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The X chromosome in immune functions: when a chromosome makes the difference

Nature Reviews Immunology volume 10, pages 594–604 (2010)Cite this article

Subjects

Key Points

  • Females are more immunoreactive than males and, although sex hormones have an important role in immune functions, the X chromosome is fundamental in shaping sex-specific immune responses.

  • X-linked specific diseases usually affect only males, simply because they are hemizygous for X chromosome alleles. The fact that females carry two X chromosomes, and therefore two different allelic options to be used by cells, means that they have two possible physiological responses.

  • Mosaicism, caused by X chromosome inactivation, is one mechanism by which females can have an immune advantage over males, but there are also other features associated with the X chromosome that can modulate differences between female and male immune responses and even lead to immunological differences between individual females.

  • Although X chromosome inactivation is expected to balance the levels of female and male gene expression, several genes located in the non-recombining regions of the sex chromosomes can escape inactivation, and females may have elevated gene expression of these genes. Moreover, females may present extreme skewing of X chromosome inactivation and show overrepresentation of one of the parental X chromosomes.

  • Escape from X chromosome silencing and X inactivation skewing may account for immune differences between the sexes. These mechanisms may be involved in the development of autoimmunity, as skewed X chromosome inactivation or reactivation of parts of the inactive X chromosome can lead to the breakdown of self tolerance.

  • The number of X-linked genes and microRNAs with an identified role in immunity is increasing, and it is possible that naturally occurring variations in these genes and microRNAs account for immunological differences between genders.

Abstract

In response to various immune challenges, females show better survival than males; the X chromosome has an important role in this immunological advantage. X chromosome-linked diseases are usually restricted to males, who have only one copy of the X chromosome; however, females are more prone to autoimmune diseases, and the X chromosome may be involved in the breakdown of self tolerance. Several hypotheses have been proposed in recent years that support a role for the X chromosome in shaping autoimmune responses. Here, we review the main mechanisms responsible for increased immune activity in females. This provides a survival advantage in the face of pathogenic insult but can also enhance the susceptibility of females to autoimmunity.

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Figure 1: The different mechanisms regulating immunity and triggered by the sex chromosomes.
Figure 2: Sex distribution of the most important autoimmune diseases.
Figure 3: Current hypotheses attesting the involvement of X chromosome anomalies in autoimmunity.

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References

  1. Aspinall, R. Longevity and the immune response. Biogerontology 1, 273–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Choudhry, M. A., Bland, K. I. & Chaudry, I. H. Gender and susceptibility to sepsis following trauma. Endocr. Metab. Immune Disord. Drug Targets 6, 127–135 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Gannon, C. J., Pasquale, M., Tracy, J. K., McCarter, R. J. & Napolitano, L. M. Male gender is associated with increased risk for postinjury pneumonia. Shock 21, 410–414 (2004).

    Article  PubMed  Google Scholar 

  4. Butterworth, M., McClellan, B. & Aklansmith, M. Influence of sex on immunoglobulin levels. Nature 214, 1224–1225 (1967).

    Article  CAS  PubMed  Google Scholar 

  5. Purtilo, D. T. & Sullivan, J. L. Immunological bases for superior survival of females. Am. J. Dis. Child. 133, 1251–1253 (1979).

    CAS  PubMed  Google Scholar 

  6. Burch, P. R. J. & Rowell, N. R. Genetic origin of some sex differences among human beings. Pediatrics 36, 658–659 (1965).

    Google Scholar 

  7. Migeon, B. R. Females are mosaics: X inactivation and sex differences in disease (Oxford University Press, New York, 2007).

    Google Scholar 

  8. Glezen, W. P. et al. Epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice. J. Pediatr. 78, 397–406 (1971).

    Article  CAS  PubMed  Google Scholar 

  9. Hall, C. B., Kopelman, A. E., Douglas, R. G., Geiman, J. M. & Meagher, M. P. Neonatal respiratory syncytial virus-infection. N. Engl. J. Med. 300, 393–396 (1979).

    Article  CAS  PubMed  Google Scholar 

  10. Kunin, C. M. Antibody distribution against non-enteropathic E. coli. Arch. Intern. Med. 110, 676–686 (1962).

    Article  Google Scholar 

  11. Thompson, D. J., Gezon, H. M., Rogers, K. D., Yee, R. B. & Hatch, T. F. Excess risk of staphylococcal infection and disease in newborn males. Am. J. Epidemiol. 84, 314–328 (1966).

