Abstract
Women have a stronger immune response and a higher frequency of most autoimmune diseases than men. While much of the difference between men and women is due to the effect of gonadal hormones, genetic differences play a major role in the difference between the immune response and disease frequencies in women and men. Here, we focus on the immune differences between the sexes that are not downstream of the gonadal hormones. These differences include the gene content of the sex chromosomes, the inactivation of chromosome X in women, the consequences of non-random X inactivation and escape from inactivation, and the states that are uniquely met by the immune system of women—pregnancy, birth, and breast feeding. While these female-specific states are temporary and involve gonadal hormonal changes, they may leave a long-lasting footprint on the health of women, for example, by fetal cells that remain in the mother’s body for decades. We also briefly discuss the immune phenotype of congenital sex chromosomal aberrations and experimental models that enable hormonal and the non-hormonal effects of the sex chromosomes to be disentangled. The increasing human life expectancy lengthens the period during which gonadal hormones levels are reduced in both sexes. A better understanding of the non-hormonal effects of sex chromosomes thus becomes more important for improving the life quality during that period.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Bibliography
Arnold AP, Chen X (2009) What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30(1):1–9. https://doi.org/10.1016/j.yfrne.2008.11.001
Ashworth A, Rastan S, Lovell-Badge R et al (1991) X-chromosome inactivation may explain the difference in viability of XO humans and mice. Nature 351(6325):406–408. https://doi.org/10.1038/351406a0
Azar P, Mejía JE, Cenac C et al (2020) TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women. JCI Insight 5(12):e136047. https://doi.org/10.1172/jci.insight.136047.doi:10.1172/jci.insight.136047
Barbosa FB, Sinicato NA, Julio PR et al (2020) Trisomy X in a patient with childhood-onset systemic lupus erythematosus. J Transl Autoimmun 3:100043. https://doi.org/10.1016/j.jtauto.2020.100043
Bardsley MZ, Kowal K, Levy C et al (2013) 47, XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr 163(4):1085–1094. https://doi.org/10.1016/j.jpeds.2013.05.037
Bianchi DW, Zickwolf GK, Weil GJ et al (1996) Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A 93(2):705–708. https://doi.org/10.1073/pnas.93.2.705
Billington WD (2003) The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to peter medawar. J Reprod Immunol 60(1):1–11. https://doi.org/10.1016/S0165-0378(03)00083-4
Burgoyne PS, Arnold AP (2016) A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol Sex Differ 7(1):68. https://doi.org/10.1186/s13293-016-0115-5
Busque L, Paquette Y, Provost S et al (2009) Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 113(15):3472–3474. https://doi.org/10.1182/blood-2008-12-195677
Camacho-Morales A, Caba M, García-Juárez M et al (2021) Breastfeeding contributes to physiological immune programming in the newborn. Front Pediatr 9:744104. https://doi.org/10.3389/fped.2021.744104
Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404. https://doi.org/10.1038/nature03479
Case LK, Wall EH, Dragon JA et al (2013) The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res 23(9):1474–1485. https://doi.org/10.1101/gr.156703.113
Chaouat G (2016) Reconsidering the Medawar paradigm placental viviparity existed for eons, even in vertebrates; without a “problem”: why are tregs important for preeclampsia in great apes? J Reprod Immunol 114:48–57. https://doi.org/10.1016/j.jri.2015.09.002
Cómitre-Mariano B, Martínez-García M, García-Gálvez B et al (2021) Feto-Maternal microchimerism: memories from pregnancy. Iscience 25(1):103664. https://doi.org/10.1016/j.isci.2021.103664
