Abstract
The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences might provide important insight into mechanisms of pathogenesis and progression of the disease in patients. MS occurs more frequently in women than in men, indicating that sex-related factors have an effect on an individual's susceptibility to developing the condition. These factors include hormonal, genetic and environmental influences, as well as gene–environment interactions and epigenetic mechanisms. Interestingly, women do not have a poorer prognosis than men with MS despite a higher incidence of the disease and more-robust immune responses, which suggests a mechanism of resilience. Furthermore, the state of pregnancy has a substantial effect on disease activity, characterized by a reduction in relapse rates during the third trimester but an increased relapse rate in the postpartum period. However, pregnancy has little effect on long-term disability in women with MS. The unravelling of the mechanisms underlying these clinical observations in the laboratory and application of the results to the clinical setting is a unique and potentially fruitful strategy to develop novel therapeutic approaches for MS.
Key Points
-
Women are at increased risk of developing multiple sclerosis (MS) but have a reduced relapse rate during pregnancy, indicating that sex-related factors are important in disease pathogenesis and activity
-
While women have a higher incidence of MS and a more robust immune response, male patients can demonstrate a more progressive disease course
-
The effects of sex-related factors on disease relapse should be considered separately from the effects on disease progression
-
Sex hormones and sex chromosomes can independently contribute to disease incidence and progression
-
Sex-related factors might exert different, even opposing, effects on the peripheral immune system and the CNS
-
The increasing difference in MS incidence between men and women is likely to be attributable to the interaction of sex-specific factors with autosomal genes, environmental factors and/or behavioural factors
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Koch-Henriksen, N. & Sørensen, P. S. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9, 520–532 (2010).
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. 339, 285–291 (1998).
Whitacre, C. C., Reingold, S. C. & O'Looney, P. A. A gender gap in autoimmunity. Science 283, 1277–1278 (1999).
Duquette, P. et al. The increased susceptibility of women to multiple sclerosis. Can. J. Neurol. Sci. 19, 466–471 (1992).
Voskuhl, R. R., Pitchekian-Halabi, H., MacKenzie-Graham, A., McFarland, H. F. & Raine, C. S. Gender differences in autoimmune demyelination in the mouse: implications for multiple sclerosis. Ann. Neurol. 39, 724–733 (1996).
Papenfuss, T. L. et al. Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains. J. Neuroimmunol. 150, 59–69 (2004).
Okuda, Y., Okuda, M. & Bernard, C. C. Gender does not influence the susceptibility of C57BL/6 mice to develop chronic experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein. Immunol. Lett. 81, 25–29 (2002).
Kantarci, O. H. et al. IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis. Genes Immun. 6, 153–161 (2005).
Confavreux, C., Vukusic, S. & Adeleine, P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126, 770–782 (2003).
Runmarker, B., Andersson, C., Odén, A. & Andersen, O. Prediction of outcome in multiple sclerosis based on multivariate models. J. Neurol. 241, 597–604 (1994).
Pozzilli, C. et al. 'Gender gap' in multiple sclerosis: magnetic resonance imaging evidence. Eur. J. Neurol. 10, 95–97 (2003).
Weatherby, S. J. et al. A pilot study of the relationship between gadolinium-enhancing lesions, gender effect and polymorphisms of antioxidant enzymes in multiple sclerosis. J. Neurol. 247, 467–470 (2000).
Antulov, R. et al. Gender-related differences in MS: a study of conventional and nonconventional MRI measures. Mult. Scler. 15, 345–354 (2009).
Barkhof, F. et al. Predicting gadolinium enhancement status in MS patients eligible for randomized clinical trials. Neurology 65, 1447–1454 (2005).
Stone, L. A. et al. Blood–brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing–remitting multiple sclerosis: relationship to course, gender, and age. Neurology 45, 1122–1126 (1995).
Libert, C., Dejager, L. & Pinheiro, I. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594–604 (2010).
Kantarci, O. H. et al. Interferon gamma allelic variants: sex-biased multiple sclerosis susceptibility and gene expression. Arch. Neurol. 65, 349–357 (2008).
Moldovan, I. R., Cotleur, A. C., Zamor, N., Butler, R. S. & Pelfrey, C. M. Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens. J. Neuroimmunol. 193, 161–169 (2008).
Pelfrey, C. M., Cotleur, A. C., Lee, J. C. & Rudick, R. A. Sex differences in cytokine responses to myelin peptides in multiple sclerosis. J. Neuroimmunol. 130, 211–223 (2002).
