Abstract

MEM83 is an inserted domain (I-domain)-specific antibody that up-regulates the interaction of LFA-1 with ICAM-1 through an outside-in activation mechanism. We demonstrate here that there is no change in the affinity of the MEM83 antibody for the I-domain in either its low (wild-type) or high affinity form and that MEM83 does not enhance the binding of the wild-type I-domain to ICAM-1. Furthermore, we show that the antibody acts as an activating agent to induce LFA-1/ICAM-1-dependent homotypic cell aggregation only as an IgG, but not as a Fab fragment. On the basis of these data, we propose an avidity-based mechanism that requires no direct activation of the LFA-1 I-domain by the binding of the antibody; rather, activation is enhanced when there is an interaction with both arms of the IgG. A molecular model of the antibody interaction with LFA-1 illustrates the symmetry and accessibility of the two MEM83 epitopes across the LFA-1/ICAM-1 heterotetramer. We hypothesize that MEM83 stabilizes adjacent LFA-1 molecules in their active form by the free energy that is gained from the binding of the I-domains to each arm of the IgG. This leads to stabilization of the open state of the integrin and outside-in signaling. Our model supports a mechanism in which both affinity and avidity regulation are required in the activation of LFA-1.

Highlights

  • The interaction of leukocyte function-associated antigen-1 (LFA-1)4 and intercellular adhesion molecules (ICAMs) plays a key role in the immune system and in the development of arteriosclerosis, autoimmune diseases, and inflammation [1,2,3,4,5]

  • We demonstrate here that there is no change in the affinity of the MEM83 antibody for the I-domain in either its low or high affinity form and that MEM83 does not enhance the binding of the wild-type I-domain to ICAM-1

  • We show that the antibody acts as an activating agent to induce LFA-1/ICAM-1dependent homotypic cell aggregation only as an IgG, but not as a Fab fragment

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Summary

Introduction

The interaction of leukocyte function-associated antigen-1 (LFA-1)4 and intercellular adhesion molecules (ICAMs) plays a key role in the immune system and in the development of arteriosclerosis, autoimmune diseases, and inflammation [1,2,3,4,5]. MEM83 is an inserted domain (I-domain)-specific antibody that up-regulates the interaction of LFA-1 with ICAM-1 through an outside-in activation mechanism. On the basis of these data, we propose an avidity-based mechanism that requires no direct activation of the LFA-1 I-domain by the binding of the antibody; rather, activation is enhanced when there is an interaction with both arms of the IgG.

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