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An Update on the Pathogenesis of Skin Damage in Lupus

  • Systemic Lupus Erythematosus (G Tsokos, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Lupus erythematosus (LE) is characterized by broad and varied clinical forms ranging from a localized skin lesion to a life-threatening form with severe systemic manifestations. The overlapping between cutaneous LE (CLE) and systemic LE (SLE) brings difficulties to physicians for early accurate diagnosis and sometimes may lead to delayed treatment for patients. We comprehensively review recent progress about the similarities and differences of the main three subsets of LE in pathogenesis and immunological mechanisms, with a particular focus on the skin damage.

Recent Findings

Recent studies on the mechanisms contributing to the skin damage in lupus have shown a close association of abnormal circulating inflammatory cells and abundant production of IgG autoantibodies with the skin damage of SLE, whereas few evidences if serum autoantibodies and circulating inflammatory cells are involved in the pathogenesis of CLE, especially for the discoid LE (DLE). Till now, the pathogenesis and molecular/cellular mechanism for the progress from CLE to SLE are far from clear. But more and more factors correlated with the differences among the subsets of LE and progression from CLE to SLE have been found, such as the mutation of IRF5, IFN regulatory factors and abnormalities of plasmacytoid dendritic cells (PDCs), Th1 cells, and B cells, which could be the potential biomarkers for the interventions in the development of LE.

Summary

A further understanding in pathogenesis and immunological mechanisms for skin damage in different subsets of LE makes us think more about the differences and cross-links in the pathogenic mechanism of CLE and SLE, which will shed a light in predictive biomarkers and therapies in LE.

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References

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

  1. Baltaci M, Fritsch P. Histologic features of cutaneous lupus erythematosus. Autoimmun Rev. 2009;8(6):467–73.

    Article  PubMed  Google Scholar 

  2. Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol. 1981;4(4):471–5.

    Article  CAS  PubMed  Google Scholar 

  3. Frances C, et al. Classification of dermatologic manifestations in lupus erythematosus. Ann Med Interne (Paris). 2003;154(1):33–44.

    Google Scholar 

  4. Kuhn A, Sticherling M, Bonsmann G. Clinical manifestations of cutaneous lupus erythematosus. J Dtsch Dermatol Ges. 2007;5(12):1124–37.

    Article  PubMed  Google Scholar 

  5. Werth VP. Cutaneous lupus: insights into pathogenesis and disease classification. Bull NYU Hosp Jt Dis. 2007;65(3):200–4.

    PubMed  Google Scholar 

  6. Wieczorek IT, et al. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 2014;150(3):291–6.

    Article  PubMed  Google Scholar 

  7. Ortona E, et al. Sex-based differences in autoimmune diseases. Ann Ist Super Sanita. 2016;52(2):205–12.

    CAS  PubMed  Google Scholar 

  8. Skonieczna K, Woźniacka A, Czajkowski R, Styczyński J, Krenska A, Robak E, et al. X-linked TLR7 gene polymorphisms are associated with diverse immunological conditions but not with discoid lupus erythematosus in Polish patients. Postepy Dermatol Alergol. 2018;35(1):26–32.

    Article  PubMed  PubMed Central  Google Scholar 

  9. • Skonieczna K, et al. Genetic similarities and differences between discoid and systemic lupus erythematosus patients within the Polish population. Postepy Dermatol Alergol. 2017;34(3):228–32. In this study, researchers have compared the frequencies of SNPs located inSTAT4,ITGAM, andTNXBgenes among DLE, SLE, and healthy controls, suggesting certain differences in the molecular background between DLE and SLE.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vera-Recabarren MA, García-Carrasco M, Ramos-Casals M, Herrero C. Cutaneous lupus erythematosus: clinical and immunological study of 308 patients stratified by gender. Clin Exp Dermatol. 2010;35(7):729–35.

    Article  CAS  PubMed  Google Scholar 

  11. Petersen MP, Möller S, Bygum A, Voss A, Bliddal M. Epidemiology of cutaneous lupus erythematosus and the associated risk of systemic lupus erythematosus: a nationwide cohort study in Denmark. Lupus. 2018;27(9):1424–30.

