Biomedical subjects

Tomas Olsson

Publications and source records attributed to Tomas Olsson.

At least 19 recordsLinked to original sources

PubMed2026

DNA methylation landscape of cerebrospinal fluid cells in multiple sclerosis: an epigenome-wide association study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors. METHODS: We profiled genome-wide DNA methylation in cerebrospinal fluid (CSF) cells from people with MS (pwMS) and matched controls. Differentially methylated positions (DMPs) and regions (DMRs) were integrated with transcriptomic data, T-cell chromatin annotations, and pathway analyses. Protocadherin gamma (PCDHγ) expression was assessed in primary CD4+ T-cell subsets and confirmed by flow cytometry. FINDINGS: We identified 2710 DMPs and 4330 DMRs associating with genes that were enriched in immune signalling, adhesion and migration processes, and were accompanied by corresponding RNA changes. MS-associated methylation changes enriched in the cohesin chromatin-regulation pathway localised to T-cell regulatory regions, and this pathway included multiple protocadherin (PCDH) genes, which displayed consistent methylation and expression changes in CSF cells of pwMS compared to controls. PCDHγ cluster gene expression was detected in CD4+ T-cell subsets, and flow cytometry confirmed PCDHγ protein expression in peripheral blood T cells. Moreover, co-expression analysis suggests a role of PCDH genes in aryl hydrocarbon receptor (AHR) signalling. Protein-level validation showed fewer PCDHγ-positive CD4+ T cells in pwMS and activation-induced PCDHγ upregulation after T-cell stimulation. INTERPRETATION: DNA methylation changes in CSF resident cells reflect dysregulated T cell activation and migration in pwMS and suggest involvement of protocadherin molecules in MS pathogenesis. FUNDING: European Research Council, Swedish Research Council, Swedish Brain Foundation, Swedish MS Foundation, Knut and Alice Wallenberg Foundation, European Union and others.

Humans↗

PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗

PubMed2006

Combined-cross analysis of genome-wide linkage scans for experimental autoimmune encephalomyelitis in rat.

Unbiased genetic analysis of experimental autoimmune encephalomyelitis (EAE) can provide insights into the pathogenesis of multiple sclerosis. To date five genome-wide scans using F2 crosses between different inbred rats have been performed with the aim of defining EAE-regulating quantitative trait loci (QTLs) as the starting point for identification of the underlying genes. We here report the first combined-cross analysis of three F2 crosses previously performed in our group. The majority of QTLs was shared between the different strain combinations and was therefore reproduced by the combined-cross analysis. Consequently, combined-cross analysis improved the power to detect QTLs with modest effects and narrowed QTL confidence intervals. The findings also demonstrate a lack of power in previous F2 crosses and encourage future use of larger populations. Moreover, the allelic states of shared QTLs could be established, thus providing critical information for narrowing QTLs and identifying the key polymorphism by subsequent haplotype analysis.

Animals↗

PubMed2006

Genetics of autoimmune neuroinflammation.

Detection of gene variants affecting the risk for multiple sclerosis provides insights into mechanisms central for autoaggressive neuroinflammation. Major histocompatibility complex (MHC) class II genes, and probably also MHC class I genes, regulate both human multiple sclerosis and rodent experimental autoimmune encephalomyelitis. However, the functional understanding of the MHC regulation requires further experimentation. Genome scans in human multiple sclerosis have failed to demonstrate significant non-MHC loci with genome-wide significance, but approximately 50 such loci have been described in different rodent experimental autoimmune encephalomyelitis models. Positional cloning of individual rodent genes is difficult, but genes or small genome regions now emerge. Association studies in large human cohorts are needed to confirm the human relevance of rodent genes and such cohorts will also be used for single nucleotide polymorphism-based whole-genome screening. It is realistic to assume that several non-MHC genes regulating autoimmune neuroinflammation, including target tissue responses, will be pinpointed in the next ten years. At the moment there are a few hot candidates, including MHC2TA, PRKCA and IL7R.

