Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response.

Understanding the molecular basis of a rare inherited disease, Leu-CAM deficiency in humans, has underscored the importance of the cellular component of inflammation and unravelled the complex series of homotypic and heterotypic cell interactions necessary for mobilization of leukocytes to infected sites. Furthermore, this disease has shown that several apparently distinct cellular inflammatory responses (e.g. aggregation, adhesion to endothelium, directed migration and phagocytosis) are mechanistically related and mediated by a set of molecules which belong to a larger group of adhesion molecules (Integrins) mediating similar phenomena critical for immune surveillance, lymphocyte homing, morphogenesis and thrombogenesis. This disease also showed the relative biologic importance of CD11/CD18 in leukocytes. CD11/CD18 are more critical for the functions of phagocytic cells as compared to lymphocytes although similar inhibitory effects of anti-CD11/CD18 mAbs can be demonstrated in vitro. Expression and function of CD11/CD18 is regulated at several levels which include formation of stable heterodimers, qualitative changes in the receptor and quantitative changes in the levels of expression of the receptors and their ligands. We have identified inherited single amino acid substitutions on CD18 which impair heterodimer formation and cell surface expression, thus accounting for the pathogenesis of Leu-CAM deficiency. We also found a stimulus-induced phosphorylation of CD18, which is transient in nature when elicited through other surface receptors. This may be important in regulation of CD11/CD18 receptor avidity, recycling, endocytosis and cross-talk with other receptors. Finally, realization of the profound impairment in the acute cellular inflammatory response present in Leu-CAM deficiency has permitted novel ways of controlling the inflammatory response in several situations were inflammation serves an injurious rather than a beneficial role to the host.