Inflammation

and Repair - 3

Dr.CSBR.Prasad, M.D.

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DIAPEDESIS

(Transmigration)

Migration of Leukocytes through

the interendothelial gaps

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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

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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

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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

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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.

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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

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PHAGOCYTOSIS

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PHAGOCYTOSIS

Ingestion and processing of particulate

material by phagocytic cells

– Particulate matter can be:

• Tissue debri, bacteria, other foreign cells

– Phagocytic cells:

• PMNs, MØ

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PHAGOCYTOSIS

Phagocytic cells are two types:

1.Microphages (neutrophils) or

2.Macrophages (monocytes / histiocytes)

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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

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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

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What is C3b and Fc ?

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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

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Activation

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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

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Activation The biologic activities

resulting from

leukocyte activation

include

Chemotaxis

Modulation of AM

Elaboration of AA

Metabolites

Secretion /

Degranulation

Oxidative burst

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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

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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)

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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

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E N D

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