Wolinsky, J. S., Shochat, T., Weiss, S. & Ladkani, D. Glatiramer acetate treatment in PPMS: why males appear to respond favorably. J. Neurol. Sci. 286, 92–98 (2009).
Koch, M., Kingwell, E., Rieckmann, P. & Tremlett, H. The natural history of secondary progressive multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 81, 1039–1043 (2010).
Voskuhl, R. R. & Palaszynski, K. Sex hormones and experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neuroscientist 7, 258–270 (2001).
Jansson, L., Olsson, T. & Holmdahl, R. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J. Neuroimmunol. 53, 203–207 (1994).
Matejuk, A. et al. 17β-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. J. Neurosci. Res. 65, 529–542 (2001).
Gold, S. M. & Voskuhl, R. R. Estrogen and testosterone therapies in multiple sclerosis. Prog. Brain Res. 175, 239–251 (2009).
Palaszynski, K. M., Loo, K. K., Ashouri, J. F., Liu, H. & Voskuhl, R. R. Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J. Neuroimmunol. 146, 144–152 (2004).
Smith-Bouvier, D. L. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 205, 1099–1108 (2008).
Palaszynski, K. M. et al. A yin–yang effect between sex chromosome complement and sex hormones on the immune response. Endocrinology 146, 3280–3285 (2005).
Spach, K. M. et al. Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J. Immunol. 182, 1789–1793 (2009).
Teuscher, C. et al. Evidence that the Y chromosome influences autoimmune disease in male and female mice. Proc. Natl Acad. Sci. USA 103, 8024–8029 (2006).
Ebers, G. C. et al. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 363, 1773–1774 (2004).
Chao, M. J. et al. Parent-of-origin effects at the major histocompatibility complex in multiple sclerosis. Hum. Mol. Genet. 19, 3679–3689 (2010).
Gregg, C., Zhang, J., Butler, J. E., Haig, D. & Dulac, C. Sex-specific parent-of-origin allelic expression in the mouse brain. Science 329, 682–685 (2010).
Gabory, A., Attig, L. & Junien, C. Sexual dimorphism in environmental epigenetic programming. Mol. Cell. Endocrinol. 304, 8–18 (2009).
Fox, H. S., Bond, B. L. & Parslow, T. G. Estrogen regulates the IFN-gamma promoter. J. Immunol. 146, 4362–4367 (1991).
Ramagopalan, S. V. et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5, e1000369 (2009).
Chao, M. J. et al. MHC transmission: insights into gender bias in MS susceptibility. Neurology 76, 242–246 (2011).
Orton, S. M. et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 5, 932–936 (2006).
Dunn, S. E. et al. Peroxisome proliferator-activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med. 204, 321–330 (2007).
Ponsonby, A. L. et al. Offspring number, pregnancy and risk of first clinical demyelinating event: the Ausimmune study. Neurology http://dx.doi.org/10.1212/WNL.0b013e31824c4648.
Sicotte, N. L. et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch. Neurol. 64, 683–688 (2007).
Gold, S. M., Chalifoux, S., Giesser, B. S. & Voskuhl, R. R. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J. Neuroinflammation 5, 32 (2008).
Alonso, A. et al. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch. Neurol. 62, 1362–1365 (2005).
Weinshenker, B. G., Hader, W., Carriere, W., Baskerville, J. & Ebers, G. C. The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario. Neurology 39, 1438–1440 (1989).
Villard-Mackintosh, L. & Vessey, M. P. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 47, 161–168 (1993).
Thorogood, M. & Hannaford, P. C. The influence of oral contraceptives on the risk of multiple sclerosis. Br. J. Obstet. Gynaecol. 105, 1296–1299 (1998).
Hernán, M. A., Hohol, M. J., Olek, M. J., Spiegelman, D. & Ascherio, A. Oral contraceptives and the incidence of multiple sclerosis. Neurology 55, 848–854 (2000).
Airas, L. et al. Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin. Exp. Immunol. 151, 235–243 (2008).
De Las Heras, V., De Andrés, C., Téllez, N. & Tintoré, 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. 13, 981–984 (2007).
Fernández Liguori, N. et al. Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study). Mult. Scler. 15, 555–562 (2009).
Finkelsztejn, A. et al. The Brazilian database on pregnancy in multiple sclerosis. Clin. Neurol. Neurosurg. 113, 277–280 (2010).
