What does inflammation allow?
Allows
inflammatory cells
,
plasma proteins
(e.g., complement), and
fluid
to exit blood vessels and enter the interstitial space
What are 2 types of inflammation?
Divided into
acute
and
chronic
inflammation
What is acute inflammation? Characterized by?
Immediate
response with
limited specificity
(
innate immunity
Characterized by presence of
edema
and
neutrophils
in tissue
What does acute inflammation arise in response to? (2)
Infection
- to eliminate pathogen
Tissue necrosis
- to clear necrotic debris
What are mediators of acute inflammation? (5)
- Toll-like receptors (TLRs)
- Arachidonic acid (AA) metabolites
- Mast cells
- Complement
- Hageman factor (Factor XII)
What cells are TLRs present on?
Present on cells of the
innate immune system
(e.g., macrophages and dendritic cells)
What are TLRs activated by? How are gram-negative bacteria recognized by TLRs?
Activated by pathogen-associated molecular patterns (
PAMPs
) that are commonly shared by microbes
CD14
(a co-receptor for
TLR4
) on
macrophages
recognizes
lipopolysaccharide
(a
PAMP
) on the outer membrane of
gram-negative
bacteria
What does TLR activation result in?
Upregulation of
NF-kappaB
, a nuclear transcription factor that activates
immune response genes
leading to production of multiple
immune mediators
What cells are TLRs also present on? Play a role in?
TLRs are also present on cells of
adaptive immunity
(e.g., lymphocytes) and play an important role in mediating
chronic inflammation
Where is AA released from? And then acted upon by?
AA is released from the
phospholipid cell membrane
by
phospholipase A2
and then acted upon by
cyclooxygenase
or
5-lipoxygenase
What does cyclooxygenase produce? Functions?
Cyclooxygenase produces
prostaglandins
(PG):
- PGI2, PGD2, and PGE2 mediates
vasodilation
and increased
vascular permeability
- PGE2 also mediates
pain
and
fever
What does 5-lipoxygenase produce? Functions?
5-lipoxygenase produces
leukotrienes
(LT):
- LTB4 attracts and activates
neutrophils
- LTC4, LTD4, and LTE4 (slow reacting substances of
anaphylaxis
) mediate
vasoconstriction, bronchospasm
, and increased
vascular permeability
Where are mast cells located?
Widely distributed throughout
connective tissue
What activates mast cells? (3)
Activated by:
1. Tissue
trauma
2. Complement proteins
C3a
and
C5a
3. Cross-linking of cell-surface
IgE
by antigen
What is the acute and delayed response of mast cells?
Immediate
response involves release of
preformed histamine granules
, which mediate
vasodilation
of arterioles and increased
vascular permeability
Delayed
response involves production of
arachidonic acid metabolites
, particularly
leukotrienes
What is complement?
Proinflammatory serum proteins
that "complement" inflammation
How does complement circulate? Activation occurs via...?
Circulate as
inactive precursors
Activation occurs via:
-
Classical
pathway - C1 binds IgG or IgM that is bound to antigen
-
Alternative
pathway - microbial products directly activate complement
-
Mannose-binding lectin
(MBL) pathway - MBL binds to mannos
What do all pathways result in?
Production of
C3 convertase
(mediates C3 -> C3a and C3b), which in turn, produces
C5 convertase
(mediates C5 -> C5a and C5b)
C5b
complexes with
C6-C9
to form the membrane attack complex (
MAC
)
What is the function of C3a and C5a?
C3a and C5a (
anaphylatoxins
)
- Trigger
mast cell degranulation
, resulting in
histamine
-mediated
vasodilation
and increased
vascular permeability
What is the function of C5a?
Chemotactic for
neutrophils
What is the function of C3b?
Opsonin
for
phagocytosis
What is the function of MAC?
Lyses microbes
by creating a hole in the cell membrane
What is Hageman factor?
Inactive proinflammatory protein
produced in
liver
How is Hageman factor activated?
Activated upon exposure to
subendothelial
or
tissue collagen
What does activatedHageman factor activate? (3)
-
Coagulation
and
fibrinolytic
systems
-
Complement
-
Kinin
system - Kinin cleaves
high-molecular-weight kininogen
(HMWK) to
bradykinin
, which mediates
vasodilation
and increased
vascular permeability
(similar to histamine), as well as
pain
What are the cardinal signs of inflammation? (4)
Redness
(rubor) and
warmth
(calor)
Swelling
(tumor)
Pain
(dolor)
Fever
What is the etiology and pathogenesis of redness and warmth in inflammation?
Due to
vasodilation
, which results in increased
blood flow
- Occurs via
relaxation
of
arteriolar smooth muscle
- Key mediators are
histamine, prostaglandins
, and
bradykinin
What is the etiology and pathogenesis of swelling in inflammation?
Due to
leakage of fluid
from
postcapillary venules
into
interstitial space
(exudate)
Key mediators are:
1.
Histamine
, which causes
endothelial cell contraction
2.
