Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) causing neurological deficits. The disease has a complex etiology comprising multiple unidentified susceptibility genes and environmental influences. Certain human leukocyte antigen (HLA) class 11 alleles are associated with an increased risk of developing MS, which provides important circumstantial evidence for a T-cell mediated autoimmune pathogenesis of the disease. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS which can be induced in a variety of species by immunisation with myelin antigens. EAE is a T-cell mediated disease and, like MS, both major histocompatibility complex (MHC) and non-MHC genes influence disease susceptibility.

The causes of organ-specific inflammatory diseases such as MS and EAE are poorly understood. Identification of susceptibility genes should allow disclosure of mechanisms causing disease and not being a consequence of it.

We have used linkage analysis to dissect genetic susceptibility to (1) spinal cordand (2) myelin oligodendrocyte glycoprotein (MOG)-induced EAE in Dark Agouti (DA) rats. Both of these disease models display a chronic/relapsing disease course and extensive demyelination in the CNS, thus offering the opportunity to dissect mechanisms causing these hallmarks of MS. We have identified several new susceptibility loci linked to phenotypes of EAE in three separate experimental crosses. Susceptibility loci for EAE are dependent on parental strains and immunisation protocol, which shows that EAE has multiple etiologies. Despite this, there is a striking colocalisation of susceptibility loci for EAE and for animal models of rheumatoid arthritis and Guillain Barré syndrome in DA rats. Such shared susceptibility loci for autoimmune diseases affecting different organs may control critical steps in the regulation of tolerance versus immunity.

Genes regulating T helper (Th)-cell differentiation have been implicated in EAE. Two of the identified susceptibility loci for EAE are linked to immunological phenotypes compatible with an influence on Th-cell differentiation, suggesting that other mechanisms are also important in controlling susceptibility versus resistance to EAE.

In conclusion, eight susceptibility loci for EAE in rats have been identified. Future work includes positional cloning of the underlying susceptibility genes by genetic finemapping, gene expression mapping, and sequencing studies. The biological role of specific genes in the disease process, and how different combinations of specific susceptibility genes for EAE contribute to overall disease susceptibility will be dissected in congenic strains. Together, this should allow definition of the different steps in the development of organ-specific neuroinflammatory disease. Such knowledge should potentially allow development of rationale treatment strategies for MS.