Adhesion Molecules

Venules control CD4+ and other cell migration from blood into the nervous system. Attachment requires cellular adhesion molecules and endothelial counter receptors to overcome the considerable shear stresses produced by blood flow. Adhesion molecules on CD4+ cells and macrophages act as functional anchors forming stable bonds with their ligands on the vascular wall. In addition to functioning as mechanical anchors, adhesion molecules function as tissue-specific recognition molecules [140-146].

Entry of CD4+ cells and macrophages into the CNS is accomplished by a series of steps including tethering or rolling, adhesion (binding), and finally transendothelial migration across the BBB [141-146]. Subsequent to their egress, they migrate through the extracellular matrix in the CNS. Selectins mediate the initial step of tethering leading to rolling [146, 154, 155] but selectin-mediated bonds are reversible. To arrest these cells on the endothelium, these low-affinity interactions must be supplemented by high-affinity adhesion molecules, the integrins [153, 154]. The integrins, including a4p1-integrin (VLA-4), are members of the endothelial immunoglobulin superfamily [156, 157]. The predominant function of the p2-integrin leukocyte function antigen-1 (LFA-1) and a4-integrins (integrin-a4p1/VLA-4) is to bind the cells to their ligands intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) [155-157]. Blocking of attachment of the a4 moiety on lymphocytes by natalizumab is highly effective treatment in MS but is complicated by a risk of progressive multifocal leukoencephalopathy (PML) [158].

Selectins expressed on leukocytes (P-selectin and L-selectin) and endothelium (E-selectin) result in rolling and slowing of the cells. P-selectin and its ligand PECAM-1 appear to play a special role in EAE and MS [159, 160]. As cells roll and are slowed by the interaction of selectins and their ligands, they respond to endothelial cell chemokines. Specific chemokines are fixed on the endothelial surface and are molecular signals that direct cells to tissues and with specific adhesion molecules confer organ specificity [145]. Chemokines are divided into four families that are specific for different T-cell subgroups [145]. Distinctive chemokine receptors on Th1 cells include CCR5 and CXCR3. In MS, all of the infiltrating Th1 cells express these chemokine receptors [161]. They play a central role in the egress of specific lymphocyte subgroups into specific target organs. Selectin binding to ligand is an activating signal that induces rapid activation of a4-integrins and p2-integrins [155-157].

From the first availability of IFN-p, about half of the population placed on this drug did not appear to benefit from it. In a prospective study, Byun and coworkers found that half of MS patients placed on IFN-p were “super-responders” [162]. They found that a number of genes were expressed in this super-responder subpopulation following their first dosage, and this predicted the clinical response. Interestingly, these genes included heparan proteoglycans [160]. Further support for the identification of IFN-p responder/nonresponder populations followed with a report by Axtell et al. in 2010 [136]. They reported that serum from Danish IFN- p-1a nonresponders contained IL-17. Most recently the evidence correlating response or nonresponse to IFN-p to polymorphisms of a specific gene rs9828519, a sodium-hydrogen channel, has been published [115]. Apart from illuminating the mechanisms of the drug response, these observations hopefully will help identify potential “super-responders” and assist in advising them in regard to their therapeutic choices for MS. This should reduce the human and financial cost of treatment failure in managing MS.

T-cell vaccine studies are continuing. The initial approach was to remove immunocompetent cells from patients by immunizing them with antigen analogous to V-beta chains of T-cell receptors that are capable recognizing encephalitogenic fragments of MBP. More recent studies have focused on using CNS antigen- stimulated cells from the patient’s own T-cell repertoire and, following irradiation, infusing these autoreactive cells back into the donors. There has been a remarkable impact on reducing sustained progression of disability patients with RRMS, and the current study is hoping to replicate these findings in patients with SPMS. A preliminary report in RRMS was encouraging for progressive MS [163].

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