The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus

  • Adam J. Fike
  • Irina Elcheva
  • Ziaur S. M. RahmanEmail author
Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus


Purpose of Review

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic associations. Here, we provide an update on recent advancements in validating SLE candidate genes and risk variants identified in genome-wide association studies (GWAS).

Recent Findings

A pairing of computational biology with new and emerging techniques has significantly increased our understanding of SLE associated variants. Specifically, generation of mutations within mice and examination of patient samples has been the dominant mechanisms for variant validation.


While progress has been made in validating some genes, the number of associated genes is growing with minimal exploration of the effects of individual variants on SLE. This indicates that further examination of SLE risk variants in a cell-type-specific manner is required for better understanding of their contributions to SLE disease mechanisms.


SLE GWAS iPSC Humanized mice 


Funding Information

Rahman laboratory research has been supported by the National Institutes of Health grants (RO1A1091670 and R21 AI128111), Department of Defense grants (PR130012 and LR170078), and Lupus Research Alliance Grant (LRA548931) to Z.S.M.R.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no financial conflicts of interest.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929–39.PubMedGoogle Scholar
  2. 2.
    Domeier PP, Schell SL, Rahman ZS. Spontaneous germinal centers and autoimmunity. Autoimmunity. 2017;50(1):4–18.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Goulielmos GN, Zervou MI, Vazgiourakis VM, Ghodke-Puranik Y, Garyfallos A, Niewold TB. The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry. Gene. 2018;668:59–72.PubMedGoogle Scholar
  4. 4.
    Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–30.PubMedGoogle Scholar
  5. 5.
    Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH, et al. Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med. 2015;175(9):1518–26.PubMedGoogle Scholar
  6. 6.
    Niewold TB. Advances in lupus genetics. Curr Opin Rheumatol. 2015;27(5):440–7.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Lawrence JS, Martins CL, Drake GL. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol. 1987;14(5):913–21.PubMedGoogle Scholar
  8. 8.
    Deng Y, Tsao BP. Advances in lupus genetics and epigenetics. Curr Opin Rheumatol. 2014;26(5):482–92.PubMedPubMedCentralGoogle Scholar
  9. 9.
    MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 2017;45(D1):D896–901.PubMedGoogle Scholar
  10. 10.
    Inshaw JRJ, Cutler AJ, Burren OS, Stefana MI, Todd JA. Approaches and advances in the genetic causes of autoimmune disease and their implications. Nature immunology. 2018.Google Scholar
  11. 11.
    • Rawlings DJ, Metzler G, Wray-Dutra M, Jackson SW. Altered B cell signalling in autoimmunity. Nat Rev Immunol. 2017;17(7):421–36. This review covers our current understanding of B cell involvement in the development of autoimmunity and presents a theory for driver and passenger variants. PubMedPubMedCentralGoogle Scholar
  12. 12.
    Corradin O, Cohen AJ, Luppino JM, Bayles IM, Schumacher FR, Scacheri PC. Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry. Nat Genet. 2016;48(11):1313–20.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jackson SW, Kolhatkar NS, Rawlings DJ. B cells take the front seat: dysregulated B cell signals orchestrate loss of tolerance and autoantibody production. Curr Opin Immunol. 2015;33:70–7.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Bronson PG, Chaivorapol C, Ortmann W, Behrens TW, Graham RR. The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol. 2012;24(5):530–7.PubMedGoogle Scholar
  15. 15.
    Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013;14(9):661–73.PubMedGoogle Scholar
  16. 16.
    Ramos PS, Criswell LA, Moser KL, Comeau ME, Williams AH, Pajewski NM, et al. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 2011;7(12):e1002406.PubMedPubMedCentralGoogle Scholar
  17. 17.
    •• Langefeld CD, Ainsworth HC, Cunninghame Graham DS, Kelly JA, Comeau ME, Marion MC, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021. This study compares a large data set of SLE patients across three different ancestries and identifies those loci which are shared vs ethnically localized. PubMedPubMedCentralGoogle Scholar
  18. 18.
    Slatkin M. Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. Nat Rev Genet. 2008;9(6):477–85.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2017;29(5):423–33.PubMedGoogle Scholar
  20. 20.
    Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101(1):5–22.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang YM, Zhou XJ, Nath SK, Sun C, Zhao MH, Zhang H. Evaluation of 10 SLE susceptibility loci in Asian populations, which were initially identified in European populations. Sci Rep. 2017;7:41399.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Odhams CA, Cortini A, Chen L, Roberts AL, Vinuela A, Buil A, et al. Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus. Hum Mol Genet. 2017;26(5):1003–17.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Odhams CA, Cunninghame Graham DS, Vyse TJ. Profiling RNA-Seq at multiple resolutions markedly increases the number of causal eQTLs in autoimmune disease. PLoS Genet. 2017;13(10):e1007071.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Martin P, McGovern A, Orozco G, Duffus K, Yarwood A, Schoenfelder S, et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat Commun. 2015;6:10069.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Pelikan RC, Kelly JA, Fu Y, Lareau CA, Tessneer KL, Wiley GB, et al. Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat Commun. 2018;9(1):2905.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Bentham J, Morris DL, Graham DSC, Pinder CL, Tombleson P, Behrens TW, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–64.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1228–33.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Alarcon-Riquelme ME, Ziegler JT, Molineros J, Howard TD, Moreno-Estrada A, Sanchez-Rodriguez E, et al. Genome-wide association study in an Amerindian ancestry population reveals novel systemic lupus erythematosus risk loci and the role of European admixture. Arthritis Rheumatol. 2016;68(4):932–43.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234–7.PubMedGoogle Scholar
  30. 30.
    Armstrong DL, Zidovetzki R, Alarcon-Riquelme ME, Tsao BP, Criswell LA, Kimberly RP, et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun. 2014;15(6):347–54.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang W, Tang H, Zhang Y, Tang X, Zhang J, Sun L, et al. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am J Hum Genet. 2013;92(1):41–51.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee YH, Bae SC, Choi SJ, Ji JD, Song GG. Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep. 2012;39(12):10627–35.PubMedGoogle Scholar
  33. 33.
    Kottyan LC, Zoller EE, Bene J, Lu X, Kelly JA, Rupert AM, et al. The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet. 2015;24(2):582–96.PubMedGoogle Scholar
  34. 34.
    Calise J, Marquez Renteria S, Gregersen PK, Diamond B. Lineage-specific functionality of an interferon regulatory factor 5 lupus risk haplotype: lack of B cell intrinsic effects. Front Immunol. 2018;9:996.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, et al. Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2010;62(2):562–73.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang J, Liu X, Meng Y, Wu H, Wu Y, Yang B, et al. Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients. Sci Rep. 2018;8(1):9442.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Gorman JA, Hundhausen C, Errett JS, Stone AE, Allenspach EJ, Ge Y, et al. The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol. 2017;18(7):744–52.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Morris DL, Sheng Y, Zhang Y, Wang YF, Zhu Z, Tombleson P, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016;48(8):940–6.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Xu L, Xia M, Guo J, Sun X, Li H, Xu C, et al. Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcgammaRIIB-T232. J Exp Med. 2016;213(12):2707–27.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, et al. Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat Med. 2005;11(10):1056–8.PubMedGoogle Scholar
  41. 41.
    Kono H, Kyogoku C, Suzuki T, Tsuchiya N, Honda H, Yamamoto K, et al. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet. 2005;14(19):2881–92.PubMedGoogle Scholar
  42. 42.
    Blank MC, Stefanescu RN, Masuda E, Marti F, King PD, Redecha PB, et al. Decreased transcription of the human FCGR2B gene mediated by the −343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet. 2005;117(2–3):220–7.PubMedGoogle Scholar
  43. 43.
    Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E, et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(2):211–6.PubMedGoogle Scholar
  44. 44.
    Jang SH, Chen H, Gregersen PK, Diamond B, Kim SJ. Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele. JCI Insight. 2017;2(1):e89569.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Martin JE, Assassi S, Diaz-Gallo LM, Broen JC, Simeon CP, Castellvi I, et al. A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet. 2013;22(19):4021–9.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Manjarrez-Orduno N, Marasco E, Chung SA, Katz MS, Kiridly JF, Simpfendorfer KR, et al. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat Genet. 2012;44(11):1227–30.PubMedPubMedCentralGoogle Scholar
  47. 47.
    International Consortium for Systemic Lupus Erythematosus G, Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40(2):204–10.Google Scholar
  48. 48.
