 18-11, PAGE 729-730
SECTION B - NONIMMUNE METABOLISM OF FOREIGN CHEMICALS
X.
Introduction, Figure 18-22, page 736
A.
Foreign chemicals are chemicals that have been synthesized since
the industrial revolution and not enough time has passed for
evolutionary adaptation - there are about 10,000 in common use
B.
Immune system can not handle most of them but rather they
undergo biotransformation or excretion or storage
XI.
Absorption
A.
Many chemicals can move into body through G.I. tract since it is
rather undiscriminating
B.
Some substances are absorbed through the lungs, especially
airborne metals
1.
Substances that enter lung are not subject to possible
biotransformation in liver as ones absorbed by intestine
2.
Substances toxic to liver are also avoided by liver
C.
Lipid solubility is critical for penetration through skin of oils, steroids
and other lipids and for things dissolved in them! (DDT)
D.
The placenta is quite vulnerable to passage of foreign substances
XII.
Storage Sites
A.
Cell proteins, bone and adipose tissue
B.
The storage sites are in equilibrium with the blood and the
substances can move in and out as plasma concentration changes
C.
Storage sites can be damaged by presence of substance or it can
be "protective"
XIII.
Excretion
A.
To be excreted a substance must be filtered or secreted across
renal tubule
1.
Small unbound molecules may be filtered
2.
Protein bound molecules are not filtered and this can be a
mixed blessing
B.
Once the substances are in the tubule they may be transformed to
more polar substance so they are not reabsorbed or they may be
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reabsorbed and just keep circulating like the enterohepatic
circulation
XIV.
Biotransformation
A.
Mainly in liver but can occur kidney, skin, placenta
1.
Most are transformed into more polar, less lipid-soluble
substances and may be rendered less toxic or it can be
made toxic! (The process does not make value judgments)
2.
Microsomal Enzyme System (MES) - hepatic enzymes
located in the hepatic cells smooth endoplasmic reticulum
a)
System is inducible
b)
Some substances can inhibit the MES
XV.
Inorganic Elements
A.
Heavy metals like mercury and lead
B.
G.I. tract does not readily absorb these but lungs can
C.
Not easily dealt with by body and can be dangerous, e.g., lead
poisoning
SECTION C - RESISTANCE TO STRESS
XVI.
A.
B.
XVII.
A.
B.
XVIII.
A.
Introduction
Stress - anything that causes the cortisol levels of the blood to
increase - varies widely among individuals
Pathway for cortisol- Figure 18-22, page 729
1.
Corticotropin releasing hormone
2.
ACTH
3.
Cortisol
Functions of Cortisol in Stress, Table 18-12, page 730
Functions (all covered previously)
1.
Effects on organic metabolism
a)
Stimulation of protein catabolism
b)
Stimulation of liver uptake of amino acids and their
conversion to glucose (gluconeogenesis)
c)
Inhibition of glucose uptake and oxidation by many
body cells ("insulin antagonism") but not by the brain
d)
Stimulation of triacylglycerol catabolism in adipose
tissue, with release of glycerol and fatty acids into
the blood
2.
Enhanced vascular reactivity, that is, increased ability to
maintain vasoconstriction in response to norepinephrine and
other stimuli
3.
Unidentified protective effects against the damaging
influences of stress 4. Inhibition of inflammation and specific
immune responses
4.
Inhibition of inflammation and specific immune responses
Cortisol's pharmacological effects and disease - effects on body due
to LARGE doses (hard to interpret)
Functions of the Sympathetic Nervous System in Stress - Fight or Flight
Functions, Table 18-13, page 731
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1.
2.
B.
XIX.
A.
B.
C.
Increased hepatic and muscle glycogenolysis
Increased breakdown of adipose tissue triacylglycerols
providing glycerol for gluconeogenesis and fatty acids for
oxidation
3.
Decreased fatigue of skeletal muscle
4.
Increased cardiac output secondary to increased cardiac
contractility and heart rate
5.
Shunting of blood from viscera to skeletal muscles by means
of vasoconstriction in the former beds and vasodilation in the
latter
6.
Increased ventilation
7.
Increased coagulability of blood
Excessive, prolonged stress is major health problem in U.S.
(Discuss)
Other Hormones Released During Stress
Aldosterone, vasopressin, growth hormone, glucagon
Insulin is usually decreased
Endorphin and B-lipotropin secretions are increased
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