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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x [10.sup.-6], OR 0.82) and the single protective effect within the CD58 locus is captured by the [rs2300747.sup.G] allele. This protective [rs2300747.sup.G] allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x [10.sup.-10]) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD[4.sup.+]CD[25.sup.high] regulatory T cells that are defective in subjects with MS. genetic | human | RNAI quantitative trait | inflammation

Byline: B. Nohe (1), H.-J. Dieterich (1), M. Eichner (2), K. Unertl (1) Keywords: Key words Albumin; Endothelium; E-Selectin; ICAM-1; VCAM-1 Abstract: Objective: Increased levels of soluble adhesion molecules, a decreased PO.sub.2/FIO.sub.2 ratio and a tendency to worsened outcome have been reported following the use of human albumin in critical illness. The reasons are not yet understood. Since albumin solutions have previously been shown to contain proinflammatory mediators, a direct upregulation of adhesion molecules by contaminated batches may explain these findings. To examine this, we studied the effects of different albumin preparations on endothelial cell adhesion molecules in vitro. Design: Experimental study. Setting: Laboratory for cell biology. Methods: Human umbilical venous endothelial cell cultures (n = 4) were incubated for 6 h at 5 mg/ml with four different human albumin solutions (HA1--4) from different manufacturers. Medium served as the control. Using flow cytometry, the effects on E-selectin, ICAM-1 and VCAM-1 expression were determined on unstimulated cells and on cells stimulated with tumour necrosis factor [alpha] at 0.5 ng/ml for 4 h. Measurements and results: On unstimulated cells, HA1 and HA4, two different batches from the same manufacturer, increased ICAM-1 by 22 % and 15 %, respectively. After stimulation, both solutions resulted in a 19 % increased expression of E-Selectin. In addition, HA4 decreased VCAM-1 on stimulated cells (pa$? 0.05). Two albumin preparations from other manufacturers did not produce significant effects. Conclusions: Some albumin solutions directly modulate adhesion molecule expression on endothelial cells. This may, at least in part, explain the previous finding of increased soluble adhesion molecules and a decreased PO.sub.2/FIO.sub.2 ratio in critically ill patients undergoing volume replacement with human albumin. Author Affiliation: (1) Department of Anaesthesiology, University of Tuebingen, Hoppe-Seyler Strasse 3, D-72076 Tuebingen, Germany email: boris.nohe@uni-tuebingen.de Tel.: + 49-70 71-2 98 11 35 Fax: + 49-70 71-29 51 95, DE (2) Department of Medical Biometry, University of Tuebingen, Hoppe-Seyler Strasse 3, D-72076 Tuebingen, Germany, DE Article note: Received: 28 May 1999*Accepted: 14 September 1999