De Sanctis V, Khater D (2019) Autoimmune diseases in Turner syndrome: an overview. Acta Biomed 90(3):341–344. https://doi.org/10.23750/abm.v90i3.8737
De Vries GJ, Rissman EF, Simerly RB et al (2002) A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22(20):9005–9014. https://doi.org/10.1523/JNEUROSCI.22-20-09005.2002
Erlebacher A (2013) Mechanisms of T cell tolerance towards the allogeneic fetus. Nat Rev Immunol 13(1):23–33. https://doi.org/10.1038/nri3361
Eskenazi B, Fenster L, Sidney S (1991) A multivariate analysis of risk factors for preeclampsia. JAMA 266(2):237–241
Fugazzola L, Cirello V, Beck-Peccoz P (2011) Fetal microchimerism as an explanation of disease. Nat Rev Endocrinol 7(2):89–97. https://doi.org/10.1038/nrendo.2010.216
Fujimoto M, Ikeda K, Nakamura T et al (2015) Development of mixed connective tissue disease and Sjögren’s syndrome in a patient with trisomy X. Lupus 24(11):1217–1220. https://doi.org/10.1177/0961203315580873
Gal-Oz ST, Maier B, Yoshida H et al (2019) ImmGen report: sexual dimorphism in the immune system transcriptome. Nat Commun 10(1):4295–4296. https://doi.org/10.1038/s41467-019-12348-6[doi]
Gammill HS, Aydelotte TM, Guthrie KA et al (2013) Cellular fetal microchimerism in preeclampsia. Hypertension 62(6):1062–1067. https://doi.org/10.1161/HYPERTENSIONAHA.113.01486
Gammill HS, Nelson JL (2010) Naturally acquired microchimerism. Int J Dev Biol 54(2–3):531–543. https://doi.org/10.1387/ijdb.082767hg
Ghisa M, Savarino V, Buda A et al (2022) Toward a potential association between eosinophilic esophagitis and Klinefelter syndrome: a case series and review of the literature. Therap Adv Gastroenterol 15:17562848221076888. https://doi.org/10.1177/17562848221076888
Ghosh MK, Chen KE, Dill-Garlow R et al (2021) Sex differences in the immune system become evident in the perinatal period in the four core genotypes mouse. Front Endocrinol (lausanne) 12:582614. https://doi.org/10.3389/fendo.2021.582614
Giltay JC, Maiburg MC (2010) Klinefelter syndrome: clinical and molecular aspects. Expert Rev Mol Diagn 10(6):765–776. https://doi.org/10.1586/erm.10.63
Gipson SAY, Hall MD (2016) The evolution of sexual dimorphism and its potential impact on host–pathogen coevolution. Evolution 70(5):959–968. https://doi.org/10.1111/evo.12922
Goswami R, Goswami D, Kabra M et al (2003) Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril 80(4):1052–1054. S001502820301121X [pii]
Gubbels Bupp MR, Jorgensen TN (2018) Androgen-Induced immunosuppression. Front Immunol 9
Guo X, Su B, Zhou Z et al (2009) Rapid evolution of mammalian X-linked testis microRNAs. BMC Genomics 10(1):97.https://doi.org/10.1186/1471-2164-10-97
Hacisuleyman E, Goff LA, Trapnell C et al (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21(2):198–206. https://doi.org/10.1038/nsmb.2764
Hamada H, Okae H, Toh H et al (2016) Allele-Specific methylome and transcriptome analysis reveals widespread imprinting in the human placenta. The American Journal of Human Genetics 99(5):1045–1058. https://doi.org/10.1016/j.ajhg.2016.08.021
Hiby SE, Walker JJ, O’Shaughnessy KM et al (2004) Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 200(8):957–965. https://doi.org/10.1084/jem.20041214
Hjerrild BE, Mortensen KH, Gravholt CH (2008) Turner syndrome and clinical treatment. Br Med Bull 86:77–93. https://doi.org/10.1093/bmb/ldn015
Hsu P, Nanan RKH (2014) Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and pre-eclampsia. Front Immunol 5:125. https://doi.org/10.3389/fimmu.2014.00125
Hughes JF, Page DC (2015) The biology and evolution of mammalian Y chromosomes. Annu Rev Genet 49(1):507–527. https://doi.org/10.1146/annurev-genet-112414-055311
