Leucocyte Adhesion Receptors
2.1 Selectins and their counter-receptors
There are three selectins. E-selectin expressed on endothelium, P-selectin expressed by platelets and endothelium and L-selectin expressed on most leucocytes [2]. All three selectins have a common structure with an N terminal lectin domain, an EGF like domain and a variable number of consensus repeats (CR) related to complement binding proteins (Figure 1). E-selectin expression is induced on human umbilical vein endothelial cells (HUVEC) in vitro by stimulation with cytokines including IL-1 and TNFa with optimal expression at 4 hours. In vivo expression is weak or absent on uninflamed tissue but induced during inflammatory processes. E-selectin is particularly well expressed in the skin where it is thought to act as an adressin for skin homing lymphocytes through it's ability to bind the carbohydrate antigen CLA expressed on a minority of blood T cells but a majority of T cells in inflamed skin [3]. Like the other selectins E-selectin binds sialylated fucosylated sugar moieties such as sialyl lewis x. Expression of these carbohydrate structures is controlled by cell specific glycotransferases including alpha 1,3 fucosyltransferases such as FucT IV and FucTVII. FucTVII appears to be particularly crucial [4]. The backbone structure which presents these carbohydrates to E-selectin include, on mouse neutrophils a receptor very closely related to a chicken fibroblast growth factor receptor (ESL-1) and in humans P-selectin glycoprotein 1 (PSGL-1), which E-selectin binds with a lower affinity than P-selectin. Interestingly the carbohydrate antigen CLA which defines skin homing T cells is expressed on a glycoform of PSGL-1[5]. P-selectin is stored in intracellular granules and expression can be rapidly upregulated on HUVEC by several mediators such as histamine, thrombin and LTC4.

Although in the mouse surface expression of P-selectin can be induced by TNFa and LPS this is not the case in humans. However both mRNA and surface expression can be induced for up to 48 hours by IL-4, IL-3 and IL-13 [6,7 and personal observation respectively]. P-selectin binds PSGL-1 which is expressed on most leucocytes although expression and function are often dissociated, especially on peripheral blood T cells which all express PSGL-1, but only about 20% bind P-selectin [8] . L-selectin is constitutively expressed but shed on cellular activation as a result of the actions of a membrane bound metalloproteinase. It is the peripheral lymph node homing receptor and several receptors for L-selectin have been identified on lymph node HEV's. These include GlyCAM-1, CD34 and in the mouse MadCAM-1. Like PSGL-1 these L-selectin ligands all contain mucin like regions rich in O-linked sugars such as sialyl lewis x. The ligand for L-selectin on inflamed venular endothelium has not been identified. L-selectin can also bind to PSGL-1 and has been shown to contribute to leucocyte accumulation on HUVECs under flow conditions [9]. Selectins mediate capture of leucocytes under flow conditions. Selectin/carbohydrate bonds mediate a rolling type of interaction . There is considerable overlap in selectin function and single gene deletion mice are relatively healthy. However Type 11 LAD in which all three selectins are dysfunctional and a combined E and P-selectin 'knock out' mouse both show profound immunodeficiency [10].

2.2 Integrins and their Counter-Structures
Integrins are a large superfamily of heterodimeric glycoproteins involved in a wide range of biological functions including maintenance of tissue homeostasis through binding to matrix proteins [11]. Only a limited number of integrins have been shown to be involved in leucocyte migration. The b2 (CD18) leucocyte integrins comprise four members CD11a-d/CD18. CD11a/CD18 (LFA-1) is expressed on all leucocytes and is involved in a range of functions including transmigration through endothelium and T cell activation. It has three receptors ICAM-1 and 2 expressed on endothelium and ICAM-3 expressed on most leucocytes. CD11b/CD18 (Mac-1) is expressed on myelocytes and CD11c/CD18 (p,150.95) is well expressed on tissue macrophages. CD11d/CD18 has as yet been little studied but is well expressed on eosinophils and appears to bind VCAM-1 [12]. Mac-1 binds ICAM-1 and has a diverse number of other ligands. It also mediates ICAM-1 independent, granulocyte binding to endothelium through an as yet undefined receptor. Impaired expression of the CD18 integrins as in LAD type 1 leads to profound immunodeficiency, largely as a result of impaired neutrophil migration. ICAM-1 expression is induced on a large number of cell types including epithelium, endothelium and haematopoietic cells by cytokine stimulation.

