Transcript Document

revised: 9/27/04 AM
Chapter 2: Innate Immunity
 Innate immunity is germline encode (you are born with it
ready to go)
 It has made the self/nonself discrimination on an evolutionary
time-scale
 It uses few receptors that recognize features common to many
microorganisms
Therefore, parts of it are always active or can be activated
quickly
Innate immunity is the first line of defense. Without innate
immunity nearly every microorganism would be pathogenic
No
memory
Innate
too
Most surface epithelia
are constantly exposed to
microorganisms. Many
microorganisms grow on
these surfaces (e.g., skin,
gut) or must cross an
epithelial barrier (skin,
gut, respiratory) to enter
the body.
Lots of macrophages in the liver,
lungs, spleen and near epithelial
surfaces
phagocytes = neutrophils and
macrophages
Mucus prevents
attachment; tears,
saliva wash away
microorganisms
Skin provides a
physical/chemical
barrier to invasion
(thick, tough, dry,
acidic, toxic)
inflammation
complement
receptor
Also, macrophages may release
toxic molecules including reactive
oxygen species, nitric oxide and
other (see figure 2.6)
Cytokine activate
macrophage, dendritic cells
and cause inflammation
Inflammation induced when macrophages bind bacteria
products:
1. Delivers effector cells to the site of the infection and
augments macrophages that are already there
2. Creates a barrier to the spread of the microorganisms
(captures microorganisms, blood clot prevents
microorganisms from entering the circulation)
3. Repairs the damage
The macrophages’ affects on endothelial cells (the cells that line
the blood vessels and largely control inflammation by
controlling the flow of cells and fluids out of the post-capillary
venules) result form release of prostaglandins, leukotrienes and
cytokines such as IL-1 and tumor necrosis factor-a (TNF).
Blood coagulation stops bleeding and prevents pathogens from
entering the circulation.
Agents produced by phagocytes (macrophages and/or neutrophils)
upon bacterial stimulation
Summary
Macrophages that bind bacterial products (and other stuff)
release cytokines* that cause inflammation (heat, redness,
swelling and pain).
This first delivers neutrophils and blood proteins (such as
complement and immunoglobulins), then, hours later, other
inflammatory cells (monocytes, as well as B and T cells) and
more blood proteins to augment the macrophages already
there.
Blood clots stop bleeding, trap microorganisms, keep
microorganisms from entering the circulation
Repair damage
*including prostaglandins, leukotrienes, TNF (these have big
effects on endothelial cells and affect trafficking of cells out of
the blood and into the lymphatics).
The Complement System
Discovered as a heat-labile antibacterial substance in immune serum
kills bacteria
non immune (normal) serum…………… no
immune serum………………………….. yes
heated* immune serum………………….no
heated immune serum plus
non-immune serum…………………. yes
Conclusion: Two components are needed for bacterial
inactivation: a heat-stable immune component (antibody) and a
heat-labile non immune component (complement). (there is
something in normal serum that complements immune serum)
*560C for 30 minutes or 600C for 5 minutes
The complement system is comprised of many proteins that
react with each other and with other compounds to
1. Opsonize (make stuff easily phagocytized)
2. Kill cells
3. Induce inflammation
vasoactive, chemoattractant, phagocyte activator
Complement activation results in an enzyme cascade* that
amplifies the response and thus requires tight regulation
*one enzyme activates a second enzyme and the second enzyme activate a
third enzyme and ….
Three pathways to activate complement
C3 convertase is an
enzyme that activates C3
C3
(anaphylotoxins)
C3 convertase
C3a +C3b
Several components are
activated by cleavage
into two pieces; a small
piece designated with an
“a” and a big piece
designated with a “b.”
For example,
C3  C3a + C3b.
C3 is inactive but C3a
and C3b are both active.
Initiation of the
classical pathway
is with C1
C1 is activated
by antibody ( this
will be dealt with
later) and can be
activated by itself
on the surface of
certain bacteria
Binding of two of
the C1q heads to
the surface of a
bacteria activate
C1r to cleave and
activate C1s
Figure 2.11
C4
C1s
C4b are C2b combined
to form C4b2b
C4a + C4b
C2
C1s
C2a + C2b
C4b2b
C3
C3a + C3b
C4b2b is a C3 convertase (there are others)
Mannan-binding lectin
(MBL) is similar to C1
but it binds to mannose
then activates C4 and C2.
