Chapter 3 Innate Immunity

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Chapter 3 Innate Immunity
Macrophage interacting with Bacteria
Oct 3, 5 12, 2006
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• ????????
• ????????????????? (innate immunity)? ?????????
• ???????????? (pattern recognition receptor,PRR)?
• ?????????? (inflammatory response)?
• ???? Toll-like receptors ? ?????
• ???????????????

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• Innate immunity is the most ancient
• defense against microbes.
• Some forms of innate immunity has
• been found in all multicellular plants
• and animals.
• Adaptive immunity evolved in jawed
• vertebrates and is a much more recent
• evolutionary invention than innate
• immunity.

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Anatomical Barriers
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Skin and Epithelial Barriers to Infection
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• How does the innate immune response initiate?
• The host has sensors to detect the invader.
• Soluble or membrane-bound molecules of
• the host can precisely discriminate between
• self (host) and nonself (pathogen).
• These molecular sensors recognize broad
• structural motifs (???) that are present in
• microbes but are absent from the host.

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• Pattern Recognition Receptors (PRR)
• Because the molecular sensors recognize
• particular patterns, such receptors of the
  host are
• called pattern recognition receptors (PRR)
• The patterns found on pathogens are called
• pathogen-associated molecular patterns (PAMP)
• PRRs soluble e.g., complement system
• membrane-bound Toll-like
  receptors (TLR)
• - PAMPs combinations of sugars, certain
  proteins,
• particular lipid-bearing
  molecules, and
• some nucleic acid motifs

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Inflammation
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Localized Inflammatory Response described by
the Romans almost 2000 years ago
Swelling Redness
Heat Pain Loss of
function (2nd century by a Greek
physician, Galen ??, 129 -200
A.D.)
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Vasodilation increase in vascular diameter
rise of blood volume in
the area ? heats
the tissue and causes it to redden Edema
increase of vascular permeability
leakage of fluid from the blood vessels
? accumulation of fluid that swells the
tissue Extravasation adherence of leukocytes to
endothelium ?
pass through capillaries and into the
tissues Phagocytosis leukocytes phagocytose
invading pathogens
release molecular mediators
recruit and activate effector cells
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Inflammation
vasoactive chemotactic exudate chemotaxis extravas
ation
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Soluble mediators released by inflammatory
cells 1. Cytokines hormone- or
growth-factor-like proteins
that communicate via cell receptors to
induce specific cell activities,
e.g., interleukin-1
(IL-1), IL-6 tumor
necrosis factor a (TNF-a) 2. Chemokines a
subgroup of cytokines whose activity is
their capacity to act as
chemoattractants
(agents that cause cells to move toward
higher concentrations of the
agent)
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A major role of the cells attracted to the
inflamed site is phagocytosis of invading
organisms
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Leukocyte extravasation is essential for
inflammation rolling ? activation ?
arrest/adhesion ? migration
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Interaction between Neutrophils and Endothelium

• Cellular Adhesion Molecules (CAMs)
• Mucin-like CAMs
• Selectins
• Integrins
• Ig-superfamily CAMs

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Soluble Molecules
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Antimicrobial peptides are produced at the site
of infection or injury and act locally

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Paneth cells provide host defense against
microbes in the small intestines. They are
functionally similar to neutrophils (also
phagocytic and containing lysozymes). When
exposed to bacterial antigens, Paneth cells
secrete a number of antimicrobial molecules into
the lumen of the crypt, thereby contributing to
maintenance of the gastrointestinal barrier.

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Crypt ??
Secretion of defensins by paneth cells within
intestinal crypts serves as a primary barrier to
bacterial infection
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Paneth cells
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Soluble Pattern Recognition Receptors Acute phase
response (APR) proteins - Complement
- C-reactive protein (CRP) -
Mannose-binding lectin (MBL) Lipopolysaccharide-b
inding protein (LBP) Nucleotide-binding
oligomerization domain (NOD)
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Acute phase response (APR) proteins Complement
system (Chapt 7) C-reactive protein (CRP) A
pentameric protein, which binds
phosphorylcholine, which is present on the
surface of many microbes. CRP bound to a microbe
promotes uptake by phagocytes and activates a
complement-mediated attack on the
microbe. Mannose-binding lectin (MBL)
Recognizes mannose-containing molecular patterns
found on microbes but not on vertebrate cells.
MBL directs a complement attack on the microbes
to which it binds.
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Lipopolysaccharide-binding protein (LBP)
recognizes lipopolysaccharide (LPS), a component
of the outer cell wall of Gram negative (G -)
bacteria.
(LPS)
of G (-) bacteria
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Nucleotide-binding oligomerization domain (NOD)
proteins are cytosolic proteins which recognize
degraded products of peptidoglycans of Gram
positive (G ) bacteria.
Relative structure of gram negative (top) and
gram positive (bottom) cell walls. The major
differences lie in the thickness of the rigid
peptidoglycan layer and in the presence of an
outer membrane. In gram negative cells, the
peptidoglycan layer is very thin, being only a
few molecules thick, whereas in gram positive
cells this layer is very thick.
peptidoglycan
outer membrane
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gram-positive anthrax bacilli
Grams stain (with crystal violet) of
cerebrospinal fluid
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Effectors of Innate Immune Responses to Infection
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Membrane-associated Pattern Recognition Receptors
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Structure of a Toll-like Receptor (TLR)
(XLXXLXLXX)
highly conserved among all members of the TIR
family
Toll/IL-1R
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(Myeloid differentiation factor 88)
(IL-1R-associated kinase)
(TNFR-associated factor)
(TGF?-activated kinase)
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Cell Types of Innate Immunity
(ROS) (RNS)
Interferon ? TNF?
Interleukin 1 (IL-1) Interleukin 6 (IL-6) Tumor
necrosis Factor ? (TNF?)
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(phox)
activated by phagocytosis
The O2 consumed by phagocytes to support ROS
production by the phox enzyme is provided by a
metabolic process known as the respiratory
burst, during which O2 uptake by the cell
increases severalfold.
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Generation of Nitric Oxide (NO) in
Phagocytes L-arginine O2 NADPH ? NO
L-citrulline NADP
inducible nitric oxide synthetase (iNOS) NO
accounts for much of the antimicrobial activity
of macrophages against bacteria, fungi,
parasitic worms and protozoa.
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Adaptive Immunity Has to be Initiated by Innate
Immunity
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Ubiquity of Innate Immunity Well-developed system
of innate immunity in non-vertebrate phyla Sea
squirt complement-like lectins (??)
Toll-like receptors Fruit fly NF?B family
pathway antibacterial peptide
diptericin prophenoloxidase
cascades deposition of
melanin around invading organisms
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Tomato other plants - generation of
oxidative bursts - raising of internal pH -
localized death of infected regions - induction
of chitinase digest fungal wall - induction
of a-1,3 glucanase digest bacterial walls -
antimicrobial peptides - nonpeptide organic
molecules, such as phytoalexins, that have
antibiotic activity - isolate cells in the
infected area by strengthening the walls of
surrounding cells
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• Questions
• What are the differences between innate
• immunity and adaptive immunity?
• 2. Describe an inflammatory response.
• 3. Examples of pattern recognition and the
  receptors for pattern recognition.
• 4. How does a phagocyte kill pathogens?
• 5. How does a dendritic cell bridge innate
  immunity to adaptive immunity?