Next Article in Journal
Health Behavior and Health and Psychosocial Planning for Retirement among Spanish Health Professionals
Next Article in Special Issue
The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis
Previous Article in Journal
The Number of Comorbidities Predicts Renal Outcomes in Patients with Stage 3–5 Chronic Kidney Disease
Previous Article in Special Issue
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations

J. Clin. Med. 2018, 7(12), 494; https://doi.org/10.3390/jcm7120494

Review
The Short and Long-Term Effects of Pregnancy on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
The University of Queensland, Centre for Clinical Research, Brisbane, QLD 4029, Australia
Received: 1 October 2018 / Accepted: 21 November 2018 / Published: 28 November 2018

Abstract

:
The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS and reduced activity of autoimmune encephalomyelitis (EAE). However, in women with multiple sclerosis, this benefit is not always sufficient to protect against a rebound of disease activity if disease-modulating therapy is ceased for pregnancy. There is concern that use of assisted reproductive therapies can be associated with relapses of MS, but more data are required. It is thought that the beneficial effects of pregnancy are due to the pregnancy-associated changes in the maternal immune system. There is some evidence of this in human studies and studies of EAE. There is also evidence that having been pregnant leads to better long-term outcome of MS. The mechanism for this is not fully understood but it could result from epigenetic changes resulting from pregnancy or parenthood. Further studies of the mechanisms of the beneficial effects of pregnancy could provide information that might be used to produce new therapies.
Keywords:
multiple sclerosis; pregnancy; experimental autoimmune encephalomyeltis; epigenetics

1. Introduction

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS) [1,2]. The characteristic pathological features are inflammation and demyelination that occur in plaques, usually around a vein. There is also axonal degeneration, and as disease progresses there is microglial activation in so-called normal appearing white matter. The finding of lymphocytic infiltrates suggests that this is an immune mediated disease. Genetic studies show that the risk of MS is associated with genes of the immune system, most notably the genes of the human leukocyte antigen (HLA) region [3,4,5], but also other genes of the adaptive and innate immune systems. T and B lymphocytes and antibodies are thought to participate in MS pathology, and several CNS antigens have been proposed as the target of the immune attack [6,7]. In the peripheral blood of patients with MS, there is evidence of immune activation. This includes increased levels of T cells reactive with CNS antigens, and increased activated T cells [8,9]. Recently it has also been found that the gut microbiota influences the development of MS, possibly through immune effects [10], and that MS patients can have poor health for some years before presentation with neurological symptoms (this has been termed the “MS prodrome”) [11,12,13]. These findings of a role for the gut microbiota and as MS prodrome suggest that we need to reconsider the origins of MS.
Experimental autoimmune encephalomyelitis (EAE) has been used as a model of MS since the similarity between EAE and MS was noted in 1946 [14]. EAE can be induced by injection of CNS antigens and adjuvant or by adoptive transfer of T cells reactive to CNS antigens [15]. However, EAE differs from MS in needing to be induced, rather than occurring spontaneously. Usually EAE is induced with purified antigens, most commonly myelin basic protein (MBP), myelin proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), although a wide range of CNS antigens can be used [16]. The clinical course of EAE varies according to the inoculating antigen and the recipient strain (Table 1) [17,18,19,20,21,22,23,24,25].
Pregnancy involves physiological changes in the mother, including elevation of cardiac output, increased basal metabolic rate, increased lipid levels, and weight gain [27,28,29,30]. In pregnancy there are changes in the levels of hormones such as estriol, progesterone, prolactin, early pregnancy factor (EPF), alpha-fetoprotein [31], and leptin [32], and elevated levels of growth factors such as insulin-like growth factor (IGF) [33]. The physiological changes in pregnancy must be the net effect of all these hormones. After delivery, there is a rapid decline in the levels of pregnancy hormones and maternal physiology rapidly returns to normal, although during lactation the levels of prolactin and oxytocin are elevated [34]. It is thought that the changes in maternal physiology during pregnancy and lactation are mediated through the effects of pregnancy hormones [35]. These hormones have immunological and neuroprotective effects as summarized in Table 2.
The physiological changes in pregnancy include alterations in the maternal immune system. Immune changes in pregnancy tend to suppress the maternal immune system, and this is thought to be important in preventing rejection of the fetus, which contains foreign (paternal) antigens [44,45,46,47,48,49,50,51]. During pregnancy, there are increased Th2 responses and reduced Th1- and Th17-responses [35,52,53]. In pregnant women there are increased levels of circulating regulatory T cells (Treg) cells [54,55]. Other evidence of increased Treg activity in pregnancy comes from findings of increased foxp3 expression and increased functional suppression in pregnant and estrogen-treated rats [56]. The increased level of Treg cells in pregnancy is thought to be due to the effects on the immune system of estradiol [57]. The changes have been reported to include a shift to Th2 immune responses and a shift to greater humoral than cell mediated immunity [58]. B cells also show changes in pregnancy, with increases in regulatory B cells [59].
In the first part of the 20th century, MS was thought to be worse in pregnancy [60,61]. This idea was re-inforced by several influential case reports [62,63,64] and it was considered that pregnancy was a precipitant of MS [65]. However, a study by Tillman in 1950 cast doubt in the previously held view that pregnancy was not advisable in MS [61] and instead found that relapses of MS occurred after delivery. Further studies indicated that MS was better (fewer relapses) in pregnancy and relapses occurred post-partum. The issue of pregnancy and MS is currently of great interest and there have been a number of previous reviews of pregnancy in MS [66,67,68,69,70,71]. This review will provide an update on the data concerning the short and long-term effect of pregnancy in MS. It will also include a review of the effects of pregnancy in EAE. This has not been previously reviewed and could provide evidence of possible underlying mechanisms that are relevant to MS.

