Linkage Analysis of Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis in the Rat Identifies a Locus Controlling Demyelination on Chromosome 18

ArticleinHuman Molecular Genetics 8(12):2183-90 · December 1999with1 Reads
DOI: 10.1093/hmg/8.12.2183 · Source: PubMed
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) with a complex etiology comprising a genetically determined predisposition and a suspected auto- immune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which can be used to define susceptibility loci for autoimmune neuroinflammation. We have recently established a chronic relapsing EAE model characterized by inflammation and focal demyelination in the CNS by immunizing a variety of rat strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This model is more MS-like than any other rodent EAE model described up to now. Here we present the first systematic genome search for chromosomal regions linked to phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide significant susceptibility locus linked to demyelination was identified on chromosome 18. This region has not been described in inflammatory diseases affecting other organs and the responsible gene or genes may thus be nervous system specific. Other chromosomal regions showing suggestive linkage to phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The chromosome 10 and 12 regions have previously been linked to arthritis in DA rats, suggesting that they harbour immunoregulatory genes controlling general susceptibility to autoimmune diseases. We conclude that identification of susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18 may disclose important disease pathways for chronic inflammatory demyelinating diseases of the CNS such as MS.
    • "While this 'danger' concept has been well validated for EAE models established in immunologically immature SPF mice [27], the question is warranted whether danger signals are (always) needed for the activation of autoreactive T and B cells present in the pathogen-educated immune system of conventionally housed primates. We are aware of only few exceptions to the rule, namely the inbred DA rat strain, in which EAE can be induced by immunization with recombinant rat MOG in IFA [28] and the outbred common marmoset in which EAE can be induced with MOG34-56 peptide in IFA [11]. The observation that CFA can be replaced with IFA in EAE induction protocols for non-human primates has important implications. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund's adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund's adjuvant (IFA). Method: Marmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48. Results: Despite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14-36 and 24-46, but reactivity against the pathogenically most relevant peptide 34-56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism. Conclusions: Immunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated.
    Full-text · Article · Sep 2015
    • "Three more arthritis mapping studies and two in EAE utilizing DA/K x E3 F2 inter-crosses could verify the first four QTLs and identified new QTLs on chromosome 20 (MHC region), 10, 1, and 181516171819. Dahlman et al. used a DA/K x ACI F2 cross in EAE to identify QTLs on chr 4, 7, 10, 12, 13, 15, 18, and X [20]. The QTLs on chr 4, 10, 12, 15 were later confirmed in DA/K x PVG.1AV1 advanced intercross line (AIL)212223242526. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The DA rat strain is particularly susceptible to the induction of a number of chronic inflammatory diseases, such as models for rheumatoid arthritis and multiple sclerosis. Here we sequenced the genomes of two DA sub-strains and two disease resistant strains, E3 and PVG, previously used together with DA strains in genetically segregating crosses. Results The data uncovers genomic variations, such as single nucleotide variations (SNVs) and copy number variations that underlie phenotypic differences between the strains. Comparisons of regional differences between the two DA sub-strains identified 8 genomic regions that discriminate between the strains that together cover 38 Mbp and harbor 302 genes. We analyzed 10 fine-mapped quantitative trait loci and our data implicate strong candidates for genetic variations that mediate their effects. For example we could identify a single SNV candidate in a regulatory region of the gene Il21r, which has been associated to differential expression in both rats and human MS patients. In the APLEC complex we identified two SNVs in a highly conserved region, which could affect the regulation of all APLEC encoded genes and explain the polygenic differential expression seen in the complex. Furthermore, the non-synonymous SNV modifying aa153 of the Ncf1 protein was confirmed as the sole causative factor. Conclusion This complete map of genetic differences between the most commonly used rat strains in inflammation research constitutes an important reference in understanding how genetic variations contribute to the traits of importance for inflammatory diseases. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-391) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2014
    • "One of the very few studies in EAE that used a reciprocal backcross design in mice similarly demonstrated that 50% of EAE loci depend on parental transmission, although this result was based on a total of two out of four identified QTLs [38] . Parent-oforigin dependent loci on chromosomes 6, 10 and 18 identified in this study have been previously reported39404142 as well as the majority of identified loci that did not depend on parental transmission [22,39404142. Replication of EAE loci in independent populations and strain combinations is important as it justifies investments in further candidate gene identification, which canFigure 3. Maternal transmission of the disease-predisposing allele. A) A logarithm of the odds (LOD) plot of chromosome 4 shows linkage for disease onset in F1xPVG offspring (peak at 144 Mb indicated by *) but not in PVGxF1 offspring, with the maternally transmitted DA allele predisposing for earlier onset of disease compared to the PVG allele. "
    [Show abstract] [Hide abstract] ABSTRACT: Parent-of-origin effects comprise a range of genetic and epigenetic mechanisms of inheritance. Recently, detection of such effects implicated epigenetic mechanisms in the etiology of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. We here sought to dissect the magnitude and the type of parent-of-origin effects in the pathogenesis of experimental neuroinflammation under controlled environmental conditions. We investigated inheritance of an MS-like disease in rat, experimental autoimmune encephalomyelitis (EAE), using a backcross strategy designed to identify the parental origin of disease-predisposing alleles. A striking 37-54% of all detected disease-predisposing loci depended on parental transmission. Additionally, the Y chromosome from the susceptible strain contributed to disease susceptibility. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors and increased the disease variance explained by the identified factors by 2-4-fold. The majority of loci displayed an imprinting-like pattern whereby a gene expressed only from the maternal or paternal copy exerts an effect. In particular, a locus on chromosome 6 comprises a well-known cluster of imprinted genes including the paternally expressed Dlk1, an atypical Notch ligand. Disease-predisposing alleles at the locus conferred lower Dlk1 expression in rats and, together with data from transgenic overexpressing Dlk1 mice, demonstrate that reduced Dlk1 drives more severe disease and modulates adaptive immune reactions in EAE. Our findings suggest a significant epigenetic contribution to the etiology of EAE. Incorporating these effects enables more powerful and precise identification of novel risk factors with diagnostic and prognostic implications for complex disease.
    Full-text · Article · Mar 2014
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