The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View
Abstract
:1. Introduction
2. Estrogens
Estrogen Receptors
3. Estrogen Effects on the Immune System: Focus on MS
3.1. Innate Immune Cells
3.2. T Cells
3.3. B Cells
4. Estrogens Modulate the T Helper Epigenome in MS
5. Estrogens as a Potential MS Therapy
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Dendrou, C.A.; Fugger, L.; Friese, M.A. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015, 15, 545–558. [Google Scholar] [CrossRef] [PubMed]
- Durelli, L.; Conti, L.; Clerico, M.; Boselli, D.; Contessa, G.; Ripellino, P.; Ferrero, B.; Eid, P.; Novelli, F. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β. Ann Neurol. 2009, 65, 499–509. [Google Scholar] [CrossRef] [PubMed]
- Langrish, C.L.; Chen, Y.; Blumenschein, W.M.; Mattson, J.; Basham, B.; Sedgwick, J.D.; McClanahan, T.; Kastelein, R.A.; Cua, D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 2005, 201, 233–240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 2007, 13, 1173–1175. [Google Scholar] [CrossRef] [Green Version]
- Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 2008, 172, 146–155. [Google Scholar] [CrossRef]
- Rolla, S.; Bardina, V.; De Mercanti, S.; Quaglino, P.; De Palma, R.; Gned, D.; Brusa, D.; Durelli, L.; Novelli, F.; Clerico, M. Th22 cells are expanded in multiple sclerosis and are resistant to IFN-β. J. Leukoc. Biol. 2014, 96, 1155–1164. [Google Scholar] [CrossRef]
- Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502–1517. [Google Scholar] [CrossRef]
- Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sørensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.; Barkhof, F.; et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014, 83, 278–286. [Google Scholar] [CrossRef] [Green Version]
- Westerlind, H.; Ramanujam, R.; Uvehag, D.; Kuja-Halkola, R.; Boman, M.; Bottai, M.; Lichtenstein, P.; Hillert, J. Modest familial risks for multiple sclerosis: A registry-based study of the population of Sweden. Brain 2014, 137, 770–778. [Google Scholar] [CrossRef]
- Sadovnick, A.D.; Armstrong, H.; Rice, G.P.; Bulman, D.; Hashimoto, L.; Paty, D.W.; Hashimoto, S.A.; Warren, S.; Hader, W.; Murray, T.J. A population-based study of multiple sclerosis in twins: Update. Ann. Neurol. 1993, 33, 281–285. [Google Scholar] [CrossRef]
- Hollenbach, J.A.; Oksenberg, J.R. The immunogenetics of multiple sclerosis: A comprehensive review. J. Autoimmun. 2015, 64, 13–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2; Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.A.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011, 476, 214–219. [Google Scholar] [PubMed]
- Belbasis, L.; Bellou, V.; Evangelou, E.; Ioannidis, J.P.A.; Tzoulaki, I. Environmental risk factors and multiple sclerosis: An umbrella review of systematic reviews and meta-analyses. Lancet Neurol. 2015, 14, 263–273. [Google Scholar] [CrossRef]
- Handel, A.E.; Williamson, A.J.; Disanto, G.; Handunnetthi, L.; Giovannoni, G.; Ramagopalan, S.V. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS ONE 2010, 5. [Google Scholar] [CrossRef] [PubMed]
- Zhang, P.; Wang, R.; Li, Z.; Wang, Y.; Gao, C.; Lv, X.; Song, Y.; Li, B. The risk of smoking on multiple sclerosis: A meta-analysis based on 20,626 cases from case-control and cohort studies. PeerJ. 2016, 4. [Google Scholar] [CrossRef]
- McDowell, T.-Y.; Amr, S.; Culpepper, W.J.; Langenberg, P.; Royal, W.; Bever, C.; Bradham, D.D. Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis. Neuroepidemiology 2011, 37, 52–57. [Google Scholar] [CrossRef]
- Glenn, J.D.; Mowry, E.M. Emerging Concepts on the Gut Microbiome and Multiple Sclerosis. J. Interferon Cytokine Res. 2016, 36, 347–357. [Google Scholar] [CrossRef] [Green Version]
- Kotzamani, D.; Panou, T.; Mastorodemos, V.; Tzagournissakis, M.; Nikolakaki, H.; Spanaki, C.; Plaitakis, A. Rising incidence of multiple sclerosis in females associated with urbanization. Neurology 2012, 78, 1728–1735. [Google Scholar] [CrossRef]
- Wend, K.; Wend, P.; Krum, S.A. Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging. Front. Endocrinol (Lausanne) 2012, 3. [Google Scholar] [CrossRef]
- Fish, E.N. The X-files in immunity: Sex-based differences predispose immune responses. Nat. Rev. Immunol. 2008, 8, 737–744. [Google Scholar] [CrossRef]
- Voci, C. Testicular hypofunction and multiple sclerosis: Cause or consequence? Ann Neurol. 2014, 76, 765. [Google Scholar] [CrossRef] [PubMed]