Invernizzi P, Miozzo M, Selmi C et al (2005) X chromosome monosomy: a common mechanism for autoimmune diseases. J Immunol 175(1):575–578. https://doi.org/10.4049/jimmunol.175.1.575
Jørgensen KT, Rostgaard K, Bache I et al (2010) Autoimmune diseases in women with turner’s syndrome. Arthritis Rheum 62(3):658–666. https://doi.org/10.1002/art.27270
Kanaan SB, Onat OE, Balandraud N et al (2016) Evaluation of X chromosome inactivation with respect to HLA genetic susceptibility in rheumatoid arthritis and systemic sclerosis. PLoS ONE 11(6):e0158550
Kaneko S, Li X (2018) X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci Adv 4(6):eaar5598. https://doi.org/10.1126/sciadv.aar5598
Kho EM, McCowan LME, North RA et al (2009) Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol 82(1):66–73. https://doi.org/10.1016/j.jri.2009.04.011
Kinder JM, Stelzer IA, Arck PC et al (2017) Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol 17(8):483–494. https://doi.org/10.1038/nri.2017.38
Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16(10):626–638. https://doi.org/10.1038/nri.2016.90
Lahn BT, Page DC (1999) Four evolutionary strata on the human X chromosome. Science 286(5441):964–967. https://doi.org/10.1126/science.286.5441.964
Lambert NC (2009) The price of silence. Arthritis Rheum 60(11):3164–3167. https://doi.org/10.1002/art.24962
Lewandowski JP, Lee JC, Hwang T et al (2019) The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis. Nat Commun 10(1):5137–5144. https://doi.org/10.1038/s41467-019-12970-4
Liu K, Kurien BT, Zimmerman SL et al (2016) X chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47, XXX in systemic lupus erythematosus and Sjögren’s syndrome. Arthritis Rheumatol 68(5):1290–1300. https://doi.org/10.1002/art.39560
Lokossou GAG, Kouakanou L, Schumacher A et al (2022) Human breast milk: from food to active immune response with disease protection in infants and mothers. Front Immunol 13:849012. https://doi.org/10.3389/fimmu.2022.849012
Lopes AM, Burgoyne PS, Ojarikre A et al (2010) Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of turner syndrome. BMC Genomics 11:82–82. https://doi.org/10.1186/1471-2164-11-82
Lovell-Badge R, Robertson E (1990) XY female mice resulting from a heritable mutation in the primary testis-determining gene Tdy. Development 109(3):635–646. https://doi.org/10.1242/dev.109.3.635
Lu Y, Liu X, Xie M et al (2017) The NF-κB-Responsive long noncoding RNA FIRRE regulates posttranscriptional regulation of inflammatory gene expression through interacting with hnRNPU. J Immunol 199(10):3571–3582. https://doi.org/10.4049/jimmunol.1700091
Luo X, Ikeda Y, Schlosser DA et al (1995) Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene. Mol Endocrinol 9(9):1233–1239. https://doi.org/10.1210/mend.9.9.7491115
Mak W, Nesterova TB, de Napoles M et al (2004) Reactivation of the paternal X chromosome in early mouse embryos. Science 303(5658):666–669. https://doi.org/10.1126/science.1092674
Masoudian P, Nasr A, de Nanassy J et al (2016) Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol 214(3):328–339. https://doi.org/10.1016/j.ajog.2015.11.020
McCartney SA, Kolarova T, Kanaan SB et al (2022) Increased fetal microchimerism in immune and stem cell subsets in preeclampsia. Am J Reprod Immunol:e13666. https://doi.org/10.1111/aji.13666
Miga KH, Koren S, Rhie A et al (2020) Telomere-to-telomere assembly of a complete human X chromosome. Nature 585(7823):79–84. https://doi.org/10.1038/s41586-020-2547-7
Migeon BR (2007) Why females are mosaics, x-chromosome inactivation, and sex differences in disease. Gend Med 4(2):97–105. https://doi.org/10.1016/S1550-8579(07)80024-6
Migeon BR (2020) X-linked diseases: susceptible females. Genet Med 22(7):1156–1174. https://doi.org/10.1038/s41436-020-0779-4
Miyakawa H, Iyonaga K, Arima S et al (1997) A superfemale with primary Sjögren’s syndrome which involved systemic organs. J Intern Med 242(3):261–265. https://doi.org/10.1046/j.1365-2796.1997.00190.x
