Download The influence of the E-selectin 128R polymorphism on leukocyte

The influence of the E-selectin 128R polymorphism on leukocyte-endothelial cell
interactions
The three selectins form a family of vascular cell adhesion proteins, each of which is a
single chain glycoprotein made up of a N-terminal lectin domain, an epidermal
growth factor-like domain (EGF) and a series of repeated complement control protein
repeat (CCP) modules, a trans-membrane domain and a cytoplasmic tail 1.
Functionally, selectins act as cell surface lectins, which bind glycoproteins (and
possibly also glycolipids) on EC and leukocytes. The binding of selectins to their
ligands show fast on-off kinetics, leading under flow conditions to leukocyte rolling
on endothelium rather than arrest. The capacity of specific glycoproteins to bind
selectins is determined both by their protein backbone and by their precise
glycosylation.
E-selectin is a smaller molecule than P-selectin, with six CRP domains in human and
mouse, and four in pig 2-4. It is exclusively expressed by activated EC, and expression
is low to undetectable on resting EC. E-selectin is present on intimal endothelium
overlying cellular plaques5-7 and in the adventitial neovasculature of atherosclerotic
vessels 5, 8. Direct involvement of E-selectin in the pathogenesis of atherosclerosis is
suggested by a study showing that LDL-receptor knockout mice deficient in both Eand P-selectin have a reduction in advanced atheromatous lesions, whereas mice
deficient in only P-selectin have a reduction in fatty streaks but are not protected from
more advanced lesions 9, 10.
We have examined the functional consequence of an E-selectin polymorphism, in
which arginine is substituted for serine at position 128 in the EGF domain. The 128R
E-selectin polymorphism, which has an allele frequency in Caucasians of
approximately 10%, has been found to be present at significantly increased frequency
in patients with clinical manifestations of atherosclerosis in Germany 11, Italy 12, USA
13
and Japan 14. Furthermore, Ellsworth et al (2001) 15 found that R128 was associated
with coronary calcification in women under 50 years, suggesting that the
polymorphism is associated with underlying atherosclerosis and not simply with
thrombotic complications. The polymorphism has also been linked to post-angioplasty
restenosis 16, 17, SLE (Hajeer et al, 2000), and enhanced coagulation during
endotoxemia 18.
E-selectin 128R had been shown in a simple static adhesion assay to have enhanced
ligand-binding function compared with the more common 128S E-selectin 19. We
established stable CHO cell transfectants expressing E-selectin 128S and 128R at
equal surface density and shown that E-selectin 128R but not 128S caused transient
tethering at physiological shear (2 Dyns/cm2) of K562 proerythroid cells, which lack
fucosyl-transferases IV and VII and which therefore do not express sialyl Lewis X,
the carbohydrate that is normally required for E-selectin binding. Our work has
established that E-selectin 128R is a gain-of-function variant under physiological flow
conditions, with the potential to exacerbate inflammatory responses in vivo 20.
Furthermore, we found that E-selectin 128R recognises a subpopulation of memory
lymphocytes not recognised by E-selectin 128S 21.
Based upon these data, we are currently exploring further the hypothesis that
expression of E-selectin 128R modifies immune-mediated inflammatory reactions by
leading to an inappropriate selection of lymphocyte subsets into tissues, depending on
the coexpression of other adhesion molecules and chemoattractants. This work is
funded by a Wellcome Trust Project Grant.
Reference List
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