- Schumacher, M.; Hussain, R.; Gago, N.; Oudinet, J.P.; Mattern, C.; Ghoumari, A.M. Progesterone synthesis in the nervous system: Implications for myelination and myelin repair. Front Neurosci. 2012, 6, 10. [Google Scholar] [CrossRef] [PubMed]
- 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]
- 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]
- Finkelsztejn, A.; Brooks, J.B.B.; Paschoal, F.M.; Fragoso, Y.D. 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]
- Hughes, S.E.; Spelman, T.; Gray, O.M.; Boz, C.; Trojano, M.; Lugaresi, A.; Izquierdo, G.; Duquette, P.; Girard, M.; Grand’Maison, F.; et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult. Scler. 2014, 20, 739–746. [Google Scholar] [CrossRef]
- Javadian, A.; Salehi, E.; Bidad, K.; Sahraian, M.A.; Izad, M. Effect of estrogen on Th1, Th2 and Th17 cytokines production by proteolipid protein and PHA activated peripheral blood mononuclear cells isolated from multiple sclerosis patients. Arch. Med. Res. 2014, 45, 177–182. [Google Scholar] [CrossRef]
- 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] [Green Version]
- Patas, K.; Engler, J.B.; Friese, M.A.; Gold, S.M. Pregnancy and multiple sclerosis: Feto-maternal immune cross talk and its implications for disease activity. J. Reprod. Immunol. 2013, 97, 140–146. [Google Scholar] [CrossRef]
- 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]
- Santner-Nanan, B.; Peek, M.J.; Khanam, R.; Richarts, L.; Zhu, E.; Fazekas de St Groth, B.; Nanan, R. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J. Immunol. 2009, 183, 7023–7030. [Google Scholar] [CrossRef] [PubMed]
- Sánchez-Ramón, S.; Navarro A, J.; Aristimuño, C.; Rodríguez-Mahou, M.; Bellón, J.M.; Fernández-Cruz, E.; de Andrés, 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]
- Aluvihare, V.R.; Kallikourdis, M.; Betz, A.G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 2004, 5, 266–271. [Google Scholar] [CrossRef] [PubMed]
- Desai, M.K.; Brinton, R.D. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front. Endocrinol. 2019, 10. [Google Scholar] [CrossRef]
- Gubbels Bupp, M.R.; Potluri, T.; Fink, A.L.; Klein, S.L. The Confluence of Sex Hormones and Aging on Immunity. Front. Immunol. 2018, 9, 1269. [Google Scholar] [CrossRef]
- Watson, C.S.; Alyea, R.A.; Cunningham, K.A.; Jeng, Y.-J. Estrogens of multiple classes and their role in mental health disease mechanisms. Int. J. Womens Health 2010, 2, 153–166. [Google Scholar] [CrossRef] [Green Version]
- Björnström, L.; Sjöberg, M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 2005, 19, 833–842. [Google Scholar] [CrossRef]
- Webb, P.; Nguyen, P.; Valentine, C.; Lopez, G.N.; Kwok, G.R.; McInerney, E.; Katzenellenbogen, B.S.; Enmark, E.; Gustafsson, J.A.; Nilsson, S.; et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol. Endocrinol. 1999, 13, 1672–1685. [Google Scholar] [CrossRef]
- Safe, S. Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam. Horm. 2001, 62, 231–252. [Google Scholar]
- Caizzi, L.; Ferrero, G.; Cutrupi, S.; Cordero, F.; Ballaré, C.; Miano, V.; Reineri, S.; Ricci, L.; Friard, O.; Testori, A.; et al. Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells. Proc. Natl. Acad Sci. U S A 2014, 111, 4892–4897. [Google Scholar] [CrossRef]
- Zhao, C.; Dahlman-Wright, K.; Gustafsson, J.-Å. Estrogen receptor β: An overview and update. Nucl. Recept. Signal 2008, 6. [Google Scholar] [CrossRef] [PubMed]
- Reid, G.; Denger, S.; Kos, M.; Gannon, F. Human estrogen receptor-alpha: Regulation by synthesis, modification and degradation. Cell. Mol. Life Sci. 2002, 59, 821–831. [Google Scholar] [CrossRef] [PubMed]
- Flouriot, G.; Brand, H.; Denger, S.; Metivier, R.; Kos, M.; Reid, G.; Sonntag-Buck, V.; Gannon, F. Identification of a new isoform of the human estrogen receptor-alpha (hER-α) that is encoded by distinct transcripts and that is able to repress hER-α activation function 1. EMBO J. 2000, 19, 4688–4700. [Google Scholar] [CrossRef] [PubMed]
- Denger, S.; Reid, G.; Kos, M.; Flouriot, G.; Parsch, D.; Brand, H.; Korach, K.S.; Sonntag-Buck, V.; Gannon, F. ERalpha gene expression in human primary osteoblasts: Evidence for the expression of two receptor proteins. Mol. Endocrinol. 2001, 15, 2064–2077. [Google Scholar]
- Wang, Z.; Zhang, X.; Shen, P.; Loggie, B.W.; Chang, Y.; Deuel, T.F. Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem. Biophys. Res. Commun. 2005, 336, 1023–1027. [Google Scholar] [CrossRef]
- Perissi, V.; Rosenfeld, M.G. Controlling nuclear receptors: The circular logic of cofactor cycles. Nat. Rev. Mol. Cell Biol. 2005, 6, 542–554. [Google Scholar] [CrossRef]
