Transmigration

Transmigration, also called diapedesis, is the fourth step in the leukocyte extravasation cascade during acute inflammation, following margination, rolling (mediated by selectins), and firm adhesion (mediated by integrins such as LFA-1 binding ICAM-1). After firm adhesion to endothelium, leukocytes migrate along the endothelial surface to find intercellular junctions, then extend pseudopodia and squeeze between endothelial cells (paracellular route) or occasionally through individual endothelial cells (transcellular route) to exit the vasculature. PECAM-1 (CD31), expressed on both leukocytes and endothelial junctions, is critical for this process via homophilic interactions. Once through the endothelium, leukocytes must also traverse the basement membrane, which involves secretion of matrix metalloproteinases (MMPs, especially collagenases) to degrade collagen. After transmigration, leukocytes follow a chemotactic gradient (e.g., C5a, IL-8, LTB4, bacterial products) to reach the site of infection or injury. Clinically, defects in this cascade cause leukocyte adhesion deficiency (LAD) syndromes: LAD-1 (defective integrins/CD18) impairs firm adhesion, while LAD-2 (defective selectin ligand, fucosylation defect) impairs rolling—both result in recurrent bacterial infections, delayed wound healing, absent pus formation, and elevated peripheral neutrophil counts due to failure of margination and extravasation. Understanding this cascade is essential for understanding the pathophysiology of inflammation and related immunodeficiencies tested on USMLE Step 1.