Abstract
Background: Multiple sclerosis (MS) patients are protected from relapses during pregnancy and have an increased relapse risk after delivery. It is unknown how pregnancy controls disease-contributing CD4+ T helper (Th) cells and whether this differs in MS patients who experience a postpartum relapse. Here, we studied the effector phenotype of Th cells in relation to pregnancy and postpartum relapse occurrence in MS.Methods: Memory skewing and activation of effector Th subsets were analyzed in paired third trimester and postpartum blood of 19 MS patients with and without a postpartum relapse and 12 healthy controls. Ex vivo results were associated with circulating levels of pregnancy-induced hormones and mirrored in vitro by exposing proliferating Th cells to corresponding serum samples.Results: Based on HSNE-guided analyses, we found that effector memory proportions of Th cells were increased in postpartum vs. third trimester samples from MS patients without a postpartum relapse. This was not seen for relapsing patients or healthy controls. CXCR3 was upregulated on postpartum memory Th cells, except for relapsing patients. These changes were verified by adding sera from the same individuals to proliferating Th cells, but did not associate with third trimester cortisol, estradiol or progesterone levels. For relapsing patients, activated memory Th cells of both third trimester and postpartum samples produced higher levels of pro-inflammatory cytokines.Conclusion: Effector Th cells are differentially regulated during pregnancy in MS patients, likely via serum-related factors beyond the studied hormones. The pro-inflammatory state of memory Th cells during pregnancy may predict a postpartum relapse.
Highlights
Women with multiple sclerosis (MS) have a reduced relapse rate of ∼70% in the third trimester of pregnancy [1], which coincides with high levels of pregnancy-induced hormones, such as estradiol, progesterone and cortisol [2]
The addition of pregnancy-related hormones dampens disease activity [8,9,10], whereas reduced basal levels aggravate the disease course [11, 12]. These observations are linked to altered effector T helper (Th) cell functions [8,9,10,11,12], the exact impact of pregnancy on ex vivo effector Th cells in MS patients and how this corresponds to increased postpartum relapse risk remains to be elucidated
Third trimester expanded disability status scale (EDSS) scores were similar between patients that did or did not experience a clinically-defined postpartum relapse, as described previously [17] (Table 1)
Summary
Women with multiple sclerosis (MS) have a reduced relapse rate of ∼70% in the third trimester of pregnancy [1], which coincides with high levels of pregnancy-induced hormones, such as estradiol, progesterone and cortisol [2]. The addition of pregnancy-related hormones dampens disease activity [8,9,10], whereas reduced basal levels aggravate the disease course [11, 12]. These observations are linked to altered effector Th cell functions [8,9,10,11,12], the exact impact of pregnancy on ex vivo effector Th cells in MS patients and how this corresponds to increased postpartum relapse risk remains to be elucidated.
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