- Métivier, R.; Penot, G.; Hübner, M.R.; Reid, G.; Brand, H.; Kos, M.; Gannon, F. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 2003, 115, 751–763. [Google Scholar] [CrossRef]
- Cicatiello, L.; Scafoglio, C.; Altucci, L.; Cancemi, M.; Natoli, G.; Facchiano, A.; Iazzetti, G.; Calogero, R.; Biglia, N.; De Bortoli, M.; et al. A genomic view of estrogen actions in human breast cancer cells by expression profiling of the hormone-responsive transcriptome. J. Mol. Endocrinol. 2004, 32, 719–775. [Google Scholar] [CrossRef] [Green Version]
- Hah, N.; Danko, C.G.; Core, L.; Waterfall, J.J.; Siepel, A.; Lis, J.T.; Kraus, W.L. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 2011, 145, 622–634. [Google Scholar] [CrossRef]
- Le Dily, F.; Beato, M. Signaling by Steroid Hormones in the 3D Nuclear Space. Int J Mol Sci 2018, 19. [Google Scholar] [CrossRef]
- Fullwood, M.J.; Liu, M.H.; Pan, Y.F.; Liu, J.; Xu, H.; Mohamed, Y.B.; Orlov, Y.L.; Velkov, S.; Ho, A.; Mei, P.H.; et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 2009, 462, 58–64. [Google Scholar] [CrossRef] [PubMed]
- Quintin, J.; Le Péron, C.; Palierne, G.; Bizot, M.; Cunha, S.; Sérandour, A.A.; Avner, S.; Henry, C.; Percevault, F.; Belaud-Rotureau, M.-A.; et al. Dynamic estrogen receptor interactomes control estrogen-responsive trefoil Factor (TFF) locus cell-specific activities. Mol. Cell. Biol. 2014, 34, 2418–2436. [Google Scholar] [CrossRef] [PubMed]
- Bretschneider, N.; Kangaspeska, S.; Seifert, M.; Reid, G.; Gannon, F.; Denger, S. E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements. Mol Oncol 2008, 2, 182–190. [Google Scholar] [CrossRef] [Green Version]
- Hsu, P.-Y.; Hsu, H.-K.; Singer, G.A.C.; Yan, P.S.; Rodriguez, B.A.T.; Liu, J.C.; Weng, Y.-I.; Deatherage, D.E.; Chen, Z.; Pereira, J.S.; et al. Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping. Genome Res. 2010, 20, 733–744. [Google Scholar] [CrossRef] [Green Version]
- Lavinsky, R.M.; Jepsen, K.; Heinzel, T.; Torchia, J.; Mullen, T.M.; Schiff, R.; Del-Rio, A.L.; Ricote, M.; Ngo, S.; Gemsch, J.; et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 2920–2925. [Google Scholar] [CrossRef] [Green Version]
- Rosenfeld, M.G.; Lunyak, V.V.; Glass, C.K. Sensors and signals: A coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 2006, 20, 1405–1428. [Google Scholar] [CrossRef] [PubMed]
- Khan, D.; Ansar Ahmed, S. The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases. Front. Immunol. 2016, 6. [Google Scholar] [CrossRef]
- Navarro, F.C.; Herrnreiter, C.; Nowak, L.; Watkins, S.K. Estrogen Regulation of T-Cell Function and Its Impact on the Tumor Microenvironment. Gend. Genome 2018, 2, 81–91. [Google Scholar] [CrossRef] [Green Version]
- Kovats, S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 2015, 294, 63–69. [Google Scholar] [CrossRef] [Green Version]
- Kim, H.-R.; Lee, J.-H.; Heo, H.-R.; Yang, S.-R.; Ha, K.-S.; Park, W.S.; Han, E.-T.; Song, H.; Hong, S.-H. Improved hematopoietic differentiation of human pluripotent stem cells via estrogen receptor signaling pathway. Cell Biosci 2016, 6. [Google Scholar] [CrossRef]
- Murphy, A.J.; Guyre, P.M.; Wira, C.R.; Pioli, P.A. Estradiol regulates expression of estrogen receptor ERalpha46 in human macrophages. PLoS ONE 2009, 4, e5539. [Google Scholar] [CrossRef] [PubMed]
- Staples, J.E.; Gasiewicz, T.A.; Fiore, N.C.; Lubahn, D.B.; Korach, K.S.; Silverstone, A.E. Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J. Immunol. 1999, 163, 4168–4174. [Google Scholar] [PubMed]
- Erlandsson, M.C.; Ohlsson, C.; Gustafsson, J.A.; Carlsten, H. Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus. Immunology 2001, 103, 17–25. [Google Scholar] [CrossRef] [PubMed]
- Phiel, K.L.; Henderson, R.A.; Adelman, S.J.; Elloso, M.M. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol. Lett. 2005, 97, 107–113. [Google Scholar] [CrossRef] [PubMed]
- Pierdominici, M.; Maselli, A.; Colasanti, T.; Giammarioli, A.M.; Delunardo, F.; Vacirca, D.; Sanchez, M.; Giovannetti, A.; Malorni, W.; Ortona, E. Estrogen receptor profiles in human peripheral blood lymphocytes. Immunol. Lett. 2010, 132, 79–85. [Google Scholar] [CrossRef] [PubMed]
- Lin, A.H.Y.; Li, R.W.S.; Ho, E.Y.W.; Leung, G.P.H.; Leung, S.W.S.; Vanhoutte, P.M.; Man, R.Y.K. Differential Ligand Binding Affinities of Human Estrogen Receptor-α Isoforms. PLOS ONE 2013, 8, e63199. [Google Scholar] [CrossRef] [PubMed]
