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Title: Innate immunity is germline encode (you are born with it ready to go)


1
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 molecular
    patterns 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

2
The response to an infection occurs in three
phases
innate immunity early induced innate
immunity adaptive immunity
No memory
Innate too
and memory cells
3
Where to you find pathogens?
(CTL)
(TH1)
4
How do pathogens damage tissues?
bacteria
bacteria
viruses
5
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.
6
Stages of an infection
Lots of macrophages in the liver, lungs, spleen
and near epithelial surfaces
To lymph node
i.e., antibody, TH1, CTL
Skin provides a physical/chemical barrier to
invasion (thick, tough, dry, acidic, toxic)
Mucus prevents attachment tears, saliva wash
away microorganisms (prevent adherence)
phagocytes neutrophils and macrophages
inflammation
7

Epithelial barriers to pathogens
8
Macrophages are activated by pathogens. They
kill pathogens and initiate inflammation
Toll-like receptor (TLR)(also see figure 2-16
2-17) .
Macrophages release cytokines to affect other
cells (e.g., endothelial cells) and cause
inflammation. Cytokines from non-macrophages may
activate macrophage, dendritic cells and cause
inflammation
Also, macrophages may release toxic molecules
including reactive oxygen species, nitric oxide
and other (see figure 2.9)
9
Anti-bacterial agents produced by phagocytes
(macrophages and/or neutrophils) upon bacterial
stimulation
Reactive oxygen species (ROS)
10
Inflammation Inflammation is induced when
macrophages bind bacterial products (e.g., LPS,
peptidoglycan) (lots of other causes of
inflammation) 1. Release toxic compounds and
cytokines. Cytokines cause effector cells and
molecules to leave the blood and enter the site
of the infection cytokine stimulate 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
What is the cause of the heat, redness, swelling
and pain associated with inflammation?
11
Continued from the previous page (1. deliver
effectors, 2. coagulate blood)
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 from release of
prostaglandins, leukotrienes and cytokines such
as IL-1, IL-8 and tumor necrosis factor-a (TNF).
Blood coagulation stops bleeding and prevents
pathogens from entering the circulation.
12
Extravasation of monocytes and differentiation
into macrophages
Adhesion molecules
See figure 2.49 for a little more detail
13
Summary of Inflammation Initiated by Macrophages
Macrophages that bind bacterial products (and
other stuff) release cytokines and other
molecules that cause inflammation (heat,
redness, swelling and pain). They also release
compounds that are toxic to most bacteria (e.g.,
reactive oxygen species)
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 (non immunological)
including prostaglandins, leukotrienes, IL-8,
TNF (among their effects are effects on
endothelial cells and thus trafficking of cells
out of the blood into interstitial tissue and out
of interstitial tissues into the lymphatics).
14
Comparison of receptors for target recognition in
the innate and adaptive immunity
TCR is the antigen receptor for T cells, antibody
for B cells
(Germline encoded)
Generally, one specificity per B or T cell
B and T cell need to be activated
(one specificity per cell)
15
Receptors of innate immunity recognize molecular
patterns that are common to many pathogen
(pattern-recognition receptors)
Mannose-binding lectin (MBL)
no binding
binding
also, scavenger receptors
Go to slide 38
16
Fig 2-12
17
Naive T cell activation requires signaling from
an activate antigen presenting cell (e.g.,
dendritic cell) that expresses co-stimulatory
molecules on its surface
Langerhans cell is a type of immature dendritic
cell
antigen
1 2
(anergy)
Adjuvants are compounds that enhance the adaptive
immune response when mixed with antigens. Some
work by inducing expression of co-stimulators
such as CD80/CD86
Which is signal 1 and which is signal 2?
Mature dendritic cell
18
no
yes
no
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)
19
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 .
20
Enzyme cascades for signal amplification
Case 1
100 products/sec/enzyme1
6000 products/min/enzyme1
6000 more products in minute 2
Case 2
For case 2, in the second minute there are 6000
aEnzyme1s. So, 6000 products/min/aEnzyme1 X
6000aEnzyme1 gt36,000,000 products in minute 2
21
Three pathways to activate complement
(MBL)
22
Several components are activated by cleavage into
two pieces a small piece and a big piece. For
example, C3 ? C3a C3b.C3 is inactive but C3a
and C3b are both active.
(anaphylotoxins)
Disregard old slide that says small piece is a
and big piece is b
23
C1
C1C1qC1rC1s
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
24
MASP-1 and MASP-2 are serine proteases
Mannan-binding lectin (MBL) is similar to C1 but
it binds to mannose then activates C4 and C2 as
is shown in the next slide for C1. MB-lectin
pathway is particularly important in children
that do not have much antibody
25
C2b
C1
C4b2a3b
C4b2a
C4b2a
Note old version has 4b2b, this version has 4b2a
C4b2a is a C3 convertase (there are others)
26
Like C1, MBL (lectin pathway) activates C4 and C2
to make the C4b2b C3-convertase
27
Complement activation by the Alternative Pathway
Figure 2.32
For C3, there is spontaneous cleavage or
tickover that occurs whether bacteria are
present or absent
C3b is quickly inactivated in solution but is
stabilized when it binds to bacteria surfaces
C3bBb is a C3 convertase
Continued on the next slide
28
Complement activation by the Alternative Pathway,
continued
From the previous slide
Host cell surface (e.g., human)
Bacterium surface
29
Signal amplification by C3b and the alternative
pathway(recall, C3b comes from the classical,
lectin and alternative pathways)
C3b from classical, MBL or alternative pathways
30
amplification
C3 convertase makes C3b. C3b binds to factor B
factor B is cleaved by Factor D. The resultant
C3bBb is a C3 convertase.
31
C4b2b and C3bBb are C3 convertases but if you add
another C3b then
C4b2b3b and C3b2Bb are C5 convertases
C5 convertase
C5 C5a C5b
32
Distribution and function of complement receptors

