Biomedical Engineering Reference
In-Depth Information
LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Adhesion Molecules in Tethering and Rolling
In the i rst step of leukocyte recruitment, cells in blood l ow tether to the endothelial
cells in specii c areas of post-capillary venules and roll at reduced velocity across
the luminal surface (Fuhlbrigge and Weishaupt 2007, Ley
et al.
2007). h e primary
molecules mediating tethering and rolling are vascular E-selectin (CD62E) and P-
selectin (CD62P). P-selectin is produced by all endothelia and stored in organelle
bodies for rapid transport to the luminal surface in response to inl ammatory stimuli.
E-selectin, in contrast, is expressed constitutively on post-capillary venules in skin
but not in other tissues, although it can be induced in all vessels by inl ammation
(Chong
et al.
2004). While P-selectin glycoprotein ligand-1 (PSGL-1, CD162) is the
sole major ligand on leukocytes for P-selectin, carbohydrate epitope(s) recognized
by E-selectin can be expressed on at least three distinct glycoproteins, PSGL-1,
CD43, and CD44. h ese scaf old glycoproteins are dif erentially expressed and
decorated with relevant carbohydrate(s) at distinct stages of development in the
various populations of circulating leukocytes (Fuhlbrigge
et al.
1997, 2006, Dimitrof
et al.
2001). We believe, however, that the full repertoire of E-selectin ligands is yet
to be discovered. Creation of selectin ligands requires the glycosylation of these
carrier or scaf old glycoproteins with sialylated, fucosylated carbohydrate epitopes
similar or identical to sialyl-Lewis
x
. As a group, these functional ligand structures
are recognized by a specii c monoclonal antibody called HECA-452 and termed
cutaneous lymphocyte-associated antigen (CLA) (Fuhlbrigge
et al.
1997). CLA is
a distinctive marker for skin homing leukocytes expressed by the vast majority
of T cells in uninl amed skin and at sites of cutaneous inl ammation (Clark
et al.
2006). Production of CLA and related carbohydrate epitopes is regulated by key
glycosyltransferases including α1,3-fucosyltransferase-IV (FucT-IV) and FucT-
VII. In addition to E- and P-selectin, very late antigen 4 (VLA-4, integrin α
4
β
1
) can
also mediate tethering and rolling through interaction with its ligand, vascular cell
adhesion molecule 1 (VCAM-1) expressed on endothelia. h e interplay between
integrin and selectin-mediated rolling on dermal endothelium at baseline and in
disease remains to be dei ned.
Adhesion Molecules in Activation
To enter a target tissue, leukocytes need to adhere i rmly to vessel walls in the
area. Details of the molecules involved in this process are discussed in a recent
review (Ley
et al.
2007). Briel y, cells moving at the hydrodynamic velocity of
blood pass through the vessels too quickly to sense local environmental signals
or form stable interactions with endothelial cells. Cells that have tethered and are
rolling move at an order of magnitude slower velocity and maintain close contact