Tissue damage
, resulting in
endothelial cell disruption
What is the pathogenesis of pain in inflammation?
Bradykinin
and
PGE2
sensitive sensory nerve endings
What is the pathogenesis of fever in inflammation?
Pyrogens
(e.g., LPS from bacteria) cause
macrophages
to release
IL-1
and
TNF
, which increase
cyclooxygenase
activity in perivascular cells of the
hypothalamus
- Increased
PGE2 raises temperature set point
What are the 7 steps of neutrophil arrival and function?
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and Chemotaxis
5. Phagocytosis
6. Destruction of phagocytosed material
7. Resolution
What is margination?
-
Vasodilation slows blood flow
in postcapillary venules
- Cells
marginate
from center of flow to the
periphery
What is rolling?
Selectin "speed bumps"
are upregulated on
endothelial cells
:
-
P-selectin
release from
Weibel-Palade bodies
is mediated by
histamine
-
E-selectin
is induced by
TNF
and
IL-1
Selectins bind
sialyl Lewis X
on
leukocytes
Interaction results in
rolling of leu
What is adhesion?
- Cellular adhesion molecules (
ICAM
and
VCAM
) are upregulated on
endothelium
by
TNF
and
IL-1
-
Integrins
are upregulated on
leukocytes
by
C5a
and
LTB4
- Interaction between
CAMs
and
integrins
result in firm
adhesion of leukocytes to the vessel wall
What is the etiology of leukocyte adhesion deficiency? Clinical features? (3)
Most commonly due to an
autosomal recessive
defect of
integrins
(
CD18
subunit)
Clinical features include:
-
Delayed separation of the umbilical cord
-
Increased circulating neutrophils
(due to impaired adhesion of marginated pool of leukocytes)
-
Recurre
What is transmigration and chemotaxis?
- Leukocytes
transmigrate
across the
endothelium
of
postcapillary venules
and move towards
chemical attractants
(
chemotaxis
)
-
Neutrophils
are attracted by
bacterial products, IL-8, C5a
, and
LTB4
What is phagocytosis?
Consumption of
pathogens
or
necrotic tissue
- Phagocytosis is enhanced by
opsonins
(
IgG
and
C3b
)
Pseudopods
extend from leukocytes to form
phagosomes
, which are
internalized
and merge with
lysosomes
to produce
phagolysosomes
What is Chediak-Higashi syndrome?
Protein trafficking
defect (
autosomal recessive
) characterized by
impaired phagolysosome formation
What are clinical features of Chediak-Higashi syndrome? (6)
1. Increased risk of
pyogenic infections
2.
Neutropenia
(due to intramedullary death of neutrophils)
3.
Giant granules in leukocytes
(due to fusion of granules arising from the Golgi apparatus)
4.
Defective primary hemostasis
(due to abnormal dense granul
What is the pathogenesis of destruction of phagocytosed material?
O2-dependent killing
is the most effective mechanism
HOCl
generated by
oxidative burst
in
phagolysosomes
destroys phagocytosed microbes:
- O2 is converted to O2
- by NADPH oxidase (
oxidative burst*)
- O2
- is converted to H2O2 by
superoxide dismutase* (S
What is chronic granulomatous disease (CGD)? Etiology? Inheritance pattern?
Characterized by
poor O2-dependent killing
:
- Due to
NADPH oxidase defect
(X-linked or autosomal recessive)
What does CGD lead to? Diagnosis?
Leads to
recurrent infection
and
granuloma formation
with
catalase-positive organisms
, particularly Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia, and Aspergillus
Nitroblue tetrazolium test
is used to screen for CGD
- Leukocyt
What does MPO deficiency result in? NBT result?
Results in
defective conversion of H2O2 to HOCl
:
- Increased risk for
Candida infections
- However, most patients are
asymptomatic
-
NBT is normal
: respiratory burst (O2 to H2O2) is intact
What is O2-independent killing?
O2-independent killing is less effective than O2-dependent killing and occurs via
enzymes
present in
leukocyte secondary granules
(e.g.,
lysozyme
in macrophages and
major basic protein
in eosinophils)
What is resolution?
Neutrophils undergo
apoptosis
and disappear within 24 hours after resolution of the inflammatory stimulus
What is the role of macrophages in acute inflammation? Derived from?
Macrophages predominate after neutrophils and peak
2-3 days
after inflammation begins
- Derived from
monocytes
in blood
How do macrophages arrive in tissue?
Arrive in tissue via the margination, rolling, adhesion, and transmigration sequence
What is the function of macrophages?
Ingest organisms via
phagocytosis
(augmented by
opsonins
) and destroy phagocytosed material using enzymes (e.g.,
lysozyme
) in
secondary granules
(
O2-independent killing
)
What is another function of macrophages? Outcomes include? (4)
Manage the
next step
of the inflammatory process
Outcomes include:
1.
Resolution and healing
- anti-inflammatory cytokines (e.g.,
IL-10
and
TGF-beta
) are produced by macrophages
2.
Continued acute inflammation
- marked by
persistent pus formation
;
IL-8