Biomedical Engineering Reference
In-Depth Information
3
BioSpi Model of Autoreactive Lymphocyte Recruitment
in Inflamed Brain Venules
In this section we briefly describe the physiology of the lymphocytes interactions
with endothelial surface, then we shows our specification of the 4-phases of
lymphocyte recruitment, and finally, we discusses the results of the stochastic
simulation.
3.1
Molecular Mechanisms of the 4-Phases Model
of Lymphocyte Recruitment
A critical event in the pathogenesis of multiple sclerosis, an autoimmune disease
of the central nervous system, is the migration of the lymphocytes from the brain
vessels into the brain parenchyma. The extravasation of lymphocytes is mediated
by highly specialized groups of cell adhesion molecules and activation factors.
The process leading to lymphocytes migration, illustrated in Fig.
1
,isdivided
into four main kinetic phases: (1) initial contact with the endothelial membrane
(tethering) and rolling along the vessel wall; (2) activation of a G-protein, induced
a
b
Selectins/Mucins
PSGL-1/E
−
& P
−
Selectin
Integrins
α
4
β
1
/VCAM-1
LFA
−
1/1CAM
−
1
leukocyte
1.Tethering and rolling
2.Firm arrest
Hematic flow
3.Diapedesis
Activation
of G protein
Activation
of integrins
Fig. 1
(
a
) The process leading to lymphocyte extravasation is a finely regulated sequence of
steps controlled by both adhesion molecules and activating factors. It involves:
1
. initial contact
(tethering) and rolling along the vessel wall mediated by selectins (PSGL-1/E- and P-selectin)
and integrins(˛
4
ˇ
1
/VCAM-1) and (LFA-1/ICAM-1);
2
. chemoattractant-induced heterotrimeric G
protein-dependent intracellular biochemical changes leading to integrins activation;
3
. integrin-
dependent firm arrest, due principally to LFA-1/ICAM-1 interaction: and
4
. diapedesis, i.e. the
passage of the lymphocytes through the wall of a blood vessel into the surrounding tissues. (
b
)
Transversal section of inflamed brain. The
black arrows
indicate the sites of inflammation at which
the lymphocytes extravasation occur
