The trait of MS: Altered transcription regulation of nuclear receptors networks operate in the pre-disease state

Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We conducted a gene expression study in healthy subjects that subsequently developed the disease. Gene expression profiles (HG U133A and A2, Affymetrix, 22,215 transcripts) of peripheral blood mononuclear cells were analyzed in 9 healthy subjects (mean age 19.8+1.1 years) up to 9 years (mean 5.11.2 years) before onset of MS (MS to be, MS2b), 11 age-, gender-, and origin-matched subjects that remained MS-free (MSf), and 31 clinically isolated syndrome (CIS) patients. Most informative genes (p<0.05) and significant biological processes were compared. 1051 genes (611 up-regulated, 440 down-regulated) were significantly different between MS2b and MSf subjects. MS2b signature was characterized by down-regulation of the nuclear receptor (NR) family genes including NR subfamily 4 group A member1 (NR4A1, p=0.01), member 3 (NR4A3, p=0.01), NR subfamily 2 group F member 2 (NR2F1, p=0.03) and vitamin D receptor (VDR, p=0.02), all known to be involved in T-cell regulation by apoptosis. Comparison between MS2b and CIS operating networks demonstrated evolution of the altered NR dependent apoptosis regulation. Decreased NR4A1 expression was verified at the mRNA and protein level in an independent cohort of 20 relapsing-remitting MS patients. The identified MS trait is associated with suppressed transcription of NR networks that leads to altered apoptosis of activated T cells and the development of clinical disease. MS2b subjects have already an ongoing process that eventually will lead to clinical disease and our finding are of importance as they suggest the possibility of early detection and prevention of MS.

64

Achiron A, Grotto I, Balicer R, Magalashvili D, Feldman A, Gurevich M