- Schmiedel, B.J.; Singh, D.; Madrigal, A.; Valdovino-Gonzalez, A.G.; White, B.M.; Zapardiel-Gonzalo, J.; Ha, B.; Altay, G.; Greenbaum, J.A.; McVicker, G.; et al. Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell 2018, 175, 1701–1715.e16. [Google Scholar] [CrossRef] [Green Version]
- Cunningham, M.; Gilkeson, G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011, 40, 66–73. [Google Scholar] [CrossRef]
- Laffont, S.; Seillet, C.; Guéry, J.-C. Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function. Front. Immunol. 2017, 8, 108. [Google Scholar] [CrossRef] [Green Version]
- Laffont, S.; Rouquié, N.; Azar, P.; Seillet, C.; Plumas, J.; Aspord, C.; Guéry, J.-C. X-Chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-α production of plasmacytoid dendritic cells from women. J. Immunol. 2014, 193, 5444–5452. [Google Scholar] [CrossRef]
- Tiwari-Woodruff, S.; Morales, L.B.J.; Lee, R.; Voskuhl, R.R. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment. PNAS 2007, 104, 14813–14818. [Google Scholar] [CrossRef] [PubMed]
- Tay, T.L.; Hagemeyer, N.; Prinz, M. The force awakens: Insights into the origin and formation of microglia. Curr. Opin. Neurobiol. 2016, 39, 30–37. [Google Scholar] [CrossRef] [PubMed]
- Villa, A.; Rizzi, N.; Vegeto, E.; Ciana, P.; Maggi, A. Estrogen accelerates the resolution of inflammation in macrophagic cells. Sci Rep 2015, 5, 15224. [Google Scholar] [CrossRef] [PubMed]
- Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocr. Rev. 2016, 37, 372–402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, R.Y.; Mangu, D.; Hoffman, A.S.; Kavosh, R.; Jung, E.; Itoh, N.; Voskuhl, R. Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis. Brain 2018, 141, 132–147. [Google Scholar] [CrossRef]
- Wu, W.; Tan, X.; Dai, Y.; Krishnan, V.; Warner, M.; Gustafsson, J.-Å. Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 3543–3548. [Google Scholar] [CrossRef]
- 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] [Green Version]
- Fox, H.S.; Bond, B.L.; Parslow, T.G. Estrogen regulates the IFN-gamma promoter. J. Immunol. 1991, 146, 4362–4367. [Google Scholar]
- Arellano, G.; Ottum, P.A.; Reyes, L.I.; Burgos, P.I.; Naves, R. Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Front. Immunol. 2015, 6, 492. [Google Scholar] [CrossRef] [Green Version]
- Grasso, G.; Muscettola, M. The Influence of Beta-Estradiol and Progesterone on Interferon Gamma Production in Vitro. Int. J. Neurosci. 1990, 51, 315–317. [Google Scholar] [CrossRef]
- Gilmore, W.; Weiner, L.P.; Correale, J. Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J. Immunol. 1997, 158, 446–451. [Google Scholar] [PubMed]
- Karpuzoglu, E.; Phillips, R.A.; Gogal, R.M.; Ansar Ahmed, S. IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: Role of IL-27 but not IL-12. Mol. Immunol. 2007, 44, 1808–1814. [Google Scholar] [CrossRef] [PubMed]
- Haghmorad, D.; Salehipour, Z.; Nosratabadi, R.; Rastin, M.; Kokhaei, P.; Mahmoudi, M.B.; Amini, A.A.; Mahmoudi, M. Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice. J Immunotoxicol 2016, 13, 885–896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Matalka, K.Z. The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. Neuro Endocrinol. Lett. 2003, 24, 185–191. [Google Scholar]
- Karpuzoglu-Sahin, E.; Zhi-Jun, Y.; Lengi, A.; Sriranganathan, N.; Ansar Ahmed, S. Effects of long-term estrogen treatment on IFN-gamma, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine 2001, 14, 208–217. [Google Scholar] [CrossRef]
- Verthelyi, D.; Klinman, D.M. Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology 2000, 100, 384–390. [Google Scholar] [CrossRef]
- Piccinni, M.P.; Giudizi, M.G.; Biagiotti, R.; Beloni, L.; Giannarini, L.; Sampognaro, S.; Parronchi, P.; Manetti, R.; Annunziato, F.; Livi, C. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J. Immunol. 1995, 155, 128–133. [Google Scholar]
- Druckmann, R.; Druckmann, M.-A. Progesterone and the immunology of pregnancy. J. Steroid Biochem. Mol. Biol. 2005, 97, 389–396. [Google Scholar] [CrossRef]
- Polanczyk, M.J.; Carson, B.D.; Subramanian, S.; Afentoulis, M.; Vandenbark, A.A.; Ziegler, S.F.; Offner, H. Cutting edge: Estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J. Immunol. 2004, 173, 2227–2230. [Google Scholar] [CrossRef]
- Iannello, A.; Rolla, S.; Maglione, A.; Ferrero, G.; Bardina, V.; Inaudi, I.; De Mercanti, S.; Novelli, F.; D’Antuono, L.; Cardaropoli, S.; et al. Pregnancy Epigenetic Signature in T Helper 17 and T Regulatory Cells in Multiple Sclerosis. Front. Immunol. 2019, 9. [Google Scholar] [CrossRef]