2. Multiple Sclerosis and EAE during Pregnancy

Current evidence from numerous studies demonstrates that there are fewer relapses of MS during pregnancy, especially in the later part of pregnancy [72,73,74,75,76,77,78]. A systematic review of 22 papers confirms the findings of reduced relapses in pregnancy [79]. However, it is worth noting that the risk of relapse in pregnancy is not zero, and recent studies in the era when patients are on immunomodulatory therapies have shown a rebound of disease in women who had previously been on active treatment with long washout periods [80]. There have also been reports of severe rebound of disease during pregnancy after withdrawal of fingolimod [81], and relapses, sometimes severe, in women who had been withdrawn from treatment with natalizumab [82,83,84,85].
The reduction in relapses during pregnancy is thought to be due to the immunological changes of pregnancy, as listed above. Some of the beneficial effects of pregnancy on MS could be due to effects of the pregnancy hormones on the nervous system, either in making neuronal tissue more resistant to damage or better able to repair damage [35,36,37].
There have been some studies of the immune changes in multiple sclerosis patients during pregnancy. There are changes in cytokines and T cells in pregnant compared to non-pregnant MS patients [86]. The frequency of interferon-γ producing T cells declined during pregnancy in women with MS [87]. A decline in interferon-γ was confirmed in a further study which also showed an increase in natural killer (NK) cells and a Th1–Th2 shift, but no changes in Treg cells [88]. A conflicting result was found in another study that showed an increase in CD4 + CD25hi cells during pregnancy in patients with MS [55]. An increase in natural killer cells during pregnancy in MS was confirmed in a later study that also showed an increase in NK T cells [89]. There are changes in the expression of inflammation related genes during pregnancy in patients with multiple sclerosis [90].
There have been studies of the effects of pregnancy in EAE. EAE has a variable clinical course, according to the inoculating antigen, as shown in Table 1. The pathology of most types of EAE is characterized by microglial activation and infiltration with T cells and macrophages [16,91,92]. MBP-EAE [93] and PLP-EAE [94] can be transferred with lymphocytes, indicating that these cells are primarily responsible for these types of EAE. Disease is largely caused by Th17 cells [95,96] and is suppressed by regulatory T cells (Treg) [97]. In contrast, MOG-EAE is largely antibody mediated [98]. Acute EAE is a monophasic disease and animals do not have subsequent attacks, even if re-inoculated. The tolerance that occurs after acute EAE can be broken by mild immune suppression, suggesting that this is active tolerance [99,100]. Regulatory T cells play a role in the active control of EAE [97,101]. These features make EAE a useful model for evaluating the effects of pregnancy.
Pregnancy suppressed EAE in guinea pigs and rats [102]. Lewis rats inoculated with guinea pig spinal cord and adjuvant during the second or third weeks of pregnancy were protected against the development of disease, although rats inoculated in the first week had less protection [103]. Induction of MBP-EAE in Lewis rats during pregnancy also leads to reduced severity of disease [104]. SJL/J mice inoculated with PLP and adjuvant in the late part of pregnancy were protected against disease [105]. In PLP-induced EAE in SJL/J mice, immunization during pregnancy leads to a reduction in the incidence of EAE as well as a decrease in clinical severity, while immunization during the postpartum period leads to more severe disease [106]. In C57/BL6 mice, EAE induced with MOG 35–55 was less severe when mice were inoculated in late pregnancy [106]. In DA rats, EAE induced with bovine brain homogenate was less severe when disease was induced in pregnancy although there were relapses post-partum [107]. There have also been studies of the effects of becoming pregnant after the onset of EAE. In SJL mice inoculated with PLP 139–151 and in C57/BL6 mice inoculated with MOG 35–55, induction of pregnancy led to clinical improvement but the pathological lesions persisted [108].
There have been attempts to transfer the protective effects of pregnancy. In rats, offspring from rats with EAE in pregnancy show transient protection from EAE induced with GPSC, and rats that are suckled by mothers that have EAE in pregnancy also acquired protection [109]. Exosomes from pregnant and non-pregnant mice can suppress EAE. However, exosomes are more abundant in pregnancy and it is suggested that exosomes contribute to protection during pregnancy [110]. There is alteration of cytokine production in the spinal cord of pregnant rats with EAE compared to non-pregnant rats, and serum from pregnant rats suppressed lymphocyte proliferation in response to antigen and to phytohaemagglutinin, but not to concanvalin A, possibly indicating Treg activity [104].
There are no differences in lymphocyte proliferation or expression of activation markers when immunization occurred during pregnancy as compared with the non-pregnant controls [106]. Mice immunized during pregnancy produced less tumor necrosis factor-alpha (TNF-α) and interleukin 17 (IL-17), and showed an increased number of interleukin 10 (IL-10)-secreting cells within the CD11b+, CD11c+, CD19+, and CD4+/CD25+ Treg populations. No differences were noted in the production of interferon -gamma (IFN-γ), interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 5 (IL-5). These results suggest that when an antigen is introduced during pregnancy, an immunoregulatory rather than an immunosuppressive or Th2 environment predominates. The glucocorticoid T cell receptor is necessary for the protective effect of pregnancy in MOG-EAE [111].
EAE can be suppressed by treatment with estrogen to produce levels similar to those found in pregnancy. This has been associated with changes in the gut microbiota [112] and with changes in regulatory B cells [113]. MS can also be suppressed by estrogen therapy [114]. This is a promising approach to try to replicate the beneficial effects of pregnancy, but it must be noted that many other hormones are elevated in pregnancy.
Taken together, the studies of MS and EAE indicate there are fewer relapses during pregnancy, increased relapses post-partum, alterations in the maternal immune system with reduced immune reactivity and increased regulatory cells.

3. Post-Partum Relapses

The studies that showed fewer relapses in pregnancy also showed an increased frequency of relapses in the post-partum period [72,73,74,75,79,115,116,117]. It is most likely that this effect is due to a loss of the immune suppressive effects of the pregnancy hormones. Another possibility is the effects of the hormones that are increased in lactation, but these have complex effects on the immune system (Table 1). Post-partum relapses are important because they lead to disability [118]. However, post-partum relapses do not occur in all patients, and there have been attempts to predict post-partum relapses using clinical and immunological approaches. The frequency of relapses before pregnancy is the best predictor of relapse after pregnancy [74,119,120]. One study of 298 full-term pregnancies found that breast feeding did not influence the frequency of relapses [120]. Relapses are nor predicted by epidural anaesthesia or caesarean section [121]. There have been studies suggesting that breast-feeding is protective against relapses [122]. However, later studies found that breast-feeding did not suppress disease [123] or influence the frequency of relapses [76,120]. One study suggests that post-partum relapses correlate with increased levels of IL-8 in the first trimester [124].
Some EAE studies provide information about the post-partum period. In PLP-induced EAE in SJL/J mice, mice immunized during the postpartum period exhibit more severe disease [106]. In DA rats, EAE induced with bovine brain homogenate was less severe when disease was induced in pregnancy although there were relapses post-partum [107].
There have been some clinical studies of methods to prevent post-partum relapses. In a retrospective analysis of study of patients who were followed in a database, 20 subjects who were given monthly intravenous methylpredisolone (1 g) for six months post-partum had a lower annualized relapse rate for the first three months post-partum than those who had no treatment [125]. There have been suggestions that intravenous immunoglobulin (IVIG) could be useful in preventing post-partum relapses [126,127,128] but a meta-analysis has failed to confirm this [129].

4. Relapses with ART Pregnancies

Increasing numbers of pregnancies now occur with assisted reproduction technology (ART). This generally involves the use of hormone therapy to induce ovulation or to assist in implantation. Such hormones can include gonadotrophin-releasing hormone (GnRH) agonists, follicle-stimulating hormone, luteinizing hormone, human chorionic gonadotrophin, and progesterone. In some patients, gonadotrophin releasing hormone antagonists are also used. When high doses are used, women can experience ovarian hyperstimulation syndrome. Women can be exposed to these hormones when ovulation is induced or when embryos are implanted. When considering whether ART influences MS relapses, it is important to note that when patients are trying to become pregnant, they often cease immunomodulatory therapy for MS, with a potential for return of disease activity.
There have been reports of the effect of ART on MS, as summarized in Table 3. The studies are small and some are retrospective. Relapses of multiple sclerosis have been reported to occur after pregnancies after ART [130,131,132]. A prospective study from Argentina showed the disease activity was increased 9-fold with use of luteinizing hormone releasing hormone (LHRH) agonists [133]. Two of the studies have suggested that relapses are more likely after treatment with LHRH agonists than antagonists [130,134]. In this respect, it is worth noting that GnRH has immune stimulatory effects [135] that could possibly lead to an increase in disease activity.
However, another group found an increased relapse rate in women treated with both GnRH agonists and GnRH antagonists, and suggested that relapses could be due to either to cessation of immune therapy, or to stress, which has been suggested to trigger relapses of MS, as well as to the possible effects of the hormones used in ART [131,132]. This needs further study to resolve these issues.

5. Use of Immunomodulatory Medications in Pregnancy

Whether to use of immunomodulatory therapies during pregnancy is a common clinical issue and a concern for women with MS. The rate of pregnancy in women with MS may be increasing, as shown in a study in the United States [136], so this topic is of importance. It is recommended that most of the medications are avoided during conception, pregnancy and breast-feeding. Furthermore, there needs to be a washout period to allow for the removal of the drug before conception is attempted. This avoidance of medications during pregnancy is because of suggestions of toxicity from animal studies but also because of a lack of evidence of safety of use in humans. A recent study showed that few women in the United States use immunomodulatory therapies during pregnancy or the puerperium [77].
However, although pregnancy is protective against relapses, the rate of relapse is not zero. Furthermore, in more recent studies there have been reports of relapses during pregnancy, possibly due to a rebound effect after ceasing effective therapy. This has led to a re-consideration of the possible use of medications during pregnancy, to protect the health of the mother. There are detailed reviews of these effects [70,71]. However, because of the risk of pregnancy and post-partum relapses, there have been attempts to find medications that can be used during pregnancy. The oral therapies and the lymphocyte-depleting therapies (alemtuzumab, ocrelizumab and cladribine) are not regarded as suitable for use during conception or pregnancy [70,71]. There are no significant issues with interferon beta. There is evidence that glatiramer acetate is safe in pregnancy and during breast feeding [137]. This is not unexpected because the molecule is rapidly degraded after absorption and is unlikely to reach the foetus in during pregnancy. It needs to be administered by injection so that it is not likely to be active if it were to enter the breast milk and be ingested by an infant.
Natalizumab is a monoclonal antibody, delivered by intravenous infusion. Antibodies can cross the placenta in the later part of pregnancy (after 28 weeks) and could affect the foetus. There have been reports of the use of natalizumab throughout pregnancy in patients with active disease [85,138,139,140]. The main adverse effects that have been noted in exposed infants are anaemia and thrombocytopenia in the newborn [141]. In the future, it is likely that MS patients, particularly those with active disease, will be offered some type of therapy during pregnancy.
Although the medications are not recommended during pregnancy, many pregnancies are unplanned, and exposures to disease modifying therapies have occurred. There are registries that are attempting to collect data about the outcomes of pregnancy exposure to disease modifying therapies. If a large number of exposed pregnancies were found to have the same outcomes as unexposed pregnancies, the recommendations regarding drug use in pregnancy could be re-considered.