    Article  PubMed  Google Scholar 

  12. Tedeschi SK, Bermas B, Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol. 2013;149(2):211–8.

    Article  CAS  PubMed  Google Scholar 

  13. Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 2007;56(4):1251–62.

    Article  PubMed  Google Scholar 

  14. Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, et al. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum. 2002;47(2):202–9.

    Article  CAS  PubMed  Google Scholar 

  15. Colasanti T, et al. Autoantibodies to estrogen receptor alpha interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus. Arthritis Rheum. 2012;64(3):778–87.

    Article  CAS  PubMed  Google Scholar 

  16. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–38.

    Article  CAS  PubMed  Google Scholar 

  17. Trancart M, Cavailhes A, Balme B, Skowron F. Anastrozole-induced subacute cutaneous lupus erythematosus. Br J Dermatol. 2008;158(3):628–9.

    Article  CAS  PubMed  Google Scholar 

  18. Yell JA, Burge SM. The effect of hormonal changes on cutaneous disease in lupus erythematosus. Br J Dermatol. 1993;129(1):18–22.

    Article  CAS  PubMed  Google Scholar 

  19. Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, 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. 2008;58(8):2511–7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cooney CM, Bruner GR, Aberle T, Namjou-Khales B, Myers LK, Feo L, et al. 46,X,del(X)(q13) Turner’s syndrome women with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun. 2009;10(5):478–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee YH, Choi SJ, Ji JD, Song GG. Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. Lupus. 2016;25(6):593–601.

    Article  CAS  PubMed  Google Scholar 

  22. Laffont S, et al. X-chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-alpha production of plasmacytoid dendritic cells from women. J Immunol. 2014;193(11):5444–52.

    Article  CAS  PubMed  Google Scholar 

  23. Zeng J, et al. Novel biomarkers for systemic lupus erythematosus. Biomark Med. 2017;11(8):677–86.

    Article  CAS  PubMed  Google Scholar 

  24. Millard LG, Rowell NR. Chilblain lupus erythematosus (Hutchinson). A clinical and laboratory study of 17 patients. Br J Dermatol. 1978;98(5):497–506.

    Article  CAS  PubMed  Google Scholar 

  25. Millard LG, Rowell NR, Rajah SM. Histocompatibility antigens in discoid and systemic lupus erythematosus. Br J Dermatol. 1977;96(2):139–44.

    Article  CAS  PubMed  Google Scholar 

  26. Morris DL, et al. MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun. 2014;15(4):210–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Osmola A, Namysł J, Jagodziński PP, Prokop J. Genetic background of cutaneous forms of lupus erythematosus: update on current evidence. J Appl Genet. 2004;45(1):77–86.

    PubMed  Google Scholar 

  28. Jarvinen TM, et al. Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Exp Dermatol. 2010;19(2):123–31.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Achtman JC, Werth VP. Pathophysiology of cutaneous lupus erythematosus. Arthritis Res Ther. 2015;17:182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Werth VP, et al. Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol. 2000;115(4):726–30.

    Article  CAS  PubMed  Google Scholar 

  32. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev. 2005;4(5):253–63.

    Article  CAS  PubMed  Google Scholar 

  33. Jeffries MA, Sawalha AH. Epigenetics in systemic lupus erythematosus: leading the way for specific therapeutic agents. Int J Clin Rheumatol. 2011;6(4):423–39.

    Article  CAS  Google Scholar 

  34. Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune W, Somers E, et al. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41:60–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao M, et al. DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun. 2014;54:127–36.

    Article  CAS  PubMed  Google Scholar 

  36. Coit P, Jeffries M, Altorok N, Dozmorov MG, Koelsch KA, Wren JD, et al. Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients. J Autoimmun. 2013;43:78–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao M, et al. Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus. J Autoimmun. 2016;69:64–73.