- Prieto, G.A.; Rosenstein, Y. Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology 2006, 118, 58–65. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Polanczyk, M.J.; Hopke, C.; Vandenbark, A.A.; Offner, H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int. Immunol. 2007, 19, 337–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kebir, H.; Ifergan, I.; Alvarez, J.I.; Bernard, M.; Poirier, J.; Arbour, N.; Duquette, P.; Prat, A. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann. Neurol. 2009, 66, 390–402. [Google Scholar] [CrossRef]
- Molnár, I.; Bohaty, I.; Somogyiné-Vári, É. High prevalence of increased interleukin-17A serum levels in postmenopausal estrogen deficiency. Menopause 2014, 21, 749–752. [Google Scholar] [CrossRef] [PubMed]
- 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]
- 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] [Green Version]
- Ito, A.; Bebo, B.F.; Matejuk, A.; Zamora, A.; Silverman, M.; Fyfe-Johnson, A.; Offner, H. Estrogen treatment down-regulates TNF-alpha production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice. J. Immunol. 2001, 167, 542–552. [Google Scholar] [CrossRef]
- Wang, C.; Dehghani, B.; Li, Y.; Kaler, L.J.; Vandenbark, A.A.; Offner, H. Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology 2009, 126, 329–335. [Google Scholar] [CrossRef]
- Polanczyk, M.; Zamora, A.; Subramanian, S.; Matejuk, A.; Hess, D.L.; Blankenhorn, E.P.; Teuscher, C.; Vandenbark, A.A.; Offner, H. The Protective Effect of 17β-Estradiol on Experimental Autoimmune Encephalomyelitis Is Mediated through Estrogen Receptor-α. Am J. Pathol. 2003, 163, 1599–1605. [Google Scholar] [CrossRef]
- Lélu, K.; Laffont, S.; Delpy, L.; Paulet, P.-E.; Périnat, T.; Tschanz, S.A.; Pelletier, L.; Engelhardt, B.; Guéry, J.-C. Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J. Immunol. 2011, 187, 2386–2393. [Google Scholar] [CrossRef] [PubMed]
- Hill, L.; Jeganathan, V.; Chinnasamy, P.; Grimaldi, C.; Diamond, B. Differential roles of estrogen receptors α and β in control of B-cell maturation and selection. Mol. Med. 2011, 17, 211–220. [Google Scholar] [CrossRef] [PubMed]
- Verthelyi, D.I.; Ahmed, S.A. Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Cell. Immunol. 1998, 189, 125–134. [Google Scholar] [CrossRef] [PubMed]
- Jones, B.G.; Sealy, R.E.; Penkert, R.R.; Surman, S.L.; Maul, R.W.; Neale, G.; Xu, B.; Gearhart, P.J.; Hurwitz, J.L. Complex sex-biased antibody responses: Estrogen receptors bind estrogen response elements centered within immunoglobulin heavy chain gene enhancers. Int. Immunol 2019, 31, 141–156. [Google Scholar] [CrossRef] [PubMed]
- Grimaldi, C.M.; Cleary, J.; Dagtas, A.S.; Moussai, D.; Diamond, B. Estrogen alters thresholds for B cell apoptosis and activation. J. Clin. Invest. 2002, 109, 1625–1633. [Google Scholar] [CrossRef]
- Benedek, G.; Zhang, J.; Bodhankar, S.; Nguyen, H.; Kent, G.; Jordan, K.; Manning, D.; Vandenbark, A.A.; Offner, H. Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2016, 293, 45–53. [Google Scholar] [CrossRef] [Green Version]
- Fettke, F.; Schumacher, A.; Costa, S.-D.; Zenclussen, A.C. B Cells: The Old New Players in Reproductive Immunology. Front. Immunol. 2014, 5. [Google Scholar] [CrossRef]
- Molnarfi, N.; Schulze-Topphoff, U.; Weber, M.S.; Patarroyo, J.C.; Prod’homme, T.; Varrin-Doyer, M.; Shetty, A.; Linington, C.; Slavin, A.J.; Hidalgo, J.; et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 2013, 210, 2921–2937. [Google Scholar] [CrossRef]
- Lehmann-Horn, K.; Kinzel, S.; Weber, M.S. Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function. Int. J. Mol. Sci. 2017, 18. [Google Scholar] [CrossRef]
- Bodhankar, S.; Wang, C.; Vandenbark, A.A.; Offner, H. Estrogen-induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells. Eur. J. Immunol. 2011, 41, 1165–1175. [Google Scholar] [CrossRef] [Green Version]
- Matsushita, T.; Yanaba, K.; Bouaziz, J.-D.; Fujimoto, M.; Tedder, T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 2008, 118, 3420–3430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, J.; Benedek, G.; Bodhankar, S.; Lapato, A.; Vandenbark, A.A.; Offner, H. IL-10 producing B cells partially restore E2-mediated protection against EAE in PD-L1 deficient mice. J. Neuroimmunol. 2015, 285, 129–136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cuzzocrea, S.; Genovese, T.; Mazzon, E.; Esposito, E.; Di Paola, R.; Muià, C.; Crisafulli, C.; Peli, A.; Bramanti, P.; Chaudry, I.H. Effect of 17beta-estradiol on signal transduction pathways and secondary damage in experimental spinal cord trauma. Shock 2008, 29, 362–371. [Google Scholar] [PubMed]