a4b1 (VLA-4) is expressed on all leucocytes except neutrophils and binds VCAM-1 whose expression on endothelium is selectively upregulated by IL-4 as well as IL-13 [13]. It also binds fibronectin through a C terminal non-RGD domain. Both VLA-4 and VCAM-1 gene deletion mice are embryonic lethals because of effects on haematopoiesis and cardiac development. a4b7 also binds VCAM-1 and fibronectin as well as MadCAM-1, a receptor largely expressed by gut endothelium consistent with the role of a4b7 as a gut lymphocyte homing receptor [14]. aEb7 is expressed on a subset of T lymphocytes and binds E-cadherin so mediating localization of intraepithelial lymphocytes [15]. avb3 is expressed on endothelium and macrophages and mediates phagocytosis of apoptotic granulocytes [16]. It may also bind the widely expressed immunoglobulin like receptor PECAM which is involved in leucocyte penetration of endothelial basement membrane [17]. The CD18 integrins are unable to capture leucocytes under flow conditions only mediating binding after the cell has become attached to the endothelium and activated. In contrast the a4b1 and a4b7 integrins can bind ligand under flow conditions [18].

Leucocyte Adhesion Receptors
2.1 Selectins and their counter-receptors
There are three selectins. E-selectin expressed on endothelium, P-selectin expressed by platelets and endothelium and L-selectin expressed on most leucocytes [2]. All three selectins have a common structure with an N terminal lectin domain, an EGF like domain and a variable number of consensus repeats (CR) related to complement binding proteins (Figure 1). E-selectin expression is induced on human umbilical vein endothelial cells (HUVEC) in vitro by stimulation with cytokines including IL-1 and TNFa with optimal expression at 4 hours. In vivo expression is weak or absent on uninflamed tissue but induced during inflammatory processes. E-selectin is particularly well expressed in the skin where it is thought to act as an adressin for skin homing lymphocytes through it's ability to bind the carbohydrate antigen CLA expressed on a minority of blood T cells but a majority of T cells in inflamed skin [3].

Like the other selectins E-selectin binds sialylated fucosylated sugar moieties such as sialyl lewis x. Expression of these carbohydrate structures is controlled by cell specific glycotransferases including alpha 1,3 fucosyltransferases such as FucT IV and FucTVII. FucTVII appears to be particularly crucial [4]. The backbone structure which presents these carbohydrates to E-selectin include, on mouse neutrophils a receptor very closely related to a chicken fibroblast growth factor receptor (ESL-1) and in humans P-selectin glycoprotein 1 (PSGL-1), which E-selectin binds with a lower affinity than P-selectin. Interestingly the carbohydrate antigen CLA which defines skin homing T cells is expressed on a glycoform of PSGL-1[5]. P-selectin is stored in intracellular granules and expression can be rapidly upregulated on HUVEC by several mediators such as histamine, thrombin and LTC4.

Although in the mouse surface expression of P-selectin can be induced by TNFa and LPS this is not the case in humans. However both mRNA and surface expression can be induced for up to 48 hours by IL-4, IL-3 and IL-13 [6,7 and personal observation respectively]. P-selectin binds PSGL-1 which is expressed on most leucocytes although expression and function are often dissociated, especially on peripheral blood T cells which all express PSGL-1, but only about 20% bind P-selectin [8] . L-selectin is constitutively expressed but shed on cellular activation as a result of the actions of a membrane bound metalloproteinase. It is the peripheral lymph node homing receptor and several receptors for L-selectin have been identified on lymph node HEV's. These include GlyCAM-1, CD34 and in the mouse MadCAM-1. Like PSGL-1 these L-selectin ligands all contain mucin like regions rich in O-linked sugars such as sialyl lewis x. The ligand for L-selectin on inflamed venular endothelium has not been identified. L-selectin can also bind to PSGL-1 and has been shown to contribute to leucocyte accumulation on HUVECs under flow conditions [9]. Selectins mediate capture of leucocytes under flow conditions. Selectin/carbohydrate bonds mediate a rolling type of interaction . There is considerable overlap in selectin function and single gene deletion mice are relatively healthy. However Type 11 LAD in which all three selectins are dysfunctional and a combined E and P-selectin 'knock out' mouse both show profound immunodeficiency [10].

