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Chemokines and Autoimmune DemyelinationMichaela Fux, Jason Millward, and Trevor Owens1 IntroductionAutoimmune attack on the nervous system is considered the basis for multiplesclerosis (MS) (Compston and Coles, 2002), and is also implicated in peripheralneuropathies such as Guillain Barré Syndrome (GBS) (Kiefer et al., 2002).Myelinis probably the major target of autoimmune attack in both diseases, althoughnon-myelin antigens are also recognized by infiltrating T cells and antibodies.Destruction of myelin (demyelination) is a central feature of MS and GBS, withaccompanying inflammation viz.infiltrates of T cells and macrophages, neutrophils(depending on the subtype of disease), and B cells, again depending on diseasesubpathology.A working definition of inflammation is the presence of leukocyteswhere they don t belong, and it is instructive to consider how leukocytes in demy-elinating diseases get to be where they don t belong.This chapter will attempt toreview the role of chemokines in this inflammatory process and how they contrib-ute to the autoimmune pathology in demyelinating diseases.We will focus primarilyon central nervous system (CNS) demyelinating disease.2 Demyelinating Disease2.1 Multiple SclerosisThe most common demyelinating disease, which is also the most common neuro-logical disease of young adults, is MS.MS presents as a heterogeneous spectrumof symptoms and progressions (Compston and Coles, 2002), though the majority ofcases in Europe and North America fall into the relapsing-remitting (RR-MS) orsecondary-progressive (SP-MS) categories.Primary progressive MS shares manypathological features with both, while differing in progression and not showingthe same gender bias.The etiology of MS is unknown although many aspects of thedisease suggest a link to infection - this remains unproven.There are also geneticassociations, multiple genes conferring risk for disease or severity of progression.T.E.Lane et al.(eds.), Central Nervous System Diseases and Inflammation.175© Springer 2008 176 M.Fux et al.One of the stronger associations is with MHC (Noseworthy et al., 2000; Compstonand Coles, 2002; Keegan and Noseworthy, 2002; Dyment et al., 2004).Generalizations are helpful to understanding the role of chemokines in MS, andthey include that immune infiltration of the CNS accompanies demyelinatingpathology and axonal damage.However, heterogeneous patterns of neuropathologyhave been described in MS, based on analysis of autopsy and biopsy material.The twomost commonly-represented patterns show immune pathology, with infiltrates of Tcells and macrophages/microglia, differing principally from each other in thedegree of B cell and antibody involvement (Lucchinetti et al., 2000).Less commonpathologic patterns show hypoxia-like injury or oligodendrocyte injury, and mayreflect endogenous rather than immune-mediated disease processes.The relativerole of immune infiltration versus glial migration and activation is of obvious rele-vance to discussion of the action of specific chemokines in MS.Remyelination is evidenced in MS by so-called shadow plaques containingthinly remyelinated axons (Lassmann et al., 1997; Noseworthy et al., 2000;Compston and Coles, 2002).Remyelination in adult CNS has been studied inanimal models of demyelination induced by toxins such as lysolecithin andcuprizone (Ludwin, 1981; Blakemore et al., 2000).The process is dependent onoligodendrocyte precursor cells (OPC) which can be identified partly by expres-sion of growth factor receptors (PDGF-alpha receptor) or other markers (eg.theNG2 proteoglycan) (Zhao et al., 2005).Such precursor cells, of rodent and humanorigin, have been shown capable of remyelinating experimental lesions in miceand rats (Keirstead et al., 2005; Zhao et al., 2005).Transplants of such humanadult neural-derived precursors were effective in remyelination of mouse brain(Windrem et al., 2004).Whether OPC s originate entirely from intra-CNSsources is debated.Despite occasional reports that OPC s may derive from bonemarrow (Bonilla et al., 2002), and the observation that neurosphere-derivedneuronal precursors can enter the CNS from blood (Pluchino et al., 2003), the consensusview holds that OPC s originate from the subventricular zone and the hippocampaldentate gyrus, like neuronal precursors (Gage et al., 1998; Marshall et al., 2003).Importantly, both origins would require directed migration and cellular stay-or-go decision-making.Populations of OPC have been shown in MS brain, proxi-mal to demyelinated plaques, and it has been suggested that the persistence ofplaques at least partly reflects failure of OPC s to remyelinate demyelinatedaxons (Chang et al., 2002; Dubois-Dalcq et al., 2005).Whether and how thisfailure of OPC s to remyelinate can be ascribed to negative effects (or lack ofpositive effects) of inflammatory mediators such as cytokines and chemokineswill be discussed in this chapter.2.2 Animal Models for Demyelinating DiseaseThe two most commonly-used animal models for MS are Experimental AutoimmuneEncephalomyelitis (EAE) and Theiler s Murine Encephalomyelitis Virus (TMEV)
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