Function of Soluble CD14 in Serum from Patients with Septic Shock

Soluble CD14 (sCD14) mediates lipopolysaccharide (LPS) activation of epithelial cells in vitro and may thereby be harmful in sepsis.sCD14 function was analyzed in sera from 62 patients with septic shock and compared with data from appropriate controls. sCD14 function was measured as sCD14-dependentLPS-induced interleukin (IL)-8 release in the SW620 epithelial cell line. In these cells, IL-8 production correlated with LPS concentration and the amount of sCD14. The effect of natural or recombinant sCD14 was maximal at 100 ng/mL and blocked by anti-CD14 antibodies. Patient and control sera (0.5% final concentration) promoted induction of IL-8 by 100 ng/mL LPS in SW620 cells. In sepsis patients (highest serum sCD14), values were significantly higher than in the other groups. The LPS-induced IL-8 response was blocked by anti-CD14 and correlated with the serum CD14 level in sepsis patients. Thus, sCD14 could playa pathogenetic role in sepsi

Increased Circulating Soluble Cd14 Is Associated With High Mortality In Gram-Negative Septic Shock

The soluble glycoprotein sCD14 binds lipopolysaccharide, a complex that activates endothelial cells and that may be crucial in gram-negative sepsis, Therefore, serum sCD14 was analyzed in 54 patients with gram-negative septic shock and in 26 healthy controls, sCD14 was tested by ELISA and Western blotting, Patients had higher sCD14 concentrations than controls (median, 3.23 vs. 2.48 µg/mL, P = .002). Increased levels were associated with high mortality (median, 4.2 µg/mL in nonsurvivors vs. 2.8 µg/mL in survivors, P = .001). sCD14 was found in two isoforms (49 and 55 kDa) in monocyte cultures. In sera only one of either form was detectable. Controls had the 49-kDa form, and patients had either the 49- or 55-kDa form, but patients with high levels of sCD14 had only the 55-kDa form. Twenty-one (53%) of 39 with the 55-kDa form and 8 (57%) of 14 with the 49-kDa form died. Thus, the level of sCD14 but not its biochemical form had a prognostic value in patients with gram-negative septic shoc

Bacterial infections promote t cell recognition of self-glycolipids

Recognition of self is essential for repertoire selection, immune regulation, and autoimmunity and may be a consequence of infection. Self-induced recognition may represent the escape mechanism adopted by pathogens but may also incite autoimmune diseases. Here, we show that bacterial infection may promote activation of T cells reactive to self-glycosphingolipids (self-GSL). CD1(+) antigen-presenting cells (APCs) infected with bacteria (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, or Mycobacterium bovis-Bacillus Calmette Guerin [BCG]) or treated with the bacterial components lipopolysaccharide, lipoteichoic acid, or Pam(3)CysSerLys(4) (P3CSK4) lipopeptide acquire the capacity to stimulate self-GSL-specific T cells to cytokine release. Immediately after infection, APCs increase the endogenous GSL synthesis and stimulate GSL-specific T cells in a CD1- and T cell receptor (TCR)-dependent manner. This stimulation may contribute to inflammatory responses during bacterial infections and may predispose individuals to autoimmune diseases

Bacterial infections promote t cell recognition of self-glycolipids

Recognition of self is essential for repertoire selection, immune regulation, and autoimmunity and may be a consequence of infection. Self-induced recognition may represent the escape mechanism adopted by pathogens but may also incite autoimmune diseases. Here, we show that bacterial infection may promote activation of T cells reactive to self-glycosphingolipids (self-GSL). CD1(+) antigen-presenting cells (APCs) infected with bacteria (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, or Mycobacterium bovis-Bacillus Calmette Guerin [BCG]) or treated with the bacterial components lipopolysaccharide, lipoteichoic acid, or Pam(3)CysSerLys(4) (P3CSK4) lipopeptide acquire the capacity to stimulate self-GSL-specific T cells to cytokine release. Immediately after infection, APCs increase the endogenous GSL synthesis and stimulate GSL-specific T cells in a CD1- and T cell receptor (TCR)-dependent manner. This stimulation may contribute to inflammatory responses during bacterial infections and may predispose individuals to autoimmune diseases

Endogenous phosphatidylcholine and a long spacer ligand stabilize the lipid-binding groove of CD1b

CD1 proteins present lipid antigens to T cells. The antigens are acquired in the endosomal compartments. This raises the question of how the large hydrophobic CD1 pockets are preserved between the moment of biosynthesis in the endoplasmic reticulum and arrival to the endosomes. To address this issue, the natural ligands associated with a soluble form of human CD1b have been investigated. Using isoelectric focusing, native mass spectrometry and resolving the crystal structure at 1.8 Å resolution, we found that human CD1b is simultaneously associated with endogenous phosphatidylcholine (PC) and a 41–44 carbon atoms-long spacer molecule. The two lipids appear to work in concert to stabilize the CD1b groove, their combined size slightly exceeding the maximal groove capacity. We propose that the spacer serves to prevent binding of ligands with long lipid tails, whereas short-chain lipids might still displace the PC, which is exposed at the groove entrance. The data presented herein explain how the CD1b groove is preserved, and provide a rationale for the in vivo antigen-binding properties of CD1b