Environmental triggers of multiple sclerosis

Kakalacheva, Kristina; Lünemann, Jan D.

doi:10.1016/j.febslet.2011.04.006

Cited by 68 publications

(62 citation statements)

References 81 publications

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“…Viral infections are environmental factors known to trigger the innate immune system [8,34], leading to inflammatory responses preceding the adaptive immune response [35]. Among the receptors for innate immunity, endosomal TLRs are specialized in the recognition of pathogenic nucleic acids, such as viral and bacterial RNA, and TLR7 can also sense self-RNA [6].…”

Section: Discussionmentioning

confidence: 99%

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

et al. 2013

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The innate Toll-like receptor 7 (TLR7) detects infections by recognizing viral and bacterial single-stranded RNA. In addition to pathogen-derived RNA, immune cells expressing high levels of TLR7, such as B cells and dendritic cells (DCs), can be activated by self-RNA. During myelin-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, TLR7 expression is increased within the central nervous system (CNS). To define the contribution of TLR7 to the development of EAE, we evaluated the course of the disease in C57BL/6-Tlr7-deficient mice compared with that in WT mice and found that TLR7-deficient mice had decreased disease severity. This protection was associated with decreased myelin oligodendrocyte glycoprotein-specific T-cell activation by primed DCs, decreased circulating autoantibodies, attenuated inflammation within the CNS, and increased Foxp3 + regulatory T cells in the periphery and in the CNS. In conclusion, we show that TLR7 is involved in the maintenance of autoimmunity in the pathogenesis of EAE.Keywords: EAE r IL-10 r Multiple sclerosis r TLR7 r Treg cell IntroductionRecognition of microbial components by Toll-like receptors (TLRs) is crucial for host responses against pathogens. While most TLRs are expressed on the cell surface, others such as TLR3, -7, -8, and -9 are expressed intracellularly within endosomal compartments where they detect nucleic acids. Endosomal TLRs recognize viral double-stranded RNA (TLR3), unmethylated CpG DNA Correspondence: Dr. Marie-Laure Santiago-Raber e-mail: marie.santiago@unige.ch (TLR9), and viral single-stranded RNA or synthetic compounds such as imidazoquinolines (TLR7/TLR8) (as reviewed by Kawai and Akira [1]). Previous studies have further provided evidence for the involvement of TLR signaling in the induction of autoantibodies [2,3]. Others studies have implicated TLR7 gene duplication in the pathogenesis of autoimmune diseases such as lupus [4,5]. TLR7 is mainly expressed by B cells but also by dendritic cells (DCs), principally plasmacytoid DCs (pDCs). B cells and pDCs appear to have developed specialized mechanisms for enhancing the delivery of potential ligands to TLR7-and TLR9-containing compartments [6]. In view of the pivotal role of (i) DCs in regulating immunity and tolerance [7], (ii) B cells in the C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 46-57 Cellular immune response 47 adaptive immune response, and (iii) regulatory T (Treg) cells in maintaining T-cell tolerance, we evaluated the importance of DC, B-cell, and Treg-cell activation and generation by ligandbound TLR7 in the framework of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system (CNS), characterized by the infiltration of inflammatory cells, including autoreactive CD4 + T cells and antigen-presenting cells (APCs), which leads to demyelination and axonal damage [8]. Even though CD4 + T-cell autorea...

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Section: Discussionmentioning

confidence: 99%

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

et al. 2013

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“…MS is at present considered a complex disease, associated to an interplay between genetic and environmental conditions [28], [29], [30]. Myelin Basic protein (MBP) peptide, derived from myelin sheaths surrounding axons, is known to be one of the auto antigens important in the pathogenesis of MS [31], particularly epitope MBP 85–98 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

et al. 2013

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Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.

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“…Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system affecting more than 2.5 million people worldwide [1,2]. The incidence and prevalence of MS are well-recognized to vary across large geographic regions.…”

Section: Introductionmentioning

confidence: 99%

Application of Three Focused Cluster Detection Methods to Study Geographic Variation in the Incidence of Multiple Sclerosis in Manitoba, Canada

Torabi¹,

Green²,

Yu³

et al. 2014

Neuroepidemiology

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Background: Macroscopic geographic variation in the incidence and prevalence of MS is well-recognized. Microscopic geographic variation in the distribution of MS is also recognized, but less well-studied. Most studies have focused on prevalent cases of MS, although studies of variation in disease incidence are more relevant for developing etiologic hypotheses. We aimed to study geographic variation in the incidence of MS using three different methods. Methods: We used population-based administrative (health claims) data to identify 2,290 incident cases of MS in the province of Manitoba, Canada from 1990 to 2006. We applied three focused cluster-detection procedures, including the circular spatial scan statistic (CSS), flexible spatial scan statistic (FSS), and Bayesian disease mapping (BYM), to the dataset. Results: The CSS and FSS methods identified 30 and 26 regions as potential clusters, respectively, although the regions identified differed slightly due to the non-circular shape of some regions in Manitoba. The BYM approach identified 37 regions as potential clusters, again with some differences as compared to the other two methods. Twelve regions were identified as potential clusters by all three methods. All methods identified the western part of the city of Winnipeg as a significant cluster. Using the BYM approach, the incidence of MS was highest among areas of higher socioeconomic status. Conclusions: Two methods CSS and FSS only capture geographical variations and are not able to control for confounders at the same time which may lead to mis-identification of clusters. However, the BYM method can simultaneously identify geographical variations and control for possible confounders.

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Environmental triggers of multiple sclerosis

Cited by 68 publications

References 81 publications

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

Application of Three Focused Cluster Detection Methods to Study Geographic Variation in the Incidence of Multiple Sclerosis in Manitoba, Canada

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Environmental triggers of multiple sclerosis

Cited by 68 publications

References 81 publications

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

Application of Three Focused Cluster Detection Methods to Study Geographic Variation in the Incidence of Multiple Sclerosis in Manitoba, Canada

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TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3⁺Treg cells