Topic 2 lecture note..

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leukocytes in their transit across endothelial barriers. On T cells, CD31 ligation will upregulate the adhesive function of both 1 and 2 integrins. ************************************************************************************** E-Cadherin Epithelial cadherin is a 120-kDa cell surface glycoprotein that, when complexed with catenins, mediates Ca2+-dependent cell-cell adhesion. E-cadherin forms the key functional component of adherens junctions of all epithelial cells. It plays a major part in the establishment and maintenance of intercellular adhesion, cell polarity and tissue architecture. Loss of cadherin mediated adhesion seemed to be an important contributory factor in tumour pathogenesis. In terms of immunity, it plays a critical role in localizing intraepithelial lymphocytes to epithelial regions by binding to E7. This is particularly important for gut mucosal immunity. ************************************************************************************** Selectins Selectins are a family of transmembrane molecules, expressed on the surface of leukocytes and activated endothelial cells. Selectins contain an N-terminal extracellular domain with structural homology to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor, and two to nine consensus repeats (CR) similiar to sequences found in complement regulatory proteins. Each of these adhesion receptors is inserted via a hydrophobic transmembrane domain and possesses a short cytoplasmic tail. The initial attachment of leukocytes, during inflammation, from the blood stream is afforded by the selectin family, and causes a slow downstream movement of leukocytes along the endothelium via transient, reversible, adhesive interactions called leukocyte rolling. Each of the three selectins can mediate leukocyte rolling given the appropriate conditions. L-selectin P-selectin E-selectin
L-Selectin The smallest of the vascular selectins, a 74-100 kDa molecule, is constitutively expressed at the tips of microfolds on granulocytes, monocytes, and a vast array of circulating lymphocytes. L-selectin is important for lymphocyte homing and adhesion to high endothelial cells of post capillary venules of peripheral lymph nodes. Moreover, this adhesion molecule contributes greatly to the capture of leukocytes during the early phases of the adhesion cascade. Following capture, L-selectin is shed from the leukocyte surface after chemoattractant stimulation. L-selectin interacts with three known counter receptors or ligands, MAdCAM-1, GlyCAM-1, and CD34. In L-selectin deficient mice, or following anti-L-selectin mAb treatment, trauma-induced leukocyte rolling in mesentary or cremaster muscle venules is normal initially, but declines over time. This indicates that trauma-induced rolling in these mice is P-selectin dependent with a velocity highly comparable to that observed in wild-type mice. L- selectin is critical in mediating rolling after surgical trauma and is necessary for neutrophil recruitment after inflammation. Nevertheless, basal neutrophil trafficking appears to remain unaffected by absence of L-selectin since peripheral leukocyte and neutrophil counts in these mice were normal. Leukocyte rolling is P-selectin dependent in TNF--treated mice deficient in L-selectin, The lack of L-selectin in these mice reduces the efficiency of E-selectin-mediated rolling as shown by the sensitivity of rolling to P-selectin antibodies. These experiments consistently show that L- and P-selectin mediate leukocyte rolling, however, L-selectin alone cannot assume this task at normal velocities in vivo. L- and P- selectin cooperate in such a way that in the absence of P-selectin, L-selectin must initiate leukocyte interactions to allow slow rolling on E-selectin (but see below). In addition, L- or P- selectin must be present to mediate capture before the commencement of leukocyte rolling. Without the presence of either L- or P-selectin, rolling cannot occur. Levels of L-selectin are higher on lymph node-homing T cells, which may facilitate T cell accumulation at this site by enhancing binding to locally expressed ligands such as PNAd. P-selectin P-selectin is the largest of the known selectins at 140 kDa. It contains nine consensus repeats (CR), and is expressed in -granules of activated platelets and granules of endothelial cells. Within minutes of stimulation of the endothelial cells by inflammatory mediators such as histamine, leukotrienes, thrombin, or phorbol esters, P-selectin is surface-expressed. The primary ligand for P-selectin is PSGL-1 (P-selectin glycoprotein ligand-1) which is constitutively found on all leukocytes, and rapidly released from the cell-surface following leukocyte activation. The transient interactions between P-selectin and PSGL-1 allow leukocytes to roll along the venular endothelium. Accordingly, P- selectin is largely responsible for the rolling phase of the leukocyte adhesion cascade. P- selectin can also mediate capture when L-selectin is not present.
Page 1 and 2: Cell adhesion: Roles in lymphocyte
Page 3 and 4: compartmentalized cells such as mac
Page 5: cytokines such as IL-1, IFN-, and T
Page 9 and 10: Mucins Selectin ligands are mucins.
Page 11 and 12: Rolling Once leukocytes are capture
Page 13 and 14: targeted mice lacking CD18. This su
Page 15 and 16: CD73 is a glycosylphosphatidylinosi
Page 17 and 18: Poorly characterized **************
Page 19 and 20: Guidance of neutrophils to sites of
Page 21 and 22: Peyer’s patches. Mice deficient i
Page 23 and 24: Sunshine, vitamin D3, and dendritic
Page 25 and 26: Vitamin A and dendritic cells impri

Topic 2 lecture note..

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