    Article  CAS  PubMed  Google Scholar 

  12. Strachan, N. J. C. et al. Sexual dimorphism in campylobacteriosis. Epidemiol. Infect. 136, 1492–1495 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Green, M. S. The male predominance in the incidence of infectious diseases in children: a postulated explanation for disparities in the literature. Int. J. Epidemiol. 21, 381–386 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Restif, O. & William, A. The evolution of sex-specific immune defenses. Proc. R. Soc. Lond. B Biol. Sci. Mar 24 2010 (doi:10.1098/rspb.2010.0188).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Migeon, B. R. The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. JAMA 295, 1428–1433 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Morris, J. A. & Harrison, L. M. Hypothesis: increased male mortality caused by infection is due to a decrease in heterozygous loci as a result of a single X chromosome. Med. Hypotheses 72, 322–324 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Spolarics, Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock 27, 597–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Arnold, A. P. Sex chromosomes and brain gender. Nature Rev. Neurosci. 5, 701–708 (2004).

    Article  CAS  Google Scholar 

  19. Lleo, A., Battezzati, P. M., Selmi, C., Gershwin, M. E. & Podda, M. Is autoimmunity a matter of sex? Autoimmun. Rev. 7, 626–630 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Ozcelik, T. X chromosome inactivation and female predisposition to autoimmunity. Clin. Rev. Allergy Immunol. 34, 348–351 (2008).

    Article  PubMed  Google Scholar 

  21. Selmi, C. The X in sex: how autoimmune diseases revolve around sex chromosomes. Best Pract. Res. Clin. Rheumatol. 22, 913–922 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Deitch, E. A. et al. Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries. Am. J. Physiol. Heart Circ. Physiol. 291, 1456–1465 (2006).

    Article  CAS  Google Scholar 

  23. Nalbandian, G. & Kovats, S. Understanding sex biases in immunity — effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol. Res. 31, 91–106 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Szalay, L. et al. Androstenediol administration after trauma-hemorrhage attenuates inflammatory response, reduces organ damage, and improves survival following sepsis. Am. J. Physiol. Gastrointest. Liver Physiol. 291, 260–266 (2006).

    Article  CAS  Google Scholar 

  25. Burgoyne, P. S. et al. The genetic basis of XX–XY differences present before gonadal sex differentiation in the mouse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 350, 253–260 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. Washburn, T. C., Medearis, D. N. & Childs, B. Sex differences in susceptibility to infections. Pediatrics 35, 57–64 (1965).

    CAS  PubMed  Google Scholar 

  28. McMillen, M. M. Differential mortality by sex in fetal and neonatal deaths. Science 204, 89–91 (1979).

    Article  CAS  PubMed  Google Scholar 

  29. Forest, M. G., Cathiard, A. M. & Bertrand, J. A. Evidence of testicular activity in early infancy. J. Clin. Endocrinol. Metab. 37, 148–151 (1973).

    Article  CAS  PubMed  Google Scholar 

  30. Mage, D. T. & Donner, M. A genetic basis for the sudden infant death syndrome sex ratio. Med. Hypotheses 48, 137–142 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Morris, J. A. & Harrison, L. M. Sudden unexpected death in infancy: evidence of infection. Lancet 371, 1815–1816 (2008).

    Article  PubMed  Google Scholar 

  32. Weber, M. A. et al. Infection and sudden unexpected death in infancy: a systematic retrospective case review. Lancet 371, 1848–1853 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Notarangelo, L. et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee meeting in Budapest, 2005. J. Allergy Clin. Immunol. 117, 883–896 (2006).

    Article  PubMed  Google Scholar 

  34. Pessach, I. M. & Notarangelo, L. D. X-linked primary immunodeficiencies as a bridge to better understanding X-chromosome related autoimmunity. J. Autoimmun. 33, 17–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Teahan, C., Rowe, P., Parker, P., Totty, N. & Segal, A. W. The X-linked chronic granulomatous-disease gene codes for the β-chain of cytochrome-b-245. Nature 327, 720–721 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Bennett, C. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200–208 (2001).

    Article  CAS  Google Scholar 

  39. Mordmuller, B., Turrini, F., Long, H., Kremsner, P. G. & Arese, P. Neutrophils and monocytes from subjects with the Mediterranean G6PD variant: effect of Plasmodium falciparum hemozoin on G6PD activity, oxidative burst and cytokine production. Eur. Cytokine Netw. 9, 239–245 (1998).

