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Defense mechanisms of the respiratory epithelium
gel
•Ciliary structure & beat freq.
•Mucus viscoelasticity
•Surface tension & osmalality
sol
Other substances
•DNA
•Actin
•Proteoglycan
•Lipids
•Nitric Oxide
Submucosal Gland
Salt concentration is tightly regulated
Apical Surface of Normal Airway Epithelium
From Cell, 85(1996), 229
Innate Immunity is Comprised of
Cellular and Humoral Factors
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NK Cells
Neutrophils (PMN)
Macrophages
Dendritic Cells
Mast Cells
Basophils
Eosinophils
• Antimicrobial
substances
– Inorganic disinfectants
– Small AMP
– Large AMP
• Complement
• Cytokines
Cellular Elements of the Blood
PHAGOCYTES
MONOCYTE
NEUTROPHILS
Can discriminate between "foreign" and "self" molecules because they possess
receptors for carbohydrates that are not normally exposed on the cells of vertebrates,
such as mannose. In addition, both macrophages and neutrophils have receptors
for antibodies and complement, so that the coating of microorganisms with
antibodies, complement, or both enhances phagocytosis.
Phagocytosis
Bound pathogens are internalized in
phagosome, which become acidified
(pH 3.5 - 4.0).
Lysosomes contain enzymes,
proteins, and peptides that can
mediate intracellular antimicrobial
response.
Phagosome fuses with one or more
lysosomes to form a
phagolysosome, in which lysosomal
contents are released to destroy the
pathogen.
Macrophages that have bound and
ingested microorganisms also
contribute to the adaptive immune
response by acting as antigenpresenting cells.
Neutrophil degranulation of antimicrobial proteins and peptides
Specific (secondary)
granules are more prone
to degranulate their
contents (including
lactoferrin and
cathelicidins) into the
extracellular space. In
contrast, azurophil
(primary) granules,
containing BPI and
defensins, are
predominantly
degranulated into the
phagolysosome. To a
lesser extent, specific
granules also degranulate
into the phagolysosome
and primary granules to
the extracellular space.
Respiratory Burst Generated by Lysosomal NADPH oxidases
Myeloperoxidaseindependent
Myeloperoxidasedependent
Inflammatory Responses
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Activated macrophages also produce cytokines and other mediators to
trigger inflammatory responses.
Inflammation can also be triggered by the Complement Cascade.
Inflammation is traditionally defined by 4 Latin words, rubor, calor,
tumor and dolor, meaning redness, heat, swelling and pain.
Inflammation plays three essential roles in combating infection:
1. deliver additional effector molecules and cells to sites of infection
to augment the killing of invading microorganisms by the front-line
macrophages,
2. provide a physical barrier preventing the spread of infection, and
3. promote the repair of injured tissue.
Reflects 3 types of changes in the local blood vessel:
1. an increase in vascular diameter, leading to increased local blood
flow and a reduction in the velocity of blood flow,
2. endothelial cells lining the blood vessel are activated to express
adhesion molecules that promote the binding of circulating
leukocytes, and
3. increase in vascular permeability of local blood vessels, leading to
exit of fluid and protein from the blood and their accumulation in
the tissues.
Neutrophil Recruitment: the Multistep Model
ICAM-1
GlyCAM-1/CD34/
MadCAM-1
Neutrophil Recruitment: the Multistep Model
Sialyl-Lewis X
PSGL-1
Sialyl-Lewis X
ICAM-1
P-Selectin
E-selectin
Dendritic cells that recognize pathogens, migrate out of infected areas and into nearby
lymph nodes where fragments of pathogen are displayed to T cells.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
NEJM 343, 40(00)
The Complement System
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The complement system is a set of plasma proteins that act together to
attack extracellular forms of pathogens.
It was first discovered as an effector arm of the antibody response, but
complement can also be activated early in infection in the absence of
antibodies; complement first evolved as part of the innate immune system.
Activation of complement involves the sequential proteolysis of proteins to
generate enzymes with proteolytic activity.
The products of complement activation become covalently attached to
microbial cell surfaces or to Ab bound to microbes and to other antigens.
Complement activation is inhibited by regulatory proteins that are present
on normal host cells and absent from microbes.
There are three pathways of complement activation:
– the classical pathway, which is triggered by antibody or by direct
binding of complement component C1q to the pathogen surface;
– the MB-lectin pathway, which is triggered by mannan-binding lectin, a
normal serum constituent that binds some encapsulated bacteria; and
– the alternative pathway, which is triggered directly on pathogen
surfaces.
The 3 pathways converge at the point of cleavage of C3.
The Three Activation Pathways of Complement:
the Classical, Mannose-Binding Lectin, and Alternative Pathways.
C9
The Alternative Pathway:
Regulation of the Cleavage of C3.
In fluid phase, C3b is inactivated by hydrolysis.