Finkelsztejn, A., Brooks, J. B., Paschoal, F. M. Jr & Fragoso, Y. D. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 118, 790–797 (2011).
Vosoughi, R. & Freedman, M. S. Therapy of MS. Clin. Neurol. Neurosurg. 112, 365–385 (2010).
Vukusic, S. et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 127, 1353–1360 (2004).
Roullet, E. et al. Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients. J. Neurol. Neurosurg. Psychiatry 56, 1062–1065 (1993).
Damek, D. M. & Shuster, E. A. Pregnancy and multiple sclerosis. Mayo Clin. Proc. 72, 977–989 (1997).
Runmarker, B. & Andersen, O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 118, 253–261 (1995).
Verdru, P., Theys, P., D'Hooghe, M. B. & Carton, H. Pregnancy and multiple sclerosis: the influence on long term disability. Clin. Neurol. Neurosurg. 96, 38–41 (1994).
D'Hooghe, M. B., Nagels, G. & Uitdehaag, B. M. Long-term effects of childbirth in MS. J. Neurol. Neurosurg. Psychiatry 81, 38–41 (2010).
Jungers, P. et al. Lupus nephropathy and pregnancy. Report of 104 cases in 36 patients. Arch. Intern. Med. 142, 771–776 (1982).
Gilli, F. et al. Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS ONE 5, e8962 (2010).
Al-Shammri, S. et al. Th1/Th2 cytokine patterns and clinical profiles during and after pregnancy in women with multiple sclerosis. J. Neurol. Sci. 222, 21–27 (2004).
Gilmore, W. et al. Preliminary studies of cytokine secretion patterns associated with pregnancy in MS patients. J. Neurol. Sci. 224, 69–76 (2004).
López, C., Comabella, M., Tintoré, M., Sastre-Garriga, J. & Montalban, X. Variations in chemokine receptor and cytokine expression during pregnancy in multiple sclerosis patients. Mult. Scler. 12, 421–427 (2006).
Langer-Gould, A. et al. Interferon-γ-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch. Neurol. 67, 51–57 (2010).
Neuteboom, R. F. et al. First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. Mult. Scler. 15, 1356–1358 (2009).
Sánchez-Ramón, S. et al. Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity. Immunol. Lett. 96, 195–201 (2005).
Neuteboom, R. F. et al. Pregnancy-induced fluctuations in functional T-cell subsets in multiple sclerosis patients. Mult. Scler. 16, 1073–1078 (2010).
Frank, S. (Ed.) Endocrinology of Pregnancy (Baillière Tindall, London, 1990).
Tulchinsky, D., Hobel, C. J., Yeager, E. & Marshall, J. R. Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. Am. J. Obstet. Gynecol. 112, 1095–1100 (1972).
Kim, S., Liva, S. M., Dalal, M. A., Verity, M. A. & Voskuhl, R. R. Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 52, 1230–1238 (1999).
Yates, M. A. et al. Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 220, 136–139 (2010).
Hoffman, G. E., Le, W. W., Murphy, A. Z. & Koski, C. L. Divergent effects of ovarian steroids on neuronal survival during experimental allergic encephalitis in Lewis rats. Exp. Neurol. 171, 272–284 (2001).
Garay, L. et al. Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 15, 76–83 (2008).
Garay, L., Deniselle, M. C., Lima, A., Roig, P. & De Nicola, A. F. Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. J. Steroid Biochem. Mol. Biol. 107, 228–237 (2007).
Garay, L. et al. Protective effects of progesterone administration on axonal pathology in mice with experimental autoimmune encephalomyelitis. Brain Res. 1283, 177–185 (2009).
Spach, K. M. & Hayes, C. E. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J. Immunol. 175, 4119–4126 (2005).
Nashold, F. E., Spach, K. M., Spanier, J. A. & Hayes, C. E. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J. Immunol. 183, 3672–3681 (2009).
Mirzaei, F. et al. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann. Neurol. 70, 30–40 (2011).
Chan, J. et al. Glucocorticoid-induced apoptosis in human decidua: a novel role for 11β-hydroxysteroid dehydrogenase in late gestation. J. Endocrinol. 195, 7–15 (2007).
Gregg, C. et al. White matter plasticity and enhanced remyelination in the maternal CNS. J. Neurosci. 27, 1812–1823 (2007).
