Leukocyte molecules

Montgomery, K.F., Osborn, L., Hession, C., Tizard, R., Goff, D., Vassallo, C., Tarr, P.I., Bomsztyk, K., Lobb, R., Harlan, J.M. and Pohlman, T.H. (1991). Activation of endothelial-leukocyte molecule (ELAM-1) gene transcription. Proc. Natl Acad. Sci. USA 88, 6523-6527. 

Lex-antigenic trisaccharide (a-L-Fuc(l-3)-[p-D-Gal-(l-4)-p-D-GlcNAc]) and its sialylated structure (SLex) are terminal components of a nnmber of glycoconjugates on cell surfaces [31]. SLex serves as a ligand for the endothelial leukocyte molecule-1 (E-selectin) [32], which mediates the initial stages of adhesion of leukocytes to activated endothelial cells, and pays a critical role during inflammatory responses [33]. Lex-based carbohydrates have shown promise in therapeutic investigations related to the inflammatory process. As a result, extensive efforts have been directed toward the synthesis of SLex and related molecules [34 also see Chap. 15],... 

Cell Adhesion. The membranes of leukocytes and platelets contain a variety of components that promote ceU-surface contact. Although numerous ceU-surface molecules are likely to play a role in ceU-surface adhesion, the group of selectins are of particular interest to research on this subject. Selectins are molecules that are known to promote leukocyte—platelet adhesion. However, selectin-based models have not been able to account for the fact that platelets are allowed to pass through the filter and leukocytes are not. 

The antiinflammatory effects of statins likely result from their ability to inhibit the formation of mevalonic acid. Downstream products of this molecule include not only the end product, cholesterol, but also several isoprenoid intermediates that covalently modify ( pre-nylate ) certain key intracellular signaling molecules. Statin treatment reduces leukocyte adhesion, accumulation of macrophages, MMPs, tissue factor, and other proinflammatory mediators. By acting on the MHC class II transactivator (CIITA), statins also interfere with antigen presentation and subsequent T-cell activation. Statin treatment can also limit platelet activation in some assays as well. All these results support the concept that in addition to their favorable effect on the lipid profile, statins can also exert an array of antiinflammatory and immunomodulatory actions. 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

The vascular endothelium plays an important role in regulation of vascular tone and permeability. Dilatation of arterioles to increase blood flow and constriction of endothelial cells of postcapillary venules causing exsudation of plasma constituents illustrates the complex nature of this cell type. Moreover, by expression of adhesion molecules and secretion of chemokines endothelial cells play an important role in the recruitment of leukocytes to the inflamed area. Endothelial cells express two basic types of adhesion molecules on their surface ... 

Inflammation. Figure 1 Sequence of events in the recruitment of leukocytes in postcapillary venules adjacent to injured tissue. At the site of lesion, diverse reactive substances stimulate the endothelium to produce inflammatory cytokines, chemoattractants and other inflammatory mediators. The cytokine-activated endothelium expresses adhesion molecules that lead to the low affinity interactions between leukocytes and endothelium, which is mediated by selectins and described as rolling. Subsequently integrins mediate the firm adhesion of leukocytes, which allows emigration of the cells from venules into the interstitial compartment. Activated mast cells, PMNs and macrophages secrete cytokines (TNFa), lipid mediators (LTB4) and other inflammatory players (histamine, NO). 

Table 47-14. Some molecules involved in leukocyte-endothelial cell interactions. ...

Key PMN, polymorphonuclear leukocytes EC, endothelial cell lymphs, lymphocytes CD, cluster of differentiation iCAM, intercellular adhesion molecule LFA-1, lymphocyte function-associated antigen-1 PECAM-1, platelet endothelial cell adhesion cell molecule-1. 

CD11a/CD18,CDllb/CD18, CDllc/CD18 j Adhesion molecules (members of the 1 integrin family) Deficient in leukocyte adhesion deficiency type 1 (MIM 116920)... 

The HIV-1 coreceptors CXCR4 and CCR5 bind to ligand members of a family of molecules known as chemokines, or chemotactic cytokines. While the hallmark function of these small proteins is the direction of leukocyte trafficking, they can also participate in cellular events such as activation and costimulation (Bajetto et al. 2(X)la). Members of the chemokine family can be classified as either homeostatic or inflammatory based on their temporal expression (Charo and Ransohoff 2006 Kim 2005). Although traditionally the CNS had been thought to be protected from immune acti-... 

Koch, A.E., Burrows, J.C., Haines, G.K., Carlos, T.M. and Harlan, J.M. (1991). Immunolocalisation of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab. Invest. 64, 313-320. 

Family history of RA. Genetic studies demonstrate a strong correlation between RA and the presence of major histocompatibility complex class II human leukocyte antigens (HLA), specifically HLA-DR1 and HLA-DR4.4,5 HLA is a molecule associated with the presentation of antigens to T lymphocytes. 

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