- Yu, H.-P.; Hsieh, Y.-C.; Suzuki, T.; Choudhry, M.A.; Schwacha, M.G.; Bland, K.I.; Chaudry, I.H. Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: Up-regulation of the PI-3K/Akt pathway. J. Leukoc. Biol. 2007, 82, 774–780. [Google Scholar] [CrossRef]
- Hsieh, C.-H.; Nickel, E.A.; Chen, J.; Schwacha, M.G.; Choudhry, M.A.; Bland, K.I.; Chaudry, I.H. Mechanism of the Salutary Effects of Estrogen on Kupffer Cell Phagocytic Capacity following Trauma-Hemorrhage: Pivotal Role of Akt Activation. J. Immunol. 2009, 182, 4406. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.Y.; Buenafe, A.C.; Matejuk, A.; Ito, A.; Zamora, A.; Dwyer, J.; Vandenbark, A.A.; Offner, H. Estrogen inhibition of EAE involves effects on dendritic cell function. J. Neurosci. Res. 2002, 70, 238–248. [Google Scholar] [CrossRef]
- Bachy, V.; Williams, D.J.; Ibrahim, M.a.A. Altered dendritic cell function in normal pregnancy. J. Reprod. Immunol. 2008, 78, 11–21. [Google Scholar] [CrossRef]
- Papenfuss, T.L.; Powell, N.D.; McClain, M.A.; Bedarf, A.; Singh, A.; Gienapp, I.E.; Shawler, T.; Whitacre, C.C. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J. Immunol. 2011, 186, 3346–3355. [Google Scholar] [CrossRef]
- Bengtsson, A.K.; Ryan, E.J.; Giordano, D.; Magaletti, D.M.; Clark, E.A. 17beta-estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells. Blood 2004, 104, 1404–1410. [Google Scholar] [CrossRef]
- Habib, P.; Dreymueller, D.; Rösing, B.; Botung, H.; Slowik, A.; Zendedel, A.; Habib, S.; Hoffmann, S.; Beyer, C. Estrogen serum concentration affects blood immune cell composition and polarization in human females under controlled ovarian stimulation. J. Steroid Biochem. Mol. Biol. 2018, 178, 340–347. [Google Scholar] [CrossRef]
- Hao, S.; Zhao, J.; Zhou, J.; Zhao, S.; Hu, Y.; Hou, Y. Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors. Int. Immunopharmacol. 2007, 7, 1765–1775. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Haghmorad, D.; Amini, A.A.; Mahmoudi, M.B.; Rastin, M.; Hosseini, M.; Mahmoudi, M. Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J. Neuroimmunol. 2014, 277, 85–95. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Garnier, L.; Laffont, S.; Lélu, K.; Yogev, N.; Waisman, A.; Guéry, J.-C. Estrogen Signaling in Bystander Foxp3neg CD4+ T Cells Suppresses Cognate Th17 Differentiation in Trans and Protects from Central Nervous System Autoimmunity. J. Immunol. 2018, 201, 3218–3228. [Google Scholar] [CrossRef] [PubMed]
- Kim, D.H.; Park, H.J.; Park, H.S.; Lee, J.U.; Ko, C.; Gye, M.C.; Choi, J.M. Estrogen receptor α in T cells suppresses follicular helper T cell responses and prevents autoimmunity. Exp. Mol. Med. 2019, 51, 41. [Google Scholar] [CrossRef] [PubMed]
- Karim, H.; Kim, S.H.; Lapato, A.S.; Yasui, N.; Katzenellenbogen, J.A.; Tiwari-Woodruff, S.K. Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination. PNAS 2018, 115, 6291–6296. [Google Scholar] [CrossRef]
- DuPage, M.; Bluestone, J.A. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat. Rev. Immunol. 2016, 16, 149–163. [Google Scholar] [CrossRef]
- Yosef, N.; Regev, A. Writ large: Genomic dissection of the effect of cellular environment on immune response. Science 2016, 354, 64–68. [Google Scholar] [CrossRef] [Green Version]
- Mukasa, R.; Balasubramani, A.; Lee, Y.K.; Whitley, S.K.; Weaver, B.T.; Shibata, Y.; Crawford, G.E.; Hatton, R.D.; Weaver, C.T. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 2010, 32, 616–627. [Google Scholar] [CrossRef]
- Wei, G.; Wei, L.; Zhu, J.; Zang, C.; Hu-Li, J.; Yao, Z.; Cui, K.; Kanno, Y.; Roh, T.-Y.; Watford, W.T.; et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009, 30, 155–167. [Google Scholar] [CrossRef] [PubMed]
- Schmidl, C.; Delacher, M.; Huehn, J.; Feuerer, M. Epigenetic mechanisms regulating T-cell responses. J. Allergy Clin. Immunol. 2018, 142, 728–743. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Noack, M.; Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014, 13, 668–677. [Google Scholar] [CrossRef] [PubMed]
- Kleinewietfeld, M.; Hafler, D.A. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin. Immunol. 2013, 25, 305–312. [Google Scholar] [CrossRef] [Green Version]
- Rudra, D.; deRoos, P.; Chaudhry, A.; Niec, R.E.; Arvey, A.; Samstein, R.M.; Leslie, C.; Shaffer, S.A.; Goodlett, D.R.; Rudensky, A.Y. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat. Immunol. 2012, 13, 1010–1019. [Google Scholar] [CrossRef] [Green Version]