    Chung SA, Brown EE, Williams AH, Ramos PS, Berthier CC, Bhangale T, et al. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol. 2014;25(12):2859–70.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Nath SK, Han S, Kim-Howard X, Kelly JA, Viswanathan P, Gilkeson GS, et al. A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet. 2008;40(2):152–4.PubMedGoogle Scholar
  50. 50.
    Rhodes B, Furnrohr BG, Roberts AL, Tzircotis G, Schett G, Spector TD, et al. The rs1143679 (R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes. Ann Rheum Dis. 2012;71(12):2028–34.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Maiti AK, Kim-Howard X, Motghare P, Pradhan V, Chua KH, Sun C, et al. Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM. Hum Mol Genet. 2014;23(15):4161–76.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Faridi MH, Khan SQ, Zhao W, Lee HW, Altintas MM, Zhang K, et al. CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest. 2017;127(4):1271–83.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Deng Y, Zhao J, Sakurai D, Sestak AL, Osadchiy V, Langefeld CD, et al. Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis. 2016;75(11):2007–13.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Jacob CO, Eisenstein M, Dinauer MC, Ming W, Liu Q, John S, et al. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc Natl Acad Sci U S A. 2012;109(2):E59–67.PubMedGoogle Scholar
  55. 55.
    Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010;6(2):e1000841.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Lessard CJ, Sajuthi S, Zhao J, Kim K, Ice JA, Li H, et al. Identification of a systemic lupus erythematosus risk locus spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol. 2016;68(5):1197–209.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Lu X, Zoller EE, Weirauch MT, Wu Z, Namjou B, Williams AH, et al. Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression. Am J Hum Genet. 2015;96(5):731–9.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Marquez A, Vidal-Bralo L, Rodriguez-Rodriguez L, Gonzalez-Gay MA, Balsa A, Gonzalez-Alvaro I, et al. A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 2017;76(1):286–94.PubMedGoogle Scholar
  59. 59.
    Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD, Maggadottir SM, et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med. 2015;21(9):1018–27.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Dai X, James RG, Habib T, Singh S, Jackson S, Khim S, et al. A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. J Clin Invest. 2013;123(5):2024–36.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest. 2011;121(9):3635–44.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, Concannon P, Buckner JH. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol. 2007;179(7):4704–10.PubMedGoogle Scholar
  63. 63.
    Godsell J, Rudloff I, Kandane-Rathnayake R, Hoi A, Nold MF, Morand EF, et al. Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus. Sci Rep. 2016;6:34604.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Sakurai D, Zhao J, Deng Y, Kelly JA, Brown EE, Harley JB, et al. Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression. PLoS Genet. 2013;9(10):e1003870.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(9):1059–61.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Wu J, Yang S, Yu D, Gao W, Liu X, Zhang K, et al. CRISPR/cas9 mediated knockout of an intergenic variant rs6927172 identified IL-20RA as a new risk gene for multiple autoimmune diseases. Genes Immun. 2018.Google Scholar
  67. 67.
    Wu H, Boackle SA, Hanvivadhanakul P, Ulgiati D, Grossman JM, Lee Y, et al. Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2007;104(10):3961–6.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2010;107(36):15838–43.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Deng Y, Zhao J, Sakurai D, Kaufman KM, Edberg JC, Kimberly RP, et al. MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet. 2013;9(2):e1003336.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Liu G, Tsuruta Y, Gao Z, Park YJ, Abraham E. Variant IL-1 receptor-associated kinase-1 mediates increased NF-kappa B activity. J Immunol. 2007;179(6):4125–34.PubMedGoogle Scholar
  71. 71.
    Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358(9):900–9.Google Scholar
  72. 72.
    Guthridge JM, Lu R, Sun H, Sun C, Wiley GB, Dominguez N, et al. Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet. 2014;94(4):586–98.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Adrianto I, Wang S, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. Arthritis Rheum. 2012;64(11):3695–705.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Chrabot BS, Kariuki SN, Zervou MI, Feng X, Arrington J, Jolly M, et al. Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis. Genes Immun. 2013;14(8):471–8.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Fu Q, Zhao J, Qian X, Wong JL, Kaufman KM, Yu CY, et al. Association of a functional IRF7 variant with systemic lupus erythematosus. Arthritis Rheum. 2011;63(3):749–54.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Chang Y, Sheng Y, Cheng Y, Lin Y, Zhu Z, Wen L, et al. Downregulated expression of LBH mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. J Dermatol. 2016;43(1):99–102.PubMedGoogle Scholar
  77. 77.