Riskind, P. N., Massacesi, L., Doolittle, T. H. & Hauser, S. L. The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine. Ann. Neurol. 29, 542–547 (1991).
Nociti, V. et al. Multiple sclerosis attacks triggered by hyperprolactinemia. J. Neurooncol. 98, 407–409 (2010).
Yamasaki, K. et al. Hyperprolactinemia in optico-spinal multiple sclerosis. Intern. Med. 39, 296–299 (2000).
Nelson, L. M., Franklin, G. M. & Jones, M. C. Risk of multiple sclerosis exacerbation during pregnancy and breast-feeding. JAMA 259, 3441–3443 (1988).
Airas, L., Jalkanen, A., Alanen, A., Pirttilä, T. & Marttila, R. J. Breast-feeding, postpartum and prepregnancy disease activity in multiple sclerosis. Neurology 75, 474–476 (2010).
Portaccio, E. et al. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 77, 145–150 (2011).
Langer-Gould, A. et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch. Neurol. 66, 958–963 (2009).
Hellwig, K., Haghikia, A., Agne, H., Beste, C. & Gold, R. Protective effect of breastfeeding in postpartum relapse rate of mothers with multiple sclerosis. Arch. Neurol. 66, 1580–1581 (2009).
Lambert, N. & Nelson, J. L. Microchimerism in autoimmune disease: more questions than answers? Autoimmun. Rev. 2, 133–139 (2003).
Basso, O. et al. Multiple sclerosis in women having children by multiple partners. A population-based study in Denmark. Mult. Scler. 10, 621–625 (2004).
Abramsky, O. Pregnancy and multiple sclerosis. Ann. Neurol. 36 (Suppl.), S38–S41 (1994).
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. 169, 1084–1091 (2002).
Kipp, M. & Beyer, C. Impact of sex steroids on neuroinflammatory processes and experimental multiple sclerosis. Front. Neuroendocrinol. 30, 188–200 (2009).
Wise, P. M., Dubal, D. B., Wilson, M. E., Rau, S. W. & Böttner, M. Minireview: neuroprotective effects of estrogen-new insights into mechanisms of action. Endocrinology 142, 969–973 (2001).
Enmark, E. & Gustafsson, J. A. Oestrogen receptors—an overview. J. Intern. Med. 246, 133–138 (1999).
Weiss, D. J. & Gurpide, E. Non-genomic effects of estrogens and antiestrogens. J. Steroid Biochem. 31, 671–676 (1988).
Yates, M. A., Li, Y., Chlebeck, P. J. & Offner, H. GPR30, but not estrogen receptor-α, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol. BMC Immunol. 11, 20 (2010).
Blasko, E. et al. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J. Neuroimmunol. 214, 67–77 (2009).
Wang, C. et al. Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J. Immunol. 182, 3294–3303 (2009).
Liu, H. B. et al. Estrogen receptor α mediates estrogen's immune protection in autoimmune disease. J. Immunol. 171, 6936–6940 (2003).
Polanczyk, M. et al. The protective effect of 17β-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-α. Am. J. Pathol. 163, 1599–1605 (2003).
Morales, L. B. et al. Treatment with an estrogen receptor α ligand is neuroprotective in experimental autoimmune encephalomyelitis. J. Neurosci. 26, 6823–6833 (2006).
Elloso, M. M., Phiel, K., Henderson, R. A., Harris, H. A. & Adelman, S. J. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands. J. Endocrinol. 185, 243–252 (2005).
Garidou, L. et al. Estrogen receptor α signaling in inflammatory leukocytes is dispensable for 17β-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis. J. Immunol. 173, 2435–2442 (2004).
Spence, R. D. et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proc. Natl Acad. Sci. USA 108, 8867–8872 (2011).
Tiwari-Woodruff, S., Morales, L. B., Lee, R. & Voskuhl, R. R. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment. Proc. Natl Acad. Sci. USA 104, 14813–14818 (2007).
Du, S., Sandoval, F., Trinh, P., Umeda, E. & Voskuhl, R. Estrogen receptor-β ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease. Eur. J. Immunol. 41, 140–150 (2011).
Du, S., Sandoval, F., Trinh, P. & Voskuhl, R. R. Additive effects of combination treatment with anti-inflammatory and neuroprotective agents in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 219, 64–74 (2010).
Tiwari-Woodruff, S. & Voskuhl, R. R. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. J. Neurol. Sci. 286, 81–85 (2009).