6. Long Term Effects of Pregnancy on the Clinical Course of MS

The long-term effects of parity on MS is less certain. Some earlier studies suggested that parity is associated with better long-term outcome [69,142,143,144]. A retrospective study from Turkey suggested that parity had a beneficial effect on transition from relapsing to secondary progressive MS [145]. However, this could arise because women with more severe MS might decide not to have children or to have fewer children.
However, there is accumulating evidence that parity is beneficial. A prospective study examined the association between past pregnancy, offspring number, and risk of a first episode of demyelination [146]. The study demonstrated that higher parity was associated with reduced risk of a first episode of clinical demyelination and the results were consistent with a cumulative beneficial effect of pregnancy. In another study using the MSBase registry, where patients were matched according to clinical characteristics, pregnancy was 4.5 times more potent than first-line disease modifying therapies (interferon-beta, glatiramer acetate) in preventing long-term disability accrual, and any time spent pregnant (including induced and spontaneous abortions) was beneficial [147]. Other evidence of a benign effect of parity on MS is the findings that having been pregnant does not increase the risk of secondary progression of disease [148] and that women with children with different partners do not have greater risk of disability as might be expected to occur if the immune response to paternal genes was harmful [149].
For parity to have a long-term effect on MS, it would be expected that there would be permanent changes that persist after the woman is no longer pregnant and hormone levels have returned to normal. This could lead to accumulation of changes with successive pregnancies, due to the cumulative effects of pregnancy hormones, or to the effects of the experience of parenthood. One possible mechanism could be epigenetics, with changes in DNA methylation, leading to changes in gene expression. It is known that hormones such as estrogen can cause epigenetic changes [150,151]. It is also known that life experiences, such as stress and emotional well-being, can lead to epigenetic changes [152,153]. This could lead to cumulative epigenetic changes with parity and parenthood. If this is the mechanism by which prior pregnancies leads to better outcome of MS, it would be important to know which genes are involved. It can be speculated that such epigenetic changes could occur in immune-related processes or in processes to do with repair of the nervous system.

7. Effects of Pregnancy on Risk of Developing MS

Given the immune effects of pregnancy, it has been questioned whether pregnancy influences the development of MS. In a study from Denmark, parents of both sexes had a lower risk of MS than childless persons [154]. Because this effect was seen in both men and women, it was thought not to result of having been pregnant. It was thought that this could be due to reverse causality, as it is known that even before diagnosis of MS there are health changes [11,12,13]. Possibly those with poor health are less likely to decide to become parents than those with good health. This could lead to parenthood seeming to be protective from MS. However, one can speculate that parenthood could be protective in both sexes, possibly through epigenetic changes, similar to those proposed above for the effect of parity on the long-term outcome of MS.

