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Designed for UG pathology teaching.
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Inflammation
and Repair - 3
Dr.CSBR.Prasad, M.D.
V3-CSBRP-Apr-2012
DIAPEDESIS
(Transmigration)
Migration of Leukocytes through
the interendothelial gaps
V3-CSBRP-Apr-2012
Diapedesis
• It occurs mostly thru post capillary venules
• Chemokines stimulate the PMNs to
emigrate in to interstitium
• PMNs leave the vessel thru inter
endothelial gaps
• In the interstitium they travel towards the
site of injury
V3-CSBRP-Apr-2012
Adhesion molecules (AM) involved
in diapedesis
• AM present in between the endothelial
cells and in the interstitium facilitate this
process
• These include:
PECAM-1 or CD31
Several junctional AMs
V3-CSBRP-Apr-2012
Diapedesis
• Must then cross basement membrane
– Collagenases
• PMNs secrete collagenases to dissolve
basement membrane
• Then they reach the site of injury by
Chemotaxis
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Summary of DIAPEDESIS
Insertion of pseudopodia
which widens the intercellular gaps
Passage through the gaps
by ameboid movement
Passage through the basement membrane
either by mechanical disruption or possibly by
enzyme (collagenase) effect
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WOW!
Neutrophil Transendothelial Migration (Diapedesis)
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Chemotaxis of Leukocytes
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Chemotaxis
In the intestitium leucocytes reach the site of
injury by traveling along the concentration
gradient created by the chemokines -
Chemotaxis
V3-CSBRP-Apr-2012
Chemotaxis
Def: Chemotaxis is a process by which the
leucocytes travel towards and along the
chemical concentration gradient.
Concentration gradient is created by
chemokines
Highest concentration occurs at the center of
injury
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This is a diagram showing the effect of chemokine concentration
gradient on chemotaxis direction. The attracted cell moves through
the gradient toward the higher concentration of chemokine.
V3-CSBRP-Apr-2012
Chemotaxis
• Leukocytes follow chemical gradient to the site of injury
• Chemotactic agents: include – Soluble bacterial products
– Complement components (C5a)
– Cytokines (chemokine family e.g., IL-8)
– LTB4 (AA metabolite)
• Chemotactic agents bind surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements
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Chemotactic substances will bind to
leukocyte receptors, initiating a stimulus –
receptor interaction that leads to activation
of intracellular contractile proteins
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Leukocytes:
– Extend pseudopods with overlying
surface adhesion molecules (integrins)
that bind ECM during chemotaxis
– Leucocytes walk towards the injury
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Chemotaxis
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When they reach the site…
• PMNs able to adhere to the intercellular
matrix by binding of integrins to CD44
• By this mechanism they are retained at the
site where they are needed most
V3-CSBRP-Apr-2012
PHAGOCYTOSIS
V3-CSBRP-Apr-2012
PHAGOCYTOSIS
Ingestion and processing of particulate
material by phagocytic cells
– Particulate matter can be:
• Tissue debri, bacteria, other foreign cells
– Phagocytic cells:
• PMNs, MØ
V3-CSBRP-Apr-2012
PHAGOCYTOSIS
Phagocytic cells are two types:
1.Microphages (neutrophils) or
2.Macrophages (monocytes / histiocytes)
V3-CSBRP-Apr-2012
PHAGOCYTOSIS
The process of phagocytosis involves:
1. Adhesion – Immobilizes the particles
2. Engulfment by extending pseudopodia
3. Fusion of the lysosomes with the phagocytic vacuole
4. Degradation / Intracellular microbial killing
V3-CSBRP-Apr-2012
Phagocytosis
Recognition and
attachment of
the particle to
be ingested
Engulfment
formation of a
phagocytic
vacuole
Killing
degradation
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Process of Phagocytosis
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PHAGOCYTOSIS
The process of phagocytosis:
Adhesion
• Collectins, C3b, Fc portion of Ig
Opsonization:
Coating the particle by opsonins
Complement C3b
Immunoglobulins IgG
Opsonization facilitates phagocytosis
V3-CSBRP-Apr-2012
What is C3b and Fc ?
V3-CSBRP-Apr-2012
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PHAGOCYTOSIS
The process of phagocytosis:
Opsonins:
Like sauce making the bread palatable,
opsonins make particles palatable for
phagocytes
Opsonization facilitates phagocytosis
PMNs and MØ has receptors for C3b & Fc
V3-CSBRP-Apr-2012
Activation
V3-CSBRP-Apr-2012
Activation
• When the leucocytes gets stimulated by
the cytokines, they get activated
• With activation:
– AM are modulated / potentiated
– Chemotaxis is potentiated
– Elaborate AA metabolites
– Secretion / Degranulation
– Oxidative out burst
V3-CSBRP-Apr-2012
Activation The biologic activities
resulting from
leukocyte activation
include
Chemotaxis
Modulation of AM
Elaboration of AA
Metabolites
Secretion /
Degranulation
Oxidative burst
V3-CSBRP-Apr-2012
Defects in Leucocyte Function
Can be genetic / acquired
Results in increased vulnerability to infections
• Defects in leucocyte adheshion
• Defects in phagolysosome function
– Chediak - Higashi syndrome
• Defects in microbicidal activity
– Chronic Granulomatous Disease
V3-CSBRP-Apr-2012
Defects in Leucocyte Function
GENETIC
• LAD1 beta chain of CD11/CD18 integrins
• LAD2 fucosyl tranferase required for synthesis of
sialyated oligosccharide (receptor for selectin)
• CGD (decreased oxidative burst) – X-linked (NADPH oxidase – membrane component)
– Autosomal recessive (NADPH oxidase - cytoplasmic)
– MPO deficiency (absent MPO-H2O2 system)
• Chediak-Higashi syndrome (protein involved in
organelle membrane fusion)
V3-CSBRP-Apr-2012
Defects in Leucocyte Function
ACQUIRED
• Thermal injury, diabetes, malignancy, sepsis, immunodeficiencies
• Chemotaxis
• Hemodialysis, diabetes mellitus
• Adhesion
• Leukemia, anemia, sepsis, diabetes, neonates, malnutrition
• Phagocytosis and Microbicidal activity
V3-CSBRP-Apr-2012
E N D
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