Crawford, D. K. et al. Oestrogen receptor β ligand: a novel treatment to enhance endogenous functional remyelination. Brain 133, 2999–3016 (2010).
Saijo, K., Collier, J. G., Li, A. C., Katzenellenbogen, J. A. & Glass, C. K. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145, 584–595 (2011).
Sicotte, N. L. et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann. Neurol. 52, 421–428 (2002).
Soldan, S. S., Alvarez-Retuerto, A. I., Sicotte, N. L. & Voskuhl, R. R. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J. Immunol. 171, 6267–6274 (2003).
Gold, S. M. et al. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERα). Lab. Invest. 89, 1076–1083 (2009).
US National Library of Medicine. A combination trial of copaxone plus estriol in relapsing remitting multiple sclerosis (RRMS) (Estriol in MS). ClinicalTrials.gov [online], (2012).
US National Library of Medicine. POPART'MUS: Prevention of Post Partum Relapses with Progestin and Estradiol in Multiple Sclerosis. ClinicalTrials.gov [online], (2011).
Vukusic, S. et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. J. Neurol. Sci. 286, 114–118 (2009).
Munoz-Suano, A., Kallikourdis, M., Sarris, M. & Betz, A. G. Regulatory T cells protect from autoimmune arthritis during pregnancy. J. Autoimmun. http://dx.doi.org/10.1016/j.jaut.2011.09.007.
Munoz-Suano, A., Hamilton, A. B. & Betz, A. G. Gimme shelter: the immune system during pregnancy. Immunol. Rev. 241, 20–38 (2011).
Tafuri, A., Alferink, J., Möller, P., Hämmerling, G. J. & Arnold, B. T cell awareness of paternal alloantigens during pregnancy. Science 270, 630–633 (1995).
Mor, G. & Cardenas, I. The immune system in pregnancy: a unique complexity. Am. J. Reprod. Immunol. 63, 425–433 (2010).
Fallon, P. G. et al. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17, 7–17 (2002).
Wegmann, T. G., Lin, H., Guilbert, L. & Mosmann, T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol. Today 14, 353–356 (1993).
Chaouat, G. The Th1/Th2 paradigm: still important in pregnancy? Semin. Immunopathol. 29, 95–113 (2007).
Trowsdale, J. & Betz, A. G. Mother's little helpers: mechanisms of maternal-fetal tolerance. Nat. Immunol. 7, 241–246 (2006).
Saito, S., Nakashima, A., Shima, T. & Ito, M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol. 63, 601–610 (2010).
Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).
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 112, 38–43 (2004).
Santner-Nanan, B. et al. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J. Immunol. 183, 7023–7030 (2009).
Peters, A., Lee, Y. & Kuchroo, V. K. The many faces of Th17 cells. Curr. Opin. Immunol. 23, 702–706 (2011).
Acknowledgements
R. R. Voskuhl's research work was supported by the NIH (grants RO1 NS051591, R21 NS071210 and K24 NS062117); the National Multiple Sclerosis Society (grants RG3915, RG4033, RG4363); the Skirball Foundation; the Conrad Hilton Foundation; and the Sherak Family Fund. S. M. Gold's research work is supported by the European Union (grant RG268381) and a grant from the Hamburg Research and Science Foundation.
Author information
Authors and Affiliations
Contributions
R. R. Voskuhl and S. M. Gold contributed equally to researching data for the article, discussion of content, writing the article, and review and/or editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The University of California Los Angeles holds a use patent for oestriol for the treatment of multiple sclerosis: R. R. Voskuhl is an inventor of this treatment. Dr Voskuhl also provides consulting advice on treatments for multiple sclerosis to Adeona Pharmaceuticals with compensation capped at a maximum of $10,000 per year. S. M. Gold declares no competing interests.
Rights and permissions
About this article
Cite this article
Voskuhl, R., Gold, S. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8, 255–263 (2012). https://doi.org/10.1038/nrneurol.2012.43
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2012.43
This article is cited by
-
Interplay between androgen and CXCR4 chemokine signaling in myelin repair
Acta Neuropathologica Communications (2024)
-
Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice
Nature Communications (2023)
-
β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males
Cellular and Molecular Neurobiology (2023)
-
X chromosome agents of sexual differentiation
Nature Reviews Endocrinology (2022)
-
Mechanisms of sex hormones in autoimmunity: focus on EAE
Biology of Sex Differences (2020)