8. Conclusions

The effects of MS on pregnancy and the effects of pregnancy on MS are common issues of concern for people with MS. Knowledge of this field is advancing and it is possible to provide information to address these concerns. It is now clear that pregnancy is not harmful, that there can be short term and possible long term beneficial effects. However, despite the beneficial effects of pregnancy there has been an understanding that in many women, treatment with pregnancy could be justified, and there is an increased emphasis on obtaining data that could provide more information about the risks and benefit of such treatment.
The mechanisms by which pregnancy reduces relapses and by which parity leads to a beneficial effect on outcome are still not fully understood. Further work in this area would be a great value, because understanding the mechanisms of the beneficial effects of pregnancy might lead to strategies to improve outcome of disease.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Reich, D.S.; Lucchinetti, C.F.; Calabresi, P.A. Multiple Sclerosis. N. Engl. J. Med. 2018, 378, 169–180. [Google Scholar] [CrossRef] [PubMed]
  2. Thompson, A.J.; Baranzini, S.E.; Geurts, J.; Hemmer, B.; Ciccarelli, O. Multiple sclerosis. Lancet 2018, 391, 1622–1636. [Google Scholar] [CrossRef]
  3. Patsopoulos, N.A.; Barcellos, L.F.; Hintzen, R.Q.; Schaefer, C.; van Duijn, C.M.; Noble, J.A.; Raj, T.; Gourraud, P.A.; Stranger, B.E.; Oksenberg, J.; et al. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet. 2013, 9, e1003926. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Beecham, A.H.; Patsopoulos, N.A.; Xifara, D.K.; Davis, M.F.; Kemppinen, A.; Cotsapas, C.; Shah, T.S.; Spencer, C.; Booth, D.; Goris, A.; et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 2013, 45, 1353–1360. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011, 476, 214–219. [Google Scholar] [CrossRef] [PubMed][Green Version]
  6. Hohlfeld, R.; Dornmair, K.; Meinl, E.; Wekerle, H. The search for the target antigens of multiple sclerosis, part 1: Autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 2016, 15, 198–209. [Google Scholar] [CrossRef]
  7. Hohlfeld, R.; Dornmair, K.; Meinl, E.; Wekerle, H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 2016, 15, 317–331. [Google Scholar] [CrossRef]
  8. Khoury, S.J.; Guttmann, C.G.; Orav, E.; Kikinis, R.; Jolesz, F.A.; Weiner, H.L. Changes in activated t cells in the blood correlate with disease activity in multiple sclerosis. Arch. Neurol. 2000, 57, 1183–1189. [Google Scholar] [CrossRef] [PubMed]
  9. Kaskow, B.J.; Baecher-Allan, C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8. [Google Scholar] [CrossRef] [PubMed]
  10. Chu, F.; Shi, M.; Lang, Y.; Shen, D.; Jin, T.; Zhu, J.; Cui, L. Gut Microbiota in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis: Current Applications and Future Perspectives. Mediat. Inflamm. 2018, 2018, 8168717. [Google Scholar] [CrossRef] [PubMed]
  11. Disanto, G.; Zecca, C.; MacLachlan, S.; Sacco, R.; Handunnetthi, L.; Meier, U.C.; Simpson, A.; McDonald, L.; Rossi, A.; Benkert, P.; et al. Prodromal symptoms of multiple sclerosis in primary care. Ann. Neurol. 2018, 83, 1162–1173. [Google Scholar] [CrossRef] [PubMed]
  12. Hogg, T.; Wijnands, J.M.A.; Kingwell, E.; Zhu, F.; Lu, X.; Evans, C.; Fisk, J.D.; Marrie, R.A.; Zhao, Y.; Tremlett, H. Mining healthcare data for markers of the multiple sclerosis prodrome. Mult. Scler. Relat. Disord. 2018, 25, 232–240. [Google Scholar] [CrossRef] [PubMed]
  13. Wijnands, J.M.A.; Kingwell, E.; Zhu, F.; Zhao, Y.; Hogg, T.; Stadnyk, K.; Ekuma, O.; Lu, X.; Evans, C.; Fisk, J.D.; et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: A matched cohort study. Lancet Neurol. 2017, 16, 445–451. [Google Scholar] [CrossRef]
  14. Kabat, E.A.; Wolf, A.; Bezer, A.E. The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterologous and homologous brain tissue with adjuvants. J. Exp. Med. 1947, 85, 117–130. [Google Scholar] [CrossRef] [PubMed]
  15. Van der Star, B.J.; Vogel, D.Y.; Kipp, M.; Puentes, F.; Baker, D.; Amor, S. In vitro and in vivo models of multiple sclerosis. CNS Neurol. Disord. Drug Targets 2012, 11, 570–588. [Google Scholar] [CrossRef] [PubMed]
  16. Gold, R.; Linington, C.; Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 Years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 2006, 129, 1953–1971. [Google Scholar] [CrossRef] [PubMed]
  17. Pender, M.P. The pathophysiology of myelin basic protein-induced acute experimental allergic encephalomyelitis in the Lewis rat. J. Neurol. Sci. 1988, 86, 277–289. [Google Scholar] [CrossRef][Green Version]
  18. McCombe, P.A.; Harness, J.; Pender, M.P. Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein. J. Neuroimmunol. 1999, 97, 60–69. [Google Scholar] [CrossRef][Green Version]
  19. Greer, J.M.; Sobel, R.A.; Sette, A.; Southwood, S.; Lees, M.B.; Kuchroo, V.K. Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein. J. Immunol. 1996, 156, 371–379. [Google Scholar] [PubMed]
  20. Chalk, J.B.; McCombe, P.A.; Smith, R.; Pender, M.P. Clinical and histological findings in proteolipid-protein- induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Distribution of demyelination differs from that in EAE induced by other antigens. J. Neurol. Sci. 1994, 123, 154–161. [Google Scholar] [CrossRef]
  21. Chalk, J.B.; McCombe, P.A.; Pender, M.P. Conduction abnormailites are restricted to the central nervous system in experimental autoimmune encephalomyelitis induced by inoculation with proteolipid protein but not myelin basic protein. Brain 1994, 117, 975–986. [Google Scholar] [CrossRef] [PubMed][Green Version]
  22. Lu, E.; Wang, B.W.; Guimond, C.; Synnes, A.; Sadovnick, D.; Tremlett, H. Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic review. Neurology 2012, 79, 1130–1135. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Kuchroo, V.K.; Sobel, R.A.; Yamamura, T.; Greenfield, E.; Dorf, M.E.; Lees, M.B. Induction of experimental allergic encephalomyelitis by myelin proteolipid-protein-specific T cell clones and synthetic peptides. Pathobiology 1991, 59, 305–312. [Google Scholar] [CrossRef] [PubMed]
  24. Greer, J.M.; Kuchroo, V.K.; Sobel, R.A.; Lees, M.B. Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178–191) for SJL mice. J. Immunol. 1992, 149, 783–788. [Google Scholar] [PubMed]
  25. Schluesener, H.J.; Sobel, R.A.; Linington, C.; Weiner, H.L. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J. Immunol. 1987, 139, 4016–4021. [Google Scholar] [PubMed]
  26. Kibler, R.F.; Fritz, R.B.; Chou, F.; Jen Chou, C.H.; Peacocke, N.Y.; Brown, N.M.; McFarlin, D.E. Immune response of Lewis rats to peptide C1 (residues 68–88) of guinea pig and rat myelin basic proteins. J. Exp. Med. 1977, 146, 1323–1331. [Google Scholar] [CrossRef] [PubMed]
  27. Granger, J.P. Maternal and fetal adaptations during pregnancy: Lessons in regulatory and integrative physiology. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002, 283, R1289–R1292. [Google Scholar] [CrossRef] [PubMed]
  28. Lain, K.Y.; Catalano, P.M. Metabolic changes in pregnancy. Clin. Obstet. Gynecol. 2007, 50, 938–948. [Google Scholar] [CrossRef] [PubMed]
  29. Forsum, E.; Lof, M. Energy metabolism during human pregnancy. Annu. Rev. Nutr. 2007, 27, 277–292. [Google Scholar] [CrossRef] [PubMed]
  30. Tan, E.K.; Tan, E.L. Alterations in physiology and anatomy during pregnancy. Best. Pract. Res. Clin. Obstet. Gynaecol. 2013, 27, 791–802. [Google Scholar] [CrossRef] [PubMed]
