Genetic regulation of neuroinflammation : A translational approach

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), causing demyelination and axonal damage. As other complex diseases with an inflammatory or autoimmune component, MHC is a strong regulator of the disease and acts in concert with multiple nonMHC genes and environmental factors. Recent studies have identified a number of risk alleles for MS, but the etiology and molecular mechanism underlying disease remains largely unknown. In order to identify new candidate genes and define mechanisms for neuroinflammation, myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) in rats has been used as a model for MS. MOG induced EAE share several disease characteristics with MS, including T and Bcell involvement, demyelination and distribution of lesions in the CNS. High resolution linkage analysis in an advanced intercross line (AIL) was used for the definition and positioning of narrow EAEregulating regions on rat chromosome 10; Eae18a and Eae18b. Eae18a was further analyzed using synteny comparisons in humans, rats and mice within genetic regions that show linkage or association to MS and EAE, respectively. A 0.88 Mb consensus region, including 13 candidate genes for regulation of neuroinflammation, was identified. Eae18b regulates severity of EAE and inflammation and demyelination in the CNS. The region contains a cluster of genes coding for chemokines involved in chemotaxis and activation of immune cells. In rats, Ccl2, Ccl11 and Ccl1 were shown to be cisregulated and subsequent congenic experiments puts focus on genetically determined Ccl11 expression in periphery and CNS as a key regulator of neuroinflammation. We also present the first evidence for a role of Ccl12 in MOGEAE regulation. Association studies including MS patient and controls from four Nordic populations revealed association to polymorphisms in CCL2, CCL13 and CCL1, with a possible interaction from the HLADRB1*15 haplotype. In addition, CCL2 titers in the cerebrospinal fluid of patients are regulated by the genotype in the CCL2 gene. We also investigated the immune response in rat congenics including the Mhc2ta gene. We thereby confirmed that the Vra4 region regulates MHC class II expression on microglia and other antigen presenting cells after nerve injury, and after in vivo and in vitro stimulations. The region also regulates susceptibility and severity of EAE, and we suggest the Mhc2ta regulated MHC class II expression as a mechanism for EAE regulation. In conclusion, we have identified 13 candidate genes for Eae18a and present evidence for the involvement of CCL2, CCL13, CCL1, Ccl11 and Mhc2ta, in the regulation of MS and EAE