Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4+ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.
Highlights
Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is characterized by mononuclear cell infiltration, demyelination, and neuronal death [1,2,3]
The aim of this review is to highlight the involvement of a C-C class chemokine/receptor axis, consisting of C-C chemokine ligands 17 (CCL17) and 22 (CCL22), and C-C chemokine receptor 4 (CCR4), in CNS autoimmunity
IFN-β therapy suppresses MS disease activity [81] and high-dose IFN-β formulations have been shown to suppress CCL17 levels in peripheral blood [82]. These findings suggest that CCL17 and CCL22 concentrations in the Cerebrospinal fluid (CSF) of patients with MS may be influenced by treatments
Summary
Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is characterized by mononuclear cell infiltration, demyelination, and neuronal death [1,2,3]. Encephalitogenic Th cells are recruited to the CNS to re-encounter the cognate antigen on local and CNS-invading antigen presenting cells [4,10] These immune-cell trafficking processes, which are integral to CNS immunity, are orchestrated by chemokines, which are small chemotactic polypeptides. The aim of this review is to highlight the involvement of a C-C class chemokine/receptor axis, consisting of C-C chemokine ligands 17 (CCL17) and 22 (CCL22), and C-C chemokine receptor 4 (CCR4), in CNS autoimmunity. To this end, we review clinical studies on the expression of CCR4 and its ligands in MS. The potential of this chemokine/receptor axis as a novel therapeutic target for MS will be discussed
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