Publications by authors named "Ellen Iacobaeus"

18 Publications

  • Page 1 of 1

Multiple sclerosis and COVID-19: The Swedish experience.

Acta Neurol Scand 2021 May 24. Epub 2021 May 24.

Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

The COVID-19 pandemic has brought challenges for healthcare management of patients with multiple sclerosis (MS). Concerns regarding vulnerability to infections and disease-modifying therapies (DMTs) and their complications have been raised. Recent published guidelines on the use of DMTs in relation to COVID-19 in MS patients have been diverse between countries with lack of evidence-based facts. In Sweden, there exists a particular interest in anti-CD20 therapy as a possible risk factor for severe COVID-19 due to the large number of rituximab-treated patients off-label in the country. Rapid responses from the Swedish MS Association (SMSS) and the Swedish MS registry (SMSreg) have resulted in national guidelines on DMT use for MS patients and implementation of a COVID-19 module in the SMSreg. Recently updated guidelines also included recommendations on COVID-19 vaccination with regard to the different DMTs. Social distancing policies forced implementation of telemedicine consultation to replace in-person consultations as part of regular MS health care. Patient-reported outcome measures (PROMs) in SMSreg have been useful in this respect. This paper reports our experiences on the progress of national MS health care during the COVID-19 pandemic, in addition to offering an overview of the present scientific context.
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http://dx.doi.org/10.1111/ane.13453DOI Listing
May 2021

Multipel skleros och covid-19 – kunskapen ännu begränsad.

Lakartidningen 2020 10 30;117. Epub 2020 Oct 30.

professor, överläkare, institutionen för neurovetenskap, Uppsala universitet; Neurologi, Akademiska sjukhuset, Uppsala.

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October 2020

Aggressive multiple sclerosis (1): Towards a definition of the phenotype.

Mult Scler 2020 06 12:1352458520925369. Epub 2020 Jun 12.

Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.
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http://dx.doi.org/10.1177/1352458520925369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412876PMC
June 2020

Aggressive multiple sclerosis (2): Treatment.

Mult Scler 2020 06 12:1352458520924595. Epub 2020 Jun 12.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.
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http://dx.doi.org/10.1177/1352458520924595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412878PMC
June 2020

Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis-A Phase I Study.

J Clin Med 2019 Dec 2;8(12). Epub 2019 Dec 2.

Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute, 141 52 Stockholm, Sweden.

Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1-2 × 10 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3 Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects.
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http://dx.doi.org/10.3390/jcm8122102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947442PMC
December 2019

The Complement System Is Essential for the Phagocytosis of Mesenchymal Stromal Cells by Monocytes.

Front Immunol 2019 20;10:2249. Epub 2019 Sep 20.

Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Mesenchymal stromal cell (MSC) therapy is a promising tool in the treatment of chronic inflammatory diseases. This has been ascribed to the capacity of MSC to release a large variety of immune-modulatory factors. However, all aspects of the mode of therapeutic MSC action in different diseases remain unresolved, mainly because most of the infused MSC are undetectable in the circulation within hours after infusion. The aim of this study was to elucidate the fate of MSC after contact with plasma. We found that upon contact with blood, complement proteins including C3b/iC3b are deposited on MSC. Importantly, we also found that complement bound to MSC enhanced their phagocytosis by classical and intermediate monocytes via a mechanism that involves C3 but not C5. Thus, we describe for the first time a mechanism which might explain, at least partly, why MSC are not found in the blood circulation after infusion. Our results indicate that MSC immune-modulatory effects could be mediated by monocytes that have phagocytosed them.
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http://dx.doi.org/10.3389/fimmu.2019.02249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763726PMC
October 2020

Phenotypic and functional alterations of myeloid-derived suppressor cells during the disease course of multiple sclerosis.

Immunol Cell Biol 2018 09 19;96(8):820-830. Epub 2018 Apr 19.

Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system involving dysregulated encephalitogenic T cells. Myeloid-derived suppressor cells (MDSCs) have been recognized for their important function in regulating T-cell responses. Recent studies have indicated a role for MDSCs in autoimmune diseases, but their significance in MS is not clear. Here, we assessed the frequencies of CD14 HLA-DR monocytic MDSCs (Mo-MDSCs) and CD33 CD15 CD11b HLA-DR granulocytic MDSCs (Gr-MDSCs) and investigated phenotypic and functional differences of Mo-MDSCs at different clinical stages of MS and in healthy subjects (HC). Increased frequencies of Mo-MDSCs (P < 0.05) and Gr-MDSCs (P < 0.05) were observed in relapsing-remitting MS patients during relapse (RRMS-relapse) compared to stable RRMS (RRMS-rem). Secondary progressive MS (SPMS) patients displayed a decreased frequency of Mo-MDSCs and Gr-MDSCs compared to HC (P < 0.05). Mo-MDSCs within RRMS patients expressed significantly higher cell surface protein levels of CD86 and CD163 compared to SPMS patients. Mo-MDSCs within SPMS exhibited decreased mRNA expression of interleukin-10 and heme oxygenase 1 compared to RRMS and HC. Analysis of T-cell regulatory function of Mo-MDSCs demonstrated T-cell suppressive capacity in RRMS and HCs, while Mo-MDSCs of SPMS promoted autologous T-cell proliferation, which aligned with a differential cytokine profile compared to RRMS and HCs. This study is the first to show phenotypic and functional shifts of MDSCs between clinical stages of MS, suggesting a role for MDSCs as a therapeutic target to prevent MS disease progression.
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http://dx.doi.org/10.1111/imcb.12042DOI Listing
September 2018

The national incidence of PML in Sweden, 1988-2013.

Neurology 2018 02 10;90(6):e498-e506. Epub 2018 Jan 10.

From the Department of Clinical Neuroscience, Division of Neurology (E.I., R.H., T.O., L.B.), Neuroimmunology Unit, Center for Molecular Medicine, Department of Clinical Neuroscience (T.O., L.B.), and Center for Pharmacoepidemiology (S. Burkill, S. Bahmanyar, C.B.) and Clinical Epidemiology Unit (M.F., S.M.), Department of Medicine, Solna, Karolinska Institutet, Stockholm; Clinical Epidemiology and Biostatistics (S.M.), School of Medical Sciences, Örebro University, Sweden; and Department of Epidemiology and Public Health (S.M.), University College London, UK.

Objective: To investigate the incidence of progressive multifocal leukoencephalopathy (PML) and patient characteristics in Sweden between 1988 and 2013.

Methods: All PML diagnoses in Sweden between 1988 and 2013 were identified in the National Patient Register. Information to validate the diagnosis and patient characteristics was obtained from medical records.

Results: Medical record review classified 108 out of 250 patients (43%) as definite (n = 84), probable (n = 4), or possible (n = 20) PML according to diagnostic criteria. Accurate diagnoses were more common in records obtained from neurology departments (82% of patients seen in neurology departments) compared with other departments (31%) ( < 0.001). The incidence of PML increased from a largely stable level at 0.026 (95% confidence interval [CI] 0.021-0.031) per 100,000 individuals per year during 1988-2010 to 0.11 (95% CI 083-0.137) during 2011-2013, during which time there was a notable increase ( < 0.001). Hematologic malignancies (n = 34), HIV/AIDS (n = 33), and autoimmune disease (n = 23) were the most common underlying diseases. Treatment with a monoclonal antibody prior to PML diagnosis was identified in 26 patients.

Conclusion: An increased incidence of PML in Sweden was observed and coincided with the prior use of monoclonal antibody treatment. The high level of misdiagnosis emphasizes the importance of immediate contact with a neurology center upon suspicion of PML.
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http://dx.doi.org/10.1212/WNL.0000000000004926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818018PMC
February 2018

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination.

Stem Cells Transl Med 2017 10 23;6(10):1840-1851. Epub 2017 Sep 23.

Division of Clinical Immunology, Department of Laboratory Medicine, Finland.

Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRβ), CD73, CD271, alpha-smooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146 PDGFRβ Ki67 cells and CD73 CD271 PDGFRβ Ki67 cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146 PDGFRβ Ki67 and CD73 CD271 PDGFRβ Ki67 MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146 PDGFRβ Ki67 MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73 CD271 adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS. Stem Cells Translational Medicine 2017;6:1840-1851.
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http://dx.doi.org/10.1002/sctm.17-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430046PMC
October 2017

Consensus guidelines for lumbar puncture in patients with neurological diseases.

Alzheimers Dement (Amst) 2017 18;8:111-126. Epub 2017 May 18.

Department of Geriatrics, Kalmar County Hospital, Kalmar, Sweden.

Introduction: Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain.

Methods: We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III).

Results: Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications.

Discussion: When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.
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http://dx.doi.org/10.1016/j.dadm.2017.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454085PMC
May 2017

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience.

J Neurol Neurosurg Psychiatry 2014 Oct 19;85(10):1116-21. Epub 2014 Feb 19.

Department of Neuroscience, Uppsala University, Uppsala, Sweden Department of Neurology, Uppsala University Hospital, Uppsala, Sweden.

Background: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

Methods: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

Results: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

Conclusions: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.
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http://dx.doi.org/10.1136/jnnp-2013-307207DOI Listing
October 2014

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

Mult Scler 2013 Nov 21;19(13):1802-9. Epub 2013 May 21.

Neurological Laboratory, Innogentecis and Roche, VU University Medical Center, Netherlands.

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.
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http://dx.doi.org/10.1177/1352458513488232DOI Listing
November 2013

The expression of VEGF-A is down regulated in peripheral blood mononuclear cells of patients with secondary progressive multiple sclerosis.

PLoS One 2011 May 6;6(5):e19138. Epub 2011 May 6.

Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institute Solna, Center for Molecular Medicine, Stockholm, Sweden.

Background: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS.

Methodology/principal Findings: VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS.

Conclusions/significance: Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089609PMC
May 2011

Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course.

Mult Scler 2011 Mar 6;17(3):335-43. Epub 2010 Dec 6.

Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska University Hospital, Stockholm, Sweden.

Background: Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments.

Objective: Here we validate the potential role of CSF CXCL13 as a biomarker for aspects of MS in a large amount of clinical material, the majority collected at early diagnostic work-up.

Methods: CXCL13 was measured by ELISA in 837 subjects: relapsing-remitting MS (RRMS; n=323), secondary progressive MS (SPMS; n=40), primary progressive MS (PPMS; n=24), clinically isolated syndrome (CIS; n=79), other neurological diseases (ONDs; n=181), ONDs with signs of inflammation or viral/bacterial infections (iONDs; n=176) and healthy controls (n=14).

Results: Subjects with viral/bacterial infections had extremely high CXCL13 levels compared to all included groups (p<0.0001). CXCL13 was otherwise significantly higher in MS compared to the remaining controls (p<0.0001), and CIS (p<0.01). A significant and positive correlation between CXCL13 and relapse rate, the results obtained for the Expanded Disability Status Scale (EDSS) and the number of lesions detected by MRI was demonstrated. CXCL13 was increased in CIS conversion to clinically definite MS (p<0.001). Oligoclonal immunoglobulin band (OCB)-positive CIS or MS had significantly increased CXCL13 levels compared to OCB-negative CIS or MS (p<0.001 and p<0.0001, respectively).

Conclusion: CXCL13 was associated with disease exacerbations and unfavourable prognosis in RRMS. Increased CXCL13 was not specific for MS since subjects with viral/bacterial infections exhibited even higher levels. High levels predicted CIS conversion to MS. We suggest that measurement of CSF CXCL13 can be part of the armamentarium in the diagnostic and prognostic work-up in MS and be of help in future treatment decisions.
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http://dx.doi.org/10.1177/1352458510389102DOI Listing
March 2011

Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.

Nat Genet 2007 Sep 29;39(9):1108-13. Epub 2007 Jul 29.

Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden.

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.
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http://dx.doi.org/10.1038/ng2106DOI Listing
September 2007

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

Genetics 2005 May 16;170(1):283-9. Epub 2005 Feb 16.

Center for Molecular Medicine, Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1534/genetics.104.035261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449709PMC
May 2005