Cell Migration


   Here we see a blood vessel lined with endothelial cells with a normal flow of blood containing lymphocytes. We are going to follow one particular lymphocyte to see how it migrates through the endothelium and out into the surrounding tissues.

   As the vessel widens into what is known as a venule, the blood flow decreases and the lymphocytes slow down.

   In the presence of an infection such as bacteria, an immune response takes place and cytokines such as interleukin 1 and tumour necrosis factor are released from tissue cells and resident macrophages. In addition, peptides of the complement system cause mast cells to degranulate.

   Cytokines such as interleukin 1 and tumour necrosis factor act on the endothelium to induce adhesion molecules, while chemokines attach to the endothelium to act as stimulators of migration.

The cytokines induce the expression of adhesion molecules on the surface of endothelial cells complementary to those on the lymphocytes. Molecules on the endothelial cells such as E-selectin interact with carbohydrate molecules on the surface of the lymphocyte such as CD15.

   These interactions cause the lymphocytes to slow down and roll along the endothelium enabling them to sample other adhesion molecules which have been induced onto its surface.

Amongst these are the chemokines which bind to the lymphocyte and trigger an activation mechanism causing an influx of calcium ions into the cell and the activation of another group of adhesion molecules onto its surface.

These adhesion molecule proteins called LFA1 and VLA4 interact with other adhesion molecule proteins on the surface of the endothelium called ICAM1 and VCAM1 respectively.

These latter molecules can also be induced onto the endothelial surface by cytokines such as tumour necrosis factor thereby contributing to the overall induction process. This multi-point adhesion onto the endothelium is called pavementing.

Both the adhesion molecules on the lymphocyte and those on the endothelium are each attached to their respective cell's cytoskeleton. This can be thought of as a molecular motor which acts like a tractor enabling the lymphocyte to pull itself down and out through the endothelium.

   With a firm anchoring point to move against, the lymphocyte proceeds to extend its pseudopod down into the intercellular junction between the endothelial cells which retract as they are pushed down.

When the pseudopod makes contact with the basement membrane, the cell moves new adhesion molecules down to its leading edge enabling it to form a new anchoring point.

   The lymphocyte now releases granules from this leading edge. These contain destructive enzymes such as collagenase and elastase, which puncture the basement membrane allowing the cell to squeeze down through the damaged area and migrate out into the tissue. This migratory process is called diapedesis.

  The damaged endothelium then seals over again and reforms.

   The lymphocyte then migrates towards the site of infection under chemical stimuli in a process known as chemotaxis.

    Another feature of inflammation is an increase in capillary permeability. Mediators from activated mast cells such as histamine;cauce the endothelial cells to retract. This allows larger serum molecules such as antibody and complement to leak into the inflamed area.

    These mediators can also act on the smooth muscle in the blood vessel wall, increasing the diameter of arterioles and producing enhanced blood flow.

    This causes increased supply of serum molecules and cells to the inflammatory site.