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1976 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1977

inflammation, as well as to CD34 constitutively expressed by cells of the lymph nodes and Peyer patches, has structural features of both a
high endothelial venules. mucin and an immunoglobulin superfamily molecule. It can bind both
Adhesion of leukocytes to the endothelium at the site of inflamma- L-selectin and the leukocyte integrin α β , expressed by a subset of
4 7
tion results in their rolling along the luminal surface, which slows their memory T cells. It is believed to interact with L-selectin through its
movement and brings them into contact with a wide variety of chemi- mucin (carbohydrate) domain and with α β through its immunoglob-
4 7
cal mediators that trigger the next stage of leukocyte emigration—tight ulin domains. Until recently, identified protein ligands for L-selectin
adhesion to the endothelial surface. These mediators include sur- (MAdCAM-1 and CD34) have been demonstrated to bind to L-selectin
246
face-bound chemokines, new adhesion molecules expressed by the only in the context of lymphocyte homing, although recent evidence
247
255
endothelium in response to inflammatory cytokines, PAF, soluble now suggests that they may play a role in rolling during inflammation.
248
chemokines, and ligands that crosslink leukocyte CD31 250–252 and Interestingly, intravital microscopy shows that leukocytes may roll on
249
seem to work by stimulating the activation of leukocyte integrin adhe- already adherent leukocytes and platelets through the interactions of
sion molecules by so-called inside-out signaling. This process involves L-selectin and PSGL-1 to amplify the inflammatory process. 256,257
a conformational change and/or clustering of the two chains of these PAF is made and secreted acutely by leukocytes, mast cells, and
heterodimeric surface molecules such that the affinity or avidity, respec- endothelial cells at the site of inflammation. PAF (1-alkyl-2-acetyl-sn-
253
tively, for their ligands on the surfaces of endothelial cells is increased. glycero-3-phosphocholine) is produced enzymatically from phosphati-
The ligands identified are members of a third family of adhesion mole- dyl choline in the plasma membrane. Although its role as an activator of
cules, the immunoglobulin gene superfamily. 254 neutrophils in this environment has been established, it appears to be
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Table 115–4 lists some of the more common leukocyte/endothelial a relatively weak agonist of platelet activation in this location.
CAM pairs participating in the inflammatory response. It is interesting Adherent leukocytes migrate to nearby interendothelial junc-
to note that the mucosal addressin MAdCAM-1, a unique molecule tions by repeated cycles of adhesion in the front and disadhesion in
expressed by endothelial cells of high endothelial venules of mesenteric the rear. 254,258 At the junction, additional distinct molecular interactions

TABLE 115–4. Common Leukocyte–Endothelial Cell Adhesion Molecule Pairs in Inflammation
CD and Integrin Leukocytes Endothelial Counter
Leukocyte Molecule Nomenclature Expressing Action Ligand CD Number
L-selectin CD62L PMN, Mo, T, B, NK Tethering, rolling MAdCAM-1 * Pending
GP105–120 CD34
PSGL-1 CD162 PMN, Mo, T, B, NK Tethering, rolling P-selectin CD62P
Sialyl LewisX CD15s PMN, Mo, T, B, NK Tethering, rolling E-selectin CD62E
†
ESL-1 , CLA †
LFA-1 CD11a/CD18 PMN, Mo, T, B, NK Tight adhesion ICAM-1 CD54
(α β ) ICAM-2 CD102
L 2
ICAM-3 CD50
Adhesion, diapedesis JAM-A Pending
Mac-1 CD11b/CD18 PMN, Mo, NK Tight adhesion ICAM-1 CD54
VLA-4 CD49d/CD29 Mo, B, Eo > NK, T Tight adhesion § VCAM-1 CD106
‡
Rolling
PECAM-1 CD31 PMN, Mo, NK Diapedesis PECAM-1 CD31
Subsets of T
CD99 CD99 All leukocytes to Diapedesis CD99 CD99
varying degrees
JAM-C? Pending T Diapedesis JAM-C? Pending

B, B lymphocytes; CLA, cutaneous lymphocyte antigen; Eo, eosinophils; ESL-1, E-selectin ligand; GP, glycoprotein; ICAM, intercellular adhesion
molecule; JAM, junctional adhesion molecule; MAdCAM-1, mucosal addressin cell-adhesion molecule; Mo, monocytes; NK, natural killer cells;
PECAM, platelet endothelial adhesion molecule; PMN, polymorphonuclear neutrophils; PSGL, P-selectin glycoprotein ligand; T, T lymphocytes
VCAM, vascular cell adhesion molecule; VLA, very-late antigen.
PMN, neutrophils;*MAdCAM-1 and CD34 have been shown to be important for homing of T cells to lymph nodes via high endothelial venules.
The protein structures bearing the L-selectin ligands, including CD15s, at sites of inflammation have not been identified.
† ESL-1, a protein with homology to fibroblast growth factor receptor, has been identified in mice. CLA, a molecule on the surface of skin-homing
T cells related to PSGL-1, directs them to skin via E-selectin expressed on dermal venules.
‡ Expression of VLA-4 on granulocytes is limited to eosinophils and basophils. Adult human neutrophils do not express it under normal
circumstances.
§ Although VLA-4/VCAM-1 interactions are generally thought to be important for tight adhesion of leukocytes to endothelium, there are
reports 319,320 that leukocytes can use VLA-4 to roll on endothelial VCAM-1, as well.

Kaushansky_chapter 115_p1967-1984.indd 1977 9/18/15 10:09 AM