VLA4

VLA-4, short for very late antigen-4, is a cell-surface integrin also known as integrin α4β1. It is a heterodimer composed of the alpha-4 (ITGA4) and beta-1 (ITGB1) subunits. VLA-4 is expressed on many leukocytes, including subsets of lymphocytes and monocytes, and it contributes to cell adhesion and signaling events that regulate immune cell trafficking.

The primary ligands of VLA-4 are vascular cell adhesion molecule-1 (VCAM-1) on activated endothelial cells and certain alternatively spliced forms of fibronectin in the extracellular matrix. By binding these ligands, VLA-4 mediates firm adhesion of leukocytes to the endothelium and supports their transmigration into tissues during immune surveillance and inflammatory responses. It also participates in the retention of hematopoietic cells in the bone marrow and can influence cell migration in various physiological and pathological contexts.

Clinically, VLA-4 is a target of monoclonal antibody therapies. Natalizumab, an antibody against the α4 subunit, blocks both VLA-4 and α4β7 integrins, reducing leukocyte trafficking to the brain and gut. It is approved for relapsing forms of multiple sclerosis and for Crohn’s disease but carries a risk of progressive multifocal leukoencephalopathy and other infections due to immune modulation. Therapies targeting α4-containing integrins illustrate the balance between dampening pathological inflammation and preserving essential immune surveillance.

In research, VLA-4 serves as a model of integrin-mediated adhesion and is studied to understand leukocyte extravasation, inflammatory diseases, and metastatic processes where cell adhesion to endothelium or extracellular matrix is a factor.