Margination

• Definition: a process by which leukocytes are distributed peripherally along the endothelial surface
• Mechanism: The two main mechanisms that allow for margination are rouleaux formation and dilation of post-capillary venules.
  • Rouleaux formation
    • The liver releases increased amounts of fibrinogen in response to cytokines released by macrophd fibrinogen → rouleaux formation → neutrophils are pushed against endothelium of the venules
    • Increased fibrinogen → rouleaux formation → neutrophils are pushed against endothelium of the venules
    • For RBCs
      • This occurs due to elevated levels of circulating proteins, which disrupts the repulsive electrostatic charge on the erythrocyte surface and causes stacked aggregation.
      • Classically linked to lymphoproliferative/plasma cell disorders such as multiple myeloma and Waldenstrom macroglobulinemia, which generate high levels of monoclonal paraprotein (immunoglobulins).

Rolling

• Definition: a transient weak interaction of leukocytes with endothelial cells that causes them to move slowly along the blood vessel periphery in areas of inflammation in preparation for adhesion
• Mechanism: mediated by adhesion molecules (selectins)
  • On endothelial cells
    • P-selectin
      • Stored in Weibel-Palade bodies
      • Histamine-mediated release within the endothelium in response to inflammation
    • E-selectin: released in response to inflammatory mediators such as TNF and IL-1
    • Other: GlyCAM-1, CD34
  • On leukocytes
    • Neutrophils and other leukocytes express Sialyl-LewisX and L-selectin, respectively.
    • Deficiency of the adhesion molecule Sialyl-LewisX causes Leukocyte adhesion deficiency type 1 type 2.

Leukocyte adhesion

• Definition: the firm binding of leukocytes to endothelium prior to migrating out of the vasculature
• Mechanism: mediated by adhesion molecules
  • On endothelial cells
    • Intercellular adhesion molecule (ICAM, also called CD54)
    • Vascular adhesion molecule (VCAM, also called CD106)
    • Both upregulated by TNF and IL-1
  • On neutrophils and lymphocytes
    • Neutrophils: lymphocyte function-associated antigen-1 (LFA-1)
      • Belongs to β2-integrin family
      • Composed of CD18 and CD11a
      • Binds to ICAM
    • Lymphocytes and monocytes β1-integrin (also called VLA-4) binds to VCAM
    • Expression of integrins is activated by leukotriene B4 (LTB4) and C5a.
    • The deficiency of a CD18 integrin subunit causes Leukocyte adhesion deficiency type 1.

Diapedesis (transmigration)

• Definition: the transmigration of leukocytes across endothelial barriers (can occur paracellularly or transcellularly)
• Mechanism
  • Leukocytes leave the blood vessel by moving between endothelial cells.
  • Neutrophils release type IV collagenase, which dissolves the basement membrane and allows them to exit the interstitial space.
  • Requires expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, also called CD31), an endothelial cell adhesion molecule (ECAM) on neutrophils, endothelial cells, and platelets

Migration

• Definition: the process by which leukocytes travel through the interstitium to the site of inflammation after leaving the blood vessels
• Mechanism: Occurs via chemotaxis, which is mediated by chemoattractants
  • Leukotrienes: e.g., LTB4
  • Platelet-activating factor (PAF)
  • Chemokines: e.g., IL-8
  • Kallikrein: a serine protease enzyme that activates bradykinin and regulates blood pressure
  • Complement fragments, e.g., C5a