Morohashi K, Tsuboi-Asai H, Matsushita S et al (1999) Structural and functional abnormalities in the spleen of an mFtz-F1 gene-disrupted mouse. Blood 93(5):1586–1594
Mousavi MJ, Mahmoudi M, Ghotloo S (2020) Escape from X chromosome inactivation and female bias of autoimmune diseases. Mol Med 26(1):127. https://doi.org/10.1186/s10020-020-00256-1
Navarro-Cobos MJ, Balaton BP, Brown CJ (2020) Genes that escape from X-chromosome inactivation: Potential contributors to Klinefelter syndrome. Am J Med Genet C Semin Med Genet 184(2):226–238. https://doi.org/10.1002/ajmg.c.31800
Nelson JL (2012) The otherness of self: microchimerism in health and disease. Trends Immunol 33(8):421–427. https://doi.org/10.1016/j.it.2012.03.002
Okamoto I, Otte AP, Allis CD et al (2004) Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303(5658):644–649. https://doi.org/10.1126/science.1092727
Otter M, Schrander-Stumpel CTRM, Curfs LMG (2010) Triple X syndrome: a review of the literature. Eur J Hum Genet 18(3):265–271. https://doi.org/10.1038/ejhg.2009.109
Ozbalkan Z, Bagişlar S, Kiraz S et al (2005) Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 52(5):1564–1570. https://doi.org/10.1002/art.21026
Ozcelik T, Uz E, Akyerli CB et al (2006) Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity. Eur J Hum Genet 14(6):791–797. https://doi.org/10.1038/sj.ejhg.5201614
Palaszynski KM, Smith DL, Kamrava S et al (2005) A yin-yang effect between sex chromosome complement and sex hormones on the immune response. Endocrinology 146(8):3280–3285. https://doi.org/10.1210/en.2005-0284
Panimolle F, Tiberti C, Spaziani M et al (2021) Non-organ-specific autoimmunity in adult 47, XXY Klinefelter patients and higher-grade X-chromosome aneuploidies. Clin Exp Immunol 205(3):316–325. https://doi.org/10.1111/cei.13616
Petropoulos S, Edsgärd D, Reinius B et al (2016) Single-Cell RNA-Seq reveals lineage and X chromosome dynamics in human preimplantation embryos. Cell 165(4):1012–1026. https://doi.org/10.1016/j.cell.2016.03.023
Pinheiro I, Dejager L, Libert C (2011) X-chromosome-located microRNAs in immunity: might they explain male/female differences? BioEssays 33(11):791–802. https://doi.org/10.1002/bies.201100047
Rae W, Gao Y, Bunyan D et al (2015) A novel FOXP3 mutation causing fetal akinesia and recurrent male miscarriages. Clin Immunol 161(2):284–285. https://doi.org/10.1016/j.clim.2015.09.006
Rhie A, Nurk S, Cechova M et al (2022) The complete sequence of a human Y chromosome. bioRxiv:2022.12.01.518724. https://doi.org/10.1101/2022.12.01.518724
Rice WR (1992) Sexually antagonistic genes: experimental evidence. Science 256(5062):1436
Robillard PY, Hulsey TC, Alexander GR et al (1993) Paternity patterns and risk of preeclampsia in the last pregnancy in multiparae. J Reprod Immunol 24(1):1–12. https://doi.org/10.1016/0165-0378(93)90032-d
Robillard P, Dekker G, Chaouat G et al (2011) Epidemiological studies on primipaternity and immunology in preeclampsia–a statement after twelve years of workshops. J Reprod Immunol 89(2):104–117. https://doi.org/10.1016/j.jri.2011.02.003
Robinson DP, Huber SA, Moussawi M et al (2011) Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis. Biol Sex Differ 2:8–8. https://doi.org/10.1186/2042-6410-2-8
Rolff J (2002) Bateman’s principle and immunity. Proc Biol Sci 269(1493):867–872. https://doi.org/10.1098/rspb.2002.1959
Sabapatha A, Gercel-Taylor C, Taylor DD (2006) Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences1. Am J Reprod Immunol 56(5–6):345–355. https://doi.org/10.1111/j.1600-0897.2006.00435.x
San Roman AK, Godfrey AK, Skaletsky H et al (2023) The human inactive X chromosome modulates expression of the active X chromosome. Cell Genom 3(2):100259. doi:10.1016/j.xgen.2023.100259.
