Hoppenbrouwers IA, Aulchenko YS, Ebers GC, Ramagopalan SV, Oostra BA, van Duijn CM, Hintzen RQ
Genes Immun 2008 Apr 10
MS Centre ErasMS, Erasmus MC, Department of Neurology, Rotterdam, The Netherlands
HLA-DRB1 is the major locus associated with risk for Multiple Sclerosis (MS). A recent genome-wide study showed three additional Single-Nucleotide Polymorphisms (SNPs), within the IL-2RA and IL-7RA genes respectively, also to be associated with MS.
Consistent association but lower significance was found for 13 other SNPs.
In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population.
Apart from the Human Leukocyte Antigen locus, the EVI5 gene on Chromosome 1 was confirmed as a novel risk gene, with Odds Ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P=0.01).
The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS.
On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P=0.03 and OR 1.15; P=0.04).
This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.
Genes and Immunity advance online publication, 10 April 2008; doi:10.1038/gene.2008.22.
IL-2RA And IL-7RA Genes Confer Susceptibility For Multiple Sclerosis In Two Independent European Populations
Weber F, Fontaine B, Cournu-Rebeix I, Kroner A, Knop M, Lutz S, Müller-Sarnowski F, Uhr M, Bettecken T, Kohli M, Ripke S, Ising M, Rieckmann P, Brassat D, Semana G, Babron MC, Mrejen S, Gout C, Lyon-Caen O, Yaouanq J, Edan G, Clanet M, Holsboer F, Clerget-Darpoux F, Müller-Myhsok B
Genes Immun 2008 Mar 20
Max Planck Institute of Psychiatry, Munich, Germany
Multiple Sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden.
MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene.
The well-established Human Leukocyte Antigen (HLA) association does not completely explain the genetic impact on disease susceptibility.
However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes.
Recently, associations with two Single Nucleotide Polymorphisms (SNPs) in the IL-2RA gene (rs12722489, rs2104286) and one SNP in the IL-7RA gene (rs6897932) have been reported by several groups.
These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA).
We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5.
The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.
Genes and Immunity advance online publication, 20 March 2008; doi:10.1038/gene.2008.14.
Cutting Edge: Involvement Of The Type 1 IFN Production And Signaling Pathway In LipoPolySaccharide-Induced IL-10 Production
Chang EY, Guo B, Doyle SE, Cheng G
J Immunol 2007 Jun 1;178(11):6705-9
University of California, Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA 90095, USA
Macrophages respond to LPS by the rapid activation of ProInflammatory Cytokine that serve to initiate host defense against microbial invasion.
To prevent injury to the host from excess production of these Cytokines, IL-10 is up-regulated to feedback inhibit the ProInflammatory response.
However, the molecular events responsible for LPS-induced up-regulation of IL-10 remain to be elucidated.
In this study, we provide evidence that production of and signaling by Type 1 IFN is required for LPS-induced IL-10 up-regulation.
In addition, we demonstrate that defect in Type 1 IFN production and signaling results in a trend toward LPS-mediated superinduction of ProInflammatory genes and Cytokines in bone marrow-derived Macrophages.
Our findings suggest a novel AntiInflammatory role for the Type 1 IFN production and signaling pathway in regulating LPS response in bone marrow-derived Macrophages.
Type 1 Interferons As Anti-Inflammatory Mediators
Etty N. Benveniste and Hongwei Qin
Sci STKE 2007 Dec 11;2007(416):pe70
University of Alabama at Birmingham, Department of Cell Biology, Birmingham, AL 35294–0005, USA
The Type 1 Interferons (IFNs), Interferon- and IFN-ß, are Cytokines that have AntiViral, AntiProliferative, and ImmunoModulatory activities. Data are now emerging that suggest that Type 1 IFNs are also important mediators of AntiInflammatory Responses.
These findings, largely driven by studies to explain the beneficial effects of IFN-ß in the treatment of Multiple Sclerosis, an Autoimmune Disease of the Central Nervous System, offer a number of mechanisms for the AntiInflammatory properties of Type 1 IFNs.
Type 1 IFNs, through their ability to induce the ImmunoSuppressive Cytokine InterLeukin-10 (IL-10), mediate the inhibition of ProInflammatory gene products.
In addition, Type 1 IFNs induce other ImmunoSuppressive mediators such as suppressor of Cytokine signaling–1 (SOCS-1) and TristeTraPolin (TTP), which act by divergent mechanisms to restore homeostasis to the Immune System.
