Abstract
Among several autoimmune diseases, one of the main risk factors is the female gender, and much consideration has been given to the involvement of female hormones in their etiology. B-cell activating factor (BAFF) is a key factor in survival and maturation of B cells and is overexpressed in several autoimmune patients although the mechanism behind this feature is unclear. In murine models, BAFF expression could be upregulated by exogenous estrogen treatment in splenocytes; however, no evidence of this relationship was available in humans. Here, leukocytes from healthy male and female individuals were collected and cultivated in the presence or absence of estrogen or progesterone. BAFF gene expression was accessed by quantitative PCR and compared between treated and untreated group of cells. In the presence of estrogen, BAFF expression was upregulated by more than 5 times in both genders. When exposed to progesterone, the female-originated cells showed increased expression, while the cells of male origin a significant downregulation of BAFF. Our results suggest that female hormones can modulate the expression of BAFF, a key cytokine in autoimmune pathways, in human immune cells. These data might contribute to the understanding of the etiology as well as the gender bias featured by several autoimmune disorders.
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References
Askanase AD (2004) Estrogen therapy in systemic lupus erythematosus. Treat Endocrinol 3:19–26
Bourdeau V et al (2004) Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol 18:1411–1427. doi:10.1210/me.2003-0441
Butts CL, Bowers E, Horn JC, Shukair SA, Belyavskaya E, Tonelli L, Sternberg EM (2008) Inhibitory effects of progesterone differ in dendritic cells from female and male rodents. Gend Med 5:434–447. doi:10.1016/j.genm.2008.11.001
Coquery CM et al (2015) BAFF regulates follicular helper t cells and affects their accumulation and interferon-gamma production in autoimmunity. Arthritis Rheumatol 67:773–784. doi:10.1002/art.38950
Dimas AS et al (2012) Sex-biased genetic effects on gene regulation in humans. Genome Res 22:2368–2375. doi:10.1101/gr.134981.111
Driscoll MD, Sathya G, Muyan M, Klinge CM, Hilf R, Bambara RA (1998) Sequence requirements for estrogen receptor binding to estrogen response elements. J Biol Chem 273:29321–29330
Eilertsen GO, Van Ghelue M, Strand H, Nossent JC (2011) Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: a case-control study. Rheumatology 50:2197–2205. doi:10.1093/rheumatology/ker282
Groom J et al (2002) Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Investig 109:59–68. doi:10.1172/JCI14121
Hughes GC (2012) Progesterone and autoimmune disease. Autoimmun Rev 11:A502–A514. doi:10.1016/j.autrev.2011.12.003
Lee JH, Ulrich B, Cho J, Park J, Kim CH (2011) Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J immunol 187:1778–1787. doi:10.4049/jimmunol.1003919
Lettre G, Rioux JD (2008) Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet 17:R116–R121. doi:10.1093/hmg/ddn246
Lockshin MD (2006) Sex differences in autoimmune disease. Orthop Clin North Am 37:629–633. doi:10.1016/j.ocl.2006.08.002
Luetjens CM et al (2006) Tissue expression of the nuclear progesterone receptor in male non-human primates and men. J Endocrinol 189:529–539. doi:10.1677/joe.1.06348
Manzi S et al (2012) Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 71:1833–1838. doi:10.1136/annrheumdis-2011-200831
Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genom 7:497–508
Morimoto S et al (2007) Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: the role of BAFF in T cell-dependent B cell pathogenic autoantibody production. Rheumatology 46:1083–1086. doi:10.1093/rheumatology/kem097
Nebel D, Jonsson D, Norderyd O, Bratthall G, Nilsson BO (2010) Differential regulation of chemokine expression by estrogen in human periodontal ligament cells. J Periodontal Res 45:796–802. doi:10.1111/j.1600-0765.2010.01308.x
Panchanathan R, Choubey D (2013) Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity. Mol Immunol 53:15–23. doi:10.1016/j.molimm.2012.06.013
Phiel KL, Henderson RA, Adelman SJ, Elloso MM (2005) Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 97:107–113. doi:10.1016/j.imlet.2004.10.007
Pierdominici M et al (2010) Estrogen receptor profiles in human peripheral blood lymphocytes. Immunol Lett 132:79–85. doi:10.1016/j.imlet.2010.06.003
Shen H, Panchanathan R, Rajavelu P, Duan X, Gould KA, Choubey D (2010) Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity. J Mol Cell Biol 2:284–290. doi:10.1093/jmcb/mjq023
Shoenfeld Y, Tincani A, Gershwin ME (2012) Sex gender and autoimmunity. J Autoimmun 38:J71–J73. doi:10.1016/j.jaut.2011.12.007
Tan IJ, Peeva E, Zandman-Goddard G (2015) Hormonal modulation of the immune system: a spotlight on the role of progestogens. Autoimmun Rev 14:536–542. doi:10.1016/j.autrev.2015.02.004
Whitacre CC (2001) Sex differences in autoimmune disease. Nat immunol 2:777–780. doi:10.1038/ni0901-777
Yahata T et al (2001) Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein. Genes Dev 15:2598–2612. doi:10.1101/gad.906301
Zandman-Goddard G, Peeva E, Shoenfeld Y (2007) Gender and autoimmunity. Autoimmun Rev 6:366–372. doi:10.1016/j.autrev.2006.10.001
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This study was funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Grant Number 23038.008120/2010-11).
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Drehmer, M.N., Suterio, D.G., Muniz, Y.C.N. et al. BAFF Expression is Modulated by Female Hormones in Human Immune Cells. Biochem Genet 54, 722–730 (2016). https://doi.org/10.1007/s10528-016-9752-y
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DOI: https://doi.org/10.1007/s10528-016-9752-y