Leukocyte adhesion and integrin activation pathways. (A) Leukocyte adhesion cascade. Leukocytes circulating in the blood stream are first captured by the vessel wall, followed by rolling, slow rolling, full activation, and arrest. After arrest, leukocytes further spread and crawl along the vessel until they transmigrate the vessel wall. Rolling is mediated by selectin-ligand interactions, and arrest requires β₂ integrin activation. (B) Integrin activation states and pathways. Integrins are heterodimeric proteins, consisting of an α and a β subunit. Integrin activation means the resting bent low affinity integrins acquire an H⁺ conformation with extended legs and an open headpiece. The open αI domain binds ligand ICAM-1 on the endothelium. Extended (E⁺) and H⁺ integrins with open αI domain conformations are reported by 2 monoclonal Abs, KIM127 and mAb24, respectively. Canonical integrin activation occurs through E⁺ before acquiring open αI conformation with H⁺. The alternative pathway starts with headpiece opening (H⁺) before acquiring full activation with extension and open headpiece (E⁺H⁺).