Inheritance of autoimmune neuroinflammation

Abstract

Multiple sclerosis (MS) is a chronic neuro-inflammatory disease with anticipated complex etiology. Susceptibility to MS is conferred by numerous genes, with very low odds ratios that explain minute fractions of disease. This indicates that unknown factors are responsible for the remaining genetic contribution, termed the missing heritability.

Due to the similarities to MS pathogenesis, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats as a model for autoimmune neuroinflammation. Inbred rat strains show varying susceptibility to MOG-EAE, which can be explored in different experimental populations to identify influences on disease, including constituents of the missing heritability. This thesis aims to identify components contributing to the heritability of autoimmune neuroinflammation.

We established congenic strains, a backcross (BC) and an advanced intercross line (AIL) to genetically map influences on EAE. The polygenic nature of neuroinflammation was demonstrated in these populations (Papers I, II and III). The BC identified 16 quantitative trait loci (QTL) that regulate EAE (Paper III), while one AIL region was resolved to four QTLs (Paper I: Eae24-Eae27) and another was resolved to two QTLs (Paper II: Eae23a and Eae23b). This enabled identification of a candidate gene for Eae23b, ZEB1 (Paper II), which is involved in interleukin 2 (IL2) regulation. In Paper I, we demonstrated that epistatic interactions influence EAE, and that allele combinations are more important than individual QTL effects. Additionally, we identified parent-of-origin effects, a likely component of the missing heritability, to significantly contribute to the inheritance of EAE (Paper III).

These findings illustrate the genetic complexity involved in inheritance of autoimmune neuroinflammation, and prompted us to explore the use of a heterogeneous stock (HS) of rats to map EAE. In pilot studies (Paper IV), we determined that the HS can deliver highresolution mapping, and influence from non-major histocompatibility complex (MHC) can be mapped, enabling the study of epistatic interactions involving the MHC.

A mixed genetic and epigenetic model of inheritance for autoimmune neuroinflammation is beginning to emerge. This indicates that genes, environment and their interactions, mediated by epigenetic mechanisms, contribute to neuroinflammation. Identifying constituents of this inheritance model will help us understand autoimmune neuroinflammation, and by extrapolation MS.