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Mechanical Barriers to
microorganisms
•Skin epithelial cells joined by
The Innate Immune System tight junctions
•Intestinal epithelium
•Longitudinal flow of air or
fluid across epithelium
•Constant flushing of the
urinary bladder
Jan 19, 2005
Substances that inhibit
microbial growth Acute Phase Response
• Lysozyme in the blood, saliva, sweat, • The acute phase response involves a
tears
shift in the proteins secreted by the
• Acidic pH in stomach liver into the blood plasma.
• Digestive enzymes, pepsin in the stomach • In the acute phase response, levels of
• Antibacterial peptides (defensins) in some plasma proteins go down, while
intestine
levels of others increase. It occurs in
• Friendly flora in gut, reproductive tract, response to infection, burns, trauma,
skin,intestine compete for attachment
and nutrients, and themselves can and neoplasia.
produce anti-microbial substances
Acute Phase Response Acute Phase Response
• TNF, IL-1, and IL-6 are produced by • TNF and IL-1 induce haptocytes to
activated macrophages (including produce one set of acute phase
Kupfer cells in the liver), i.e., proteins including serum amyloid
macrophages that have been protein.
stimulated by LPS, C5a, or • IL-6 induces another set including
chemokines. fibrinogen, C-reactive protein,
mannose-binding protein.
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IL -6 a n d T N F
L IV E R Tumor Necrosis Factor
A c u te p h a s e p ro te in s
S e r u m a m y lo id p ro te in • TNFα (cachetin) is selectively cytotoxic
C -re a c t iv e p ro te in
F ib r in o g e n for many tumor cells. Secreted by
M a n n o s e -b in d in g p ro te in macrophages, monocytes, T and B
lymphoctyes.
•
B one M arrow
N e u t ro p h il m o b iliz a t io n
TNFβ (lymphotoxin, LTa) 35% homologous
P h a g o c y to s is with TNFα. Important as a mediator of
H y p o tha la m us
inflammation. Sources are T and B
lymphocytes.
L y m p h o c y te s
I n c re a s e d B o d y T e m p e ra t u re
• Each binds to TNF-RI and TNF-RII
I n c re a s e a c tiv a t io n
D e c re a s e d v ira l a n d
b a c te r ia l re p lic a t io n
Acute Phase Proteins
• Two acute phase proteins are important Acute Phase Proteins
because they mimic the action of
antibodies. • C-reactive protein, mannose-binding
• The acute phase protein, C-reactive protein.
protein, binds to phosphorylcholine on • These two acute-phase proteins
microbial surfaces (and not mammalian
mimic some of the properties of
cells) to opsonize the microbe, and initiate
the complement cascade. antibodies before an antibody
response has a chance to become
• A second protein, mannose-binding
protein , is a calcium-dependent lectin established.
that binds to mannose moieties on
bacterial surfaces.
CRP -Acute Phase Proteins Contact System
• Inflammation can be activated by the
Contact System, solid, anionic surface
can initiate a cascade of events
leading to inflammation.
• Synthetic or foreign materials that
can incite this response include: glass,
plastics, dextran sulfate,
carrageenan, and cellulose sulfate.
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Contact System Contact System
• Naturally occurring substances • The end results of the liberation of bradykinin
by the kallikrein-kinin system include
include: constriction of:
• sodium urate (the inciting • uterine and gastrointestinal smooth muscle,
metabolite of gout); • constriction of coronary and pulmonary
• calcium pyrophosphate crystals
vasculature, mucosal inflammation,
• bronchoconstriction, edema,
(pseudogout); • hypotension, flushing, pain, and rhinitis.
• homocysteine (homocystinuria).
Complement Pathway
Physical Trauma
• If Mast Cells are damaged or • Complement components may become
activated, they release Histamine. activated by two pathways:
• This causes vascular endothelial cells • the classical complement pathway,
to become permeable to plasma fluids. and
• Extravasation • the alternative (or properdin)
pathway.
