Leukocyte Function :

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Leukocyte Function Inflammation
Prasit Chanarat
Department of Clinical Microscopy Faculty of
Associated Medical Sciences Chiang Mai University
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Inflammatory Three major stages
1. Dilation of capillaries to increase
blood flow 2. Microvascular structural change
and escape of plasma proteins from the
blood stream 3. Leukocyte transmigration through
endothelium and accumulation at the
site of injuries
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Five steps of the leukocyte adhesion cascade
1. Capture 2. Rolling 3. Slow rolling 4. Firm
adhesion 5. Transmigration
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Capture

• Leukocyte contact with the activated endothelium
• P-selectin is the primary adhesion molecule
• Ligand for P-selectin is PSGL-1 (P-selectin
  glycoprotein ligand)
• L-selectin also exhibits an important role in
  capture

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Selectin

• Family of transmembrane molecule
• Homology to calcium-dependent lectin and
  epidermal growth factor
• 2-9 concensus repeated domain
• L-selectin-smallest of the vascular selectin
  found on most leukocytes
• P-selectin the largest selectin, express on
  activated platelet and endothelial cell
• E-selectin express on activated endothelial
  cell

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Selectin ligand

• All selectin can recognize glycoprotein and or
  glycolipid containing tetrasaccharide sialyl-
  LewisX (sialyl-CD15)
• Sialyl-CD15 found on all myeloid cells,
  composed of sialic acid, galactose, fucrose,
  N-acetyl-galactosamine
• PSGL-1 contains sialyl-LewisX
• CD24 - another P-selectin ligand (important
  for tumor cell binding to P-selectin)

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L-Selectin ligand

• GlyCAM-1 (Glycosylation-dependent cell adhesion
  molecule)
• CD34
• MAdCAM-1 (Mucosal addressin cell adhesion
  molecule)
• PSGL-1

E-Selectin ligands

• Are still not known

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Rolling

• P-selectin is the most important selectin
  involve rolling
• PSGL-1 express on lymphocyte, monocyte,
  eosinophil, PMN,
• L-selectin/E-selectin also take part in
  rolling and less efficient in P-selectin

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Slow rolling

• Require expression of E-selectin and CD18
  integrin
• CD18 integrin is the most efficient way to
  curb leukocyte
• VLA-4 (Alpha-4 1 integrin) may be importent
  role (very late antigen - 4, CD49d/CD29, alpha
  4, beta 1)

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CD18 Deficiency

• Severe inflammatory defect
• Skin ulceration
• elevate PMN count and IgG
• increase susceptibility to Strept. pneumonia
• severe defect in leukocyte adhesion/T-cell
  activation
• defect in leukocyte recruitment to peritonitis
• lack of PMN recruitment to the skin
• leukocte adhesion deficiency Type 1 (LAD-1)
• early lethality

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Integrin

• Heterodimeric transmembrane glycoprotein family
• large (alpha) and small (beta) subunit of sizes
  120-170 KDa and 90-100 KDa
• Mg2 and Ca2 binding sites
• Beta-2 -integrin includes 4 heterodimers
• CD11a/CD18 (lymphocyte function -
  associated antigen - 1, LFA-1)
• CD11b/CD18 (Mac-1) PMN/macrophage
• CD11c/CD18 (p150,95)
• CD11d/CD18
• Beta-1-integrin - VLA4, CD49d/CD29, Alpha4
  beta 1 (VLA4 binds to ligand VCAM-1)

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• LFA-1 and Mac-1 bind to ICAM-1 and ICAM-2
• ICAM-2 deficiency - prolonged eosinophillic
  infiltrate but have no inflammatory defect
• ICAM-1 -mild inflammatory defect
• VLA-4 express on macrophage, eosinophil,
  lymphocyte
• VCAM-1 deficiency - die before birth due to
  morphogenetic failure unrelated to the
  inflammation

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Transmigration

• Leukocyte migrates across resting endothelium
• Add IL-8 or fMLP - 50-90 PMN can
  transmigrate
• Endothelial cells secrete chemoattractant
• - lymphotactin
• - I-309/Rantes/MIP-1beta/MIP1-alpha
• - MCP-2/MCP-3/MCP-1
• - IL-8, NAP-2, GCP-2, GRO-gamma,
• GRO-beta, GRO-alpha

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Mast cell mediator

• Histamine/Serotonin - Vasodilation, increase
  vascular permeability
• Neutrophil chemotactic factor/Eosinophil
  chemotactic factor - chemotaxis
• Vasoactive intestinal peptide/ Thromboxane
  A2/Prostaglandin E2 (D2) - vasodilation
• Leukotriene beta4/leukotriene D4/Platelet
  activating factor - increase vascular
  permeability

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Adhesion molecules

• Integrin - beta1 (VLAs 1-6)/beta2
  (LFA/Mac-1)/beta 3 (GPIIb/IIIa)
• Ig supergene - ICAM-1/ICAM-2/ VCAM-1
• Selectin - L-selectin (LAM-1)/E-selectin
  (ELAM-1)/P-selectin (GMP-140)
• Vascular aggressin - LAM-1, Leu8, H-CAM
  (CD44), VCA-4, LFA-1

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Classic inflammatory lymphokines

• Migration inhibitory factors
• Macrophage activating factor
• Macorphage chemotactic factor
• Lymphotoxin (Cachexin)
• Lymphocte stimulating factor
• Proliferation inhibitory factor

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Classic inflammatory lymphokines

• Aggregation factor
• Interferon
• Lymphocyte permeability factor
• Transfer factor
• Skin reactive factor
• Cytophilic factor
• Leukocyte inhibitory factor
• Osteoclast activating factor