Mediterr J Rheumatol 2019;30(3):162-6
Sex and autoimmune disease: Four mechanisms pointing at women
Authors Information
1Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
2BIOMETRA Department, University of Milan, Italy
  1. Selmi C, Gershwin ME. Sex and autoimmunity: proposed mechanisms of disease onset and severity. Expert Rev Clin Immunol 2019;15(6): 607-15. [https://doi.org/10.1080/1744666X.2019.1606714] [PMID: 31033369]
  2. Generali E, Ceribelli A, Stazi MA, Selmi C. Lessons learned from twins in autoimmune and chronic inflammatory diseases. J Autoimmun 2017;83: 51-61. [https://doi.org/10.1016/j.jaut.2017.04.005] [PMID: 28431796]
  3. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16(10):626-38. [https://doi.org/10.1038/nri.2016.90] [PMID: 27546235]
  4. Kinder JM, Stelzer IA, Arck PC, Way SS. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol 2017;17(8):483-94. [https://doi.org/10.1038/nri.2017.38] [PMID: 28480895] [PMCID: PMC5532073]
  5. La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett 2014;162(1 Pt A):41-8. [https://doi.org/10.1016/j.imlet.2014.06.013] [PMID: 24996040]
  6. Iaccarino L, Ghirardello A, Zen M, Villalta D, Tincani A, Punzi L, et al. Polarization of TH2 response is decreased during pregnancy in systemic lupus erythematosus. Reumatismo 2012;64(5):314-20. [https://doi.org/10.4081/reumatismo.2012.314] [PMID: 23256107]
  7. Doria A, Cutolo M, Ghirardello A, Zen M, Villalta D, Tincani A, et al. Effect of pregnancy on serum cytokines in SLE patients. Arthritis Res Ther 2012;14(2):R66. [https://doi.org/10.1186/ar3782] [PMID: 22417776] [PMCID: PMC3446434]
  8. Doria A, Iaccarino L, Arienti S, Ghirardello A, Zampieri S, Rampudda ME, et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol 2006;22(2):234-41. [https://doi.org/10.1016/j.reprotox.2006.04.001] [PMID: 16704920]
  9. van den Brandt S, Zbinden A, Baeten D, Villiger PM, Østensen M, Förger F. Risk factors for flare and treatment of disease flares during pregnancy in rheumatoid arthritis and axial spondyloarthritis patients. Arthritis Res Ther 2017;19(1):64. [https://doi.org/10.1186/s13075-017-1269-1] [PMID: 28320445] [PMCID: PMC5359860]
  10. Urowitz MB, Ibañez D, Jerome D, Gladman DD.. The effect of menopause on disease activity in systemic lupus erythematosus. J Rheumatol 2006;33(11):2192-8. [PMID: 16981295]
  11. Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76(3):476-85. [https://doi.org/10.1136/annrheumdis-2016-209770] [PMID: 27457513] [PMCID: PMC5446003]
  12. Talsania M, Scofield RH. Menopause and Rheumatic Disease. Rheum Dis Clin North Am 2017;43(2):287-302. [https://doi.org/10.1016/j.rdc.2016.12.011] [PMID: 28390570] [PMCID: PMC5385852]
  13. Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun 2012;38(2-3):J187-92. [https://doi.org/10.1016/j.jaut.2011.11.012] [PMID: 22178198]
  14. Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M. Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 2009;33(1):12-6. [https://doi.org/10.1016/j.jaut.2009.03.005] [PMID: 19356902]
  15. Villanueva-Ortega E, Ahedo B, Fonseca-Sánchez MA, Pérez-Durán J, Garibay-Nieto N, Macías-Galavíz MT, et al. Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease. Int J Immunogenet 2017;44(4):153-7. [https://doi.org/10.1111/iji.12323] [PMID: 28627089]
  16. Sharma R, Harris VM, Cavett J, Kurien BT, Liu K, Koelsch KA, et al. Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjogren's Syndrome. Arthritis Rheumatol 2017;69(11):2187-92. [https://doi.org/10.1002/art.40207] [PMID: 28692793]
  17. Invernizzi P, Miozzo M, Oertelt-Prigione S, Meroni PL, Persani L, Selmi C, et al. X monosomy in female systemic lupus erythematosus. Ann N Y Acad Sci 2007;1110:84-91. [https://doi.org/10.1196/annals.1423.010] [PMID: 17911423]
  18. Invernizzi P. The X chromosome in female-predominant autoimmune diseases. Ann N Y Acad Sci, 2007;1110:57-64. [https://doi.org/10.1196/annals.1423.007] [PMID: 17911420]
  19. Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 2004;363(9408):533-5. [https://doi.org/10.1016/S0140-6736(04)15541-4]
  20. Selmi C, Invernizzi P, Miozzo M, Podda M, Gershwin ME. Primary biliary cirrhosis: does X mark the spot? Autoimmun Rev 2004;3(7-8):493-9. [https://doi.org/10.1016/j.autrev.2004.05.003] [PMID: 15546796]
  21. Invernizzi P, Miozzo M, Selmi C, Persani L, Battezzati PM, Zuin M, et al. X chromosome monosomy: a common mechanism for autoimmune diseases. J Immunol 2005;175(1):575-8. [https://doi.org/10.4049/jimmunol.175.1.575] [PMID: 15972694]
