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Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii -infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co-receptor CD14 (sCD14) in plasma from R. conorii -infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii . Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood. [ABSTRACT FROM AUTHOR]

Abstract: Background: Subjects with familial hypercholesterolemia (FH) are associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among subjects with heterozygous FH. The purpose of this study was to investigate whether FH subjects with an identical mutation in the low-density lipoprotein (LDL) receptor gene have a high-density lipoprotein (HDL)3 that is characterized by a less atheroprotective functions than that of healthy controls and within subgroups of FH. Design: Twenty-two adults &#60;75 years of age with FH and 17 healthy sex- and age-matched controls were included. HDL3 was isolated and the composition was characterized from each subject, and its ability to suppress tumor necrosis factor(TNF)-α stimulated expression of ICAM-1 on HUVEC was investigated. In addition, plasma level of soluble sICAM-1 and VCAM-1 was measured. Results: Compared to controls, FH subjects had lower content of phospholipids in their HDL3 subfraction and a higher serum ICAM-1 level. No differences in sVCAM-1 were observed. HDL3 isolated from FH with body mass index(BMI)>25 and from FH subjects with premature CAD contained higher content of triglycerides compared to the HDL3 from FH subjects with BMI&#60;25 and without CAD, respectively. Most important, when testing the function of HDL3 in the two FH subgroups characterized by elevated BMI and premature CAD, lower inhibition of ICAM-1 expression on HUVEC was observed. Conclusions: The altered composition of HDL3 from FH subjects with BMI>25 and FH subjects with premature CAD may be responsible for a HDL3 subfraction with less protective properties assessed as inhibition of ICAM-1 expression on HUVEC consequently leading to more proatherogenic endothelial surface. [Copyright &y& Elsevier]