Leukocyte adhesion is of pivotal functional importance and this has resulted in extensive research and rapid develonient in the field. Leukocyte adhesion involves members of three molecular families: integrins, members of the immunoglobulin superfatnily and carbohydrate binding selectins and sialoadhesins. Recently, considerable structural information on leukocyte integrins and members of the immunoglobulin superfrtinily of adhesion molecules has been obtained. This fact. combined with the identification of several novel adhesion molecules. has increased our understanding o f how they function at the molecular level. Furthermore, the important issue of how integrins are activated to become adhesive is rapidly advancing,.. It is clearly evident that the knowledge accuniulated from basic research will increasingly be applied in clinical medicine. In this review we focus on two iinportant families of adhesion molecules. Norc. This Review will be reprinted in EJR Kei?cw.\ 1997 which will be av;iil;ible in April I99X.A number of different leukocytes are known and most probably more subgroups will be found concomitantly with the development in typing procedures. 111 addition, the cells rnay represent different stages of differentiation. An individual leukocyte m 11 s t be able to interact with a number of fundamentally different cells. often modified in various ways. and sometimes with the extracellular matrix or foreign microbes. These facts may partially be the reason that many different leukocyte adhesion systems and molecules exist. In addition i t is certainly useful for the organism to have a certain redundancy i n adhcsion molecule expression and function. which could seciire vital functions cven if some adhesion functions are lost or weakened.Cellular immunology used to be largely phenomenal and not inolecular. But with the development of monoclonal antibody and inolecular cloning techniques, combined with the rapid advance in structural elucidation. present day immunology is certainly ii molecular science, and in inany respects in the forefiont of modern biomedical research. In fact, a number of dcvelopinents in other fields of present day biomedical research originate from breakthroughs in iinmunology. and an excellent exaniple is leukocyte adhesion. Although much remains poorly understood, adhesion receptor-ligand interactions are now appreciated to such an extent that much can be applied t o several other areas of research.But research on leiikocytc adhesion is not rewarding only from a basic point of view. Undoubtedly. the large interest in this field steins from iiuinerous potential clinical applications. Many of the iniljor diseases affecting mankind. like cardiovnscular disease. stroke, chronic and iicute inflammations. cancer. malaria, and inany bacterial and viral infections directly involve leukocyte adhesion molecules. Therefore. it comes as no surprise

Leukocyte adhesion is of pivotal functional importance. Without adequate adhesion, T lymphocytes and natural killer cells are not cytotoxic, B cells cannot develop into antibody secreting plasma cells, leukocytes do not home into inflamed tissues and myeloid cells are not able to phagocytize or exhibit chemotactic responses. During evolution several leukocyte adhesion molecules have developed belonging to a few molecular families. Among these, the leukocyte-specific integrins (beta 2 integrins, CD11/CD18 molecules) are among the most important. Much progress has taken place during the past few years, and at present we have a considerable knowledge of their structure and function. Inflammation is critically dependent on integrin activity, and its regulation forms the topic of this short review.

Leukocyte adhesion involves at least three molecular families of adhesion proteins: the leukocyte integrins CD11/CD18, the intercellular adhesion molecules (ICAMs) and the carbohydrate-binding L-, E- and P-selectins. The intercellular adhesion molecules are well-known ligands for the CD11/CD18 integrins. We now show that E-selectin specifically binds to the sialyl Lex carbohydrate epitopes of leukocyte integrins. Thus, the different families of leukocyte adhesion molecules form an integrated adhesion network.

The N-linked oligosaccharides were released from purified human intercellular adhesion molecule (ICAM)-3 by hydrazinolysis. Approximately 6 mol of oligosaccharides were released from 1 mol of ICAM-3. The oligosaccharides reduced with NaB[ 3 H] 4 were separated into neutral and acidic fractions by paper electrophoresis. Most of the acidic oligosaccharides were converted to neutral ones by digestion with sialidase, indicating that they are sialyl derivatives. The neutral and sialidase-treated acidic oligosaccharides were fractionated by serial lectin column chromatography followed by Bio-Gel P-4 column chromatography. Structural studies of each oligosaccharide by sequential exo-and endo-glycosidase digestion and by methylation analysis revealed that N-linked oligosaccharides of ICAM-3 are mainly of tri-and tetra-antennary complex-type, about 60% of which contain two to three poly N-acetyllactosamine chains terminated with the type 1 structure and those without the type 1 structure per oligosaccharide. In addition, a small amount of the high mannose-type oligosaccharide with six a-mannose residues, which could act as a ligand for the dendritic cellspecific ICAM-3 grabbing nonintegrin, was detected.Keywords: ICAM-3; human leukocytes; N-linked oligosaccharides.In response to immunological and inflammatory stimuli, leukocytes adhere to each other and to other cell types, such as platelets and vascular endothelial cells. The adhesive proteins can be grouped into the immunoglobulin superfamily, and the integrin and selectin families, and have specific biological roles (reviewed in [1±3]). The intercellular adhesion molecule (ICAM) family consists of five members, which contain two to nine immunoglobulin domains. ICAM-1 and -2 are expressed on vascular endothelial cells [4±6], ICAM-3 mainly on resting leukocytes [7±9], ICAM-4, previously known as the Landsteiner±Wiener blood group antigen, on red blood cells [10], and ICAM-5 on neuronal cells of the telencephalon of the brain [11]. For mice deficient in ICAM-1, it was shown that no cytotoxicity is associated with T lymphocytes and NK cells and homing of leukocytes was impaired [12].ICAM-3 (CD50) contains five immunoglobulin domains and binds to CD11a/CD18 (LFA-1) and CD11d/CD18 integrin molecules [13], and is thus involved in initiation of the immune response [14]. In fact, upon activation it becomes phosphorylated on some of the two tyrosine and five serine residues in its cytoplasmic domain by p56 lck and p59 fyn tyrosine kinases and/or protein kinase C, respectively [15,16].Recent studies have shown that the carbohydrates of ICAM-3 act as ligands of the novel dendritic cell adhesion molecule, DC-SIGN, and the interaction is essential for dendritic-cell-mediated T cell proliferation [17]. Furthermore, removal of N-linked oligosaccharides from ICAM-3 resulted in decreased binding of ICAM-3 to LFA-1 [18]. These results indicate that N-linked oligosaccharides attached to ICAM-3 are important for leukocyte functions. However, no carbohydrate structures have been determined...

Leukocyte adhesion is of pivotal functional importance, because most leukocyte functions depend on cell-cell contact. It must be strictly controlled, both at the level of specificity and strength of interaction, and therefore several molecular systems are involved. The most important leukocyte adhesion molecules are the selectins, the leukocyte-specific beta2-integrins and the intercellular adhesion molecules. The selectins induce an initial weak contact between cells, whereas firm adhesion is achieved through integrin intercellular adhesion molecular binding. Although studies during the past twenty years have revealed several important features of leukocyte adhesion much is still poorly understood, and further work dealing with several aspects of adhesion is urgently needed. In this short essay, we review some recent developments in the field.