Adhesion molecules and disease

The physiological relevance of adhesion molecule function is elegantly demonstrated by naturally occurring defects in the expression and/or function of adhesion molecules, which consequently leads to disease. The inherited bleeding disorder, Glanz-mann's thrombasthenia, is caused by loss of expression and/or function of the aH1,P-integrin on platelets. Consequently, platelet aggregation, which is necessary to prevent excessive loss of blood during injury, fails to occur. The importance of adhesive functions of the p?-integrins has been demonstrated by a syndrome termed leukocyte adhesion deficiency (LAD-1). Patients afflicted with this disease lack expression of the 32-integr'n subunit, and the adherent function of their macrophages and granulocytes is essentially absent. As a result, affected individuals have severely reduced life expectancies and suffer from recurrent bacterial and fungal infections.

Recently, a syndrome, termed LAD-2, with a similar phenotype to that of LAD-1 has been characterized. LAD-2 results from a defect in fucose metabolism, which impairs the expression of the carbohydrate ligands recognized by selectins. The neutrophils of afflicted individuals fail to bind endothelial cells, further demonstrating the importance of adhesion molecules in normal physiological cell functions.

The in vivo relevance of adhesion molecules in the immune response has also been demonstrated experimentally in a variety of ways. Altered expression and/or function of adhesion molecules has been noted in various disease states. The functional relevance of these findings has been demonstrated by in vivo blocking studies using antibodies specific for adhesion molecules, soluble adhesion receptors, blocking peptides or carbohydrates, and antisense oligonucleotides. Thus, targeting of adhesion molecules with these reagents has been shown to be effective in many different animal models of human disease, including models of ischemia/reperfusion injury, acute inflammation, allograft rejection during organ transplantation and various chronic inflammatory disorders such as rheumatoid arthritis. In most of these studies, the primary focus has been on blocking or modulating leukocyte or lymphocyte attachment to endothelial cells. Modulation of adhesion molecule expression has also been shown to be effective in inhibiting tumor cell growth and metastasis.

The use of homologous recombination in embryonic stem cells to generate mice deficient in expression of various adhesion molecules has also been utilized to uncover the function of these molecules in vivo. Mice lacking expression of several individual integrin a and p subunits have been produced. For the most part, these integrin mutations have been either embryonic or neonatal lethal in phenotype, emphasizing the global importance of integrins in embryonic development. Mice lacking expression of signaling components linked to integrins, such as ppl25hAK, also fail to develop normally. Mice lacking expression of the 37-integrin subunit are viable, but exhibit defects in development of gut-associated lymphoid tissue, presumably due to the inability of T cells to migrate into this tissue site. L-selectin, E-selectin and P-selectin knockout mice have also been individually generated, confirming the importance of these molecules in leukocyte-endo-thelial interactions. E-selectin-deficient mice present with little change in phenotype from wild-type. However, mice genetically deficient for both E- and P-selectin show a synergistic reduction in neutrophil and lymphocyte adhesion to endothelium, confirming roles for both P- and E-selectin in this process.

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