Induction of an Immune Response

After an antigen (a 'non-self' molecular entity) has entered the body, it is recognized by the cells of the immune system. An important step in eliciting an efficient immune response to an

172 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs PBMC

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Inciting stimulus

Figure 7.1. Leucocyte recruitment to sites of inflammation takes place via strictly regulated expression of adhesion molecules by the leucocytes (peripheral blood mononuclear cells, PBMC) and endothelial cells (EC). (1) Tethering of the leucocytes is mediated by interactions between members of the selectin family and their sialyl Lewis X (sLex) counterparts. Subsequent chemokine-mediated cellular activation leads to strong adhesion (2) and trans-endothelial migration (3) of the leucocytes into the underlying tissue. These processes are mediated by members of the integrin and immunoglobulin superfamily (IgSF) and homotypic interactions of the IgSF member CD31, among others. Cellular movement through the extracellular matrix (4) is facilitated by interactions between integrins and their extracellular matrix ligands, and a variety of chemokines and their respective receptors.

Inciting stimulus

Figure 7.1. Leucocyte recruitment to sites of inflammation takes place via strictly regulated expression of adhesion molecules by the leucocytes (peripheral blood mononuclear cells, PBMC) and endothelial cells (EC). (1) Tethering of the leucocytes is mediated by interactions between members of the selectin family and their sialyl Lewis X (sLex) counterparts. Subsequent chemokine-mediated cellular activation leads to strong adhesion (2) and trans-endothelial migration (3) of the leucocytes into the underlying tissue. These processes are mediated by members of the integrin and immunoglobulin superfamily (IgSF) and homotypic interactions of the IgSF member CD31, among others. Cellular movement through the extracellular matrix (4) is facilitated by interactions between integrins and their extracellular matrix ligands, and a variety of chemokines and their respective receptors.

antigen is the recruitment of leucocyte subsets to the site of antigen presence or entry. The immune system is subsequently capable of efficiently eliminating the antigen.

The recruitment and migration of leucocytes into inflamed tissues is a carefully orchestrated process (Figure 7.1). It consists of sequential steps mediated by different families of adhesion molecules expressed by both the leucocytes and the endothelial cells at the site of inflammation [4]. Of these adhesion molecules, the selectin family mediates the initial contact and subsequent rolling of the leucocyte on the endothelium. It consists of three members, i.e. E- (endothelial), P- (platelet) and L- (leucocyte) selectin. Activated endothelial cells express E- and P-selectin. P-selectin is also expressed on platelets, whereas L-selectin is only expressed on subsets of leucocytes [5].

If during the rolling process the leucocyte is correctly activated, the affinity of the members of the integrin family of adhesion molecules on the leucocyte membrane increases. Examples of activating factors are cytokines such as interleukin (IL)-6 and IL-8, which can be produced by the activated endothelial cells, and chemokines such as monocyte chemotactic proteins (MCPs), growth related proteins (GROs) and interferon ^-inducible protein 10 (IP-10) [6]. The so-called counter receptors for integrins on the endothelium are members of the immunoglobulin superfamily (IgSF) and encompass Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). These molecules are highly expressed by activated endothelial cells in inflammatory sites. The interaction of integrins on the leucocyte with the immunoglobulin superfamily members on the endothelium mediates the firm attachment of the leucocyte, followed by transmigration into the tissue. In this latter process Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1, CD31) and a variety of matrix metalloproteases (MMPs) exert important functions. Although initially identified as an IgSF member with a main function in cell-cell contact, PECAM-1 was recently shown to be a modulator of vascular cell activation as well [7]. MMPs play a role in the degradation of the basal membrane and the migration of the leucocyte through the tissue in the direction of the antigen [8-11].

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