- Yosef, N.; Shalek, A.K.; Gaublomme, J.T.; Jin, H.; Lee, Y.; Awasthi, A.; Wu, C.; Karwacz, K.; Xiao, S.; Jorgolli, M.; et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 2013, 496, 461–468. [Google Scholar] [CrossRef]
- Ciofani, M.; Madar, A.; Galan, C.; Sellars, M.; Mace, K.; Pauli, F.; Agarwal, A.; Huang, W.; Parkhurst, C.N.; Muratet, M.; et al. A validated regulatory network for Th17 cell specification. Cell 2012, 151, 289–303. [Google Scholar] [CrossRef]
- Guan, H.; Nagarkatti, P.S.; Nagarkatti, M. CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. J. Immunol. 2011, 186, 6955–6964. [Google Scholar]
- Coquet, J.M.; Middendorp, S.; van der Horst, G.; Kind, J.; Veraar, E.A.M.; Xiao, Y.; Jacobs, H.; Borst, J. The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity 2013, 38, 53–65. [Google Scholar] [CrossRef]
- Feng, Y.; Arvey, A.; Chinen, T.; van der Veeken, J.; Gasteiger, G.; Rudensky, A.Y. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 2014, 158, 749–763. [Google Scholar] [CrossRef]
- Zheng, Y.; Josefowicz, S.; Chaudhry, A.; Peng, X.P.; Forbush, K.; Rudensky, A.Y. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010, 463, 808–812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, X.; Liang, Y.; LeBlanc, M.; Benner, C.; Zheng, Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 2014, 158, 734–748. [Google Scholar] [CrossRef] [PubMed]
- Yue, X.; Trifari, S.; Äijö, T.; Tsagaratou, A.; Pastor, W.A.; Zepeda-Martínez, J.A.; Lio, C.-W.J.; Li, X.; Huang, Y.; Vijayanand, P.; et al. Control of Foxp3 stability through modulation of TET activity. J. Exp. Med. 2016, 213, 377–397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ohkura, N.; Hamaguchi, M.; Morikawa, H.; Sugimura, K.; Tanaka, A.; Ito, Y.; Osaki, M.; Tanaka, Y.; Yamashita, R.; Nakano, N.; et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012, 37, 785–799. [Google Scholar] [CrossRef]
- Polansky, J.K.; Kretschmer, K.; Freyer, J.; Floess, S.; Garbe, A.; Baron, U.; Olek, S.; Hamann, A.; von Boehmer, H.; Huehn, J. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 2008, 38, 1654–1663. [Google Scholar] [CrossRef]
- Samstein, R.M.; Arvey, A.; Josefowicz, S.Z.; Peng, X.; Reynolds, A.; Sandstrom, R.; Neph, S.; Sabo, P.; Kim, J.M.; Liao, W.; et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012, 151, 153–166. [Google Scholar] [CrossRef]
- Kitagawa, Y.; Ohkura, N.; Kidani, Y.; Vandenbon, A.; Hirota, K.; Kawakami, R.; Yasuda, K.; Motooka, D.; Nakamura, S.; Kondo, M.; et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol. 2017, 18, 173–183. [Google Scholar] [CrossRef]
- Morikawa, H.; Ohkura, N.; Vandenbon, A.; Itoh, M.; Nagao-Sato, S.; Kawaji, H.; Lassmann, T.; Carninci, P.; Hayashizaki, Y.; Forrest, A.R.R.; et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 5289–5294. [Google Scholar] [CrossRef] [Green Version]
- Nakatsukasa, H.; Oda, M.; Yin, J.; Chikuma, S.; Ito, M.; Koga-Iizuka, M.; Someya, K.; Kitagawa, Y.; Ohkura, N.; Sakaguchi, S.; et al. Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. Int. Immunol. 2019, 31, 335–347. [Google Scholar] [CrossRef]
- Garg, G.; Muschaweckh, A.; Moreno, H.; Vasanthakumar, A.; Floess, S.; Lepennetier, G.; Oellinger, R.; Zhan, Y.; Regen, T.; Hiltensperger, M.; et al. Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation. Cell Rep. 2019, 26, 1854–1868.e5. [Google Scholar] [CrossRef] [Green Version]
- Schmidl, C.; Hansmann, L.; Andreesen, R.; Edinger, M.; Hoffmann, P.; Rehli, M. Epigenetic reprogramming of the RORC locus during in vitro expansion is a distinctive feature of human memory but not naïve Treg. Eur. J. Immunol. 2011, 41, 1491–1498. [Google Scholar] [CrossRef] [PubMed]
- Chen, R.-Y.; Fan, Y.-M.; Zhang, Q.; Liu, S.; Li, Q.; Ke, G.-L.; Li, C.; You, Z. Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter. J. Immunol. 2015, 194, 4019–4028. [Google Scholar] [CrossRef] [PubMed]
- Sicotte, N.L.; Liva, S.M.; Klutch, R.; Pfeiffer, P.; Bouvier, S.; Odesa, S.; Wu, T.C.J.; Voskuhl, R.R. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann. Neurol. 2002, 52, 421–428. [Google Scholar] [CrossRef] [PubMed]
- Voskuhl, R.R.; Wang, H.; Wu, T.C.J.; Sicotte, N.L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J.T.; Corboy, J.R.; et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: A randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016, 15, 35–46. [Google Scholar] [CrossRef]
- Vukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E.E.; Cornu, C.; Confavreux, C.; Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis Study Group. 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. 2009, 286, 114–118. [Google Scholar] [CrossRef] [PubMed]
- Pozzilli, C.; De Giglio, L.; Barletta, V.T.; Marinelli, F.; Angelis, F.D.; Gallo, V.; Pagano, V.A.; Marini, S.; Piattella, M.C.; Tomassini, V.; et al. Oral contraceptives combined with interferon β in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2015, 2. [Google Scholar] [CrossRef] [PubMed]
- Christianson, M.S.; Mensah, V.A.; Shen, W. Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen. Maturitas 2015, 80, 133–139. [Google Scholar] [CrossRef]
- Smith, R.; Studd, J.W. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J. R. Soc. Med. 1992, 85, 612–613. [Google Scholar] [CrossRef]
- Schirmer, L.; Velmeshev, D.; Holmqvist, S.; Kaufmann, M.; Werneburg, S.; Jung, D.; Vistnes, S.; Stockley, J.H.; Young, A.; Steindel, M.; et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 2019, 573, 75–82. [Google Scholar] [CrossRef]
- Jäkel, S.; Agirre, E.; Mendanha Falcão, A.; van Bruggen, D.; Lee, K.W.; Knuesel, I.; Malhotra, D.; Ffrench-Constant, C.; Williams, A.; Castelo-Branco, G. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 2019, 566, 543–547. [Google Scholar] [CrossRef]
- Yeung, M.S.Y.; Djelloul, M.; Steiner, E.; Bernard, S.; Salehpour, M.; Possnert, G.; Brundin, L.; Frisén, J. Publisher Correction: Dynamics of oligodendrocyte generation in multiple sclerosis. Nature 2019, 566, E9. [Google Scholar] [CrossRef] [PubMed]
- Montalban, X.; Gold, R.; Thompson, A.J.; Otero-Romero, S.; Amato, M.P.; Chandraratna, D.; Clanet, M.; Comi, G.; Derfuss, T.; Fazekas, F.; et al. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult. Scler. 2018, 24, 96–120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cell Type | Effect in Immune System | References | Effect in EAE/MS | References |
---|---|---|---|---|
Neutrophils | ↓ TNF-α, IL-6, IL-1β | [113] | ||
↓ Chemotaxis (iNOS, CINC-1, CINC-2β, CINC-3) | [114] | |||
Macrophages | ↓ TNF-α, IL-6, IL-1β | [115] | ||
↓ iNOS and T-bet | [75] | ↓ iNOS and T-bet | [75] | |
↑ IL-10 | [75] | ↑ IL-10 | [75] | |
Dendritic Cells | ↑ Differentiation (IL-8, and CCL2) | [116,117] | ↑ Differentiation (IL-8, and CCL2) | [116] |
↓ iNOS, T-bet, TNF-α, IFN-γ, IL-12, PD-L1, PD-L2 | [75,116,117,118] | ↓ iNOS, T-bet, TNF-α, IFN-γ, IL-12, PD-L1, PD-L2 | [75,116,118] | |
↑ IL-10 | [75,117] | ↑ IL-10 | [75] | |
↑ IL-6, IFN-γ | [119] | |||
Microglia | ↑ M2 polarization | [77,120] | ↑ M2 polarization | [77] |
↓ Activation | [76] | ↓ Activation | [76] | |
↓ NF-kB, IL-1β | [73] | |||
↑ IL-10 | [73] | |||
NK | ↓ Cytotoxic activity | [121] | ||
↑ Activation of CD3+CD56+CD8+ cells | [122] | ↑ Activation of CD3+CD56+CD8+ cells | [122] | |
T cells | ↑ Treg/Th2 | [120,123] | ↑ Treg/Th2 | [123,124] |
↓ Th17/Th1 | [123,125] | ↓ Th17/Th1, T cell infiltration in CNS | [123,125] | |
↓ TFH cell response | [126] | ↓ TFH cell response | [126] | |
↓ T CD8+ cells | [120] | |||
↑↓ IFN-γ | [78,79,80,81,82,83] | ↓ IFN-γ | [79,80,81,83,127] | |
↑↓ TNF-α | [81,98,123] | ↓ TNF-α | [81,98,123] | |
↑ IL-10, IL-4, TGF-β | [83,84] | ↑ IL-10, IL-4, TGF-β | [83] | |
↓ IL-17 and IL-23 | [123] | ↓ IL-17 and IL-23 | [123,127] | |
↓ NF-kB, iNOS | [76] | ↓ NF-kB, iNOS | [76] | |
↑ PD-1, CTLA4, FOXP3, GATA3 | [83,90,92,93] | ↑ PD-1, CTLA4, FOXP3, GATA3 | [83,90,92,93] | |
↓ RORC, T-bet | [90,123] | ↓ RORC, T-bet | [90,123] | |
B cells | ↑ IL-10 | [77] | ↑ IL-10 | [77] |
↑ PD-L1 | [110,111,125] | ↑ PD-L1 | [110,111,125] |
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Maglione, A.; Rolla, S.; Mercanti, S.F.D.; Cutrupi, S.; Clerico, M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells 2019, 8, 1280. https://doi.org/10.3390/cells8101280
Maglione A, Rolla S, Mercanti SFD, Cutrupi S, Clerico M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells. 2019; 8(10):1280. https://doi.org/10.3390/cells8101280
Chicago/Turabian StyleMaglione, Alessandro, Simona Rolla, Stefania Federica De Mercanti, Santina Cutrupi, and Marinella Clerico. 2019. "The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View" Cells 8, no. 10: 1280. https://doi.org/10.3390/cells8101280
APA StyleMaglione, A., Rolla, S., Mercanti, S. F. D., Cutrupi, S., & Clerico, M. (2019). The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells, 8(10), 1280. https://doi.org/10.3390/cells8101280