Evidence for Common Autoimmune Disease Genes Controlling Onset, Severity, and Chronicity Based on Experimental Models for Multiple Sclerosis and Rheumatoid Arthritis

Abstract

The pathogenicity of multiple sclerosis is still poorly understood, but identification of susceptibility genes using the animal model experimental allergic encephalomyelitis (EAE) could provide leads. Certain genes may be shared between different autoimmune diseases, and identification of such genes is of obvious importance. To locate gene regions involved in the control of EAE and to compare the findings with the susceptibility loci recently identified in a model for rheumatoid arthritis (pristane-induced arthritis), we made crosses between the encephalomyelitis- and arthritis-susceptible rat strain DA and the resistant E3 strain. Genetic analysis of animals produced in a F2 intercross identified 11 loci associated with specific EAE-associated traits. Interestingly, five of these loci were situated at the same position as major loci controlling pristane-induced arthritis and showed similarities in inheritance pattern and subphenotype associations. Our results show that different phases of EAE are controlled by different sets of genes and that common genes are likely to be involved in different autoimmune diseases.

Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations

“…The part of mouse chromosome 11, containing three Eae loci, is homologous to a locus on rat chromosome 10, which was demonstrated to correlate with development of EAE (30). Eae18 on mouse chromosome 18 is homologous to rat chromosome 18, in which suggestive linkage to severity and duration of disease was reported (31). Interestingly, this locus is close to the MBP gene (http://www.informatics.jax.org).…”

“…No Eae locus has previously been reported on mouse chromosome 5, but three arthritis loci have recently been identified on the middle part of the chromosome: proteoglycan-induced arthritis (Pgia16) (32) and Borrelia burgdorferi-associated arthritis (Bbaa2 and Bbaa3) (33). In addition, a homologous region on chromosome 12 in the rat, linked to EAE, has been identified (31).…”

RGMA and IL21R show association with experimental inflammation and multiple sclerosis

“…26 Interestingly, the QTL overlaps loci that regulate EAE and PIA. 27,28 Defining genes behind this region might therefore unravel genetically controlled pathways that regulate inflammation in general. Here we aimed first to fine-map candidate genes responsible for the regulation of EAE and PIA in vivo, as well as for in vitro cytokine production after stimulation with lipopolysaccharide (LPS), and secondly to determine whether any of the human homologous genes associate with MS or ex vivo cytokine production.…”

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

“…Previous MOG-EAE loci identified in DA ϫ ACI and DA ϫ PVG.1AV1 intercrosses (16,20) are represented by white boxes. Other identified loci in other cross combinations and with different induction protocols are indicated with gray boxes (17,18). Because proper confidence intervals are lacking for many of the previously reported QTLs, they are depicted in their approximate positions as based on linkage maps available from http://ratmap.ims.utokyo.ac.jp/cgi-bin/comparative_home.pl, http://www.informatics.jax.org/.…”

“…There is experimental evidence supporting the notion that certain QTLs specifically enhance disease severity and/or chronicity, while not affecting the disease incidence (18). Eae16 belongs to this category, as it displayed association with disease severity and duration, but not incidence.…”