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. OBJECTIVES: To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments. DESIGN: Comparison study. SETTING: Italian referral center for MS. PATIENTS: 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. MAIN OUTCOME MEASURES: 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.
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. OBJECTIVES: To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments. DESIGN: Comparison study. SETTING: Italian referral center for MS. PATIENTS: 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. MAIN OUTCOME MEASURES: 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: Simona Perga; Serena Martire; Francesca Montarolo; Nicole D Navone; Andrea Calvo; Giuseppe Fuda; Alberto Marchet; Daniela Leotta; Adriano Chiò; Antonio Bertolotto Journal: Neurotox Res Date: 2017-03-23 Impact factor: 3.911
Authors: H Takahashi; H Tsuboi; H Asashima; T Hirota; Y Kondo; M Moriyama; I Matsumoto; S Nakamura; T Sumida Journal: Clin Exp Immunol Date: 2017-07-21 Impact factor: 4.330
Authors: Wanjing Shang; Yong Jiang; Michael Boettcher; Kang Ding; Marianne Mollenauer; Zhongyi Liu; Xiaofeng Wen; Chang Liu; Piliang Hao; Suwen Zhao; Michael T McManus; Lai Wei; Arthur Weiss; Haopeng Wang Journal: Proc Natl Acad Sci U S A Date: 2018-04-09 Impact factor: 11.205
Authors: Michael Hecker; Brigitte Katrin Paap; Robert Hermann Goertsches; Ole Kandulski; Christian Fatum; Dirk Koczan; Hans-Peter Hartung; Hans-Juergen Thiesen; Uwe Klaus Zettl Journal: PLoS One Date: 2011-12-27 Impact factor: 3.240
Authors: Katherine E Williams; Olga Miroshnychenko; Eric B Johansen; Richard K Niles; Rajeshwari Sundaram; Kurunthachalam Kannan; Matthew Albertolle; Yan Zhou; Namrata Prasad; Penelope M Drake; Linda C Giudice; Steven C Hall; H Ewa Witkowska; Germaine M Buck Louis; Susan J Fisher Journal: J Proteomics Date: 2014-10-13 Impact factor: 4.044