2.2 Integrins and their Counter-Structures
Integrins are a large superfamily of heterodimeric glycoproteins involved in a wide range of biological functions including maintenance of tissue homeostasis through binding to matrix proteins [11]. Only a limited number of integrins have been shown to be involved in leucocyte migration. The b2 (CD18) leucocyte integrins comprise four members CD11a-d/CD18. CD11a/CD18 (LFA-1) is expressed on all leucocytes and is involved in a range of functions including transmigration through endothelium and T cell activation. It has three receptors ICAM-1 and 2 expressed on endothelium and ICAM-3 expressed on most leucocytes. CD11b/CD18 (Mac-1) is expressed on myelocytes and CD11c/CD18 (p,150.95) is well expressed on tissue macrophages. CD11d/CD18 has as yet been little studied but is well expressed on eosinophils and appears to bind VCAM-1 [12]. Mac-1 binds ICAM-1 and has a diverse number of other ligands. It also mediates ICAM-1 independent, granulocyte binding to endothelium through an as yet undefined receptor. Impaired expression of the CD18 integrins as in LAD type 1 leads to profound immunodeficiency, largely as a result of impaired neutrophil migration. ICAM-1 expression is induced on a large number of cell types including epithelium, endothelium and haematopoietic cells by cytokine stimulation.

a4b1 (VLA-4) is expressed on all leucocytes except neutrophils and binds VCAM-1 whose expression on endothelium is selectively upregulated by IL-4 as well as IL-13 [13]. It also binds fibronectin through a C terminal non-RGD domain. Both VLA-4 and VCAM-1 gene deletion mice are embryonic lethals because of effects on haematopoiesis and cardiac development. a4b7 also binds VCAM-1 and fibronectin as well as MadCAM-1, a receptor largely expressed by gut endothelium consistent with the role of a4b7 as a gut lymphocyte homing receptor [14]. aEb7 is expressed on a subset of T lymphocytes and binds E-cadherin so mediating localization of intraepithelial lymphocytes [15]. avb3 is expressed on endothelium and macrophages and mediates phagocytosis of apoptotic granulocytes [16]. It may also bind the widely expressed immunoglobulin like receptor PECAM which is involved in leucocyte penetration of endothelial basement membrane [17]. The CD18 integrins are unable to capture leucocytes under flow conditions only mediating binding after the cell has become attached to the endothelium and activated. In contrast the a4b1 and a4b7 integrins can bind ligand under flow conditions [18].

4.0 In vivo studies of adhesion receptor antagonists in models of allergic inflammation
In vivo models of allergen challenge in a variety of animal species have been used extensively to investigate whether inflammatory markers, particularly eosinophil counts, and measures of BHR, can be modulated by adhesion receptor antagonists (usually mAb). Inhibitory effects have been demonstrated using antibodies against a number of receptors including anti-VLA-4, Mac-1, LFA-1, ICAM-1, VCAM-1 and E-selectin although differences in degree and pattern of inhibition have been observed depending on the species used and the exact conditions. Most support has been gained for an important role of VLA-4 and VCAM-1 in both eosinophil and T lymphocyte migration into the airways after allergen challenge and this has given impetus to the development of VLA-4 antagonists in clinical trials. However some studies have also shown an inhbitory effect with anti-ICAM-1 and eosinophil and T cell migration has been reduced in P-selectin deficient mice (81-94).

Summary and Conclusions
Considerable progress has been made in our understanding of the molecular mechanisms involved in leukocyte adhesion interactions. Migration through endothelium is a staged process with each stage offering a level of control over the cell specificity and degree of migration. Although the structure and function of the receptors involved in leukocyte migration have been well characterised the contribution each makes to the pattern of leucocyte accumulation in asthma has still not been completely defined although a number of interesting observations have been made. There is good evidence for an important role for VLA-4/VCAM in mediating eosinophil transmigration into the lung in asthma. P-selectin may also be important. VLA-4 is attractive as a therapeutic target for eosinophils because of it's lack of expression on neutrophils. The receptors controlling migration of other cells, in particular T cells and monocytes have been less well studied. Results using monoclonal antibodies in a number of animal models suggest that adhesion receptor blockade may be an effective anti-inflammatory strategy in asthma. The development of drugs that can be used to test this hypothesis in the clinic are awaited with considerable interest.

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