Leukocyte function-associated antigen-1 and Very Late Antigen-4 integrins (LFA-1 and VLA-4)

Leukocyte function-associated antigen-1 (LFA-1) and Very Late Antigen-4 (VLA-4) are essential heterodimeric integrins expressed on the surface of various leukocytes, including T-cells and B-cells. LFA-1 is composed of the alpha-L (CD11a) and beta-2 (CD18) subunits, while VLA-4 consists of alpha-4 (CD49d) and beta-1 (CD29) subunits (UniProt P20333, P13612). These receptors mediate the firm adhesion of leukocytes to the vascular endothelium by binding to their respective ligands, Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1), which is a critical step in the recruitment of immune cells to sites of inflammation (Nature Reviews Immunology, 2002). Due to their central role in leukocyte trafficking, they are significant therapeutic targets for autoimmune and inflammatory diseases. For instance, Natalizumab is a monoclonal antibody targeting the alpha-4 subunit of VLA-4 used in multiple sclerosis, and Lifitegrast is a small molecule antagonist of LFA-1 used for dry eye disease (FDA). However, therapeutic modulation of these integrins is associated with serious risks, most notably Progressive Multifocal Leukoencephalopathy (PML), a rare brain infection resulting from impaired CNS immune surveillance (NEJM, 2005).

Other names

CD11a/CD18CD49d/CD29Integrin alpha-L beta-2Integrin alpha-4 beta-1ITGAL/ITGB2ITGA4/ITGB1LFA-1VLA-4

Antagonism of integrin-ligand interactions (e.g., LFA-1/ICAM-1 and VLA-4/VCAM-1) to inhibit leukocyte recruitment and extravasation into inflamed tissues.