lewis-y-antigen and Inflammation

Thrombomodulin (TM), a widely expressing glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. TM appears to exhibit anti-inflammatory ability through both protein C-dependent and -independent pathways. We presently have demonstrated that recombinant N-terminal lectinlike domain of TM (rTMD1) functions as a protective agent against sepsis caused by Gram-negative bacterial infections. rTMD1 caused agglutination of Escherichia coli and Klebsiella pneumoniae and enhanced the macrophage phagocytosis of these Gram-negative bacteria. Moreover, rTMD1 bound to the Klebsiella pneumoniae and lipopolysaccharide (LPS) by specifically interacting with Lewis Y antigen. rTMD1 inhibited LPS-induced inflammatory mediator production via interference with CD14 and LPS binding. Furthermore, rTMD1 modulated LPS-induced mitogen-activated protein kinase and nuclear factor-kappaB signaling pathway activations and inducible nitric oxide synthase expression in macrophages. Administration of rTMD1 protected the host by suppressing inflammatory responses induced by LPS and Gram-negative bacteria, and enhanced LPS and bacterial clearance in sepsis. Thus, rTMD1 can be used to defend against bacterial infection and inhibit LPS-induced inflammatory responses, suggesting that rTMD1 may be valuable in the treatment of severe inflammation in sepsis, especially in Gram-negative bacterial infections.

Topics: Animals; Binding Sites; Cell Line; Gram-Negative Bacterial Infections; Humans; Inflammation; Klebsiella pneumoniae; Lewis Blood Group Antigens; Ligands; Lipopolysaccharides; Macrophages; Male; MAP Kinase Signaling System; Mice; NF-kappa B; Protein Structure, Tertiary; Recombinant Proteins; Sepsis; Signal Transduction; Thrombomodulin

Lewis antigens occur in human gastric epithelium and in Helicobacter pylori lipopolysaccharide; their expression is polymorphic in both. Autoimmune mechanisms induced by bacterial Lewis expression have been proposed to cause gastritis. The aim of this study was to examine the relationship between bacterial and host gastric Lewis expression, as determined by the erythrocyte Lewis(a/b) phenotype, and between gastric histopathology and bacterial Lewis expression.. H. pylori Lewis expression was determined by enzyme immunoassays, erythrocyte Lewis phenotype was assessed by agglutination tests, and gastric histopathology was scored blindly.. The host Lewis phenotype was (a+b-) in 15, (a-b+) in 34, and (a-b-) in 17 patients, therefore expressing Lewis x, y, or neither as their major gastric epithelial Lewis type 2 antigen. H. pylori from patients with Lewis(a+b-) expressed Lewis x more than y (1147 +/- 143 vs. 467 +/- 128 optical density units [ODU]; P = 0.006), isolates from patients with Lewis(a-b+) expressed Lewis x less than y (359 +/- 81 vs. 838 +/- 96 ODU; P = 0.0001), and isolates from Lewis(a-b-) patients expressed Lewis x and y approximately equally. Gastritis was unrelated to H. pylori Lewis expression.. In mimicking host gastric epithelium, H. pylori cells not only express Lewis x and y, but the relative proportion of expression corresponds to the host Lewis phenotype, suggesting selection for host-adapted organisms.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Erythrocytes; Female; Gastric Mucosa; Gastritis; Genotype; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Lewis Blood Group Antigens; Lewis X Antigen; Male; Middle Aged; Phenotype; Pyloric Antrum