CoChat
Sign Up
Cited by 52Multiple Sclerosis Research StudiesPsoriasis: Treatment and PathogenesisT-cell and B-cell Immunology

Environmental control of autoimmune inflammation in the central nervous system

Open access
Rothhammer, Veit, Quintana, Francisco J·2016·Current Opinion in Immunology
DOI 10.1016/j.coi.2016.09.002PMC PMC5125858
Open this paper in CoChat — free account

Abstract

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system (CNS), which causes severe disability and requires extensive medical attention and treatment. While the infiltration of pathogenic immune cells into the CNS leads to the formation of inflammatory lesions in its initial relapsing-remitting stage, late stages of MS are characterized by progressive neuronal loss and demyelination even without continued interaction with the peripheral immune compartment. Several genetic and environmental factors modulate and influence these processes on multiple levels. Genetic variants confer a predisposition for the development of MS, but are not accessible to therapeutic intervention as of today. However, migration studies suggest that environmental factors influence disease development, activity and progression. This article reviews mechanisms of disease pathogenesis in MS and their modulation by environmental factors such as geographical localization, the gut microbiome and the diet.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.coi.2016.09.002

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • True pathogenic antigens causing the breakdown have not been identified for many autoimmune diseases, including rheumatoid arthritis and other tissue-specific disorders.

    “However, true pathogenic antigens causing the breakdown have not been identified for many autoimmune diseases, including RA and other tissue-specific disorders (229–231).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [230]

