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  • Review Article
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Gene-function studies in systemic lupus erythematosus

Abstract

The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3′–5′ DNA exonuclease TREX1. In addition, genome-wide association studies have identified single-nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O-acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE.

Key Points

  • Heritable factors, modulated by environmental, hormonal and epigenetic influences, underlie the development of systemic lupus erythematosus (SLE)

  • In a few cases, single mutations or low copy numbers of particular genes strongly determine the development of SLE; these single-gene defects can be found in genes encoding TREX1 and early components of the complement pathway

  • Most patients exhibit a complex combination of small-effect alleles that independently cannot account for SLE development

  • Examples of genes whose products are expressed at altered levels or function abnormally in SLE include PPP2CA, immunoglobulin receptor genes, ITGAM and SIAE

  • Epigenetic modifications, including CpG-DNA methylation and histone modifications, also have a role in the development of SLE, by altering the expression of relevant genes

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Figure 1: Variants of the exonuclease TREX1 contribute to both lupus-like phenomena and SLE.
Figure 2: Genetic and epigenetic factors promote inflammation by increasing PP2Ac levels in SLE T cells.
Figure 3: Increased levels of CREMα and SLAMF expression contribute to the proinflammatory phenotype of SLE T cells.

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References

  1. Harley, J. B., Kelly, J. A. & Kaufman, K. M. Unraveling the genetics of systemic lupus erythematosus. Springer Semin. Immunopathol. 28, 119–130 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Alarcon-Segovia, D. et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 52, 1138–1147 (2005).

    Article  PubMed  Google Scholar 

  3. Deapen, D. et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 35, 311–318 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Harley, J. B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Kozyrev, S. V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Moser, K. L., Kelly, J. A., Lessard, C. J. & Harley, J. B. Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun. 10, 373–379 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sestak, A. L., Furnrohr, B. G., Harley, J. B., Merrill, J. T. & Namjou, B. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann. Rheum. Dis. 70 (Suppl. 1), i37–i43 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Harley, I. T., Kaufman, K. M., Langefeld, C. D., Harley, J. B. & Kelly, J. A. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat. Rev. Genet. 10, 285–290 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Atkinson, J. P. Complement deficiency: predisposing factor to autoimmune syndromes. Clin. Exp. Rheumatol. 7 (Suppl. 3), S95–S101 (1989).

    PubMed  Google Scholar 

  11. Ptacek, T., Li, X., Kelley, J. M. & Edberg, J. C. Copy number variants in genetic susceptibility and severity of systemic lupus erythematosus. Cytogenet. Genome Res. 123, 142–147 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Aitman, T. J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39, 721–723 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cook, H. T. & Botto, M. Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythematosus. Nat. Clin. Pract. Rheumatol. 2, 330–337 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Wu, Y. L. et al. Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus. Cytogenet. Genome Res. 123, 131–141 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Manderson, A. P., Botto, M. & Walport, M. J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Truedsson, L., Bengtsson, A. A. & Sturfelt, G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40, 560–566 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Davies, K. A., Peters, A. M., Beynon, H. L. & Walport, M. J. Immune complex processing in patients with systemic lupus erythematosus. In vivo imaging and clearance studies. J. Clin. Invest. 90, 2075–2083 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Korb, L. C. & Ahearn, J. M. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J. Immunol. 158, 4525–4528 (1997).

    CAS  PubMed  Google Scholar 

  21. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Bussone, G. & Mouthon, L. Autoimmune manifestations in primary immune deficiencies. Autoimmun. Rev. 8, 332–336 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Carroll, M. C. A protective role for innate immunity in systemic lupus erythematosus. Nat. Rev. Immunol. 4, 825–831 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Figueroa, J. E. & Densen, P. Infectious diseases associated with complement deficiencies. Clin. Microbiol. Rev. 4, 359–395 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kavanagh, D. et al. New roles for the major human 3′-5′ exonuclease TREX1 in human disease. Cell Cycle 7, 1718–1725 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Hedrich, C. M. et al. Chilblain lupus erythematosus—a review of literature. Clin. Rheumatol. 27, 949–954 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Lee-Kirsch, M. A. et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J. Mol. Med. 85, 531–537 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Gunther, C., Meurer, M., Stein, A., Viehweg, A. & Lee-Kirsch, M. A. Familial chilblain lupus—a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1. Dermatology 219, 162–166 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Hedrich, C. M. & Tsokos, G. C. Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases. Trends Mol. Med. 17, 714–724 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ablasser, A., Hertrich, C., Waβermann, R. & Hornung, V. Nucleic acid driven sterile inflammation. Clin. Immunol. http://dx.doi.org/10.1016/j.clim.2013.01.003.

