Leukocyte adhesion and chemotaxis

• leukocyte migration


  - move from blood to inflammation sites and activate immune response

  - directional control co-ordinated by tissue expression of adhesion molecules and chemical stimuli for migration

  - on arrival at sites: participate in host defence, inflammation and repair/resolution

  
• migration steps


  1. tethering

  2. rolling

  3. activation

  4. adhesion

  5. transmigration

  
• adhesion molecules in migration

  selectins, integrins, intercellular adhesion molecules (CAMs)

  
• selectins (tethering and rolling)


  - allow cells to adhere to carbohydrates on the surfaces of other cells

  - lectin-like adhesion molecules

  
• L-selectin


  - constitutive expression on leukocytes

  - activates leukocytes - transient increase in binding, molecules cluster on surface, rapid shedding by proteolytic cleavage
• P-selectin


  - constitutive in platelets

  - rapidly translocated to cell surface after cell activation
• E-selectin


  - endothelial expression induced by cytokines or LPS

  - requires de novo protein synthesis - slow (2-6hrs)
• integrins (adhesion and flattening)


  - 2-stranded proteins expressed on leukocytes/other cell surfaces

  - involved in firm adhesion

  - require signals from chemokines

  - alpha and beta chain (18a + 8B = 24 combos)

  - beta integrins involved in leukocyte adhesion

  
• integrin regulation

  - basal expression = inactive, bent

  - activation = conformational change - increased affinity and clustering of integrins

  
• CAMs

  - members of immunoglobulin superfamily

  - expressed on inflamed endothelium

  - ligands for integrins

  - ICAM-2 = basally expressed on endothelium

  - ICAM-1 = induced by cytokines IL-1,TNF
• transmigration


  - usually paracellular (between endothelial cells) but can cross cells (transcellular)

  - mediated by interaction between CAMs, integrins etc

  - chemo attractants direct migration
• matrix metalloproteinases (MMPs)

  - zinc-binding

  - degrade extracellular matrix

  - promote migration through cellular junctions

  - modulate expression of adhesion molecules and chemokines
• chemotaxis


  movement by a cell or organism in reaction to a chemical stimulus
• chemoattractants


  signalling molecules that guide cell movement
• chemokines


  - chemotactic cytokines

  - produced in response to IL-1, TNF, bacteria

  - G-protein coupled receptors

  - mainly neutrophil and T cell attractants = CXC

  - CC = not neutrophil
• chemokine receptors

  - 20 types

  - 7 transmembrane structure that couples to G-protein for signal transduction

  - 4 families = CXC, CC, CX3C, XC

  - acute = neutrophils

  - chronic = monocytes/lymphocytes

  
• disease

  - leukocyte adhesion deficiency caused by defect in adhesion molecule expression

  - HIV uses CXCR4 and CCR5 chemokine receptors to enter T cells