    The gut microbiome and dietary factors section mentions rheumatoid arthritis only in connection with the gut microbiome. The mechanisms of disease pathogenesis section discusses immune cells in multiple sclerosis, but neither section says that pathogenic antigens remain unidentified in rheumatoid arthritis or other tissue-specific autoimmune diseases. Searches for unidentified pathogenic antigens and autoantigens found no passage addressing that claim; page numbers were not available in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. [1]Dilokthornsakul P Multiple sclerosis prevalence in the United States commercially insured population Neurology 86 1014 1021 2016 26888980 PMC4799713
  2. [2]Kingwell E Incidence and prevalence of multiple sclerosis in Europe: a systematic review BMC Neurol 13 128 2013 24070256 PMC3856596
  3. [3]Lublin FD Defining the clinical course of multiple sclerosis: the 2013 revisions Neurology 83 278 286 2014 24871874 PMC4117366
  4. [4]Wingerchuk DM Carter JL Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies Mayo Clin Proc 89 225 240 2014 24485135
  5. [5]Willer CJ Twin concordance and sibling recurrence rates in multiple sclerosis Proc Natl Acad Sci U S A 100 12877 12882 2003 14569025 PMC240712
  6. [6]Ebers GC Sadovnick AD Risch NJ A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group Nature 377 150 151 1995 7675080
  7. [7]Ascherio A Munger KL Lunemann JD The initiation and prevention of multiple sclerosis Nat Rev Neurol 8 602 612 2012 23045241 PMC4467212
  8. Bashinskaya VV Kulakova OG Boyko AN Favorov AV Favorova OO A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches Hum Genet 134 1143 1162 2015 This review gives an overview over of the approaches of genome-wide association studies (GWAS) and hypothesis-driven approaches for the detection of risk loci for MS 26407970
  9. [9]Welter D The NHGRI GWAS Catalog, a curated resource of SNP-trait associations Nucleic Acids Res 42 D1001 1006 2014 24316577 PMC3965119
  10. [10]Ramagopalan SV Rare variants in the CYP27B1 gene are associated with multiple sclerosis Ann Neurol 70 881 886 2011 22190362
  11. [11]Patsopoulos NA Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci Ann Neurol 70 897 912 2011 22190364 PMC3247076
  12. [12]Sadovnick AD Genetic background of multiple sclerosis Autoimmunity reviews 11 163 166 2012 21619948
  13. [13]Hemmer B Kerschensteiner M Korn T Role of the innate and adaptive immune responses in the course of multiple sclerosis Lancet Neurol 14 406 419 2015 25792099
  14. [14]Mahad DH Trapp BD Lassmann H Pathological mechanisms in progressive multiple sclerosis Lancet Neurol 14 183 193 2015 25772897
  15. [15]Wang Y An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling Nature communications 5 4432 2014 PMC4118494 25043484
  16. [16]Farrokhi V Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis Clin Transl Immunology 2 e8 2013 25505950 PMC4232052
  17. Rothhammer V Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor Nat Med 2016 This research article shows direct effects of tryptophan metabolites generated by commensal bacteria and host enzymes on the activation of anti-inflammatory pathways in astrocytes PMC4899206 27158906
  18. [18]Acheson ED Bachrach CA Wright FM Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables Acta Psychiatr Scand Suppl 35 132 147 1960 13681205
  19. [20]Alonso A Hernan MA Temporal trends in the incidence of multiple sclerosis: a systematic review Neurology 71 129 135 2008 18606967 PMC4109189
  20. [21]Berg-Hansen P Moen SM Harbo HF Celius EG High prevalence and no latitude gradient of multiple sclerosis in Norway Mult Scler 20 1780 1782 2014 24603884
  21. [22]Koch-Henriksen N Sorensen PS Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere? J Neurol Sci 311 58 63 2011 21982346
  22. [23]Taylor BV Latitudinal variation in incidence and type of first central nervous system demyelinating events Mult Scler 16 398 405 2010 20167594
  23. [24]Simpson S Jr Blizzard L Otahal P Van der Mei I Taylor B Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis J Neurol Neurosurg Psychiatry 82 1132 1141 2011 21478203
  24. [25]McLeod JG Hammond SR Kurtzke JF Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration Journal of neurology 258 1140 1149 2011 21264474 PMC3101360
  25. [26]Marsh-Wakefield F Byrne SN Photoimmunology and Multiple Sclerosis Curr Top Behav Neurosci 26 117 141 2015 25608722
  26. [27]Simon KC Munger KL Ascherio A Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics Curr Opin Neurol 25 246 251 2012 22547098 PMC4815910
  27. [28]Munger KL Vitamin D intake and incidence of multiple sclerosis Neurology 62 60 65 2004 14718698
  28. [29]Ashtari F Toghianifar N Zarkesh-Esfahani SH Mansourian M Short-term effect of high-dose vitamin D on the level of interleukin 10 in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial Neuroimmunomodulation 22 400 404 2015 26401986
  29. [30]Stein MS A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis Neurology 77 1611 1618 2011 22025459
  30. [31]Rosecrans R Dohnal JC Seasonal vitamin D changes and the impact on health risk assessment Clin Biochem 47 670 672 2014 24525255
  31. [32]Spelman T Seasonal variation of relapse rate in multiple sclerosis is latitude dependent Ann Neurol 76 880 890 2014 25283272
  32. [33]Brzezinski A Melatonin in humans The New England journal of medicine 336 186 195 1997 8988899
  33. [35]Chen SJ Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis Int Immunopharmacol 31 169 177 2016 26735612
  34. [36]Alvarez-Sanchez N Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance Brain Behav Immun 50 101 114 2015 26130320
  35. [37]Emamgholipour S Hossein-Nezhad A Sahraian MA Askarisadr F Ansari M Evidence for possible role of melatonin in reducing oxidative stress in multiple sclerosis through its effect on SIRT1 and antioxidant enzymes Life Sci 145 34 41 2016 26679105
  36. [38]Kaur C Ling EA Antioxidants and neuroprotection in the adult and developing central nervous system Curr Med Chem 15 3068 3080 2008 19075654
  37. Belbasis L Bellou V Evangelou E Ioannidis JP Tzoulaki I Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses Lancet Neurol 14 263 273 2015 This review gives an overview of the most relevant published work on environmental risk factors for MS based on their statistic validity. IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA), infectious mononucleosis and smoking were identified as most valid risk factors 25662901