Complement Pathway .
Complement Pathway
•See handout on the
complement system.
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Inflammation
• The inflammatory response results in: Inflammation
• the leakage of fluids into the
extravascular space (edema); • A primary activity of the
• The leakage of macromolecules such inflammatory response is often to
as fibrinogen and formation of an activate neutrophils--and to cause
extravascular matrix (induration); them to migrate from the blood
vasculature to the extravascular
• The migration of cells (primarily tissues.
neutrophils) from the postcapillary
venules to the extravascular space
(extravasation). • The absence of neutrophils is
essentially incompatible with life.
Neutrophils Neutrophils
• Neutrophils are distinct from other
white blood cells, because of the
presence of enzyme containing
granules in the cytoplasm.
• There are about 3 to 6 x 103
neutrophils present per milliliter of
blood.
• Each day 1011 neutrophils are released
into the bloodstream.
Neutrophils Neutrophils
• Some chemoattractants that stimulate neutrophils
• An important element in the • products of the complement system (specifically
C5a),
normal attack of the neutrophil is • formyl-methionyl-leucyl-phenylalanine (FMLP),
chemotaxis because it allows the • antigen-antibody complexes,
phagocytic cell to come into close • bacterially derived factors (LPS),
proximity with the • products from the lymphocyte series (MAF),
Interleukin 8 (IL8),
microorganism, abnormal cell, or
• products of arachadonic acid specifically
necrotic tissue, to allow for cell Leukotriene B4, and
killing and digestion. • Platelet Activating Factor (PAF).
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Neutrophils Neutrophils
• On the surface of the neutrophil plasma • There are two different types of granules
membrane are opsonins which are distinct from one another on the
• such as C3b (a complement component) or basis of enzyme content, morphology, and
• the Fc portion of immunoglobulins. phase in which they emerge during
• When these receptors are engaged by neutrophil maturation.
opsonized bacteria, the membrane • The two types are the azurophilic granules
invaginates and forms a phagosome. and the specific granules.
Azurophilic granules Azurophilic granules
• Some of the enzymes released by the
• Comprise one third of all mature granules azurophilic granule include
and are not synthesized in the later stages • myeloperoxodase (MPO),
of neutrophil maturation.
• elastase,
• They are predominantly microbicidial and
• neutral proteases,
digestive in function with their enzymes
working • lysozyme, and
• several acid hydrolases.
Azurophilic granules
Myeloperoxidase
• Myeloperoxidase: is a abundant granular
enzyme (accounts for 5% of dry weight of
the neutrophil).
• This enzyme combines hydrogen peroxide
with chloride ions to form hypochlorous acie
(HOCl).
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Azurophilic granules Azurophilic granules
• Lysozyme: like MPO is a microbicidial
enzyme.
• Elastase: is a serine protease which • Lysozyme digests debris from cell walls of
specifically hydrolyzes elastin. bacteria that have already been processed
• Elastin is the major component of elastic by other enzymes.
fibers whcih stretch in the walls of blood • Another function of lysozyme is to modulate
vessels, lungs, and ligaments. inflammation by suppressing neutrophil
chemotaxis and oxidative metabolism.
Macrophage
Macrophage
•Macrophages are Phagocytic
• Endothelial cell, •They express Fc Receptors and
• Kupfer cells, receptors for complement
• histiocytes, components
• microglia, •They can fuse to become
• alveolar macrophages, and multinucleated giant cells
• multinucleate phagocytes in the bone •Macrophages can secrete anti-
are called osteoclasts. microbial substances such as
reactive oxygen species, nitric
oxide, and prostaglandins.
Macrophage Macrophage
The scavenger function of
macrophages prevents the
contents of dying cells from
causing damage or inflammation, •Macrophages produce
in fact, macrophages are so cytokines such as: IFN;
effective it is hard to find dead
cells in healthy tissue--even in TNF; IL-1; IL-6;
locations such as the thymus •Chemokines such as IL-8.
where 98% of the cells die
before leaving.