    CAS  PubMed  Google Scholar 

  40. Wilmanski, J., Siddiqi, M., Deitch, E. A. & Spolarics, Z. Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages. J. Leukoc. Biol. 78, 85–94 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Smahi, A. et al. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405, 466–472 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Uzel, G. The range of defects associated with nuclear factor κB essential modulator. Curr. Opin. Allergy Clin. Immunol. 5, 513–518 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Orange, J. S. et al. The presentation and natural history of immunodeficiency caused by nuclear factor κB essential modulator mutation. J. Allergy Clin. Immunol. 113, 725–733 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Orange, J. S. et al. Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J. Allergy Clin. Immunol. 114, 650–656 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Orange, J. S., Levy, O. & Geha, R. S. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-κB activation. Immunol. Rev. 203, 21–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Vicoso, B. & Charlesworth, B. Evolution on the X chromosome: unusual patterns and processes. Nature Rev. Gen. 7, 645–653 (2006).

    Article  CAS  Google Scholar 

  47. Ohno, S. Sex Chromosomes and Sex-Linked Genes (Springer, Berlin, 1967).

    Book  Google Scholar 

  48. Nguyen, D. K. & Disteche, C. M. Dosage compensation of the active X chromosome in mammals. Nature Genet. 38, 47–53 (2006). By comparing the global X chromosome transcriptome with that of autosomes, the authors show that mammalian X chromosome gene expression is upregulated in several somatic tissues to match the levels shown by autosomal genes.

    Article  CAS  PubMed  Google Scholar 

  49. Vallender, E. J. & Lahn, B. T. How mammalian sex chromosomes acquired their peculiar gene content. Bioessays 26, 159–169 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, P. J., McCarrey, J. R., Yang, F. & Page, D. C. An abundance of X-linked genes expressed in spermatogonia. Nature Genet. 27, 422–426 (2001).

    PubMed  Google Scholar 

  51. Ross, M. T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337 (2005). This article provides the complete description of structural features of the human X chromosome, as well as a detailed analysis of its evolution and the processes that led to progressive loss of recombination between sex chromosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005). This article provides a complete profile of human X chromosome inactivation, showing for the first time that X-linked genes can escape inactivation, and that this is a heterogeneous process.

    Article  CAS  PubMed  Google Scholar 

  53. Johnston, C. M. et al. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. Plos Genet. 4, e9 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wilson, M. A. & Makova, K. D. Evolution and survival on eutherian sex chromosomes. PLoS Genet. 5, e1000568 (2009). In this paper, the authors show for the first time that X and Y homologous genes have evolved at different evolutionary rates after suppression of recombination. They also show that some XY homologous genes have acquired specific mRNA or protein expression patterns and functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ditton, H. J., Zimmer, J., Rajpert- De Meyts, E. & Vogt, P. H. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum. Mol. Genet. 13, 2333–2341 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Decker, T. et al. The TBK-1 substrate DDX3X, a DEAD-box RNA helicase, provides innate immunity to Listeria monocytogenes. Cytokine 43, 304 (2008).

    Article  Google Scholar 

  57. Soulat, D. et al. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 27, 2135–2146 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Anderson, C. L. & Brown, C. J. Polymorphic X-chromosome inactivation of the human TIMP1 gene. Am. J. Hum. Genet. 65, 699–708 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brown, C. J., Carrel, L. & Willard, H. F. Expression of genes from the human active and inactive X chromosomes. Am. J. Hum. Genet. 60, 1333–1343 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vanlaere, I. & Libert, C. Matrix metalloproteinases as drug targets in infections caused by Gram-negative bacteria and in septic shock. Clin. Microbiol. Rev. 22, 224–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hoffmann, U. et al. Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. Scand. J. Infect. Dis. 38, 867–872 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Burkhardt, J. et al. Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis. J. Rheumatol. 36, 2149–2157 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Migeon, B. R. Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend. Med. 4, 97–105 (2007). This review provides a comprehensive explanation of mosaicism in females and why males are more vulnerable to diseases than females.

    Article  PubMed  Google Scholar 

  64. Migeon, B. R. Non-random X chromosome inactivation in mammalian cells. Cytogenet. Cell Genet. 80, 142–148 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Orstavik, K. H. X chromosome inactivation in clinical practice. Hum. Genet. 126, 363–373 (2009).

    Article  PubMed  Google Scholar 

  66. Migeon, B. R. et al. Selection against lethal alleles in females heterozygous for incontinentia pigmenti. Am. J. Hum. Genet. 44, 100–106 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Fearon, E. R., Kohn, D. B., Winkelstein, J. A., Vogelstein, B. & Blaese, R. M. Carrier detection in the Wiskott Aldrich syndrome. Blood 72, 1735–1739 (1988).

