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.

Highlights

  • Pregnancy represents a physiological transitory state of immune tolerance to avoid the rejection of the fetus, and is frequently associated with reduced activity of autoimmune diseases, including multiple sclerosis (MS)

  • Principle components analysis (PCA) on the pre-selected genes revealed a clear separation between healthy donors and MS patients (Figure 1B)

  • Upon entering the second step of the analysis, we evaluated what changes in expression are detected in the MS signature, when nine months pregnant MS patients are compared with nine months pregnant healthy controls

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Summary

Introduction

Pregnancy represents a physiological transitory state of immune tolerance to avoid the rejection of the fetus, and is frequently associated with reduced activity of autoimmune diseases, including multiple sclerosis (MS). Natural course studies in MS have shown that the relapse rate during pregnancy, especially in the third trimester, decreases more than under treatment with currently approved first line treatments interferon-beta or glatiramer acetate. The lower relapse rate during pregnancy might be due to a pregnancy-associated down-regulation of cellmediated immunity. The protective effect of pregnancy in MS might be explained by the antagonistic effects of Th2 response, which inhibit the development of both pro-inflammatory Th1 and Th17 cells [7]. Pregnancy is associated with reduced activity of multiple sclerosis (MS). The biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood

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