  22. Selmi C, Feghali-Bostwick CA, Lleo A, Lombardi SA, De Santis M, Cavaciocchi F, et al. X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma. Clin Exp Immunol 2012;169(3):253-62. [https://doi.org/10.1111/j.1365-2249.2012.04621.x] [PMID: 22861365] [PMCID: PMC3445002]
  23. Castro-Santos P, Diaz-Pena R. Genomics and epigenomics in rheumatic diseases: what do they provide in terms of diagnosis and disease management? Clin Rheumatol 2017;36(9):1935-47. [https://doi.org/10.1007/s10067-017-3744-0] [PMID: 28725948]
  24. Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 2012;38(2-3):J156-69. [https://doi.org/10.1016/j.jaut.2011.11.003] [PMID: 22177232]
  25. Brodin P, Jojic V, Gao T, Bhattacharya S, Angel CJ, Furman D, et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 2015;160(1-2):37-47. [https://doi.org/10.1016/j.cell.2014.12.020] [PMID: 25594173] [PMCID: PMC4302727]
  26. Fraga MF,  Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005;102(30):10604-9. [https://doi.org/10.1073/pnas.0500398102] [PMID: 16009939] [PMCID: PMC1174919]
  27. Selmi C, Cavaciocchi F, Lleo A, Cheroni C, De Francesco R, Lombardi SA, et al. Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis. Front Immunol 2014;5:128. [https://doi.org/10.3389/fimmu.2014.00128] [PMID: 24734033] [PMCID: PMC3975093]
  28. Selmi C, Lu Q, Humble MC. Heritability versus the role of the environment in autoimmunity. J Autoimmun 2012;39(4):249-52. [https://doi.org/10.1016/j.jaut.2012.07.011] [PMID: 22980030]
  29. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005;42(5):1194-202. [https://doi.org/10.1002/hep.20907] [PMID: 16250040] [PMCID: PMC3150736]
  30. Leffers HCB, Lange T, Collins C, Ulff-Møller CJ, Jacobsen S, et al. The study of interactions between genome and exposome in the development of systemic lupus erythematosus. Autoimmun Rev 2019;18(4):382-92. [https://doi.org/10.1016/j.autrev.2018.11.005] [PMID: 30772495]
  31. Chukkapalli S, Rivera-Kweh M, Gehlot P, Velsko I, Bhattacharyya I, Calise SJ, et al. Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice. Arthritis Res Ther 2016;18(1):161. [https://doi.org/10.1186/s13075-016-1056-4] [PMID: 27405639] [PMCID: PMC4942913]
  32. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis 2005;5(4):227-36. [https://doi.org/10.1016/S1473-3099(05)70053-0] [PMID: 15792740]
  33. Love LA, Weinberg CR, McConnaughey DR, Oddis CV, Medsger TA Jr, Reveille JD, et al. Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum 2009;60(8):2499-504. [https://doi.org/10.1002/art.24702] [PMID: 19644877] [PMCID: PMC2855681]
  34. Barbhaiya M, Costenbader KH. Ultraviolet radiation and systemic lupus erythematosus. Lupus 2014;23(6):588-95. [https://doi.org/10.1177/0961203314530488] [PMID: 24763542]
  35. Zhang H, Liao X, Sparks JB, Luo XM, et al. Dynamics of gut microbiota in autoimmune lupus. Appl Environ Microbiol 2014;80(24):7551-60. [https://doi.org/10.1128/AEM.02676-14] [PMID: 25261516] [PMCID: PMC4249226]
  36. Li B, Selmi C, Tang R, Gershwin ME, Ma X. The microbiome and autoimmunity: a paradigm from the gut-liver axis. Cell Mol Immunol 2018;15(6):595-609. [https://doi.org/10.1038/cmi.2018.7] [PMID: 29706647] [PMCID: PMC6079090]
  37. Rizzetto L, Fava F, Tuohy KM, Selmi C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex. J Autoimmun 2018;92:12-34. [https://doi.org/10.1016/j.jaut.2018.05.008] [PMID: 29861127]
  38. Abdollahi-Roodsaz S, Abramson SB, Scher JU. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat Rev Rheumatol 2016;12(8):446-55. [https://doi.org/10.1038/nrrheum.2016.68] [PMID: 27256713]
  39. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013;339(6123):1084-8. [https://doi.org/10.1126/science.1233521] [PMID: 23328391]
  40. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012;150(3): 470-80. [https://doi.org/10.1016/j.cell.2012.07.008] [PMID: 22863002] [PMCID: PMC3505857]
  41. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature 2012;486(7402):222-7. [https://doi.org/10.1038/nature11053] [PMID: 22699611] [PMCID: PMC3376388]
  42. Shin JH, Park YH, Sim M, Kim SA, Joung H, Shin DM. Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res Microbiol 2019;170(4-5):192-201. [https://doi.org/10.1016/j.resmic.2019.03.003] [PMID: 30940469]
  43. Doran MF,  Pond GR, Crowson CS, O'Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;46(3):625-31. [https://doi.org/10.1002/art.509] [PMID: 11920397]
  44. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 2013;39(2):400-12. [https://doi.org/10.1016/j.immuni.2013.08.013] [PMID: 23973225] [PMCID: PMC3822899 ]