Advanced glycation end products of human beta(2) glycoprotein I modulate the maturation and function of DCs

In chronic disorders related to endothelial cell dysfunction, plasma beta(2) glycoprotein I (beta(2)GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why beta(2)GPI triggers auto-immunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified beta(2)GPI is able to interact and activate monocyte-derived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that beta(2)GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-beta(2)GPI. AGE-beta(2)GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-kappa B. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-beta(2)GPI-stimulated DCs had increased allo-stimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of beta(2)GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction. (Blood. 2011;117(23):6152-6161)