The receptor for advanced glycation end products (RAGE) contributes to the inflammatory response in many acute and chronic diseases. In this context, RAGE has been identified as a ligand for the ␤ 2 -integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds ␤ 2 -integrins, we studied RAGE ؊/؊ , Icam1 ؊/؊ , and RAGE ؊/؊ Icam1 ؊/؊ mice to define the relative contribution of each ligand for leukocyte adhesion in vivo. We show that trauma-induced leukocyte adhesion in cremaster muscle venules is strongly dependent on RAGE and ICAM-1 acting together in an overlapping fashion. Additional in vivo experiments in chimeric mice lacking endothelium-expressed RAGE and ICAM-1 located the adhesion defect to the endothelial compartment. Using microflow chambers coated with P-selectin, CXCL1, and soluble RAGE (sRAGE) demonstrated that sRAGE supports leukocyte adhesion under flow conditions in a Mac-1-but not LFA-1-dependent fashion. A static adhesion assay revealed that wild-type and RAGE ؊/؊ neutrophil adhesion and spreading were similar on immobilized sRAGE or fibrinogen. These observations indicate a crucial role of endotheliumexpressed RAGE as Mac-1 ligand and uncover RAGE and ICAM-1 as a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute traumainduced inflammatory response in vivo. IntroductionLeukocyte recruitment into inflamed tissue follows a well-defined cascade of events, beginning with the capture of free-flowing leukocytes to the vessel wall and subsequent leukocyte rolling along and adhesion to the inflamed endothelial layer. 1,2 During rolling, leukocytes get into close contact with the endothelial surface, which allows endothelial bound chemokines to interact with their specific receptors on the leukocyte surface. This triggers the activation of integrins, which leads to firm leukocyte arrest on the endothelium. In addition, integrindependent signaling events induce cytoskeletal rearrangements and cell polarization, modifications necessary in helping to prepare the attached leukocyte to spread and crawl in search for its way out of the vasculature into tissue. [2][3][4][5][6] Recent evidence has shown that the ␤ 2 -integrin Mac-1 is crucially involved in transducing Syk-dependent signaling events necessary for sustained leukocyte adhesion. [7][8][9] The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that has been identified to be a major player in chronic inflammatory conditions. 10,11 This has been mainly attributed to its strong effects on perpetuating nuclear factor-B (NF-B) activation and NF-Bdependent signaling 10,11 and its ability to induce its own expression. 10,12 Besides its function as a signaling molecule, RAGE also binds to Mac-1, which has been demonstrated under in vitro conditions. 13 In addition, a reduction of leukocyte extravasation into the inflamed peritoneal cavity was found in RAGE Ϫ/Ϫ mice after intraperitoneal application of th...

Summary The neonatal Fc receptor, FcRn, plays a central role in immunoglobulin G (IgG) transport across placental barriers. Genetic variations of FcRn‐dependent transport across the placenta may influence antibody‐mediated pathologies of the fetus and the newborn. Sequencing analysis of 20 unrelated individuals demonstrated no missense mutation within the five exons of the FcRn gene. However, a variable number of tandem repeats (VNTR) region within the FcRn promoter was observed, consisting of five different alleles (VNTR1–VNTR5). Alleles with two (VNTR2) and three (VNTR3) repeats were found to be most common in Caucasians (7·5 and 92·0%, respectively). Real‐time polymerase chain reaction revealed that monocytes from VNTR3 homozygous individuals express 1·66‐fold more FcRn transcript than do monocytes from VNTR2/VNTR3 heterozygous individuals (P = 0·002). In reporter plasmid assays, the VNTR3 allele supported the transcription of a reporter gene twice as effectively as did the VNTR2 allele (P = 0·003). Finally, under acidic conditions, monocytes from VNTR3 homozygous individuals showed an increased binding to polyvalent human IgG when compared with monocytes from VNTR2/VNTR3 heterozygous individuals (P = 0·021). These data indicate that a VNTR promoter polymorphism influences the expression of the FcRn receptor, leading to different IgG‐binding capacities.

Anti-HPA-3 alloantibodies show considerable heterogeneity, which may hamper the serologic diagnosis of FNAIT. Preservation of the alphaIIbbeta3 integrin and protection from enzymatic degradation seem to be important during PLT storage.

Our results demonstrated that the SPR method can facilitate the diagnosis of clinically relevant low-avidity HPA-1a antibodies.