MB-lectin pathway is
particularly important in
children that do not have
much antibody
The Alternative Pathway of Complement activation
For C3, there is
spontaneous cleavage or
tickover that occurs
whether bacteria are
presence or absent
C3b is quickly
inactivated in solution
but is stabilized when
it binds to bacteria
surfaces
Host(i.e. human)
Bacteria
Host(i.e. human)
Bacteria
Figure 2.17
Summary
C3b binds to factor
B, factor B is
cleaved by Factor
D. The C3bBb is a
C3 convertase so it
makes more C3b
C3b is an opsonin
C3 convertase
makes C3b. C3b
binds to factor B;
factor B is cleaved
by Factor D. The
resultant C3bBb is
a C3 convertase.
(anaphylotoxins)
Go to 2
C4b2b and C3bBb are
C3 convertases but if
you add another C3b
then:
C4b2b3b and C3b2Bb are
C5 convertases
C5
C5 convertase
C5a + C5b
Distribution and function of complement receptors
*
*
*
stimulates phagocytosis =
opsonization
*
*
*
Activates cells by
triggering
intracellular signals
Sometimes complement-mediated opsonization requires
activation of the phagocye
C3b
CR1
Anaphylatoxins
(C3a, C4a, C5a)
Anaphylactic shock can be
caused by systemic distribution
of anaphylatoxins and mast cell
degranulation
histamine
anaphylotoxins cause
mast cell degranulation
histamine
Terminal complement components and the formation
of the membrane attack complex
Anaphylotoxins
Receptors of innate immunity
Phagocytic receptors
Chemotactic receptors
Induce production/activation of other
signaling molecules (e.g., cause cytokine
production and secretion)
MB lectin binds patterns of mannan
Scavenger receptor binds certain charged particles
(anionic polymers)
LPS-binding protein (LBP) bind LPS and CD14 (see
next slide)
complement
receptor
Co-stimulators CD80
and CD86 also known
as B7.1 and B7 .2
Adjuvants are compounds
that enhance the adaptive
immune response when
mixed with antigens.
Some work by inducing
expression of costimulators such as
CD80/CD86
Induced Innate Responses to Infection
Interleukin=IL
Cytokines are proteins
or peptides. They
might act on the cell
that made them, on
neighbors or on distant
cells
The same compounds are
involved in adaptive
immune responses (TH1)
but probably more
Chemokines
Small chemoattractant
proteins that stimulate
migration and activation of
lymphocytes and
phagocytes
Q: How do chemokines,
cytokines and other
molecule affect cell
migration (trafficking)?
A: By affecting
expression of adhesion
molecules
Adhesion Molecules Direct Trafficking
(these are not receptors, why?)
Intercellular adhesion molecule (ICAM)
Figure 2.36
Rolling adhesion
neutrophil
endothelial cells
Extravasation
(the whole process)
During the first 6 hours of an typical inflammatory response, mostly neutrophils
leave the blood. After that, large numbers of monocytes (macrophages) and other
mononuclear cells also enter the tissue.
Locally, TNF
can cause
inflammation
Systemically, high
doses of TNF can
cause septic shock
and death
Chronic systemic TNF
(sometimes associated
with cancer or other
diseases) can lead to
cachexia
Systemic affects of Macrophage-produced cytokines
endogenous pyrogens
IL-6 induces synthesis of
acute-phase proteins in
the liver
Interferon- a and Interferon-b
Most cells can make
IFN-a and IFN-b in
response to virus [i.e.,
double stranded RNA
(dsRNA)]
Ribonuclease activity
Protein synthesis inhibition
Later we will see that
interferon-g is made by TH1
cells and activates
macrophages
These actions
mostly prepare
non-infected cells
to resist infection
Q: why increase
expression of
MHC class I?
Natural killer (NK) cells
Activating
receptor
NK cells kill cells that
have low levels of
MHC class I on their
surface
Q: why is that a good
idea?
Q: why do interferons
a and b attempt to
increase MHC class I
on virus-infected cells
and increase NK
activity?
Certain defense mechanism seem to fall between innate and
adaptive immunity. They use an immunoglobulin or a TCR to
bind antigens but they have limited repertoires that appears to
be germline encoded. These include:
1. A subset of T cells called gd T cells (mostly in skin and near
epithelial surfaces)
2. CD5+ B cells (i.e., B-1 B cells)(mostly in the peritoneum)
3. Natural antibodies