  31. Brunton, P.J.; Russell, J.A. Endocrine induced changes in brain function during pregnancy. Brain Res. 2010, 1364, 198–215. [Google Scholar] [CrossRef] [PubMed]
  32. Molvarec, A.; Szarka, A.; Walentin, S.; Beko, G.; Karadi, I.; Prohaszka, Z.; Rigo, J., Jr. Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod. Biol. Endocrinol. 2011, 9, 124. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Lauszus, F.F.; Klebe, J.G.; Bek, T.; Flyvbjerg, A. Increased serum IGF-I during pregnancy is associated with progression of diabetic retinopathy. Diabetes 2003, 52, 852–856. [Google Scholar] [CrossRef] [PubMed]
  34. Uvnas-Moberg, K.; Widstrom, A.M.; Werner, S.; Matthiesen, A.S.; Winberg, J. Oxytocin and prolactin levels in breast-feeding women. Correlation with milk yield and duration of breast-feeding. Acta Obstet. Gynecol. Scand. 1990, 69, 301–306. [Google Scholar] [CrossRef] [PubMed]
  35. Ysrraelit, M.C.; Correale, J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology 2018. [Google Scholar] [CrossRef] [PubMed]
  36. Tiwari-Woodruff, S.; Voskuhl, R.R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. J. Neurol. Sci. 2009, 286, 81–85. [Google Scholar] [CrossRef] [PubMed][Green Version]
  37. Khalaj, A.J.; Hasselmann, J.; Augello, C.; Moore, S.; Tiwari-Woodruff, S.K. Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects. J. Steroid Biochem. Mol. Boil. 2016, 160, 43–52. [Google Scholar] [CrossRef] [PubMed][Green Version]
  38. Shah, N.M.; Imami, N.; Johnson, M.R. Progesterone Modulation of Pregnancy-Related Immune Responses. Front. Immunol. 2018, 9, 1293. [Google Scholar] [CrossRef] [PubMed]
  39. Zhu, X.; Frechou, M.; Schumacher, M.; Guennoun, R. Cerebroprotection by progesterone following ischemic stroke: Multiple effects and role of the neural progesterone receptors. J. Steroid Biochem. Mol. Boil. 2018. [Google Scholar] [CrossRef] [PubMed]
  40. Borba, V.V.; Zandman-Goddard, G.; Shoenfeld, Y. Prolactin and Autoimmunity. Front. Immunol. 2018, 9, 73. [Google Scholar] [CrossRef] [PubMed]
  41. Cabrera-Reyes, E.A.; Limon-Morales, O.; Rivero-Segura, N.A.; Camacho-Arroyo, I.; Cerbon, M. Prolactin function and putative expression in the brain. Endocrine 2017, 57, 199–213. [Google Scholar] [CrossRef] [PubMed]
  42. Li, T.; Wang, P.; Wang, S.C.; Wang, Y.F. Approaches Mediating Oxytocin Regulation of the Immune System. Front. Immunol. 2016, 7, 693. [Google Scholar] [CrossRef] [PubMed]
  43. Zinni, M.; Colella, M.; Batista Novais, A.R.; Baud, O.; Mairesse, J. Modulating the Oxytocin System During the Perinatal Period: A New Strategy for Neuroprotection of the Immature Brain? Front. Neurol. 2018, 9, 229. [Google Scholar] [CrossRef] [PubMed]
  44. Munoz-Suano, A.; Hamilton, A.B.; Betz, A.G. Gimme shelter: The immune system during pregnancy. Immunol. Rev. 2011, 241, 20–38. [Google Scholar] [CrossRef] [PubMed]
  45. Veenstra van Nieuwenhoven, A.L.; Heineman, M.J.; Faas, M.M. The immunology of successful pregnancy. Hum. Reprod. Update 2003, 9, 347–357. [Google Scholar] [CrossRef] [PubMed][Green Version]
  46. Yip, L.; McCluskey, J.; Sinclair, R. Immunological aspects of pregnancy. Clin. Dermatol. 2006, 24, 84–87. [Google Scholar] [CrossRef] [PubMed]
  47. Mor, G.; Cardenas, I. The immune system in pregnancy: A unique complexity. Am. J. Reprod. Immunol. (NY 1989) 2010, 63, 425–433. [Google Scholar] [CrossRef] [PubMed]
  48. Racicot, K.; Kwon, J.Y.; Aldo, P.; Silasi, M.; Mor, G. Understanding the complexity of the immune system during pregnancy. Am. J. Reprod. Immunol. (NY 1989) 2014, 72, 107–116. [Google Scholar] [CrossRef] [PubMed]
  49. Polese, B.; Gridelet, V.; Araklioti, E.; Martens, H.; Perrier d’Hauterive, S.; Geenen, V. The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy. Front. Endocrinol. 2014, 5, 106. [Google Scholar] [CrossRef] [PubMed][Green Version]
  50. Schumacher, A.; Costa, S.D.; Zenclussen, A.C. Endocrine factors modulating immune responses in pregnancy. Front. Immunol. 2014, 5, 196. [Google Scholar] [CrossRef] [PubMed]
  51. Robinson, D.P.; Klein, S.L. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm. Behav. 2012, 62, 263–271. [Google Scholar] [CrossRef] [PubMed][Green Version]
  52. Doria, A.; Iaccarino, L.; Arienti, S.; Ghirardello, A.; Zampieri, S.; Rampudda, M.E.; Cutolo, M.; Tincani, A.; Todesco, S. Th2 immune deviation induced by pregnancy: The two faces of autoimmune rheumatic diseases. Reprod. Toxicol. 2006, 22, 234–241. [Google Scholar] [CrossRef] [PubMed]
  53. Saito, S.; Nakashima, A.; Shima, T.; Ito, M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol. 2010, 63, 601–610. [Google Scholar] [CrossRef] [PubMed]
  54. Somerset, D.A.; Zheng, Y.; Kilby, M.D.; Sansom, D.M.; Drayson, M.T. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 2004, 112, 38–43. [Google Scholar] [CrossRef] [PubMed][Green Version]
  55. Sanchez-Ramon, S.; Navarro, A.J.; Aristimuno, C.; Rodriguez-Mahou, M.; Bellon, J.M.; Fernandez-Cruz, E.; De, A.C. Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity. Immunol. Lett. 2005, 96, 195–201. [Google Scholar] [CrossRef] [PubMed]
  56. Polanczyk, M.J.; Hopke, C.; Huan, J.; Vandenbark, A.A.; Offner, H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J. Neuroimmunol. 2005, 170, 85–92. [Google Scholar] [CrossRef] [PubMed]
  57. Tai, P.; Wang, J.; Jin, H.; Song, X.; Yan, J.; Kang, Y.; Zhao, L.; An, X.; Du, X.; Chen, X.; et al. Induction of regulatory T cells by physiological level estrogen. J. Cell. Physiol. 2008, 214, 456–464. [Google Scholar] [CrossRef] [PubMed]
  58. Jamieson, D.J.; Theiler, R.N.; Rasmussen, S.A. Emerging infections and pregnancy. Emerg. Infect. Dis. 2006, 12, 1638–1643. [Google Scholar] [CrossRef] [PubMed]
  59. Fettke, F.; Schumacher, A.; Canellada, A.; Toledo, N.; Bekeredjian-Ding, I.; Bondt, A.; Wuhrer, M.; Costa, S.D.; Zenclussen, A.C. Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha-Fetoprotein Drives Them into Apoptosis. Front. Immunol. 2016, 7, 495. [Google Scholar] [CrossRef] [PubMed]
  60. Birk, K.; Ford, C.; Smeltzer, S.; Ryan, D.; Miller, R.; Rudick, R.A. The clinical course of multiple sclerosis during pregnancy and the puerperium. Arch. Neurol. 1990, 47, 738–742. [Google Scholar] [CrossRef] [PubMed]
  61. Tillman, A.J. The effect of pregnancy on multiple sclerosis and its management. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 1950, 28, 548–582. [Google Scholar] [PubMed]
  62. Peckham, C.H. Multiple sclerosis complicating pregnancy. N. Y. State Med. J. 1945, 45, 618–622. [Google Scholar]
  63. Birner, I.M. Pregnancy and multiple sclerosis: Case report. N. Y. State J. Med. 1945, 45, 634–635. [Google Scholar]
  64. Douglass, L.H.; Jorgensen, C.L. Pregnancy and n multiple sclerosis. Am. J. Obstet. Gynecol. 1948, 55, 332–336. [Google Scholar] [CrossRef]
  65. Denny-Brown, D. Multiple sclerosis: The clinical problem. Am. J. Med. 1952, 12, 501–509. [Google Scholar] [CrossRef]
  66. McCombe, P.A.; Greer, J.M. Female reproductive issues in multiple sclerosis. Mult. Scler. 2012, 19, 392–402. [Google Scholar] [CrossRef] [PubMed]
  67. Tsui, A.; Lee, M.A. Multiple sclerosis and pregnancy. Curr. Opin. Obstet. Gynecol. 2011, 23, 435–439. [Google Scholar] [CrossRef] [PubMed]
  68. Langer-Gould, A.; Beaber, B.E. Effects of pregnancy and breastfeeding on the multiple sclerosis disease course. Clin. Immunol. 2013, 149, 244–250. [Google Scholar] [CrossRef] [PubMed]
  69. D’Hooghe, M.B.; D’Hooghe, T.; De, K.J. Female gender and reproductive factors affecting risk, relapses and progression in multiple sclerosis. Gynecol. Obstet. Investig. 2013, 75, 73–84. [Google Scholar] [CrossRef] [PubMed]