Furthermore, Type I IFNs mediate AntiInflammatory and protective effects in a variety of Autoimmune Disease models such as Experimental Colitis, Experimental Allergic Encephalomyelitis, Experimental Arthritis, and Neonatal Inflammation.
Here, we discuss the molecular basis for the AntiInflammatory properties of Type 1 IFNs and their therapeutic potential in AutoImmune and Inflammatory Diseases.
Could Cytokines Levels Or Adhesion Molecules Expression Be Predictor Of IFN-beta Treatment Response In Multiple Sclerosis Patients?
Sega S, Horvat A, Rot U, Wraber B, Ihan A
Clin Neurol NeuroSurg 2008 Apr 5
University Clinical Centre Ljubljana, Department of Neurology, Zaloska 2, 1525 Ljubljana, Slovenia
Some patients with Relapsing/Remitting Multiple Sclerosis (RRMS) do not respond to treatment with Interferon-ß and continue to have relapses and new enhancing lesions on MRI.
The markers which would predict the treatment response are still not known.
The objectives of the study were to compare Cytokines levels (IFN-, IL-4, IL-6, IL-10) and expression of Adhesion Molecules before and during treatment in responders and nonresponders to IFN-ß treatment.
Twenty-nine patients with RRMS were enrolled in the study.
Cytokine levels were evaluated by ELISA in supernatants of IONO/PMA activated PBMC cultures (IFN-, IL-4, IL-6, IL-10), and by flow cytometry (IntraCellular IFN-, IL-4 and IL-2R expression) before and during treatment.
Expression of Adhesion Molecules (VLA-4, ICAM-1) was evaluated by flow cytometry (CD49+ and CD54+) before and during treatment.
Only 9 of 29 patients were responders to treatment according to definition (no relapse in the first 2 years of treatment).
We found significant differences in the expression of IL-2R after 1 month of treatment, IntraCellular IFN- after 6 months of treatment and IL-10 level in nonactivated PBMC cultures after 1 week of treatment.
We concluded that the differences we had found between responders and nonresponders are most probably incidental and not predictive of treatment response.
Our study shows that Cytokines levels and expression of Adhesion Molecules cannot be used as markers for treatment response.
Relapses In Multiple Sclerosis Are Associated With Increased CD8+ T-Cell Mediated CytoToxicity In CSF
Malmeström C, Lycke J, Haghighi S, Andersen O, Carlsson L, Wadenvik H, Olsson B
J NeuroImmunol 2008 Apr 5
Sahlgrenska University Hospital, Göteborg University, Sahlgrenska Academy, Department of Neurology, Göteborg, Sweden
MS is thought to be mediated by CD4+ T-Helper Cells.
To investigate the importance of CD8+ CytoToxic T-Cells in MS we analyzed peripheral blood T-Cells by DNA microarray, and Plasma and CSF levels of Granzymes from MS patients and controls.
CytoToxic gene expression was decreased in peripheral T-Cells from RRMS patients whereas plasma levels of Granzymes were unchanged.
However, Granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission.
Thus, CD8+ T-Cell-mediated CytoToxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the ImmunoPathogenesis of clinical relapses.
Predicting Clinical Progression In Multiple Sclerosis With The Magnetic Resonance Disease Severity Scale
Bakshi R, Neema M, Healy BC, Liptak Z, Betensky RA, Buckle GJ, Gauthier SA, Stankiewicz J, Meier D, Egorova S, Arora A, Guss ZD, Glanz B, Khoury SJ, Guttmann CR, Weiner HL
Arch Neurol 2008 Nov;65(11):1449-53
Brigham and Women's Hospital, Department of Neurology, Boston, MA 02115, USA
Individual Magnetic Resonance Imaging (MRI) disease severity measures, such as Atrophy or Lesions, show weak relationships to clinical status in patients with Multiple Sclerosis (MS).
To combine MS-MRI measures of disease severity into a composite score.
Design & Setting
Retrospective analysis of prospectively collected data. Community-based and referral subspecialty clinic in an academic hospital.
A total of 103 patients with MS with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom:
- 62 (60.2%) had the Relapsing/Remitting
- 33 (32.0%) the Secondary/Progressive, and
- 8 (7.8%) the Primary/Progressive form
Main Outcome Measures
Brain MRI measures included baseline T2 HyperIntense (T2LV) and T1 HypoIntense (T1LV) Lesion Volume and Brain Parenchymal Fraction (BPF), a marker of global Atrophy.
The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2.
The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV.
The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the Relapsing/Remitting form from those with the Secondary/Progressive form.
Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score.
Combining Brain MRI lesion and Atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.