    Savitsky DA, Yanai H, Tamura T, Taniguchi T, Honda K. Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus. Proc Natl Acad Sci U S A. 2010;107(22):10154–9.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis. 2012;71(3):463–8.PubMedGoogle Scholar
  79. 79.
    Ban T, Sato GR, Tamura T. Regulation and role of the transcription factor IRF5 in innate immune responses and systemic lupus erythematosus. Int Immunol. 2018.Google Scholar
  80. 80.
    Lazzari E, Jefferies CA. IRF5-mediated signaling and implications for SLE. Clin Immunol. 2014;153(2):343–52.PubMedGoogle Scholar
  81. 81.
    Xu Y, Lee PY, Li Y, Liu C, Zhuang H, Han S, et al. Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. J Immunol. 2012;188(8):4113–21.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Ban T, Sato GR, Nishiyama A, Akiyama A, Takasuna M, Umehara M, et al. Lyn kinase suppresses the transcriptional activity of IRF5 in the TLR-MyD88 pathway to restrain the development of autoimmunity. Immunity. 2016;45(2):319–32.PubMedGoogle Scholar
  83. 83.
    Lien C, Fang CM, Huso D, Livak F, Lu R, Pitha PM. Critical role of IRF-5 in regulation of B-cell differentiation. Proc Natl Acad Sci U S A. 2010;107(10):4664–8.PubMedPubMedCentralGoogle Scholar
  84. 84.
    De S, Zhang B, Shih T, Singh S, Winkler A, Donnelly R, et al. B cell-intrinsic role for IRF5 in TLR9/BCR-induced human B cell activation, proliferation, and plasmablast differentiation. Front Immunol. 2017;8:1938.PubMedGoogle Scholar
  85. 85.
    Molineros JE, Maiti AK, Sun C, Looger LL, Han S, Kim-Howard X, et al. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet. 2013;9(2):e1003222.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Soni C, Domeier PP, Wong EB, Shwetank KTN, Elias MJ, et al. Distinct and synergistic roles of FcgammaRIIB deficiency and 129 strain-derived SLAM family proteins in the development of spontaneous germinal centers and autoimmunity. J Autoimmun. 2015;63:31–46.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Dam EM, Habib T, Chen J, Funk A, Glukhova V, Davis-Pickett M, et al. The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans. Clin Immunol. 2016;173:171–80.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Wu YY, Kumar R, Iida R, Bagavant H, Alarcon-Riquelme ME. BANK1 regulates IgG production in a lupus model by controlling TLR7-dependent STAT1 activation. PLoS One. 2016;11(5):e0156302.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Kim SJ, Zou YR, Goldstein J, Reizis B, Diamond B. Tolerogenic function of Blimp-1 in dendritic cells. J Exp Med. 2011;208(11):2193–9.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Kim SJ, Gregersen PK, Diamond B. Regulation of dendritic cell activation by microRNA let-7c and BLIMP1. J Clin Invest. 2013;123(2):823–33.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Cunninghame Graham DS, Graham RR, Manku H, Wong AK, Whittaker JC, Gaffney PM, et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat Genet. 2008;40(1):83–9.PubMedGoogle Scholar
  92. 92.
    Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, Seneschal J, et al. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity. 2015;42(6):1159–70.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Cortini A, Ellinghaus U, Malik TH, Cunninghame Graham DS, Botto M, Vyse TJ. B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis. Ann Rheum Dis. 2017;76(12):2095–103.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Isken O, Maquat LE. The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet. 2008;9(9):699–712.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Pan HF, Leng RX, Tao JH, Li XP, Ye DQ. Ets-1: a new player in the pathogenesis of systemic lupus erythematosus? Lupus. 2011;20(3):227–30.PubMedGoogle Scholar
  96. 96.
    Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol. 2005;17(9):1179–91.PubMedGoogle Scholar
  97. 97.
    Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004;75(3):504–7.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, Meng X, et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet. 2011;43(9):902–7.PubMedGoogle Scholar
  99. 99.
    Wang Y, Ewart D, Crabtree JN, Yamamoto A, Baechler EC, Fazeli P, et al. PTPN22 variant R620W is associated with reduced toll-like receptor 7-induced type I interferon in systemic lupus erythematosus. Arthritis Rheumatol. 2015;67(9):2403–14.PubMedGoogle Scholar
  100. 100.
