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Loss of Braking Signals During Inflammation

2011; American Medical Association; Volume: 68; Issue: 7 Linguagem: Inglês

10.1001/archneurol.2011.32

1538-3687

Francesca Gilli, Nicole D. Navone, Simona Perga, Fabiana Marnetto, Marzia Caldano, Marco Capobianco, Annalisa Pulizzi, Simona Malucchi, Antonio Bertolotto,

Cytokine Signaling Pathways and Interactions

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.To corroborate dysregulation of genes, to evaluate the prognostic value of genes, and to study modulation of genes during different treatments.Comparison study.Italian referral center for MS.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.Gene expression levels, relapse rate, and change in Expanded Disability Status Scale.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.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.