Seminog OO, Seminog AB, Yeates D et al (2015) Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity 48(2):125–128. https://doi.org/10.3109/08916934.2014.968918
Shenoda BB, Ramanathan S, Gupta R et al (2021) Xist attenuates acute inflammatory response by female cells. Cell Mol Life Sci 78(1):299–316. https://doi.org/10.1007/s00018-020-03500-3
Smith-Bouvier DL, Divekar AA, Sasidhar M et al (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205(5):1099–1108. https://doi.org/10.1084/jem.20070850
Sood B, Clemente Fuentes RW (2022) Jacobs Syndrome. In: StatPearls, StatPearls Publishing LLC, Treasure Island (FL)
Stoehr AM, Kokko H (2006) Sexual dimorphism in immunocompetence: what does life-history theory predict? Behav Ecol 17(5):751–756. https://doi.org/10.1093/beheco/ark018
Syrett CM, Anguera MC (2019) When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity. J Leukoc Biol 106(4):919–932. https://doi.org/10.1002/JLB.6RI0319-094R
Syrett CM, Paneru B, Sandoval-Heglund D et al (2019a) Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. JCI Insight 4(7):e126751. https://doi.org/10.1172/jci.insight.126751.eCollection2019Apr4.doi:10.1172/jci.insight.126751
Syrett CM, Sindhava V, Sierra I et al (2019b) Diversity of epigenetic features of the inactive X-chromosome in NK cells, dendritic cells, and macrophages. Front Immunol 9:3087. https://doi.org/10.3389/fimmu.2018.03087
Tartaglia NR, Howell S, Sutherland A et al (2010) A review of trisomy X (47, XXX). Orphanet J Rare Dis 5:8–8. https://doi.org/10.1186/1750-1172-5-8
Thrasher BJ, Hong LK, Whitmire JK et al (2016) Epigenetic dysfunction in turner syndrome immune cells. Curr Allergy Asthma Rep 16(5):36-y. https://doi.org/10.1007/s11882-016-0612-y
Trolle C, Nielsen MM, Skakkebæk A et al (2016) Widespread DNA hypomethylation and differential gene expression in turner syndrome. Sci Rep 6:34220. https://doi.org/10.1038/srep34220
Tukiainen T, Villani A, Yen A et al (2017) Landscape of X chromosome inactivation across human tissues. Nature 550(7675):244–248. https://doi.org/10.1038/nature24265
Úbeda F, Jansen VAA (2016) The evolution of sex-specific virulence in infectious diseases. Nat Commun 7(1):13849. https://doi.org/10.1038/ncomms13849
Uz E, Mustafa C, Topaloglu R et al (2009) Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritis. Arthritis Rheum 60(11):3410–3412. https://doi.org/10.1002/art.24956
Wood GW (1994) Is restricted antigen presentation the explanation for fetal allograft survival? Immunol Today 15(1):15–18. https://doi.org/10.1016/0167-5699(94)90020-5
Yamazaki S, Akutsu Y, Shimbo A et al (2021) Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report. Pediatr Rheumatol Online J 19(1):20. https://doi.org/10.1186/s12969-021-00507-3
Youness A, Miquel C, Guéry J (2021) Escape from X chromosome inactivation and the female predominance in autoimmune diseases. Int J Mol Sci 22(3):1114. https://doi.org/10.3390/ijms22031114.doi:10.3390/ijms22031114
Zuk M (2009) The sicker sex. PLOS Pathogens 5(1):e1000267
Zuk M, Stoehr AM (2002) Immune defense and host life history. Am Nat 160(Suppl 4):S9–S22. https://doi.org/10.1086/342131
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Gal-Oz, S.T., Shay, T. (2023). Genetics of Sex Differences in Immunity. In: Klein, S.L., Roberts, C.W. (eds) Sex and Gender Differences in Infection and Treatments for Infectious Diseases. Current Topics in Microbiology and Immunology, vol 441. Springer, Cham. https://doi.org/10.1007/978-3-031-35139-6_1
Download citation
DOI: https://doi.org/10.1007/978-3-031-35139-6_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-35138-9
Online ISBN: 978-3-031-35139-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)