  70. Coyle, P.K. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther. Adv. Neurol. Disord. 2016, 9, 198–210. [Google Scholar] [CrossRef] [PubMed][Green Version]
  71. Lu, E.; Wang, B.W.; Guimond, C.; Synnes, A.; Sadovnick, A.D.; Dahlgren, L.; Traboulsee, A.; Tremlett, H. Safety of disease-modifying drugs for multiple sclerosis in pregnancy: Current challenges and future considerations for effective pharmacovigilance. Expert. Rev. Neurother. 2013, 13, 251–261. [Google Scholar] [CrossRef] [PubMed]
  72. Confavreux, C.; Hutchinson, M.; Hours, M.M.; Cortinovis-Tourniaire, P.; Moreau, T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Engl. J. Med. 1998, 339, 285–291. [Google Scholar] [CrossRef] [PubMed]
  73. De Las Heras, V.; De Andres, C.; Tellez, N.; Tintore, M. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: A descriptive study in the Spanish population. Mult. Scler. 2007, 13, 981–984. [Google Scholar] [CrossRef] [PubMed]
  74. Fernandez, L.N.; Klajn, D.; Acion, L.; Caceres, F.; Calle, A.; Carra, A.; Cristiano, E.; Deri, N.; Garcea, O.; Jaureguiberry, A.; et al. Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study). Mult. Scler. 2009, 15, 555–562. [Google Scholar] [CrossRef] [PubMed]
  75. Finkelsztejn, A.; Fragoso, Y.D.; Ferreira, M.L.; Lana-Peixoto, M.A.; ves-Leon, S.V.; Gomes, S.; Damasceno, B.P.; Mendes, M.F.; Salgado, P.R.; Correa, E.C.; et al. The Brazilian database on pregnancy in multiple sclerosis. Clin. Neurol. Neurosurg. 2010, 113, 277–280. [Google Scholar] [CrossRef] [PubMed]
  76. Jesus-Ribeiro, J.; Correia, I.; Martins, A.I.; Fonseca, M.; Marques, I.; Batista, S.; Nunes, C.; Macario, C.; Almeida, M.C.; Sousa, L. Pregnancy in Multiple Sclerosis: A Portuguese cohort study. Mult. Scler. Relat. Disord. 2017, 17, 63–68. [Google Scholar] [CrossRef] [PubMed]
  77. Houtchens, M.K.; Edwards, N.C.; Phillips, A.L. Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS. Neurology 2018. [Google Scholar] [CrossRef] [PubMed]
  78. Fares, J.; Nassar, A.H.; Gebeily, S.; Kobeissy, F.; Fares, Y. Pregnancy outcomes in Lebanese women with multiple sclerosis (the LeMS study): A prospective multicentre study. BMJ Open 2016, 6, e011210. [Google Scholar] [CrossRef] [PubMed]
  79. Finkelsztejn, A.; Brooks, J.; Paschoal, F., Jr.; Fragoso, Y. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011, 118, 790–797. [Google Scholar] [CrossRef] [PubMed][Green Version]
  80. Alroughani, R.; Alowayesh, M.S.; Ahmed, S.F.; Behbehani, R.; Al-Hashel, J. Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology 2018, 90, e840–e846. [Google Scholar] [CrossRef] [PubMed]
  81. Novi, G.; Ghezzi, A.; Pizzorno, M.; Lapucci, C.; Bandini, F.; Annovazzi, P.; Mancardi, G.L.; Uccelli, A. Dramatic rebounds of MS during pregnancy following fingolimod withdrawal. Neurol. Neuroimmunol. Neuroinflamm. 2017, 4, e377. [Google Scholar] [CrossRef] [PubMed]
  82. De Giglio, L.; Gasperini, C.; Tortorella, C.; Trojano, M.; Pozzilli, C. Natalizumab discontinuation and disease restart in pregnancy: A case series. Acta Neurol. Scand. 2015, 131, 336–340. [Google Scholar] [CrossRef] [PubMed]
  83. Verhaeghe, A.; Deryck, O.M.; Vanopdenbosch, L.J. Pseudotumoral rebound of multiple sclerosis in a pregnant patient after stopping natalizumab. Mult. Scler. Relat. Disord. 2014, 3, 279–281. [Google Scholar] [CrossRef] [PubMed]
  84. Martinelli, V.; Colombo, B.; Dalla Costa, G.; Dalla Libera, D.; Moiola, L.; Falini, A.; Comi, G.; Filippi, M. Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning. Mult. Scler. 2016, 22, 1506–1508. [Google Scholar] [CrossRef] [PubMed]
  85. Portaccio, E.; Moiola, L.; Martinelli, V.; Annovazzi, P.; Ghezzi, A.; Zaffaroni, M.; Lanzillo, R.; Brescia Morra, V.; Rinaldi, F.; Gallo, P.; et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology 2018, 90, e832–e839. [Google Scholar] [CrossRef] [PubMed]
  86. Gilmore, W.; Arias, M.; Stroud, N.; Stek, A.; McCarthy, K.A.; Correale, J. Preliminary studies of cytokine secretion patterns associated with pregnancy in MS patients. J. Neurol. Sci. 2004, 224, 69–76. [Google Scholar] [CrossRef] [PubMed]
  87. Langer-Gould, A.; Gupta, R.; Huang, S.; Hagan, A.; Atkuri, K.; Leimpeter, A.D.; Albers, K.B.; Greenwood, E.; Van Den Eeden, S.K.; Steinman, L.; et al. Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch. Neurol. 2010, 67, 51–57. [Google Scholar] [CrossRef] [PubMed]
  88. Airas, L.; Saraste, M.; Rinta, S.; Elovaara, I.; Huang, Y.H.; Wiendl, H. Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: Relevance of natural killer cells. Clin. Exp. Immunol. 2008, 151, 235–243. [Google Scholar] [CrossRef] [PubMed]
  89. De Andrés, C.; Fernández-Paredes, L.; Tejera-Alhambra, M.; Alonso, B.; Ramos-Medina, R.; Sánchez-Ramón, S. Activation of Blood CD3+CD56+CD8+ T Cells during Pregnancy and Multiple Sclerosis. Front. Immunol. 2017, 8. [Google Scholar] [CrossRef] [PubMed]
  90. Gilli, F.; Lindberg, R.L.; Valentino, P.; Marnetto, F.; Malucchi, S.; Sala, A.; Capobianco, M.; di, S.A.; Sperli, F.; Kappos, L.; et al. Learning from nature: Pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS ONE 2010, 5, e8962. [Google Scholar] [CrossRef] [PubMed]
  91. McCombe, P.A.; Fordyce, B.W.; de Jersey, J.; Yoong, G.; Pender, M.P. Expression of CD45RC and Ia antigen in the spinal cord in acute experimental allergic encephalomyelitis: An immunocytochemical and flow cytometric study. J. Neurol. Sci. 1992, 113, 177–186. [Google Scholar] [CrossRef][Green Version]
  92. McCombe, P.A.; de Jersey, J.; Pender, M.P. Inflammatory cells, microglia and MHC class II antigen-positive cells in the spinal cord of Lewis rats with acute and chronic relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 1994, 51, 153–167. [Google Scholar] [CrossRef][Green Version]
  93. Mokhtarian, F.; McFarlin, D.E.; Raine, C.S. Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature 1984, 309, 356–358. [Google Scholar] [CrossRef] [PubMed]
  94. Van der Veen, R.C.; Trotter, J.L.; Clark, H.B.; Kapp, J.A. The adoptive transfer of chronic relapsing experimental allergic encephalomyelitis with lymph node cells sensitized to myelin proteolipid protein. J. Neuroimmunol. 1989, 21, 183–191. [Google Scholar] [CrossRef]
  95. Zepp, J.; Wu, L.; Li, X. IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends Immunol. 2011, 32, 232–239. [Google Scholar] [CrossRef] [PubMed][Green Version]
  96. Rostami, A.; Ciric, B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J. Neurol. Sci. 2013, 333, 76–87. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. O’Connor, R.A.; Anderton, S.M. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J. Neuroimmunol. 2008, 193, 1–11. [Google Scholar] [CrossRef] [PubMed]
  98. Slavin, A.; Ewing, C.; Liu, J.; Ichikawa, M.; Slavin, J.; Bernard, C.C. Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity 1998, 28, 109–120. [Google Scholar] [CrossRef] [PubMed]
  99. Harness, J.; Pender, M.P.; McCombe, P.A. Cyclosporin A treatment modulates cytokine mRNA expression by inflammatory cells extracted from the spinal cord of rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein. J. Neurol. Sci. 2001, 187, 7–16. [Google Scholar] [CrossRef][Green Version]
  100. Pitarokoili, K.; Ambrosius, B.; Gold, R. Lewis Rat Model of Experimental Autoimmune Encephalomyelitis. Curr. Protoc. Neurosci. 2017, 81, 9.61.1–9.61.20. [Google Scholar] [CrossRef] [PubMed]
  101. Puentes, F.; Dickhaut, K.; Hofstatter, M.; Falk, K.; Rotzschke, O. Active suppression induced by repetitive self-epitopes Protects against EAE development. PLoS ONE 2013, 8, e64888. [Google Scholar] [CrossRef] [PubMed]
