Immunoglobulins

Immunoglobulins are plasma proteins that include all antibody molecules. Members of the immunoglobulin superfamily share structural and genetic features with immunoglobulin molecules and contain at least one immunoglobulin domain. An immunoglobulin domain is made of two $\beta$-pleated sheets held together by a disulfide bond. The vascular endothelium expresses molecules of the immunoglobulin superfamily which act as counter- receptors for leukocyte integrins. Two immunoglobulins, particularly important in the cascade, are Intercellular Adhesion Molecule-1 (ICAM-1) or CD54 and Vascular Cell Adhesion Molecule-1 (VCAM-1).

ICAM-1 (Intercellular Adhesion Molecule-1, CD54), a member of the immunoglobulin superfamily of adhesion molecules with 5 Ig like domains, is constitutively expressed on resting endothelial cells, as well as other cells, but its expression is greatly up-regulated upon cytokine stimulation. It is one of the principal ligands for the leukocyte $\beta_2$ integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac1) [DSMS91], although in the context of transmigration it seems that CD11a predominantly binds to ICAM-1, whereas CD11b is more promiscuous [SI98]. In vivo, ICAM-1 knock-out mice show significantly impaired neutrophil migration into an inflamed peritoneum [BQL$^+$95,SBR$^+$93], and ICAM-1 antibodies reduce acute and chronic inflammation in a number of animal models [CH94]. ICAM-1 antibodies reduce cytokine-activated transmigration of neutrophils in vitro, by over 85% [SRH$^+$88,LCK$^+$91]. ICAM-1 is also important in chemotactic transmigration. Antibodies inhibit neutrophil chemotactic transmigration by about 55% [FTS91].

VCAM-1 (vascular cell adhesion molecule-1 or CD106), contains six or seven immunoglobulin domains and is expressed on both large and small vessels only after the endothelial cells are stimulated by cytokines [OHT$^+$89]. The sustained expression of VCAM-1 lasts over 24 hours. Primarily, VCAM-1 is an endothelial ligand for VLA-4 (Very Late Antigen-1 or $\alpha_4 \beta_1$ of the $\beta_1$ subfamily of integrins and for integrin $\alpha_4 \beta_7$ [EOT$^+$90,BBC$^+$95]Ibbotson et al., 2001. VCAM-1 promotes the adhesion of lymphocytes, monocytes, eosinophils, and basophils. Interestingly, certain melanoma-cells can use VCAM-1 to adhere to the endothelium, and VCAM-1 may participate in monocyte recruitment to atherosclerotic sites. As a result, VCAM-1 is a potential target drug target.