  38. [40]van der Mei IA Simpson S Jr Stankovich J Taylor BV Individual and joint action of environmental factors and risk of MS Neurol Clin 29 233 255 2011 21439439
  39. [42]Group NHW The NIH Human Microbiome Project Genome Res 19 2317 2323 2009 19819907 PMC2792171
  40. [43]Kaser A Zeissig S Blumberg RS Inflammatory bowel disease Annu Rev Immunol 28 573 621 2010 20192811 PMC4620040
  41. [44]Vaahtovuo J Munukka E Korkeamaki M Luukkainen R Toivanen P Fecal microbiota in early rheumatoid arthritis J Rheumatol 35 1500 1505 2008 18528968
  42. [47]Wekerle H Berer K Krishnamoorthy G Remote control-triggering of brain autoimmune disease in the gut Curr Opin Immunol 25 683 689 2013 24161654
  43. [48]Lee YK Menezes JS Umesaki Y Mazmanian SK Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis Proc Natl Acad Sci U S A 108 Suppl 1 4615 4622 2011 20660719 PMC3063590
  44. [50]Yokote H NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora The American journal of pathology 173 1714 1723 2008 18974295 PMC2626383
  45. [51]Ochoa-Reparaz J Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis J Immunol 183 6041 6050 2009 19841183
  46. [52]Wang D Lu Z Hu L Zhang Y Hu X Macrolide antibiotics aggravate experimental autoimmune encephalomyelitis and inhibit inducible nitric oxide synthase Immunol Invest 38 602 612 2009 19811424
  47. [53]Mor F Cohen IR Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin Proc Natl Acad Sci U S A 110 2981 2986 2013 23382225 PMC3581969
  48. [55]Wang Y A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation Gut Microbes 5 552 561 2014 25006655
  49. [56]Ochoa-Reparaz J A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease Mucosal Immunol 3 487 495 2010 20531465
  50. Tremlett H Gut microbiota in early pediatric multiple sclerosis: a case-control study Eur J Neurol 2016 This is an exciting pilot study in pediatric MS demonstrating alterations in the gut microbiome of MS patients as compared to healthy controls. In MS patients, the altered microbiome is enriched in pathways relevant for neurodegeneration and affected by immunomodulatory treatment PMC4955679 27176462
  51. [58]Miller PG Bonn MB Franklin CL Ericsson AC McKarns SC TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease J Immunol 195 4668 4684 2015 26475926 PMC8449043
  52. Haghikia A Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine Immunity 43 817 829 2015 This research article shows the differential influence of dietary long and short fatty acids on Th1, Th17, and Treg differentiation locally in the gut and their subsequent relevance for disease induction in EAE 26488817
  53. Erny D Host microbiota constantly control maturation and function of microglia in the CNS Nat Neurosci 18 965 977 2015 Host microbiota influence microglia homeostasis and response to immunologic challenge via a peripheral mechanism involving short-chain fatty acids, underlining the “remote control” of the diet and the microbiome over CNS resident cell types 26030851 PMC5528863
  54. [62]Sedaghat F Jessri M Behrooz M Mirghotbi M Rashidkhani B Mediterranean diet adherence and risk of multiple sclerosis: a case-control study Asia Pac J Clin Nutr 25 377 384 2016 27222422
  55. [63]Riccio P Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study Exp Biol Med (Maywood) 241 620 635 2016 26785711 PMC4950325
  56. [64]Riccio P Rossano R Nutrition facts in multiple sclerosis ASN Neuro 7 2015 PMC4342365 25694551
  57. [65]Sedel F High doses of biotin in chronic progressive multiple sclerosis: a pilot study Mult Scler Relat Disord 4 159 169 2015 25787192
  58. [66]Hoare S Higher intake of omega-3 polyunsaturated fatty acids is associated with a decreased risk of a first clinical diagnosis of central nervous system demyelination: Results from the Ausimmune Study Mult Scler 22 884 892 2016 26362904
  59. [67]Jorg S High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells Exp Neurol 279 212 222 2016 26976739
  60. [68]Hucke S Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity J Autoimmun 67 90 101 2016 26584738
  61. [69]Kleinewietfeld M Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells Nature 496 518 522 2013 23467095 PMC3746493
  62. [70]Wu C Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1 Nature 496 513 517 2013 23467085 PMC3637879
  63. Farez MF Fiol MP Gaitan MI Quintana FJ Correale J Sodium intake is associated with increased disease activity in multiple sclerosis J Neurol Neurosurg Psychiatry 86 26 31 2015 In this observational study, high sodium intake is associated with an increase in disease activity as measured by clinical and radiological criteria, underlining experimental results in EAE 25168393 PMC12930402
  64. [72]Amirkhani A Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients Eur J Neurol 12 625 631 2005 16053472
  65. [73]Monteleone I Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract Gastroenterology 141 237 248 248 e231 2011 21600206
  66. Lamas B CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands Nat Med 22 598 605 2016 This research article shows the mutual interaction between the diet, the host and the gut microbiota and its impact on inflammatory bowel disease. Together with ref. 17, it describes a novel immunomodulatory mechanism involving ligands to AHR generated from dietary tryptophan by microbiota and host metabolism 27158904 PMC5087285

Cited by

Sorted by citations

Authors
Rothhammer, V., & Quintana, F. J.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Quintana, Francisco J
ORCID
Venue
Current Opinion in Immunology
Publisher
Elsevier BV
Published
2016-12
Volume
43
Pages
46-53
ISSN
0952-7915 (ISSN-L)
DOI
10.1016/j.coi.2016.09.002
PMC
PMC5125858
OpenAlex
W2529679074
Cited by
52
References
7
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 11 · 2019: 5 · 2018: 6 · 2017: 8
FWCI
0.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Multiple Sclerosis Society
  • International Progressive MS Alliance
  • American Cancer Society
  • Mallinckrodt Pharmaceuticals and Deutsche Forschungsgemeinschaft (DFG)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
multiple sclerosis, autoimmune inflammation, central nervous system, environmental factors, demyelination, neuronal loss, pathogenesis, genetic susceptibility, gut microbiota, diet, leukocyte migration
MeSH terms
Gastrointestinal Microbiome, Animals, Central Nervous System, Diet, Environmental Exposure, Humans, Inflammation, Multiple Sclerosis, Autoimmunity, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review