    Arechiga AF, Habib T, He Y, Zhang X, Zhang ZY, Funk A, et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol. 2009;182(6):3343–7.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Peng H, Wang W, Zhou M, Li R, Pan HF, Ye DQ. Role of interleukin-10 and interleukin-10 receptor in systemic lupus erythematosus. Clin Rheumatol. 2013;32(9):1255–66.PubMedGoogle Scholar
  102. 102.
    Zhao H, Wang L, Luo H, Li QZ, Zuo X. TNFAIP3 downregulation mediated by histone modification contributes to T-cell dysfunction in systemic lupus erythematosus. Rheumatology. 2017;56(5):835–43.PubMedGoogle Scholar
  103. 103.
    Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunenwald S, et al. TLR7 escapes X chromosome inactivation in immune cells. Science immunology. 2018;3(19).Google Scholar
  104. 104.
    Soni C, Wong EB, Domeier PP, Khan TN, Satoh T, Akira S, et al. B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J Immunol. 2014;193(9):4400–14.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Giltiay NV, Chappell CP, Sun X, Kolhatkar N, Teal TH, Wiedeman AE, et al. Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med. 2013;210(12):2773–89.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Nickerson KM, Christensen SR, Shupe J, Kashgarian M, Kim D, Elkon K, et al. TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol. 2010;184(4):1840–8.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Herlands RA, Christensen SR, Sweet RA, Hershberg U, Shlomchik MJ. T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity. 2008;29(2):249–60.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Berland R, Fernandez L, Kari E, Han JH, Lomakin I, Akira S, et al. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity. 2006;25(3):429–40.PubMedGoogle Scholar
  109. 109.
    Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4):725–39 e6.PubMedGoogle Scholar
  110. 110.
    Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007;27(5):801–10.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Sakata K, Nakayamada S, Miyazaki Y, Kubo S, Ishii A, Nakano K, et al. Up-regulation of TLR7-mediated IFN-alpha production by plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Front Immunol. 2018;9:1957.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ, et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2009;106(15):6256–61.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Hultqvist M, Olofsson P, Holmberg J, Backstrom BT, Tordsson J, Holmdahl R. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci U S A. 2004;101(34):12646–51.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet. 2017;49(3):433–7.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Simpfendorfer KR, Olsson LM, Manjarrez Orduno N, Khalili H, Simeone AM, Katz MS, et al. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum Mol Genet. 2012;21(17):3918–25.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Samuelson EM, Laird RM, Papillion AM, Tatum AH, Princiotta MF, Hayes SM. Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice. PLoS One. 2014;9(3):e92054.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Richard ML, Gilkeson G. Mouse models of lupus: what they tell us and what they don't. Lupus Sci Med. 2018;5(1):e000199.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Li W, Titov AA, Morel L. An update on lupus animal models. Curr Opin Rheumatol. 2017;29(5):434–41.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Celhar T, Fairhurst AM. Modelling clinical systemic lupus erythematosus: similarities, differences and success stories. Rheumatology. 2017;56(suppl_1):i88–99.PubMedGoogle Scholar
  120. 120.
    Pelletier S, Gingras S, Green DR. Mouse genome engineering via CRISPR-Cas9 for study of immune function. Immunity. 2015;42(1):18–27.PubMedPubMedCentralGoogle Scholar
  121. 121.
    • Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281–308. The use of CRISPR/Cas9 will be vital in the interogation of individual variants, this methods paper discussess the techniques application. PubMedPubMedCentralGoogle Scholar
  122. 122.
    Zeng J, Tang SY, Toh LL, Wang S. Generation of "off-the-shelf" natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Stem Cell Reports. 2017;9(6):1796–812.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Kennedy M, Awong G, Sturgeon CM, Ditadi A, LaMotte-Mohs R, Zuniga-Pflucker JC, et al. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2012;2(6):1722–35.PubMedGoogle Scholar
  124. 124.
    French A, Yang CT, Taylor S, Watt SM, Carpenter L. Human induced pluripotent stem cell-derived B lymphocytes express sIgM and can be generated via a hemogenic endothelium intermediate. Stem Cells Dev. 2015;24(9):1082–95.PubMedGoogle Scholar
  125. 125.
    Sontag S, Förster M, Seré K, Zenke M. Differentiation of human induced pluripotent stem cells (iPS cells) and embryonic stem cells (ES cells) into dendritic cell (DC) subsets. Bio-Protocol. 2017;7(15):e2419.Google Scholar
  126. 126.