  31. Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Namjou, B. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 12, 270–279 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ewen, C. L., Kane, K. P. & Bleackley, R. C. A quarter century of granzymes. Cell Death Differ. 19, 28–35 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Lieberman, J. Granzyme A activates another way to die. Immunol. Rev. 235, 93–104 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chowdhury, D. et al. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol. Cell 23, 133–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Ramantani, G. et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum. 62, 1469–1477 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Richards, A. et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat. Genet. 39, 1068–1070 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. O'Keefe, T. L., Williams, G. T., Davies, S. L. & Neuberger, M. S. Hyperresponsive B cells in CD22-deficient mice. Science 274, 798–801 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. O'Keefe, T. L., Williams, G. T., Batista, F. D. & Neuberger, M. S. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J. Exp. Med. 189, 1307–1313 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sjoberg, E. R., Powell, L. D., Klein, A. & Varki, A. Natural ligands of the B cell adhesion molecule CD22β can be masked by 9-O-acetylation of sialic acids. J. Cell Biol. 126, 549–562 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Guimaraes, M. J. et al. Molecular cloning and characterization of lysosomal sialic acid O-acetylesterase. J. Biol. Chem. 271, 13697–13705 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Cariappa, A. et al. B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase. J. Exp. Med. 206, 125–138 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Surolia, I. et al. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 466, 243–247 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hunt, K. A. et al. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nat. Genet. 44, 3–5 (2012).

    Article  CAS  Google Scholar 

  46. Chellappa, V. et al. M89V sialic acid acetyl esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal. PLoS ONE 8, e53453 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nath, S. K. et al. A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat. Genet. 40, 152–154 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rhodes, B. et al. The rs1143679 (R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes. Ann. Rheum. Dis. 71, 2028–2034 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. MacPherson, M., Lek, H. S., Prescott, A. & Fagerholm, S. C. A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis. J. Biol. Chem. 286, 17303–17310 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rosetti, F. et al. Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. J. Immunol. 189, 3714–3723 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Liu, Z. & Davidson, A. Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871–882 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alarcon, G. S. et al. Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort. PLoS Med. 3, e396 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Brown, E. E., Edberg, J. C. & Kimberly, R. P. Fc receptor genes and the systemic lupus erythematosus diathesis. Autoimmunity 40, 567–581 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Nimmerjahn, F. & Ravetch, J. V. Fc-receptors as regulators of immunity. Adv. Immunol. 96, 179–204 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Chen, K. et al. Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo. Blood 120, 4421–4431 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mueller, M. et al. Genomic pathology of SLE-associated copy-number variation at the FCGR2C/FCGR3B/FCGR2B locus. Am. J. Hum. Genet. 92, 28–40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. van der Pol, W. L. & van de Winkel, J. G. J. IgG receptor polymorphisms: risk factors for disease. Immunogenetics 48, 222–232 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Katsiari, C. G., Kyttaris, V. C., Juang, Y. T. & Tsokos, G. C. Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J. Clin. Invest. 115, 3193–3204 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Janssens, V., Longin, S. & Goris, J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem. Sci. 33, 113–121 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Juang, Y. T. et al. PP2A dephosphorylates Elf-1 and determines the expression of CD3ζ and FcRγ in human systemic lupus erythematosus T cells. J. Immunol. 181, 3658–3664 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Juang, Y. T. et al. Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus. J Biol. Chem. 286, 1795–1801 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Tan, W. et al. Association of PPP2CA polymorphisms with SLE susceptibility in multiple ethnic groups. Arthritis Rheum. 63, 2755–2763 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sunahori, K., Juang, Y. T. & Tsokos, G. C. Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. J. Immunol. 182, 1500–1508 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Sunahori, K., Juang, Y. T., Kyttaris, V. C. & Tsokos, G. C. Promoter hypomethylation results in increased expression of protein phosphatase 2A in T cells from patients with systemic lupus erythematosus. J. Immunol. 186, 4508–4517 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Crispin, J. C. et al. Cutting edge: Protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. J. Immunol. 188, 3567–3571 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Detre, C., Keszei, M., Romero, X., Tsokos, G. C. & Terhorst, C. SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions. Semin. Immunopathol. 32, 157–171 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Moser, K. L. et al. Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41. Arthritis Rheum. 42, 1902–1907 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Shai, R. et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum. Mol. Genet. 8, 639–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Tsao, B. P. et al. Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 46, 2928–2936 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Vyse, T. J. et al. Mapping autoimmune disease genes in humans: lessons from IBD and SLE. Novartis Found. Symp. 267, 94–107 (2005).

    CAS  PubMed  Google Scholar 

  72. Rozzo, S. J., Vyse, T. J., Drake, C. G. & Kotzin, B. L. Effect of genetic background on the contribution of New Zealand black loci to autoimmune lupus nephritis. Proc. Natl Acad. Sci. USA 93, 15164–15168 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kono, D. H. et al. Lupus susceptibility loci in New Zealand mice. Proc. Natl Acad. Sci. USA 91, 10168–10172 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hogarth, M. B. et al. Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. J. Immunol. 161, 2753–2761 (1998).