    CAS  PubMed  Google Scholar 

  68. Van den Bogaard, R. et al. Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies. Eur. J. Hum. Genet. 8, 513–518 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Gleicher, N. & Barad, D. H. Gender as risk factor for autoimmune diseases. J. Autoimmun. 28, 1–6 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Jacobson, D. L., Gange, S. J., Rose, N. R. & Graham, N. M. H. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84, 223–243 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Kast, R. E. Hypothesis – predominance of autoimmune and rheumatic diseases in females. J. Rheumatol. 4, 288–292 (1977).

    CAS  PubMed  Google Scholar 

  72. Stewart, J. J. The female X-inactivation mosaic in systemic lupus erythematosus. Immunol. Today 19, 352–357 (1998). The original description of the loss of mosaicism hypothesis. In this article, a theoretical background for this hypothesis and the main findings which corroborate it are provided.

    Article  CAS  PubMed  Google Scholar 

  73. Takeno, M. et al. Autoreactive T cell clones from patients with systemic lupus erythematosus support polyclonal autoantibody production. J. Immunol. 158, 3529–3538 (1997).

    CAS  PubMed  Google Scholar 

  74. Scofield, R. H. et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 58, 2511–2517 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Litsuka, Y. et al. Evidence of skewed X-chromosome inactivation in 47,XXY and 48,XXYY Klinefelter patients. Am. J. Med. Genet. 98, 25–31 (2001).

    Article  Google Scholar 

  76. Brix, T. H. et al. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: A possible explanation for the female predisposition to thyroid autoimmunity. J. Clin. Endocrinol. Metab. 90, 5949–5953 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Ozbalkan, Z. et al. Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum. 52, 1564–1570 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Ozcelik, T. et al. Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity. Eur. J. Hum. Genet. 14, 791–797 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Uz, E. et al. Skewed X-chromosome inactivation in scleroderma. Clin. Rev. Allergy Immunol. 34, 352–355 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Invernizzi, P. The X chromosome in female-predominant autoimmune diseases. Ann. N Y Acad. Sci. 1110, 57–64 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Chitnis, S. et al. The role of X-chromosome inactivation in female predisposition to autoimmunity. Arthritis Res. 2, 399–406 (2000). This study describes a large survey of patterns of X chromosome inactivation skewing in patients with different autoimmune diseases and in age-matched female controls. The authors provide a model showing the consequences of skewed inactivation on tolerance induction in the thymus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lu, Q. et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J. Immunol. 179, 6352–6358 (2007). This study shows for the first time that CD40L overexpression on CD4+ T cells, owing to inactive X chromosome reactivation, contributes to the pathogenesis of SLE.

    Article  CAS  PubMed  Google Scholar 

  83. Forsdyke, D. R. X chromosome reactivation perturbs intracellular self/not-self discrimination. Immunol. Cell Biol. 87, 525–528 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Zhou, Y. et al. T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus. Clin. Immunol. 132, 362–370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Subramanian, S. et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl Acad. Sci. USA 103, 9970–9975 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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). This study provides a simple and elegant way to show how wild-type female mice are more susceptible to models of autoimmune diseases than XYSry− mice with a common gonadal background.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Invernizzi, P. et al. X chromosome monosomy: a common mechanism for autoimmune diseases. J. Immunol. 175, 575–578 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Ranke, M. B. & Saenger, P. Turner's syndrome. Lancet 358, 309–314 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Elsheikh, M., Wass, J. A. H. & Conway, G. S. Autoimmune thyroid syndrome in women with Turner's syndrome — the association with karyotype. Clin. Endocrinol. 55, 223–226 (2001).

    Article  CAS  Google Scholar 

  90. Sybert, V. P. & McCauley, E. Turner's syndrome. N. Engl. J. Med. 351, 1227–1238 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Bondy, C. A. & Cheng, C. Monosomy for the X chromosome. Chromosome Res. 17, 649–658 (2009). This review describes the major effects of X chromosome monosomy on Turner's syndrome. A list of X-linked genes located in the pseudoautosomal regions is given, together with the hypothesis that haploinsufficiency for these genes may be responsible for the symptoms.

    Article  CAS  PubMed  Google Scholar 

  92. Invernizzi, P. et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 363, 533–535 (2004).

    Article  PubMed  Google Scholar 

  93. Baltimore, D. Our genome unveiled. Nature 409, 814–816 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Disteche, C. M. Escapees on the X chromosome. Proc. Natl Acad. Sci. USA 96, 14180–14182 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Disteche, C. M., Filippova, G. N. & Tsuchiya, K. D. Escape from X inactivation. Cytogenet. Genome Res. 99, 36–43 (2002). A complete and comprehensive review on the process of X inactivation, which provides a comparison between human and mouse genes that escape silencing. Considerations about the molecular characteristics of the genes that escape inactivation are also given together with possible explanations for the phenomenon.