Animals↗

PubMed2006

Genetically determined susceptibility to neurodegeneration is associated with expression of inflammatory genes.

Axonal damage, a core feature of neurological diseases, induces a retrograde reaction in neurons and surrounding glia. We determined transcriptional profiles of this reaction using Affymetrix oligonucleotide arrays. Gene expression was examined in spinal cord tissue prior to injury and following ventral root avulsion in two inbred rat strains, where the degree of neurodegeneration differs. Stringent statistical analysis revealed 278 regulated genes, whereof 245 were regulated by the injury and 68 differed between strains. Principal component analysis disclosed a common injury response pattern significantly modified by genetic background. Notably, inflammatory genes comprised the largest group of genes induced by injury and these transcripts prevailed in the strain most susceptible to neurodegeneration. In addition, levels of the strain regulated genes C1qb and Timp1 correlated with degree of neurodegeneration in a cohort of genetically heterogeneous animals. These results suggest a link between the inflammatory response elicited by nerve injury and subsequent neurodegeneration.

Animals↗

PubMed2006

Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis.

Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.

Animals↗

PubMed2006

Advanced intercross line mapping of Eae5 reveals Ncf-1 and CLDN4 as candidate genes for experimental autoimmune encephalomyelitis.

Eae5 in rats was originally identified in two F(2) intercrosses, (DA x BN) and (E3 x DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 x DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a approximately 1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis.

Animals↗

PubMed2006

Definition of a 1.06-Mb region linked to neuroinflammation in humans, rats and mice.

Unbiased identification of susceptibility genes might provide new insights into pathogenic mechanisms that govern complex inflammatory diseases such as multiple sclerosis. In this study we fine mapped Eae18a, a region on rat chromosome 10 that regulates experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We utilized two independent approaches: (1) in silico mapping based on sequence similarity between human multiple sclerosis susceptibility regions and rodent EAE quantitative trait loci and (2) linkage mapping in an F10 (DA x PVG.AV1) rat advanced intercrossed line. The linkage mapping defines Eae18a to a 5-Mb region, which overlaps one intergenomic consensus region identified in silico. The combined approach confirms experimentally, for the first time, the accuracy of the in silico method. Moreover, the shared intersection between the results of both mapping techniques defines a 1.06-Mb region containing 13 candidate genes for the regulation of neuroinflammation in humans, rats, and mice.

Animals↗

PubMed2006

Intravenous immunoglobulin for post-polio syndrome: a randomised controlled trial.

BACKGROUND: Survivors of poliomyelitis often develop increased or new symptoms decades after the acute infection, known as post-polio syndrome. Production of proinflammatory cytokines within the CNS indicates an underlying inflammatory process, accessible for immunomodulatory treatment. We did a multicentre, randomised, double-blind, placebo-controlled study of intravenous immunoglobulin in post-polio syndrome. METHODS: 142 patients at four university clinics were randomly assigned infusion of either 90 g in total of intravenous immunoglobulin (n=73) or placebo (n=69) during 3 consecutive days, repeated after 3 months. Seven patients were withdrawn from the study. Thus, 135 patients were assessed per protocol. Primary endpoints were muscle strength in a selected study muscle and quality of life as measured with the SF-36 questionnaire (SF-36 PCS). Secondary endpoints were 6-minute walk test (6MWT), timed up and go (TUG), muscle strength in muscles not chosen as the study muscle, physical activity scale of the elderly (PASE), visual analogue scale (VAS) for pain, multidimensional fatigue inventory (MFI-20), balance, and sleep quality. Outcome tests were done immediately before the first infusion and 3 months after the second infusion. This study is registered with , number NCT00160082. FINDINGS: Compared with baseline, median muscle strength differed by 8.3% between patients receiving intravenous immunoglobulin and placebo, in favour of the treatment group (p=0.029). SF-36 PCS did not differ significantly between the groups after treatment (p=0.321). Differences in the subscale vitality score (p=0.042) and PASE (p=0.018) favoured the active treatment group. MFI-20, TUG, muscle strength in the muscles not chosen as the study muscle, 6MWT, balance, and sleep quality did not differ between groups. For the whole study population there was no significant change in pain, as determined by VAS. Nevertheless, patients who reported pain at the study start improved in the intervention group but not in the placebo group (p=0.037). Intravenous immunoglobulin was well tolerated. INTERPRETATION: Intravenous immunoglobulin could be a supportive treatment option for subgroups of patients with post-polio syndrome. Further studies on responding subgroups, long-term effects, and dosing schedules are needed.