    CAS  PubMed  Google Scholar 

  75. Chatterjee, M. et al. Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. J. Immunol. 188, 1206–1212 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Chatterjee, M. et al. CD3-T cell receptor co-stimulation through SLAMF3 and SLAMF6 receptors enhances RORγt recruitment to the IL17A promoter in human T lymphocytes. J. Biol. Chem. 287, 38168–38177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Scheinbart, L. S., Johnson, M. A., Gross, L. A., Edelstein, S. R. & Richardson, B. C. Procainamide inhibits DNA methyltransferase in a human T cell line. J. Rheumatol. 18, 530–534 (1991).

    CAS  PubMed  Google Scholar 

  78. Oelke, K. et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum. 50, 1850–1860 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Ballestar, E., Esteller, M. & Richardson, B. C. The epigenetic face of systemic lupus erythematosus. J. Immunol. 176, 7143–7147 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Zhao, M. et al. Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells. J. Autoimmun. 35, 58–69 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Zhang, Y., Zhao, M., Sawalha, A. H., Richardson, B. & Lu, Q. Impaired DNA methylation and its mechanisms in CD4+ T cells of systemic lupus erythematosus. J. Autoimmun. 41, 92–99 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Yung, R. et al. Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. J. Clin. Invest. 97, 2866–2871 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Brenner, C. & Fuks, F. A methylation rendezvous: reader meets writers. Dev. Cell 12, 843–844 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Brenner, C. & Fuks, F. DNA methyltransferases: facts, clues, mysteries. Curr. Top. Microbiol. Immunol. 301, 45–66 (2006).

    CAS  PubMed  Google Scholar 

  86. Renaudineau, Y. & Youinou, P. Epigenetics and autoimmunity, with special emphasis on methylation. Keio J. Med. 60, 10–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Ballestar, E. Epigenetic alterations in autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 7, 263–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Hedrich, C. M., Rauen, T. & Tsokos, G. C. cAMP-responsive element modulator (CREM)α protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: implications in systemic lupus erythematosus. J. Biol. Chem. 286, 43429–43436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hedrich, C. M. et al. cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Proc. Natl Acad. Sci. USA 109, 16606–16611 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Liu, Y., Chen, Y. & Richardson, B. Decreased DNA methyltransferase levels contribute to abnormal gene expression in “senescent” CD4+CD28 T cells. Clin. Immunol. 132, 257–265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lal, G. et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 182, 259–273 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Zhao, M. et al. Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J. Biomed. Biotechnol. 2010, 931018 (2010).

    PubMed  PubMed Central  Google Scholar 

  93. Rauen, T., Hedrich, C. M., Juang, Y. T., Tenbrock, K. & Tsokos, G. C. cAMP-responsive element modulator (CREM)α protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus. J. Biol. Chem. 286, 43437–43446 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Singer, N. G. et al. Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes. Immunology 88, 537–543 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lu, Q. et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum. 46, 1282–1291 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Lu, Q., Wu, A. & Richardson, B. C. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J. Immunol. 174, 6212–6219 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Lu, Q. et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J. Immunol. 179, 6352–6358 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Kaplan, M. J., Lu, Q., Wu, A., Attwood, J. & Richardson, B. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J. Immunol. 172, 3652–3661 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Basu, D. et al. Stimulatory and inhibitory killer Ig-like receptor molecules are expressed and functional on lupus T cells. J. Immunol. 183, 3481–3487 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, Y., Gorelik, G. J., Strickland, F. M. & Richardson, B. C. Decreased ERK and JNK signaling contribute to gene overexpression in “senescent” CD4+CD28 T cells through epigenetic mechanisms. J. Leukoc. Biol. 87, 137–145 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Liu, Y., Kuick, R., Hanash, S. & Richardson, B. DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin. Immunol. 130, 213–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Tang, Y. et al. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 60, 1065–1075 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Amarilyo, G. & La, C. A. miRNA in systemic lupus erythematosus. Clin. Immunol. 144, 26–31 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Fan, W. et al. Identification of microRNA-31 as a novel regulator contributing to impaired interleukin-2 production in T cells from patients with systemic lupus erythematosus. Arthritis Rheum. 64, 3715–3725 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Zhu, S. et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat. Med. 18, 1077–1086 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This publication and the work generated in the authors' laboratories were supported by grants from the US National Institutes of Health (J. C. Crispín and G. C. Tsokos) and from the Alliance for Lupus Research (J. C. Crispín).

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Crispín, J., Hedrich, C. & Tsokos, G. Gene-function studies in systemic lupus erythematosus. Nat Rev Rheumatol 9, 476–484 (2013). https://doi.org/10.1038/nrrheum.2013.78

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