  102. Keith, A.B. Effect of pregnancy on experimental allergic encephalomyelitis in guinea pigs and rats. J. Neurol. Sci. 1978, 38, 317–326. [Google Scholar] [CrossRef]
  103. Mertin, L.A.; Rumjanek, V.M. Pregnancy and the susceptibility of Lewis rats to experimental allergic encephalomyelitis. J. Neurol. Sci. 1985, 68, 15–24. [Google Scholar] [CrossRef]
  104. Harness, J.; McCombe, P.A. The effects of pregnancy on myelin basic protein-induced experimental autoimmune encephalomyelitis in Lewis rats: Suppression of clinical disease, modulation of cytokine expression in the spinal cord inflammatory infiltrate and suppression of lymphocyte proliferation by pregnancy sera. Am. J. Reprod. Immunol. 2001, 46, 405–412. [Google Scholar] [PubMed]
  105. Langer-Gould, A.; Garren, H.; Slansky, A.; Ruiz, P.J.; Steinman, L. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: Evidence for a suppressive pregnancy-related serum factor. J. Immunol. 2002, 169, 1084–1091. [Google Scholar] [CrossRef] [PubMed]
  106. McClain, M.A.; Gatson, N.N.; Powell, N.D.; Papenfuss, T.L.; Gienapp, I.E.; Song, F.; Shawler, T.M.; Kithcart, A.; Whitacre, C.C. Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production. J. Immunol. 2007, 179, 8146–8152. [Google Scholar] [CrossRef] [PubMed]
  107. Barac-Latas, V.; Muhvic, D.; Radosevic-Stabic, B. The influence of pregnancy on development and course of chronic relapsing experimental autoimmune encephalomyelitis in rats: Implications for multiple sclerosis. Coll. Antropol. 2010, 34 (Suppl. 1), 267–271. [Google Scholar] [PubMed]
  108. Gatson, N.N.; Williams, J.L.; Powell, N.D.; McClain, M.A.; Hennon, T.R.; Robbins, P.D.; Whitacre, C.C. Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. J. Neuroimmunol. 2011, 230, 105–113. [Google Scholar] [CrossRef] [PubMed]
  109. Brenner, T.; Ovadia, H.; Evron, S.; Mizrachi, R.; Abramsky, O. Experimental allergic encephalomyelitis: Passive transfer of resistance during lactation. J. Neuroimmunol. 1986, 12, 317–327. [Google Scholar] [CrossRef]
  110. Williams, J.L.; Gatson, N.N.; Smith, K.M.; Almad, A.; McTigue, D.M.; Whitacre, C.C. Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity. Clin. Immunol. 2013, 149, 236–243. [Google Scholar] [CrossRef] [PubMed][Green Version]
  111. Engler, J.B.; Kursawe, N.; Solano, M.E.; Patas, K.; Wehrmann, S.; Heckmann, N.; Luhder, F.; Reichardt, H.M.; Arck, P.C.; Gold, S.M.; et al. Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc. Natl. Acad. Sci. USA 2017, 114, E181–E190. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Benedek, G.; Zhang, J.; Nguyen, H.; Kent, G.; Seifert, H.A.; Davin, S.; Stauffer, P.; Vandenbark, A.A.; Karstens, L.; Asquith, M.; et al. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J. Neuroimmunol. 2017, 310, 51–59. [Google Scholar] [CrossRef] [PubMed]
  113. Benedek, G.; Zhang, J.; Nguyen, H.; Kent, G.; Seifert, H.; Vandenbark, A.A.; Offner, H. Novel feedback loop between M2 macrophages/microglia and regulatory B cells in estrogen-protected EAE mice. J. Neuroimmunol. 2017, 305, 59–67. [Google Scholar] [CrossRef] [PubMed][Green Version]
  114. Itoh, N.; Kim, R.; Peng, M.; DiFilippo, E.; Johnsonbaugh, H.; MacKenzie-Graham, A.; Voskuhl, R.R. Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. J. Neuroimmunol. 2017, 304, 63–71. [Google Scholar] [CrossRef] [PubMed][Green Version]
  115. Jalkanen, A.; Alanen, A.; Airas, L. Pregnancy outcome in women with multiple sclerosis: Results from a prospective nationwide study in Finland. Mult. Scler. 2010, 16, 950–955. [Google Scholar] [CrossRef] [PubMed]
  116. Roullet, E.; Verdier-Tailefer, M.M.; Amarenco, P.; Ghabi, G.; Alperovitch, A.; Marteau, R. Pregnancy and multiple sclerosis: A longitudinal study of 125 remittent patients. J. Neurol. Neurosurg. Psychiatry 1993, 56, 1062–1065. [Google Scholar] [CrossRef] [PubMed]
  117. Worthington, J.; Jones, R.; Crawford, M.; Forti, A. Pregnancy and multiple sclerosis—A 3-year prospective study. J. Neurol. 1994, 241, 228–233. [Google Scholar] [CrossRef] [PubMed]
  118. Portaccio, E.; Ghezzi, A.; Hakiki, B.; Sturchio, A.; Martinelli, V.; Moiola, L.; Patti, F.; Mancardi, G.L.; Solaro, C.; Tola, M.R.; et al. Postpartum relapses increase the risk of disability progression in multiple sclerosis: The role of disease modifying drugs. J. Neurol. Neurosurg. Psychiatry 2014, 85, 845–850. [Google Scholar] [CrossRef] [PubMed]
  119. Vukusic, S.; Hutchinson, M.; Hours, M.; Moreau, T.; Cortinovis-Tourniaire, P.; Adeleine, P.; Confavreux, C.; Pregnancy in Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study): Clinical predictors of post-partum relapse. Brain 2004, 127, 1353–1360. [Google Scholar] [CrossRef] [PubMed]
  120. Portaccio, E.; Ghezzi, A.; Hakiki, B.; Martinelli, V.; Moiola, L.; Patti, F.; La, M.L.; Mancardi, G.L.; Solaro, C.; Tola, M.R.; et al. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 2011, 77, 145–150. [Google Scholar] [CrossRef] [PubMed]
  121. Pasto, L.; Portaccio, E.; Ghezzi, A.; Hakiki, B.; Giannini, M.; Razzolini, L.; Piscolla, E.; De Giglio, L.; Pozzilli, C.; Paolicelli, D.; et al. Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: The Italian cohort study. BMC Neurol. 2012, 12, 165. [Google Scholar] [CrossRef] [PubMed]
  122. Langer-Gould, A.; Huang, S.M.; Gupta, R.; Leimpeter, A.D.; Greenwood, E.; Albers, K.B.; Van Den Eeden, S.K.; Nelson, L.M. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch. Neurol. 2009, 66, 958–963. [Google Scholar] [CrossRef] [PubMed]
  123. Airas, L.; Jalkanen, A.; Alanen, A.; Pirttila, T.; Marttila, R.J. Breast-feeding, postpartum and prepregnancy disease activity in multiple sclerosis. Neurology 2010, 75, 474–476. [Google Scholar] [CrossRef] [PubMed]
  124. Neuteboom, R.F.; Verbraak, E.; Voerman, J.S.; van, M.M.; Steegers, E.A.; De Groot, C.J.; Laman, J.D.; Hintzen, R.Q. First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. Mult. Scler. 2009, 15, 1356–1358. [Google Scholar] [CrossRef] [PubMed]
  125. De Seze, J.; Chapelotte, M.; Delalande, S.; Ferriby, D.; Stojkovic, T.; Vermersch, P. Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult. Scler. 2004, 10, 596–597. [Google Scholar] [CrossRef] [PubMed]
  126. Achiron, A.; Kishner, I.; Dolev, M.; Stern, Y.; Dulitzky, M.; Schiff, E.; Achiron, R. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J. Neurol. 2004, 251, 1133–1137. [Google Scholar] [CrossRef] [PubMed]
  127. Haas, J.; Hommes, O.R. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult. Scler. 2007, 13, 900–908. [Google Scholar] [CrossRef] [PubMed]
  128. Hellwig, K.; Beste, C.; Schimrigk, S.; Chan, A. Immunomodulation and postpartum relapses in patients with multiple sclerosis. Ther. Adv. Neurol. Disord. 2009, 2, 7–11. [Google Scholar] [CrossRef] [PubMed][Green Version]
  129. Rosa, G.R.; O’Brien, A.T.; Nogueira, E.A.G.; Carvalho, V.M.; Paz, S.C.; Fragoso, Y.D. There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: Findings from a systematic review and meta-analysis. Arq. Neuropsiquiatr. 2018, 76, 361–366. [Google Scholar] [CrossRef] [PubMed]
  130. Laplaud, D.A.; Leray, E.; Barriere, P.; Wiertlewski, S.; Moreau, T. Increase in multiple sclerosis relapse rate following in vitro fertilization. Neurology 2006, 66, 1280–1281. [Google Scholar] [CrossRef] [PubMed]
  131. Hellwig, K.; Beste, C.; Brune, N.; Haghikia, A.; Muller, T.; Schimrigk, S.; Gold, R. Increased MS relapse rate during assisted reproduction technique. J. Neurol. 2008, 255, 592–593. [Google Scholar] [CrossRef] [PubMed]
