Inflammation

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Inflammation Cell migration
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Why cell migrate ?

• Signal and adhesion molecules are selective
  expressed in the venules
• Hemodynamic force is relatively low
• Endothelial surface charge is low

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Concept

• What cells will migrate?
• Depend not only on cell type, but also on state
  of differentiation or activation

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Migration is controlled by

• Adhesion molecules on both leucocytes and
  endothelium
• The presence of Chemotactic factors
• Migratory capacity activated (cytokine
  stimulated ) or not

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Model of leucocyte adhesion

• Tethering leucocyte roll slow on the surface of
  endothelium when passing thru venule
• Triggering leucocyte responses to cytokines,
  chemotactic agents and surface molecules on
  endothelium. This will activate the program of
  migration
• Latching and activation upregulate the affinity
  of leucocytes integrins.
• Migration cell contact basement membrane using
  new adhesion molecules, migrate beneath the
  endothelium
• Digestion enzyme digesting the ECM of basement
  menbrane was mobilized to the cell surface, make
  it easy to move to tissue

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Leucocyte migration across endothelium
3.2
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Migration destination differ by Lymphocytes
status

• Resting T cell migrate across HEV to secondary
  lymphoid tissues
• Activated cells migrate to site of inflammation

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Intercellular adhesion molecules

• Adhesion molecules
• Membrane-bound protein for cell-cell interaction
• link cytoskeleton to ECM connected in-out env
• Different binding sites ensure binding for more
  than one ligand.
• Clustering in patch can increase affinity/avidity

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Modulation of leukocyte adhesion

• Four ways to enhance binding of leucocytes to
  endothelium
• Membrane release of stored adhesion molecules
• Endothelial cells synthesize more adhesion
  molecules at site of inflammation
• Increase the affinity of adhesion molecules (eq.
  LFA-1)
• Reorganization of adhesion molecules and forming
  high avidity patches

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Chemokine
Weibel Palade bodies ? (legend)
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Many endothelial adhesion molecules is Ig
supergene family

• Cellular adhesion molecules included
• ICAM-1(Intercellular adhesion molecules -1)
• ICAM-2
• VCAM-1 (vascular adhesion molecules -1)
• MAdCAM-1 (Mucosal addressin CAM-)
• Constituted expressed or inducible
• CAM (Endothelial cells) interact with integrin
  (Leucocytes ), both belongs to adhesion molecules

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Integrins

• Consisted of two polypeptides (ab)
• Classified by beta chain (due to beta chain can
  associated with any alpha chains)
• b1integrin for binding to ECM
• b2 integrin for leucocyte adhesion to
  endothelium or immune cells
• b3 integrin (cytoadhesin) interaction of
  platelet and neutrophils at site of inflammation

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b2-integrin (eq. LFA-1, CR3)

• Expressed on leucocyte, binds to CAM (vascular
  endothelium)
• LFA-1binds to ICAM-1 and ICAM2
• Constituted expressed ICAM-2 determined basal
  level of leucocyte binding
• Ps brain endothelium lack ICAM-2
• Cytokine inducible ICAM-1 (8-96h) determined
  later adhesion of monocytes and lymphocytes
• CR3 binds to ICAM-1 (different binding site with
  LFA-1)
• Function in phagocytes accumulation
• Leucocyte adhesion deficiency syndrome (LAD)
  lack of b2-integrin

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Selectin

• Carbohydrate binding protein
• As an adhesion molecules on leucocytes and
• Group into
• E-selectin (endothelium)
• P-selectin (platelet)
• L-selectin (leucocytes)
• Ligands

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Selectin
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Neutrophil migration is controlled (slowing down)
by E-selectin

• E-selectin appears early in the inflammation
• Expressed after cytokine activation (IL-1, TNF-a)
  
• In 4-12h induced however, wanes by 24h
• E-selectin genetically highly expressed cells
  binds strongly with neutrophil

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Expression and induction of endothelial adhesion
molecules
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THANX for your attention
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