Learning from Nature: Pregnancy Changes the Expression of Inflammation-Related Genes in Patients with Multiple Sclerosis

Abstract

BackgroundPregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood.MethodologyWe conducted a genome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls) followed during their pregnancy. Samples were obtained before, during (i.e. at the third, sixth, and ninth month of gestation) and after pregnancy. A validation of the expression profiles has been conducted by using the same samples and an independent group of 25 MS patients and 11 healthy controls. Finally, considering the total group of 32 MS patients, we compared expression profiles of patients relapsing during pregnancy (n = 6) with those of relapse-free patients (n = 26).Principal FindingsResults showed an altered expression of 347 transcripts in non-pregnant MS patients with respect to non-pregnant healthy controls. Complementary changes in expression, occurring during pregnancy, reverted the previous imbalance particularly for seven inflammation-related transcripts, i.e. SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Longitudinal analysis showed that the overall deregulation of gene expression reverted to “normal” already within the third month of gestation, while in the post-partum gene expressions rebounded to pre-pregnancy levels. Six (18.7%) of the 32 MS patients had a relapse during pregnancy, mostly in the first trimester. The latter showed delayed expression profiles when compared to relapse-free patients: in these patients expression imbalance was reverted later in the pregnancy, i.e. at sixth month.ConclusionsSpecific changes in expression during pregnancy were associated with a decrease in disease activity assessed by occurrence of relapses during pregnancy. Findings might help in understanding the pathogenesis of MS and may provide basis for the development of novel therapeutic strategies.

Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

“…Lower transcript levels of BACH2, PTGER4 and ZFP36L1 were observed (p=0.017, p=0.006 and p=0.016, respectively) in MS patients with respect to HC (Figure 1), according to our previous data (Gilli et al, 2010). Conversely, no statistical significant differences between the two groups were determined for RGS1 (Figure 1), while its expression in both MS and HC population increased with age (p=0.037) (data not shown).…”

“…Only TNFAIP3 deregulation was confirmed (Gilli et al, 2010) and subsequently validated in a larger study including also males, showing a correlation between TNFAIP3 levels and the disease clinical course (Gilli et al, 2011).…”

“…We identified a MS signature including 347 transcripts differently modulated in MS patients compare to HC before pregnancy (Gilli et al, 2010). Among these, in this work we focused on those genes identified as novel MS risk loci in the GWAS studies (IMSGC, 2011;IMSGC, 2013).…”

Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in Multiple Sclerosis

“…Pregnancy has been shown to change the expression of four inflammation-related genes in patients with MS, which resulted in a temporary loss of the MS signature [95]. Downregulation of three of these genes encoding negative regulators of inflammation has been inversely correlated with relapse rate and EDSS in men and women in the initial phase of relapsing remitting MS [96].…”

Loss of Braking Signals During Inflammation

“…4 Of these 7 genes, 3 (ie, POLR2J, FAM49B, and STAG3L1) do not have a clearly defined role in inflammation, whereas 4 genes (ie, CXCR4, SOCS2, TNFAIP3, Abbreviations: AZA, azathioprine sodium; EDSS, Extended Disability Status Scale; GA, glatiramer acetate; IFN-␤, interferon beta; METH, methotrexate sodium; MITO, mitoxantrone hydrochloride; NAT, Natalizumab; RR, relapse rate; SPMS, secondary progressive multiple sclerosis; and ⌬EDSS, annualized changes in EDSS score.…”