Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to mediate leukocyte migration across the blood-brain barrier (BBB) in multiple sclerosis or experimental autoimmune encephalomyelitis (EAE). Here, we confirmed vascular ALCAM expression in human brain tissue samples in situ and on two different human in vitro BBB models. Antibody-mediated inhibition of ALCAM reduced diapedesis of human CD4+ Th1 but not of Th17 cells across the human BBB in vitro. In accordance to human Th1 cells, mouse Th1 cells showed reduced diapedesis across an ALCAM-/- in vitro BBB model under static but no longer under flow conditions. In contrast to the limited role of ALCAM in T cell extravasation across the BBB, we found a contribution of ALCAM to rolling, adhesion, and diapedesis of human CD14+ monocytes across the human BBB under flow and static conditions. Taken together, our study highlights the potential differences in the CNS expression of ALCAM in mouse and human and supports a prominent role for ALCAM in the multi-step extravasation of monocytes across the BBB.
Activated leukocyte cell adhesion molecule (ALCAM), also known as CD166 (cluster of differentiation 166), This protein binds to T-cell differentiation antigene CD6, and is implicated in the processes of cell adhesion and migration. It is expressed on activated T cells, activated monocytes, neurons and as reported in this study blood vessels. In this study they can model the blood brain barrier by seeing is cells migrate across a layer of brain blood vessel (endotheliaml) cells. This is a “Static” culture, Alternatively they can circulate fluid over the blood vessels to create a semblence of blood passing over vessels and this is a “flow” culture. They can do this with rodent cells and now human cells in the blood vessel culture.
In human it blocked TH1 (interferon gamma producing cells) but not Th17 (interleukin 17 producing) cells, so the immunologists would say it wont work in MS because it is a TH17 disease, what rot I say. It is not that simple
Mouse Th1 could not cross through the blood vessel cells (diapedesis) very well in the static condition but weidrly not under flow.
However, the study shows that monocytes (macrophages of the blood) use this molecule to slow themselves down as they come out of the blood stream and make contact with the blood vessel wall (rolling), sticking to the blood vessel wall (adhesion) and crossing (diapedesis). So a way to stop monocytes getting in the brain.
You can see the process in the diagram above but they make the mistake to suggest that white cells push through the gaps between the blood vessel cells. They don’t they go through the blood vessel cells and to do this they use other CAMS. on is intercellular adhesion molecule-1 (ICAM-1 = CD54) bound by molecules on the white blood cell (e.g. LFA-1) and another on called Vascular cell adhesion molecule 1 (VCAM-1 =CD106) which binds to VLA-4 (very late antigen 4 = CD49d). You know this because this is what natalizumab blocks, Whilst we are told natalizumab blocks \T cells getting into the brain, in fact the first time they showed a natalizumab to work in cell cultutre they showed blocking on a monocyte line (U937) to brain blood vessels.
If you block CD11b on monocytes (and polymorphs) you can inhibit EAE just like you can by blocking T cells.
So targeting ALCAM is a way to block monocytes getting in the brain.