  132. Hellwig, K.; Schimrigk, S.; Beste, C.; Muller, T.; Gold, R. Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis. Eur. Neurol. 2009, 61, 65–68. [Google Scholar] [CrossRef] [PubMed]
  133. Correale, J.; Farez, M.F.; Ysrraelit, M.C. Increase in multiple sclerosis activity after assisted reproduction technology. Ann. Neurol. 2012, 72, 682–694. [Google Scholar] [CrossRef] [PubMed]
  134. Michel, L.; Foucher, Y.; Vukusic, S.; Confavreux, C.; de Sèze, J.; Brassat, D.; Clanet, M.; Clavelou, P.; Ouallet, J.C.; Brochet, B.; et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J. Neurol. Neurosurg. Psychiatry 2012, 83, 796–802. [Google Scholar] [CrossRef] [PubMed][Green Version]
  135. Chen, A.; Ganor, Y.; Rahimipour, S.; Ben-Aroya, N.; Koch, Y.; Levite, M. The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nat. Med. 2002, 8, 1421–1426. [Google Scholar] [CrossRef] [PubMed]
  136. Houtchens, M.K.; Edwards, N.C.; Schneider, G.; Stern, K.; Phillips, A.L. Pregnancy rates and outcomes in women with and without MS in the United States. Neurology 2018. [Google Scholar] [CrossRef] [PubMed]
  137. Sandberg-Wollheim, M.; Neudorfer, O.; Grinspan, A.; Weinstock-Guttman, B.; Haas, J.; Izquierdo, G.; Riley, C.; Ross, A.P.; Baruch, P.; Drillman, T.; et al. Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database. Int. J. MS Care 2018, 20, 9–14. [Google Scholar] [CrossRef] [PubMed][Green Version]
  138. Hellwig, K.; Haghikia, A.; Gold, R. Pregnancy and natalizumab: Results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult. Scler. 2011, 17, 958–963. [Google Scholar] [CrossRef] [PubMed]
  139. Hoevenaren, I.A.; de Vries, L.C.; Rijnders, R.J.; Lotgering, F.K. Delivery of healthy babies after natalizumab use for multiple sclerosis: A report of two cases. Acta Neurol. Scand. 2011, 123, 430–433. [Google Scholar] [CrossRef] [PubMed]
  140. Portaccio, E.; Annovazzi, P.; Ghezzi, A.; Zaffaroni, M.; Moiola, L.; Martinelli, V.; Lanzillo, R.; Brescia Morra, V.; Rinaldi, F.; Gallo, P.; et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I Fetal risks. Neurology 2018, 90, e823–e831. [Google Scholar] [CrossRef] [PubMed]
  141. Haghikia, A.; Langer-Gould, A.; Rellensmann, G.; Schneider, H.; Tenenbaum, T.; Elias-Hamp, B.; Menck, S.; Zimmermann, J.; Herbstritt, S.; Marziniak, M.; et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014, 71, 891–895. [Google Scholar] [CrossRef] [PubMed]
  142. Runmarker, B.; Andersen, O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 1995, 118, 253–261. [Google Scholar] [CrossRef] [PubMed]
  143. D’Hooghe, M.B.; Nagels, G.; Uitdehaag, B.M. Long-term effects of childbirth in MS. J. Neurol. Neurosurg. Psychiatry 2010, 81, 38–41. [Google Scholar] [CrossRef] [PubMed]
  144. Verdru, P.; Theys, P.; D’Hooghe, M.B.; Carton, H. Pregnancy and multiple sclerosis: The influence on long term disability. Clin. Neurol. Neurosurg. 1994, 96, 38–41. [Google Scholar] [CrossRef]
  145. Altintas, A.; Najar, B.; Gozubatik-Celik, G.; Menku, S.F. Pregnancy Data in a Turkish Multiple Sclerosis Population. Eur. Neurol. 2015, 74, 296–302. [Google Scholar] [CrossRef] [PubMed]
  146. Ponsonby, A.L.; Lucas, R.M.; van der Mei, I.A.; Dear, K.; Valery, P.C.; Pender, M.P.; Taylor, B.V.; Kilpatrick, T.J.; Coulthard, A.; Chapman, C.; et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: The AusImmune Study. Neurology 2012, 78, 867–874. [Google Scholar] [CrossRef] [PubMed]
  147. Jokubaitis, V.G.; Spelman, T.; Kalincik, T.; Lorscheider, J.; Havrdova, E.; Horakova, D.; Duquette, P.; Girard, M.; Prat, A.; Izquierdo, G.; et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann. Neurol. 2016, 80, 89–100. [Google Scholar] [CrossRef] [PubMed][Green Version]
  148. Koch, M.; Uyttenboogaart, M.; Heersema, D.; Steen, C.; De, K.J. Parity and secondary progression in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 2009, 80, 676–678. [Google Scholar] [CrossRef] [PubMed][Green Version]
  149. Basso, O.; Campi, R.; Frydenberg, M.; Koch-Henriksen, N.; Bronnum-Hansen, H.; Olsen, J. Multiple sclerosis in women having children by multiple partners. A population-based study in Denmark. Mult. Scler. 2004, 10, 621–625. [Google Scholar] [CrossRef] [PubMed]
  150. Thompson, E.E.; Nicodemus-Johnson, J.; Kim, K.W.; Gern, J.E.; Jackson, D.J.; Lemanske, R.F.; Ober, C. Global DNA methylation changes spanning puberty are near predicted estrogen-responsive genes and enriched for genes involved in endocrine and immune processes. Clin. Epigenetics 2018, 10, 62. [Google Scholar] [CrossRef] [PubMed]
  151. Yang, Y.M.; Sun, D.; Kandhi, S.; Froogh, G.; Zhuge, J.; Huang, W.; Hammock, B.D.; Huang, A. Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation. Proc. Natl. Acad. Sci. USA 2018, 115, 613–618. [Google Scholar] [CrossRef] [PubMed]
  152. Pfeiffer, J.R.; Mutesa, L.; Uddin, M. Traumatic Stress Epigenetics. Curr. Behav. Neurosci. Rep. 2018, 5, 81–93. [Google Scholar] [CrossRef] [PubMed]
  153. Gapp, K.; Bohacek, J.; Grossmann, J.; Brunner, A.M.; Manuella, F.; Nanni, P.; Mansuy, I.M. Potential of Environmental Enrichment to Prevent Transgenerational Effects of Paternal Trauma. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2016, 41, 2749–2758. [Google Scholar] [CrossRef] [PubMed][Green Version]
  154. Nielsen, N.M.; Jorgensen, K.T.; Stenager, E.; Jensen, A.; Pedersen, B.V.; Hjalgrim, H.; Kjaer, S.K.; Frisch, M. Reproductive history and risk of multiple sclerosis. Epidemiology 2011, 22, 546–552. [Google Scholar] [CrossRef] [PubMed]
Table 1. Common forms of experimental autoimmune encephalomyelitis (EAE).
Table 1. Common forms of experimental autoimmune encephalomyelitis (EAE).
AntigenSpecies StudiedClinical CoursePathological FeaturesReferences
Guinea pig spinal cordRatMonophasicInflammation and demyelination[26]
Myelin basic proteinLewis ratMonophasicInflammation and demyelination, including nerve roots [17]
Myelin proteolipid proteinLewis rats, SJL miceChronic relapsingInflammation and demyelination[19,20,21]
Myelin oligodendrocyte glycoproteinMice and ratsChronic relapsingInflammation and demyelination, role for antibody[22,23,24]
Table 2. Immune and neuroprotective effects of selected hormones of pregnancy and lactation.
Table 2. Immune and neuroprotective effects of selected hormones of pregnancy and lactation.
HormoneTiming of Increased LevelsImmune EffectsReparative EffectsReferences
EstriolPregnancyAnti-inflammatoryNeuroprotective, aids remyelination[36,37]
ProgesteronePregnancyAnti-inflammatoryNeuroprotective[38,39]
ProlactinPregnancy and lactationPro-inflammatory (controversial)Possible role in neurogenesis[40,41]
OxytocinLactationComplex effectsNeuroprotection[42,43]
Table 3. Reports of relapses of multiple sclerosis (MS) with assisted reproduction technology (ART).
Table 3. Reports of relapses of multiple sclerosis (MS) with assisted reproduction technology (ART).
StudyType of StudyNo of PatientsNo of ART CyclesRelapses with GnRH Agonists Relapses with GnRH AntagonistsReference
Laplaud et al., 2006Retrospective6105/6 treatments0/4 treatments[130]
Hellwig et al., 2008Retrospective6143/9 treatments2/5 treatments[131]
Hellwig et al., 2009Prospective/retrospective2378Increased annualized relapse rate (ARR)Increased ARR[132]
Hellwig et al., 2009Prospective group10142/81/4[132]
Correale et al., 2012Prospective162615/26Not applicable[133]
Michel et al., 2012Retrospective3270Increased ARR (48 treatments)No increased ARR (19 treatments)[134]

© 2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Back to TopTop