Aged↗

PubMed2006

Effect of intravenous immunoglobulin in patients with post-polio syndrome -- an uncontrolled pilot study.

OBJECTIVE: To analyse changes in muscle strength, physical performance and quality of life during intravenous immunoglobulin (IVIg) treatment in patients with post-polio syndrome. DESIGN: Open clinical trial. PATIENTS: A total of 14 patients (6 women, 8 men; mean age 57 years, range 43-67 years) were included in the study. INTERVENTION: Treatment with 90 g IVIg (30 g daily for 3 days). MAIN OUTCOME: Muscle strength, measured with dynamic dynamometry, muscle function, by means of performing the 6-minute walk test, and quality of life, analysed by means of the SF-36 questionnaire, were performed before and after treatment. RESULTS: For quality of life there was a statistically significant improvement for all but one of the 8 multi-item scales of SF-36 when comparing data before and after treatment with IVIg. The multi-item scale most improved was Vitality. There was no significant increase in muscle strength and physical performance. CONCLUSION: Data indicate that IVIg may have a clinically relevant effect, with an improvement in quality of life. The effect may be due to a decrease in an inflammatory process in the central nervous system, which earlier has been reported in patients with past-polio syndrome after IVIg treatment. Since a possible placebo effect cannot be ruled out, a randomized controlled study is needed.

Adult↗

PubMed2006

Cortical demyelination can be modeled in specific rat models of autoimmune encephalomyelitis and is major histocompatibility complex (MHC) haplotype-related.

In recent years, a number of histopathologic studies revealed the presence of cortical demyelination in multiple sclerosis (MS). The underlying mechanisms responsible for cortical demyelination are unresolved. Recently, the presence of cortical lesions in autoimmune encephalomyelitis (EAE) induced in marmosets and Lewis rats has been demonstrated. So far, it is not known whether cortical demyelinated lesions are also present in other models of EAE. In this study, we analyzed a large spectrum of different rat strains actively immunized with myelin oligodendrocyte glycoprotein (MOG), a model strongly mimicking MS for cortical demyelination. By using sets of rat strains with the constant EAE-permissive LEW nonmajor histocompatability complex (MHC) genome, but different MHC haplotypes, we demonstrated that considerable cortical demyelination was only found in LEW.1AR1 (RT1) and LEW.1W (RT1) strains. These rat strains have the isotypes and alleles RT1.BD in the MHC II region and RT1.C in the nonclassic MHC I region in common. Because cortical demyelination was most prominent in LEW.1AR1 rats, an additional strong influence is promoted by the RT1.A MHC class I allele. Demyelination was accompanied by microglia infiltration and deposition of immunoglobulins on myelin sheaths. Our study shows that extensive cortical demyelination can be reproducibly induced in certain rat strains by active immunization with MOG. Furthermore, our findings suggest that cortical demyelination in EAE depends on particular combinations of MHC I and class II isotypes and alleles. The mechanisms for this influence and any similar effects in humans will be important to define.

Alleles↗

PubMed2006

Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis.

Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1'-dioctadecyl-6,6'-di(4sulphopentyl)-3,3,3',3'tetramethylindocarbocyanin(DiI)-labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers beta-III-tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole-cell patch-clamp technique on freshly isolated 1, DiI-labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.

