title: CD44 deficiency contributes to enhanced experimental autoimmune encephalomyelitis: a role in immune cells and vascular cells of the blood-brain barrier.
abstract: Adhesion molecule CD44 is expressed by multiple cell types and is implicated in various cellular and immunological processes. In this study, we examined the effect of global CD44 deficiency on myelin oligodendrocyte glycoprotein peptide (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Compared to C57BL/6 wild-type mice, CD44-deficient mice presented with greater disease severity, increased immune cell numbers in the central nervous system, and increased anti-MOG antibody and proinflammatory cytokine production, especially those associated with T helper 17 (Th17) cells. Further, decreased numbers of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) were observed in CD44-knockout mice throughout the disease course. CD44-knockout CD4 T cells exhibited reduced transforming growth factor-β receptor type I (TGF-β RI) expression that did not impart a defect in Treg polarization in vitro, but did correlate with enhanced Th17 polarization in vitro. Further, EAE in bone marrow-chimeric animals suggested CD44 expression on both circulating and noncirculating cells limited disease severity. Endothelial expression of CD44 limited T-cell adhesion to and transmigration through murine endothelial monolayers in vitro. Importantly, we also identified increased permeability of the blood-brain barrier in vivo in CD44-deficient mice before and following immunization. These data suggest that CD44 has multiple protective roles in EAE, with effects on cytokine production, T-cell differentiation, T-cell-endothelial cell interactions, and blood-brain barrier integrity.
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
authors: Kelly M
authors: KM
authors: Flynn
authors: Michael
authors: M
authors: Michaud
authors: Joseph A
authors: JA
authors: Madri
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D002678:Chimera; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D018960:Hyaluronan Receptors; D018836:Inflammation Mediators; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I