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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 (1) Vestweber D, Blanks JE. Mechanisms that regulate the function of the selectins and their ligands. Physiological Reviews 1999;79:181-213. (2) Bevilacqua MP, Stengelin S, Gimbrone MA, Seed B. Endothelial leukocyte adhesion molecule 1:an inducible receptor for neutrophils related to complement regulatory proteins and lectins. S 1989;243:1160-4. (3) Weller A, Isenmann S, Vestweber D. Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor . J Biol Chem 1992;267:15176-83. (4) Tsang Y, Stevens PE, Licence ST, Haskard DO, Binns RM, Robinson MK. Porcine E-selectin: cloning and functional characterization. Immunology 1995;85:140-5. (5) Davies MJ, Gordon JL, Gearing AJ, Pigott R, Woolf N, Katz D, Kyriakopoulos A. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 1993;171:223-9. (6) van der Wal AC, Das PK, Tigges AJ, Becker AE. Adhesion molecules on the endothelium and mononuclear cells in human atherosclerotic lesions. Am J Pathol 1992;141:1427-33. (7) Wood KM, Cadogan MD, Ranshaw AL, Parums DV. The distribution of adhesion molecules in human atherosclerosis. Histopathology 1993;22:437-44. (8) Ramshaw AL, Parums DV. The distribution of adhesion molecules in chronic periaortitis. Histopathology 1994;24:23-32. (9) Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 1997;99(5):1037-43. (10) Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest 1998;102(1):145-52. (11) Wenzel K, Ernst M, Rohde K, Baumann G, Sper A. DNA polymorphisms in adhesion molecule genes: a new risk factor for early atherosclerosis. Hum Genet 1996;97:15-20. (12) Ghilardi G, Biondi ML, Turri O, Guagnellini E, Scorza R. Ser128Arg gene polymorphism for E-selectin and severity of atherosclerotic arterial disease. J Cardiovasc Surg (Torino) 2004 April;45(2):143-7. (13) Ye SQ, Usher D, Virgil D, Zhang LQ, Yochim SE, Gupta R. A PstI polymorphism detects the mutation of serine128 to arginine in CD 62E gene a risk factor for coronary artery disease. J Biomed Sci 1999;6:18-21. (14) Yoshida M, Takano Y, Sasaoka T, Izumi T, Kimura A. E-selectin polymorphism associated with myocardial infarction causes enhanced leukocyte-endothelial interactions under flow conditions. Arterioscler Thromb Vasc Biol 2003 May 1;23(5):783-8. (15) Ellsworth DL, Bielak LF, Turner ST, Sheedy II PF, Boerwinkle E, Peyser PA. Gender- and age-dependent relationships between E-selectin S128R polymorphism and coronary artery calcification. Journal of Molecular Medicine 2001;79:390-8. (16) Rauchhaus M, Gross M, Schulz S, Francis DP, Greiser P, Norwig A, Weidhase L, Coats AJ, Dietz R, Anker SD, Glaser C. The E-selectin SER128ARG gene polymorphism and restenosis after successful coronary angioplasty. Int J Cardiol 2002 June;83(3):249-57. (17) Mlekusch W, Exner M, Schillinger M, Sabeti S, Mannhalter C, Minar E, Wagner O. E-Selectin and restenosis after femoropopliteal angioplasty: prognostic impact of the Ser128Arg genotype and plasma levels. Thromb Haemost 2004 January;91(1):171-9. (18) Jilma B, Marsik C, Kovar F, Wagner OF, Jilma-Stohlawetz P, Endler G. The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia. Blood 2005 November 16;105:2380-3. (19) Revelle BM, Scott D, Beck PJ. Single amino acid residues in the E- and Pselectin epidermal growth factor domains can determine carbohydrate binding specificity. J Biol Chem 1996;271:16160-70. (20) Rao RM, Clarke JL, Ortlepp S, Robinson MK, Landis RC, Haskard D.O. The S128R polymorphism of E-selectin mediates neuraminidase-resistant tethering of myeloid cells under shear flow. Eur J Immunol 2002;32:251-60. (21) Rao R, Haskard D.O., Landis RC. Enhanced recruitment of Th2 and CLA negative T lymphocytes by the S128R polymorphism of E-selectin. J Immunol 2002;169:5860-5.