Animals↗

PubMed2005

Cytokine responses during chronic denervation.

BACKGROUND: The aim of the present study was to examine inflammatory responses during Wallerian degeneration in rat peripheral nerve when the regrowth of axons was prevented by suturing. METHODS: Transected rat sciatic nerve was sutured and ligated to prevent reinnervation. The samples were collected from the left sciatic nerve distally and proximally from the point of transection. The endoneurium was separated from the surrounding epi- and perineurium to examine the expression of cytokines in both of these compartments. Macrophage invasion into endoneurium was investigated and Schwann cell proliferation was followed as well as the expression of cytokines IL-1beta, IL-10, IFN-gamma and TNF-alpha mRNA. The samples were collected from 1 day up to 5 weeks after the primary operation. RESULTS: At days 1 to 3 after injury in the epi-/perineurium of the proximal and distal stump, a marked expression of the pro-inflammatory cytokines TNF-alpha and IL-1beta and of the anti-inflammatory cytokine IL-10 was observed. Concurrently, numerous macrophages started to gather into the epineurium of both proximal and distal stumps. At day 7 the number of macrophages decreased in the perineurium and increased markedly in the endoneurium of both stumps. At this time point marked expression of TNF-alpha and IFN-gamma mRNA was observed in the endo- and epi-/perineurium of the proximal stump. At day 14 a marked increase in the expression of IL-1beta could be noted in the proximal stump epi-/perineurium and in the distal stump endoneurium. At that time point many macrophages were observed in the longitudinally sectioned epineurium of the proximal 2 area as well as in the cross-section slides from the distal stump. At day 35 TNF-alpha, IL-1beta and IL-10 mRNA appeared abundantly in the proximal epi-/perineurium together with macrophages. CONCLUSION: The present studies show that even during chronic denervation there is a cyclic expression pattern for the studied cytokines. Contrary to the previous findings on reinnervating nerves the studied cytokines show increased expression up to 35 days. The high expressions of pro-inflammatory and anti-inflammatory cytokines in the proximal epi-/perineurial area at day 35 may be involved in the formation of fibrosis due to irreversible nerve injury and thus may have relevance to the formation of traumatic neuroma.

Journal Article↗

PubMed2005

Effects of long term NOS inhibition on disease and the immune system in MOG induced EAE.

Hypothesising that systemically and intrathecally produced nitric oxide might play different roles in the EAE pathogenesis, we administered the NOS inhibitor N-nitro-methyl-L-arginine-ester intrathecally or systemically via osmotic minipumps to DA rats with MOG induced EAE. We demonstrate an protective effect of the NOS inhibitor on EAE severity, the extent of CNS inflammation, and demyelination. Intrathecal administration was more effective when compared to systemic administration. The observed effect was accompanied by enhanced anti-MOG IgG1 production. In our model, the therapeutic effect was concluded to be due to direct inhibition of the NO pathway in the CNS.

