Leukocyte Adhesion Cascade and Defect : Simplified

Capture or Tethering

• Increased vascular permeability and vasodilation are mediated by inflammatory mediators like histamine released by inflammatory cells in response to PAMPs expressed by pathogens.
• Hemoconcentration (owing to increased vascular permeability) and decreased velocity of blood flow (owing to vasodilation) leads to peripheral pooling of the leukocytes (i.e. towards the endothelium) – process called as margination.
• Following margination, capture occurs and this process is mediated by interaction between P-selectin on endothelium and PSGL-1 (P-Selectin Glycoprotein Ligand -1) on leukocytes

Rolling

Rolling occurs below the critical velocity (velocity separating freely flowing cells like RBCs and rolling leukocytes). It is mediated by selectin-addressins interaction.

Selectins

• P-selectins are expressed on the endothelial surface.
  • Remember P-selectins are found on Platelets and webel-Pallade bodies present on human endothelium.
  • P-selectins are the largest and most important of all selectins.
• L-selectins are expressed on Leukocytes
  • L-selectin is more efficient than P-selectin in mediating rolling
  • Smallest selectin (Remember: L for Little)
• E-selectins on activated endothelium
  • Responsible for slow rolling and initiation of of firm adhesion

Addressins (Selectin Ligands)

• P-selectin: PSGL-1 (expressed on blood cells and contains Sialyl Lewis-X)
• L-selectin: GlyCAM-1 (Glycosylation Dependent Cell Adhesion Molecular), MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule) and CD34
• E-selectin: Not yet known

Activation by Chemoattractants

Activators

• IL-8
• C5a
• N-formyl peptide

Activation

• Confirmational change of leukocyte to high affinity states by activation of integrins

Arrest and Adhesion

Tight binding of phagocytes to the endothelial cell.

Integrins – IgCAMs (Immunoglobulin superfamily Cellular Adhesion Molecules) mediated.

Integrins

• Contains large α and small β subunits
• Contain binding sites for divalent cations necessary for adhesive functions (Mg, Ca)
• β2 integrins: LFA-1 (Lymphocyte Function Associated), CD18
• β1 integrins: VLA-4 (Very Late Antigen)

Immunoglobulins

• LFA-1: ICAM (Intercellular Adhesion Molecule) or CD 54
• VLA-4: VCAM-1 (Vascular Cell Adhesion Moecule)

Diapedesis or Transmigration

The phagocytes extends pseudopodia through the vessel wall and extravasates into the tissues.

Mediated by: PECAM-1 in between cells and other adhesion molecules

Clinical Relevance – Leukocyte Adhesion Deficiency (LAD)

These are autosomal recessive diseases.

LAD I (Adhesion defect)

• Failure to express CD 18, which composes common β2 subunit of LFA-1 family (β2 integrins) – interaction with ICAM and VCAM on endothelium is impaired.
• First indication of defect: Omphalitis
• Recurrent, chronic bacterial infections
• Abnormally high number of granulocytes in circulation (margination defect)
• Diagnosed by evaluating expression (or lack) of CD 18 by flow cytometry.
• Defective granulocyte migration to infection site – absence of abscess or pus.
• History of delayed separation of umbilical cord stump

LAD II (Rolling defect)

• Defective fucosylation of PSGL-1 (selectin ligand) – impaired interaction with endothelial E- and P- selectins.
• Extremely rare; seen in people with Bombay blood group phenotype
• Recurrent bacterial infections with psychomotor and mental retardation
• Responds to oral fucose

LAD III (LAD-I + Glanzmann thrombasthenia)

• Due to FERMT3 mutation
• Defective signalling of β1, β2 integrins on leukocytes, αIIβ3 integrin on platelets
• Usually the first signs occur in infancy or early childhood.
• Patients present LAD-I life-threatening infections and a Glanzmann thrombasthenia-like bleeding disorder.