Hyaluronate receptor (CD44) and integrin alpha4 (CD49d) are up-regulated on T cells during MS relapses.
ABSTRACT A longitudinal study of peripheral blood T cell adhesion molecule expression was performed in 24 relapsing-remitting MS patients. There were 15 relapses in 11 patients during 15 months of observation. In comparison with remission, expression of hyaluronate receptor (CD44) was highly significant, and expression of integrin alpha4 (CD49d, VLA-4) significantly up-regulated during relapses. CD44 and CD49d are putative activity markers and CD44 a potential novel therapeutic target in MS.
- SourceAvailable from: Jorge Ivan Alvarez[Show abstract] [Hide abstract]
ABSTRACT: The delicate microenvironment of the central nervous system (CNS) is protected by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB). These barriers function in distinct CNS compartments and their anatomical basis lay on the junctional proteins present in endothelial cells for the BBB and in the choroidal epithelium for the BCB. During neuroinflammatory conditions like multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), activation or damage of the various cellular components of these barriers facilitate leukocyte infiltration leading to oligodendrocyte death, axonal damage, demyelination and lesion development. This manuscript will review in detail the features of these barriers under physiological and pathological conditions, particularly when focal immune activation promotes the loss of the BBB and BCB phenotype, the upregulation of cell adhesion molecules (CAMs) and the recruitment of immune cells.Biochimica et Biophysica Acta 02/2011; 1812(2):252-64. · 4.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: CD44 variant (CD44(v)) isoforms play important roles in the development of autoimmune disorders, including colitis and arthritis, but their role in multiple sclerosis (MS) has been explored only to a limited extent. We determined the functional relevance of CD44(v) isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44(v7) and CD44(v10) isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44(v7) and CD44(v10) expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Th1 signature genes was detected in the brains of CD44(v10-/-) mice compared with those of CD44(WT) mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44(v10-/-) brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4(hi)CD44(v10+) T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44(v7-/-) and CD44(v10-/-) mice. CD44(v7) and CD44(v10) expression contributed to EAE by increasing the longevity of autoreactive CD4(hi)panCD44(hi) T cells. Accordingly, the absence of CD44(v7) and CD44(v10) led to increased apoptosis in the inflammatory infiltrates and reduced Th1 responses, resulting in marked disease reduction. Although absent in noninflamed human brains, we detected CD44(v3), CD44(v7), and CD44(v10) isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44(v7) and CD44(v10), expressed on autoreactive CD4(hi)panCD44(hi) T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44(v) isoform regions may reduce inflammatory processes and clinical symptoms in MS.-Ghazi-Visser, L., Laman, J. D., Nagel, S., van Meurs, M., van Riel, D., Tzankov, A., Frank, S., Adams, H., Wolk, K., Terracciano, L., Melief, M.-J., Sabat, R., Günthert, U. CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells.The FASEB Journal 06/2013; · 5.48 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Remyelination of chronically demyelinated axons in multiple sclerosis (MS) requires the recruitment of endogenous cells or their replacement by transplanted, exogenous oligodendrocyte progenitor cells (OPCs). We have previously shown that an OPC line, CG4, preferentially migrates after transplantation toward focal areas of inflammatory demyelination and axon loss created by injection of zymosan in the rat spinal cord. Here we show that many transplanted CG4 cells had already migrated into the inflammatory lesion after 1 day. We demonstrate that a large number of CG4 cells that had migrated, expressed the adhesion protein, CD44, and that CD44's main ligand, hyaluronic acid (HA) was robustly expressed in the inflammatory lesion. In an in vitro migration assay, migration declined significantly following blocking of CD44 expression on CG4 cells. Likewise, migration of CG4 cells toward a zymosan lesion in vivo was inhibited when transplanted cells were exposed to a CD44 blocking antibody prior to transplantation. These findings suggest that CD44 is a key molecule in the migration of OPCs toward the focal inflammatory demyelinated lesion induced by zymosan, and may be an important in OPC repair in MS. © 2012 Wiley Periodicals, Inc.Glia 12/2012; · 5.47 Impact Factor