    Article  CAS  PubMed  Google Scholar 

  96. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Guo, X. J., Su, B., Zhou, Z. M. & Sha, J. H. Rapid evolution of mammalian X-linked testis microRNAs. BMC Genomics 10, 97 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. le Sage, C. et al. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 26, 3699–3708 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Johnnidis, J. B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Fontana, L. et al. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nature Cell Biol. 9, 775–787 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Rosa, A. et al. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc. Natl Acad. Sci. USA 104, 19849–19854 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cooper, G. S. & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge A. Bredan for critical review of the manuscript. Research in the authors' laboratory is sponsored by the Fund for Scientific Research-Flanders, the Interuniversity Attraction Poles Program of the Belgian Science Policy (IAP VI/18), the Belgische Vereniging tegen Kanker and the Flanders Institute for Biotechnology (VIB).

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  1. Claude Libert and Iris Pinheiro: These authors contributed equally to this work.

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  1. Department for Molecular Biomedical Research, and the Department of Biomedical Molecular Biology, Flanders Institute for Biotechnology (VIB), 9052 Ghent, Belgium, Ghent University, Ghent 9000, Belgium.,

    Claude Libert, Lien Dejager & Iris Pinheiro

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Glossary

X chromosome inactivation

(Also known as lyonization or silencing). A process that occurs in female mammals in which gene expression from one of the pair of X chromosomes is downregulated. This ensures that the levels of X chromosome gene expression in females matches that of males.

Pseudoautosomal regions

Small regions of sequence homology located at the tips of mammalian X and Y chromosomes where recombination still occurs during male meiosis.

Cellular mosaicism

The chimeric state of female tissues that results from random X chromosome inactivation, meaning that normal mammalian females have two genetically distinct types of cells.

Inbreeding depression

(Also known as loss of heterozygosity) is the reduced fitness of a certain population that results from breeding between close genetic relatives.

Sex-determining region of the Y chromosome

(SRY). The gene located on the Y chromosome that is responsible for male sex determination in almost all placental mammals.

Imprinting

An epigenetic process that, through methylation and histone modification, tags the chromosomes inherited from the mother or the father and results in differential gene expression in a parent-of-origin-specific manner.

Gene-dosage effects

The nearly linear relationship between the phenotype and the number of copies of the relevant gene present in the genome.

Self tolerance

Tolerance to an individual's own antigens that is achieved through both central and peripheral tolerance mechanisms, including T cell deletion, anergy and immune regulation. Without central and peripheral tolerance, the immune system could not distinguish self from foreign antigens, resulting in autoimmunity.

Chronic granulomatous disease

An inherited disorder caused by defective oxidase activity in the respiratory burst of phagocytes. It results from mutations in any of four genes that are necessary to generate the superoxide radicals required for normal neutrophil function. Affected patients suffer from increased susceptibility to recurrent infections.

Hypomorphic mutations

A type of mutation that results in a reduced level of activity of the product encoded by the mutated gene.

Purifying selection

(Also know as negative selection). The selective elimination of deleterious alleles from the population within the mechanism of natural selection.

Sexual antagonism

When an allele is favoured in one sex and selected against in the other.

Hemizygous

A diploid genotype that has only one copy of a particular gene, as in X chromosome genes in a male, or when the homologous chromosome carries a deletion.

Fitness effect

The expected contribution of an individual to the next generation.

XY homologous genes

Genes common to both sex chromosomes and therefore present in two copies in both females and males.

Skewing of X chromosome inactivation

When the process of X chromosome inactivation selects for or against alleles on the active X chromosome. This nonrandom pattern of inactivation results in overrepresentation of one of the parental X chromosomes in female tissues. Mutations in the X-inactive specific transcript (XIST) gene or chromosomal rearrangements resulting from translocations from autosomes can also lead to inactivation skewing.

Wiskott–Aldrich syndrome

(WAS). A life-threatening X-linked immunodeficiency caused by mutation in the WAS gene. It is characterized by thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies.

Fetal microchimerism

The presence of fetal cells in the mother after pregnancy.

Haploinsufficiency

Occurs when only one copy of a certain gene is present in the genome, and both copies are required for proper function.

Isochromosome-Xq

A genetic defect that results from the total deletion of the short arm of the X chromosome owing to the fusion of two long arms.

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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). https://doi.org/10.1038/nri2815

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