Animals↗

PubMed2005

CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX3CL1 (fractalkine) in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX3CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX3CL1 and CX3CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis (EAE). METHODS: The expression of CX3CL1 and its receptor CX3CR1 was studied with in situ hybridization histochemical detection of their mRNA with radio labeled cRNA probes in combination with immunohistochemical staining of phenotypic cell markers. Both healthy rat brains and brains from rats with MOG EAE were analyzed. In defined lesional stages of MOG EAE, the number of CX3CR1 mRNA-expressing cells and the intensity of the in situ hybridization signal were determined by image analysis. Data were statistically evaluated by ANOVA, followed by Tukey\primes multiple comparison test. RESULTS: Expression of CX3CL1 mRNA was present within neuronal-like cells located throughout the neuraxis of the healthy rat. Expression of CX3CL1 remained unaltered in the CNS of rats with MOG-induced EAE, with the exception of an induced expression in astrocytes within inflammatory lesions. Notably, the brain vasculature of healthy and encephalitic animals did not exhibit signs of CX3CL1 mRNA expression. The receptor, CX3CR1, was expressed by microglial cells in all regions of the healthy brain. Induction of MOG-induced EAE was associated with a distinct accumulation of CX3CR1 mRNA expressing cells within the inflammatory brain lesions, the great majority of which stained positive for markers of the microglia-macrophage lineage. Analysis in time-staged brain lesions revealed elevated levels of CX3CR1 mRNA in microglia in the periplaque zone, as well as a dramatically enhanced accumulation of CX3CR1 expressing cells within the early-active, late-active and inactive, demyelinated lesions. CONCLUSION: Our data demonstrate constitutive and regulated expression of the chemokine CX3CL1 and its receptor CX3CR1 by neurons/astrocytes and microglia, respectively, within the normal and inflamed rat brain. Our findings propose a mechanism by which neurons and reactive astrocytes may control migration and function of the surrounding microglia. In addition, the accumulation of CX3CR1 expressing cells other than microglia within the inflammatory brain lesions indicate a possible role for CX3CL1 in controlling invasion of peripheral leucocytes to the brain.

Journal Article↗

PubMed2005

Genetic dissection of neurodegeneration and CNS inflammation.

Inflammation and neurodegeneration characterize multiple sclerosis, as well as many other diseases of the central nervous system (CNS). The understanding of the molecular pathways that regulate these processes is of fundamental importance for the development of new therapies. Nerve lesions paradigms in animals can serve as important tools to dissect central features of human CNS disease and by using these models certain key regulators have also been identified. However, our knowledge of how aspects of neurodegeneration and CNS inflammation are regulated on a genomic level is very limited. Such knowledge may help to unravel disease mechanisms. By using a standardized nerve trauma model, ventral root avulsion (VRA), in a series of inbred rat strains we here demonstrate a potent genetic regulation of the degree of neuron death and glial activation. Genome wide mapping of these phenotypes in experimental rat strain crosses identifies several quantitative trait loci (QTLs) controlling nerve lesion-induced nerve cell death, local T cell accumulation and expression of MHC class II on microglia. This approach may lead to the identification of evolutionary conserved genetic polymorphisms in key controlling genes, which can serve as prime candidates for association studies in several human CNS diseases.

Animals↗

PubMed2005

MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction.

Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.

Animals↗

PubMed2005

Eae19, a new locus on rat chromosome 15 regulating experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) and its animal model, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), share a complex genetic predisposition with contributions from the major histocompatibility complex class II genes and many other genes. Linkage mapping in F(2) crosses between the susceptible DA rat strain and the resistant ACI or BN rat strains in various models of autoimmune neuroinflammation have repeatedly displayed suggestive linkage to a region on rat chromosome 15. A direct study of this region was undertaken in congenic strains by transferring resistant ACI alleles to the susceptible DA background. Phenotypic analysis demonstrated lower maximal and cumulative EAE scores in the DA.ACI-D15Rat6-D15Rat71 (C15), DA.ACI-D15Rat6-D15Rat48, D15Rat126-D15Rat71 (C15R3b), and DA.ACI-D15Rat23-D15rat71 (C15R4) strains compared to the parental DA rat strain. Linkage analysis was then performed in a (DA x PVG.AV1)F(7) advanced intercross line, resulting in a LOD score of 4.7 for the maximal EAE score phenotype at the peak marker D15Rat71 and a confidence interval of 13 Mb, overlapping with the congenic fragment defined by the C15R3b and the C15R4 strains. Thus, a new MOG-EAE locus with the designation Eae19 is identified on rat chromosome 15. There are 32 confirmed or predicted genes in the confidence interval, including immune-responsive gene 1 and neuronal ceroid lipofuscinose gene 5. Definition of loci such as Eae19 enables the characterization of genetically regulated, evolutionary conserved disease pathways in complex neuroinflammatory diseases.

Animals↗