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Macrophage
Adhesion Proteins
• Macrophages serve as antigen The majority of adhesion molecules fall
presenting cells to activate T cells into one of four families;
• Activated T cells secrete cytokines • cadherins.
that activate most or all of the
above functions of macrophages. • integrins,
• Thus, the T cells and macrophages • immunoglobulin superfamily (IgSF),
stimulate each other and this • selectins
greatly amplifies an immune
response.
CADHERINS CADHERINS
• There is strong evidence to suggest
• They play a fundamental role in that cadherins may be involved in
maintaining the integrity of invasion and metastasis of tumor
multicellular structures and cells.
• areimportant in the diapedesis of
• Finally, cadherins may play a role in
intercellular signalling due to the
lymphocytes and neutrophils discovery of kinases regulating
cytoplasmic cadherin phosphorylation.
Adhesion Proteins
INTEGRINS
The majority of adhesion molecules
fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin superfamily (IgSF),
• selectins
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INTEGRINS
Names expressed by bind to INTEGRINS
Important roles: • tumor metastasis,
• platelet • tissue migration
aggregation, during
embryogenesis.
• inflammation, • signalling
• immune pathways,
function, transmitting
• wound healing, signals both into
and out from cells
INTEGRINS INTEGRINS
Lymphocyte function-associated • Expression of the β1 integrins
antigen-1 (LFA-1, CD11a/CD18). increases significantly late in T-cell
activation, and they are thus often
This is thought to be the most called VLA for very late antigen and
important adhesion molecule for play an important part in directing
lymphocyte activation as antibodies armed effector T cells to their target
to LFA-1 effectively inhibit the tissues.
activation of both naive and armed
effector T cells.
INTEGRINS Adhesion Proteins
• Leukocyte adhesion deficiency (LAD) The majority of adhesion molecules
is a rare inherited disorder in which fall into one of four families;
key functions of leukocytes are • cadherins.
impaired, notably the migration of
neutrophils to sites of extravascaular
• integrins,
inflammation • immunoglobulin superfamily (IgSF),
• selectins
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IMMUNOGLOBULIN SUPERFAMILY
IMMUNOGLOBULIN SUPERFAMILY
NAMES Expressed by Bind to
• IgSF members are widely utilized in • CD2 (LFA-2) T-cells LFA-3
two areas involving complex • ICAM-1 (CD54) APCs, lymphocytes LFA-1
interactions among a diverse array of • ICAM-2 (CD102) APCs, lymphocytes LFA-1
cell types; • ICAM-3 (CD50) APCs LFA-1
• during nervous system • LFA-3 (CD58) APCs, lymphocytes CD2
development and • VCAM-1 (CD106) EC (activated) VLA-4
• in the regulation of the immune
system
IMMUNOGLOBULIN SUPERFAMILY IMMUNOGLOBULIN SUPERFAMILY
• ICAM-1 is expressed by antigen
presenting cells.
• Induced or upregulated by IFNγ, IL-
1β, TNFα and LPS.
• Ligands are CD11a/CD18,
IgSF CD11b/CD18, CD43 (mucin-like
vascular addressin).
• Adhesion is calcium dependent
SELECTINS
Adhesion Proteins
The majority of adhesion molecules • Are earliest expressed in
fall into one of four families; inflammatory responses
• Lead to neutrophil activation and
• cadherins. extravasation
• integrins, • L-selectin
• immunoglobulin superfamily (IgSF), • E-selectin
• selectins • P-selectin
• Bind to SLex of neutrophil
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SELECTINS
SELECTINS
• L-selectin down regulated by IL-1
• P-selectin up-regulated by thrombin,
histamine, peroxides, TNF-α, IL-4,
IL-1, and IFN-γ
• E-selectin up-regualted IL-1β, TNFα
and LPS
SELECTINS
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