    Article  PubMed  CAS  Google Scholar 

  38. Zhao M, et al. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis. 2016;75(11):1998–2006.

    Article  CAS  PubMed  Google Scholar 

  39. Renauer P, Coit P, Jeffries MA, Merrill JT, McCune W, Maksimowicz-McKinnon K, et al. DNA methylation patterns in naive CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus. Lupus Sci Med. 2015;2(1):e000101.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhou Y, Qiu X, Luo Y, Yuan J, Li Y, Zhong Q, et al. Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells. Lupus. 2011;20(13):1365–71.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang Z, Song L, Maurer K, Petri MA, Sullivan KE. Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes. Genes Immun. 2010;11(2):124–33.

    Article  CAS  PubMed  Google Scholar 

  42. Zhao M, Tan Y, Peng Q, Huang C, Guo Y, Liang G, et al. IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation. Nat Commun. 2018;9(1):583.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 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 (Oxford). 2017;56(5):835–43.

    Article  CAS  Google Scholar 

  44. Ghorai A, Ghosh U. miRNA gene counts in chromosomes vary widely in a species and biogenesis of miRNA largely depends on transcription or post-transcriptional processing of coding genes. Front Genet. 2014;5:100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Khan D, Dai R, Ansar Ahmed S. Sex differences and estrogen regulation of miRNAs in lupus, a prototypical autoimmune disease. Cell Immunol. 2015;294(2):70–9.

    Article  CAS  PubMed  Google Scholar 

  46. •• Sole C, et al. MicroRNA expression profiling identifies miR-31 and miR-485-3p as regulators in the pathogenesis of discoid cutaneous lupus. J Invest Dermatol. 2019;139(1):51–61. This report has shown a specific microRNA expression profile in DLE-affected skin as compared with SCLE.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang H, Liao X, Sparks JB, Luo XM. Dynamics of gut microbiota in autoimmune lupus. Appl Environ Microbiol. 2014;80(24):7551–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Huang C, et al. Disordered cutaneous microbiota in systemic lupus erythematosus. J Autoimmun. 2019:102391.

    Article  PubMed  Google Scholar 

  49. Reichrath J, et al. Biologic effects of light: an enlighting prospective. Anticancer Res. 2016;36(3):1339–43.

    PubMed  Google Scholar 

  50. McGrath H Jr. Ultraviolet-A1 irradiation therapy for systemic lupus erythematosus. Lupus. 2017;26(12):1239–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed M, Ruzicka T, et al. Phototesting in lupus erythematosus: a 15-year experience. J Am Acad Dermatol. 2001;45(1):86–95.

    Article  CAS  PubMed  Google Scholar 

  52. Kuhn A, Wozniacka A, Szepietowski JC, Gläser R, Lehmann P, Haust M, et al. Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a standardized protocol. J Invest Dermatol. 2011;131(8):1622–30.

    Article  CAS  PubMed  Google Scholar 

  53. Tsukazaki N, et al. Photoprovocation test and immunohistochemical analysis of inducible nitric oxide synthase expression in patients with Sjogren’s syndrome associated with photosensitivity. Br J Dermatol. 2002;147(6):1102–8.

    Article  CAS  PubMed  Google Scholar 

  54. Kuhn A, Ruland V, Bonsmann G. Photosensitivity, phototesting, and photoprotection in cutaneous lupus erythematosus. Lupus. 2010;19(9):1036–46.

    Article  CAS  PubMed  Google Scholar 

  55. Kim A, Chong BF. Photosensitivity in cutaneous lupus erythematosus. Photodermatol Photoimmunol Photomed. 2013;29(1):4–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kuhn A, Fehsel K, Lehmann P, Krutmann J, Ruzicka T, Kolb-Bachofen V. Aberrant timing in epidermal expression of inducible nitric oxide synthase after UV irradiation in cutaneous lupus erythematosus. J Invest Dermatol. 1998;111(1):149–53.

    Article  CAS  PubMed  Google Scholar 

  57. Wang PW, et al. Comparison of the biological impact of UVA and UVB upon the skin with functional proteomics and immunohistochemistry. Antioxidants (Basel). 2019:8(12).

    Article  CAS  PubMed Central  Google Scholar 

  58. Norris DA, Whang K, David-Bajar K, Bennion SD. The influence of ultraviolet light on immunological cytotoxicity in the skin. Photochem Photobiol. 1997;65(4):636–46.

