Vascular Adhesion Molecules In The

In both the acute and chronic relapsing forms of EAE an increase in leucocyte infiltration is associated with an upregulation of ICAM-1 on CNS vessels.2677-79 This adhesion molecule is reported to be present on most microvessels isolated from MS brain80 and on a third of blood vessels in active MS plaques.81 Blood vessels expressing ICAM-1 may not necessarily indicate sites of lymphocyte extravasation since ICAM-1-positive cerebral vessels appear in normal human brain,81 and in the active clinical disease of EAE the molecule is expressed on several vessels in uninvolved CNS tissue.26 By inference, other factors are required to support lymphocyte extravasation and hence disease progression. Human cerebral blood vessels normally express very little VCAM-1, but in MS high levels appear within lesions,80 especially in older, active plaques where there is concomitant expression of VLA-4 on nearby lymphocytes.82 The expression of ICAM-1 and VCAM-1 on nonendo-thelial cells of CNS blood vessels, e.g., astrocytic foot processes of smooth muscle cells, may also contribute to the migration of lymphocytes across the BBB and to the perivascular lymphocyte cuffing that is a characteristic pathological feature of MS.

An upregulation of ICAM-1 and VCAM-1 on the surface of endothelial cells is generally attributed to the activity of inflammatory cytokines such as TNF-a, IL-1, IL-4, and IFN-y.43 83-86 All of these cytokines are readily identifiable in the CNS lesions of MS,87-90 particularly in close proximity to blood vessel walls.82 91 In EAE, disease activity is exacerbated by TNF-a,92 93 antagonised by specific neutralising antibodies,94 and injection of TNF-a into rat spinal cord induces mononuclear cell infiltrates.95 However, several of the cytokines identified in MS lesions are also present in the CNS of normal and noninflammatory disease controls91 and therefore caution must be applied in interpreting cytokine expression and localisation to a particular phase of demyelination.

Lymphocyte recirculation between blood and secondary lymphoid tissue is dependent upon homing receptors (e.g., L-selectin) on the lymphocytes recognising distinct ligands (vascular addressins) expressed on specialised vessel walls known as high endothelial venules (HEV). When antiaddressin antibodies were applied to CNS sections from rats or guinea pigs with CREAE they showed strong reactivity in perivascular lesions, particularly in relapsing disease,77,79 but these findings were not confirmed by others in a mouse EAE model.96 Attempts to identify HEV-like vessels and their associated addressins in MS brain have been disappointing. One study reported that addressins were present in the plaque and periplaque areas of only one of six MS tissues examined23 and in our laboratory we have failed to identify HEVs in any of eight MS brain tissue samples examined. Unlike other chronic inflammatory diseases it seems that lymphocyte entry into the CNS of MS patients is not dependent upon recognition of addressins on HEV.

Some adhesion molecules also exist in a soluble form, and high levels of soluble ICAM-1 (sICAM-1) in blood are thought to be indicators of endothelial cell damage or hyperactivity.97 In MS, increased levels of circulating sICAM-1 are associated with the active phase of the disease98 and are directly related to serum concentrations of TNF-a and the degree of BBB damage.99 Similarly, raised levels of soluble VCAM-1 in the blood of MS patients with active disease correlate with dysfunction of the BBB.100 Whether these soluble molecules originate from T cells, macrophages, endothelial cells, or glial cells101 is not known, but by binding to ligands on the surface of leucocytes they could either interfere with recognition of endothelial ICAM-1 or VCAM-1 and impede attachment to cerebral vessels102 or induce cell activation and promote endothelial interaction.

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