Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system (CNS) with unknown etiology affecting approximately one million people worldwide.1-3 While several genetic factors have been associated with susceptibility to MS, environmental factors (especially infectious agents) also appear to be important but remain to be identified.2,3 The current working theory is that MS is a Th1-type, cell-mediated autoimmune disease.2,3
T cells in the periphery become activated and reactive to myelin-like antigens, perhaps by incidental cross-reactivity with an unidentified pathogen.2,3 Myelin-reactive T cells cross the blood-brain barrier (BBB) into the CNS, aided by upregulation of endothelial cell adhesion molecules, particularly ICAM-1.4 BBB crossing is enhanced by increased expression of matrix metalloproteinases (MMPs).5 Myelin antigens, including proteolipid protein (PLP), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG), are presented to T cells by resident CNS antigen presenting cells including microglia, astrocytes, and macrophages. As a result, an inflammation cascade is initiated with the release of inflammatory mediators that damage or destroy oligodendrocyte-formed myelin sheaths and underlying axons (Figure 1).2,3 Several lines of evidence suggest that chemokines, small secreted proteins important for regulating leukocyte trafficking, play a role in directing or maintaining T cells in regions where myelin destruction takes place.
|Figure 1. Precursor T cells become myelin-reactive following interaction with antigen presenting cells displaying myelin-cross-reactive antigens. Myelin-reactive T cells may express several chemokine receptors including CCR2, CCR5, and CXCR3. They breach the blood-brain barrier (BBB) and enter the CNS with the help of upregulated cell adhesion molecules and MMPs. In the brain they encounter myelin antigens, presented mainly by microglia, inciting an inflammatory response that damages or destroys oligodendrocyte-formed myelin sheaths and underlying neurons. [Note: figure adapted from Weiner, H.L. & D.J. Selkoe (2002) Nature 420:879.]
Much of the evidence for a role in the pathogenesis of MS results from the examination of chemokine and chemokine receptor expression patterns in MS patients. Several studies show that T cells isolated from the blood and CSF of MS patients exhibit increased levels of chemokine receptors including CCR5 and CXCR3.6,7 In addition, some studies show that elevated levels of CCR2, CCR5, CXCR3 on cells in blood and CSF are associated with relapse in individual patients, while treatment of MS with IFN-beta results in a downregulation of CXCR3 and CCR5.8-12 These chemokine receptors have also been found in the CNS, expressed on infiltrating lymphocytes in MS lesions.13,14 Ligands for CCR5 (RANTES/CCL5 and MIP-1 alpha/CCL3) and for CXCR3 (MIG/CXCL9 and IP-10/CXCL10) can be upregulated in the CSF during acute MS attacks and are also found associated with MS lesions.13,15-18 Sources for these chemokines include the blood vessel endothelium, macrophages, microglia, and astrocytes.17,18 In vitro models of transmigration show that T cells from MS patients exhibit an increased attraction to MCP-1/CCL2, MIP-1 alpha/CCL3, and RANTES/CCL5 when compared to normal controls.19,20 In addition, individuals homozygous for a polymorphism in the CCR5 gene (CCR5D32) do not express a functional receptor, and although they are not protected from MS, they do exhibit a later age of disease onset and a lower risk of clinical recurrent disease activity.21-23
Chemokines undoubtedly play critical roles in directing lymphocytes to regions of inflammation. In vitro migration studies and expression patterns associated with MS suggest that chemokines may regulate the trafficking of myelin-reactive T cells in MS lesion sites, thus contributing to inflammatory pathways associated with MS pathogenesis. Further studies will be needed to determine whether chemokines and their receptors might represent effective targets for future MS therapies.
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