Biomedical Engineering Reference
In-Depth Information
by a chemokine exposed by the inflamed endothelium and subsequent activation
of integrins (3) firm arrest and (4) crossing of the endothelium (diapedesis). For
this study, we have used a model of early inflammation in which brain venules
express E- and P-selectin, ICAM-1 and VCAM-1 [ 24 ]. The leukocyte is represented
by encephalitogenic CD4 C T lymphocytes specific for PLP139-151, cells that are
able to induce experimental autoimmune encephalomyelitis, the animal model of
multiple sclerosis.
Tethering and rolling steps are mediated by binding between cell surface
receptors and complementary ligands expressed on the surface of the endothelium.
The principal adhesion molecules involved in these phases are the selectins: the
P-selecton glyco-protein ligand-1 (PSGL-1) on the autoreactive lymphocytes and
the E- and P-selecton on the endothelial cells. The action of integrins is partially
overlaped to the action of selectins/mucins: ˛ 4 integrins and LFA-1 are also involved
in the rolling phase, but they have a less relevant role.
Chemokines have been shown to trigger rapid integrin-dependent lymphocyte
adhesion in vivo through a receptor coupled with G i proteins. Integrin-dependent
firm arrest in brain microcirculation is blocked by pertussis toxin (PTX), a molecule
able to ADP ribosylate G i proteins and block their function. Thus, as previously
shown in studies on nai ve lymphocytes homing to Peyer's patches and lymph nodes,
encephalitogenic lymphocytes also require an in situ activation by an adhesion-
triggering agonist which exerts its effect via Gi-coupled surface receptor.
The firm adhesion/arrest is mediated by lymphocyte integrins and their ligands
from the immunoglobulin superfamily expressed by the endothelium. The main
adhesion molecules involved in cell arrest is integrin LFA-1 on lymphocyte and
its counterligand ICAM-1 on the endothelium. The action of ˛ 4 integrins is partially
overlaped to the action of LFA-1: ˛ 4
integrins are involved in the arrest but they
have a less relevant role [ 24 ].
3.2
BioSpi Implementation
The system of interacting adhesion molecules that regulate the lymphocytes recruit-
ment on endothelial surface has been implemented in the biochemical stochastic
-calculus as a system composed by eight concurrent processes, corresponding
to the eight species of adhesion molecules, that regulate the cell rolling and
arrest: PSGL-1, P-Selectin, chemokines, ˛ 4 , VCAM-1, LFA-1 and ICAM-1. The
implementation of 4-phases model of lymphocyte recruitment has been divided into
three steps corresponding to the three principal involved molecular interactions:
1. Selectin-lingand interaction . The interaction between PSGL-1 on lymphocyte
and P-Selectin expressed by the endothelium is responsible for the rolling motion
of cell.
2. Integrinic activation by chemokines . The binding between the chemokines
receptors on the lymphocyte and their ligands on the endothelium triggers the
integrin-dependent adhesion of the cell on the vessel wall.
Search WWH ::




Custom Search