title: Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis.
abstract: BACKGROUND
  In a recent genome-wide transcriptional analysis, we identified a gene signature for multiple sclerosis (MS), which reverted back to normal during pregnancy. Reversion was particularly evident for 7 genes: SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1, most of which encode negative regulators of inflammation.
  
  
  OBJECTIVE
  To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments.
  
  
  METHODS
  Comparison study.
  
  
  METHODS
  Italian referral center for MS.
  
  
  METHODS
  Quantitative polymerase chain reaction measurements were performed for 274 patients with MS and 60 healthy controls. Of the 274 patients with MS, 113 were treatment-naive patients in the initial stages of their disorder who were followed up in real-world clinical settings and categorized on the basis of disease course. The remaining 161 patients with MS received disease-modifying therapies (55 patients were treated with interferon beta, 52 with glatiramer acetate, and 54 with natalizumab) for a mean (SD) of 12 (2) months.
  
  
  METHODS
  Gene expression levels, relapse rate, and change in Expanded Disability Status Scale.
  
  
  RESULTS
  We found a dysregulated gene pathway (P ≤ .006), with a downregulation of genes encoding negative regulators. The SOCS2, NR4A2, and TNFAIP3 genes were inversely correlated with both relapse rate (P ≤ .002) and change in Expanded Disability Status Scale (P ≤ .005). SOCS2 was modulated by both interferon beta and glatiramer acetate, TNFAIP3 was modulated by glatiramer acetate, and NR4A2 was not altered at all. No changes were induced by natalizumab.
  
  
  CONCLUSIONS
  We demonstrate that there is a new molecular pathogenic mechanism that underlies the initiation and progression of MS. Defects in negative-feedback loops of inflammation lead to an overactivation of the immune system so as to predispose the brain to inflammation-sensitive MS.
authors.affiliation: Clinical Neurobiology Unit, Neuroscience Institute Cavalieri Ottolenghi, University Hospital San Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano. francesca.gilli@fastwebnet.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Gilli
authors.forename: Nicole Désirée
authors.initials: ND
authors.lastname: Navone
authors.forename: Simona
authors.initials: S
authors.lastname: Perga
authors.forename: Fabiana
authors.initials: F
authors.lastname: Marnetto
authors.forename: Marzia
authors.initials: M
authors.lastname: Caldano
authors.forename: Marco
authors.initials: M
authors.lastname: Capobianco
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pulizzi
authors.forename: Simona
authors.initials: S
authors.lastname: Malucchi
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertolotto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004268:DNA-Binding Proteins; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; C539882:NR4A2 protein, human; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3