    Article  CAS  PubMed  Google Scholar 

  59. Baima B, Sticherling M. Apoptosis in different cutaneous manifestations of lupus erythematosus. Br J Dermatol. 2001;144(5):958–66.

    Article  CAS  PubMed  Google Scholar 

  60. Hill LL, Ouhtit A, Loughlin SM, Kripke ML, Ananthaswamy HN, Owen-Schaub LB. Fas ligand: a sensor for DNA damage critical in skin cancer etiology. Science. 1999;285(5429):898–900.

    Article  CAS  PubMed  Google Scholar 

  61. Baker MB, Altman NH, Podack ER, Levy RB. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med. 1996;183(6):2645–56.

    Article  CAS  PubMed  Google Scholar 

  62. Yagita H, et al. CD95 ligand in graft rejection. Nature. 1996;379(6567):682.

    Article  CAS  PubMed  Google Scholar 

  63. Blokland SLM, et al. Increased expression of Fas on group 2 and 3 innate lymphoid cells is associated with an interferon signature in systemic lupus erythematosus and Sjogren’s syndrome. Rheumatology (Oxford). 2019;58(10):1740–5.

    Article  Google Scholar 

  64. Kuhn A, Herrmann M, Kleber S, Beckmann-Welle M, Fehsel K, Martin-Villalba A, et al. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum. 2006;54(3):939–50.

    Article  PubMed  Google Scholar 

  65. Suzuki N, Sakane T. Abnormal Fas and Fas ligand expression of lymphocytes in patients with SLE. Nihon Rinsho. 1996;54(7):1955–9.

    CAS  PubMed  Google Scholar 

  66. Liphaus BL, Kiss MHB, Carrasco S, Palmeira P, Goldenstein-Schainberg C, Carneiro-Sampaio M. Increased serum sFas, sTRAIL, and reduced sFasL in juvenile-onset systemic lupus erythematosus. Clin Rheumatol. 2017;36(12):2847–52.

    Article  PubMed  Google Scholar 

  67. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179(4):1317–30.

    Article  CAS  PubMed  Google Scholar 

  68. Oke V, Vassilaki I, Espinosa A, Strandberg L, Kuchroo VK, Nyberg F, et al. High Ro52 expression in spontaneous and UV-induced cutaneous inflammation. J Invest Dermatol. 2009;129(8):2000–10.

    Article  CAS  PubMed  Google Scholar 

  69. Zahn S, Rehkämper C, Ferring-Schmitt S, Bieber T, Tüting T, Wenzel J. Interferon-alpha stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus. Br J Dermatol. 2011;165(5):1118–23.

    Article  CAS  PubMed  Google Scholar 

  70. Yin Q, et al. Ultraviolet B irradiation induces skin accumulation of plasmacytoid dendritic cells: a possible role for chemerin. Autoimmunity. 2014;47(3):185–92.

    Article  CAS  PubMed  Google Scholar 

  71. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46(1):191–201.

    Article  PubMed  Google Scholar 

  72. Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994;152(7):3685–92.

    CAS  PubMed  Google Scholar 

  73. Safi R, al-Hage J, Abbas O, Kibbi AG, Nassar D. Investigating the presence of neutrophil extracellular traps in cutaneous lesions of different subtypes of lupus erythematosus. Exp Dermatol. 2019;28(11):1348–52.

    Article  CAS  PubMed  Google Scholar 

  74. Guiducci C, Tripodo C, Gong M, Sangaletti S, Colombo MP, Coffman RL, et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med. 2010;207(13):2931–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Villanueva E, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187(1):538–52.

    Article  CAS  PubMed  Google Scholar 

  76. Wang H, et al. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 2015;67(12):3190–200.

    Article  CAS  PubMed  Google Scholar 

  77. Vermi W, Lonardi S, Morassi M, Rossini C, Tardanico R, Venturini M, et al. Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage. Immunobiology. 2009;214(9–10):877–86.