?


Activates cells by triggering intracellular
signals resulting in inflammation and phagocytosis








33
Sometimes complement-mediated opsonization
requires activation of the phagocyte
C3b
CR1
34
The small fragments of C3, C4 and C5 (C3a, C4a,
C5a) induce inflammation
Anaphylactic shock can be caused by systemic
distribution of anaphylatoxins and mast cell
degranulation
Anaphylatoxins (C3a, C4a, C5a)
35
Terminal complement components and the formation
of the membrane attack complex (MAC)
36
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37
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38
Receptors of innate immunity Phagocytic
receptors Chemotactic receptors Activate
endothelial cells resulting in exudation of cells
and fluids from the blood Induce
production/activation of other signaling
molecules (e.g., cause cytokine production and
secretion)
MB lectin binds patterns of mannans Scavenger
receptor binds certain charged particles (anionic
polymers) TLR bind various molecules (see figure
2.6 or slide 15 )
39
Induced Innate Responses to Infection
40
Cytokines are proteins or peptides. They might
act on the cell that made them, on neighbors or
on distant cells
InterleukinIL
(IL-8)
41
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
42
Adhesion Molecules Direct Trafficking (these are
not receptors, why?)
Intercellular adhesion molecule (ICAM)
43
Figure 2.44
Rolling adhesion (movie)
Extravasation (the whole process)
Movie
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.
44
Systemically, high doses of TNF can cause septic
shock and death
Locally, TNFa can cause inflammation (most TNF is
from macrophages)
Chronic systemic TNF (sometimes associated with
cancer or other diseases) can lead to cachexia (a
wasting disease loss of weight, muscle atrophy,
fatigue, weakness and loss of appetite )
45
Systemic affects of Macrophage-produced cytokines
endogenous pyrogens
46
IL-6 induces synthesis of acute-phase proteins
in the liver
This is part of the early induced innate response
4-96 hours after infection shown in slide 2
47
Interferon- a and Interferon-b
Most cells can make IFN-a and IFN-b in response
to virus e.g., in response to double stranded
RNA (dsRNA)
in all cells
Q why increase expression of MHC class I?
IFN-a and b are not to be confused with
interferon-g which is made by TH1 cells and,
among other things, activates macrophages
48
Natural killer (NK) cells
Activating receptor
NK cells kill cells that have low levels of MHC
class I on their surface
Inactivating receptor
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?
49
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
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