    Cox DBT, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, et al. RNA editing with CRISPR-Cas13. Science. 2017;358(6366):1019–27.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333(6039):218–21.PubMedGoogle Scholar
  128. 128.
    Gunawan M, Her Z, Liu M, Tan SY, Chan XY, Tan WWS, et al. A novel human systemic lupus erythematosus model in humanised mice. Sci Rep. 2017;7(1):16642.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Andrade D, Redecha PB, Vukelic M, Qing X, Perino G, Salmon JE, et al. Engraftment of peripheral blood mononuclear cells from systemic lupus erythematosus and antiphospholipid syndrome patient donors into BALB-RAG-2−/− IL-2Rgamma−/− mice: a promising model for studying human disease. Arthritis Rheum. 2011;63(9):2764–73.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Duchosal MA, McConahey PJ, Robinson CA, Dixon FJ. Transfer of human systemic lupus erythematosus in severe combined immunodeficient (SCID) mice. J Exp Med. 1990;172(3):985–8.PubMedGoogle Scholar
  131. 131.
    Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–19.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Wu H, Zhen Y, Ma Z, Li H, Yu J, Xu ZG, et al. Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci Transl Med. 2016;8(331):331ra40.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Wunderlich M, Chou FS, Link KA, Mizukawa B, Perry RL, Carroll M, et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010;24(10):1785–8.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, et al. Humanized mouse models of clinical disease. Annu Rev Pathol. 2017;12:187–215.PubMedGoogle Scholar
  135. 135.
    Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity. 2013;38(1):187–97.PubMedGoogle Scholar
  136. 136.
    Eisenberg R. Why can't we find a new treatment for SLE? J Autoimmun. 2009;32(3–4):223–30.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Ardhanareeswaran K, Mariani J, Coppola G, Abyzov A, Vaccarino FM. Human induced pluripotent stem cells for modelling neurodevelopmental disorders. Nat Rev Neurol. 2017;13(5):265–78.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Di Ruscio A, Patti F, Welner RS, Tenen DG, Amabile G. Multiple sclerosis: getting personal with induced pluripotent stem cells. Cell Death Dis. 2015;6:e1806.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Yamanaka S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell. 2012;10(6):678–84.PubMedGoogle Scholar
  140. 140.
    • Kilpinen H, Goncalves A, Leha A, Afzal V, Alasoo K, Ashford S, et al. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. 2017;546(7658):370–5. This highly comprehensive study identifies the primary sources of genetic and phenotypic variation in hIPSCs. PubMedPubMedCentralGoogle Scholar
  141. 141.
    Malik N, Rao MS. A review of the methods for human iPSC derivation. Methods Mol Biol. 2013;997:23–33.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Son MY, Lee MO, Jeon H, Seol B, Kim JH, Chang JS, et al. Generation and characterization of integration-free induced pluripotent stem cells from patients with autoimmune disease. Exp Mol Med. 2016;48:e232.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Kaneko S. In vitro generation of antigen-specific T cells from induced pluripotent stem cells of antigen-specific T cell origin. Methods Mol Biol. 2016;1393:67–73.PubMedGoogle Scholar
  144. 144.
    Kawamura F, Inaki M, Katafuchi A, Abe Y, Tsuyama N, Kurosu Y, et al. Establishment of induced pluripotent stem cells from normal B cells and inducing AID expression in their differentiation into hematopoietic progenitor cells. Sci Rep. 2017;7(1):1659.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Giacalone JC, Sharma TP, Burnight ER, Fingert JF, Mullins RF, Stone EM, et al. CRISPR-Cas9-based genome editing of human induced pluripotent stem cells. Curr Protoc Stem Cell Biol. 2018;44:5B 7 1–5B 7 22.Google Scholar
  146. 146.
    Morawski PA, Bolland S. Expanding the B cell-centric view of systemic lupus erythematosus. Trends Immunol. 2017;38(5):373–82.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Adam J. Fike
    • 1
  • Irina Elcheva
    • 2
  • Ziaur S. M. Rahman
    • 1
    Email author
  1. 1.Department of Microbiology and ImmunologyPennsylvania State University College of MedicineHersheyUSA
  2. 2.Hematology and OncologyPennsylvania State University College of MedicineHersheyUSA

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