Abstract
Leukocytes (white blood cells) circulating in the blood vessels need to exit the bloodstream to enter specific tissues or areas of inflammation. This finely tuned process is mediated by the interactions between leukocyte adhesion molecules, such as selectins and integrins (e.g., LFA-1 and VLA-4), and their adhesive partners expressed on the inner surface of the blood vessel wall. If this adhesive process is not under proper control, it could lead to severe diseases such as autoimmune diseases, asthma and atherosclerosis. Although the molecular structures of many leukocyte adhesion molecules are well understood, little is known about the molecular basis that gives rise to their bond strength.This dissertation describes a series of novel studies using the atomic force microscopy (AFM) to probe the intermolecular forces of leukocyte adhesion bonds. Based on the AFM experiments on selectin/sLeX, VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions, I concluded that a common characteristic of leukocyte adhesion bonds is the involvement of at least two activation energy barriers during bond dissociation. It is the divalent cation-dependent inner barrier that grants these interactions a tensile strength for resisting the large forces imposed by the bloodstream. In addition, the outer barriers can further stabilize leukocyte adhesion by enhancing the bond energy of the interaction, as seen in the affinity modulation of integrins. The findings described herein enhance our understanding of the basic physical nature of leukocyte adhesion and could potentially aid in the development of better therapeutic strategies to control leukocyte adhesion in harmful inflammatory responses.