Diagrammatic representation of interaction of aPL/anti-β₂GPI Abs with β₂GPI and receptor(s) on ECs. aPL/anti-β₂GPI Abs bind to domain I (DI) of β₂GPI. β₂GPI anchors to annexin A2 on the surface of ECs, possibly through domain V (DV) of the protein. Annexin A2 does not have a transmembrane domain. Hence, it is not able to transduce intracellular signaling. Other membrane proteins (ie, TLR-4 or apoER2′) may act as accessory molecules or may bind β₂GPI directly and induce phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and translocation of nuclear factor-κB (NF-κB), leading to a proinflammatory/prothrombotic phenotype (up-regulation of tissue factor and cellular adhesion molecules [ie, E-sel, ICAM-1, VCAM-1]). Reprinted from Trends in Immunology, P. Meroni, N. Rhonda, E. Raschi, and M.O. Borghi, Humoral immunity against endothelium; theory or reality? 2005;26:275-281, with permission from Elsevier.