    Article  CAS  PubMed  Google Scholar 

  78. Blomberg S, et al. Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. Lupus. 2001;10(7):484–90.

    Article  CAS  PubMed  Google Scholar 

  79. Fiore N, Castellano G, Blasi A, Capobianco C, Loverre A, Montinaro V, et al. Immature myeloid and plasmacytoid dendritic cells infiltrate renal tubulointerstitium in patients with lupus nephritis. Mol Immunol. 2008;45(1):259–65.

    Article  CAS  PubMed  Google Scholar 

  80. Wenzel J, et al. Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus. J Pathol. 2005;205(4):435–42.

    Article  CAS  PubMed  Google Scholar 

  81. Mendez-Flores S, et al. Cytokines and effector/regulatory cells characterization in the physiopathology of cutaneous lupus erythematous: a cross-sectional study. Mediat Inflamm. 2016;2016:7074829.

    Article  CAS  Google Scholar 

  82. Mendez-Flores S, et al. Inflammatory chemokine profiles and their correlations with effector CD4 T cell and regulatory cell subpopulations in cutaneous lupus erythematosus. Cytokine. 2019;119:95–112.

    Article  CAS  PubMed  Google Scholar 

  83. Farkas L, Beiske K, Lund-Johansen F. Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol. 2001;159:237–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK. High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 2007;8(6):492–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Reefman E, Kuiper H, Limburg PC, Kallenberg CG, Bijl M. Type I interferons are involved in the development of ultraviolet B-induced inflammatory skin lesions in systemic lupus erythaematosus patients. Ann Rheum Dis. 2008;67(1):11–8.

    Article  CAS  PubMed  Google Scholar 

  86. Muhammad Yusoff F, Wong KK, Mohd Redzwan N. Th1, Th2, and Th17 cytokines in systemic lupus erythematosus. Autoimmunity. 2019:1–13.

  87. Magro CM, et al. The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis. J Cutan Pathol. 2010;37(6):659–71.

    Article  PubMed  Google Scholar 

  88. Yang J, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60(5):1472–83.

    Article  PubMed  Google Scholar 

  89. Tanasescu C, Balanescu E, Balanescu P, Olteanu R, Badea C, Grancea C, et al. IL-17 in cutaneous lupus erythematosus. Eur J Intern Med. 2010;21(3):202–7.

    Article  CAS  PubMed  Google Scholar 

  90. Jabbari A, et al. Dominant Th1 and minimal Th17 skewing in discoid lupus revealed by transcriptomic comparison with psoriasis. J Invest Dermatol. 2014;134(1):87–95.

    Article  CAS  PubMed  Google Scholar 

  91. Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J, et al. Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum. 2007;56(6):1910–20.

    Article  CAS  PubMed  Google Scholar 

  92. Gilliam JN, Hurd ER. Comparison of circulating T and B lymphocytes in discoid versus systemic lupus erythematosus. Clin Immunol Immunopathol. 1976;6(2):149–55.

    Article  CAS  PubMed  Google Scholar 

  93. Vital EM, Wittmann M, Edward S, Yusof MYM, MacIver H, Pease CT, et al. Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. Arthritis Rheumatol. 2015;67(6):1586–91.

    Article  CAS  PubMed  Google Scholar 

  94. Wouters CH, Diegenant C, Ceuppens JL, Degreef H, Stevens EA. The circulating lymphocyte profiles in patients with discoid lupus erythematosus and systemic lupus erythematosus suggest a pathogenetic relationship. Br J Dermatol. 2004;150(4):693–700.

    Article  CAS  PubMed  Google Scholar 

  95. Grassi M, Capello F, Bertolino L, Seia Z, Pippione M. Identification of granzyme B-expressing CD-8-positive T cells in lymphocytic inflammatory infiltrate in cutaneous lupus erythematosus and in dermatomyositis. Clin Exp Dermatol. 2009;34(8):910–4.

    Article  CAS  PubMed  Google Scholar 

  96. Robak E. Lymphocyctes Tgammadelta in clinically normal skin and peripheral blood of patients with systemic lupus erythematosus and their correlation with disease activity. Mediat Inflamm. 2001;10(4):179–89.

    Article  CAS  Google Scholar 

  97. Merola JF, Prystowsky SD, Iversen C, Gomez-Puerta JA, Norton T, Tsao P, et al. Association of discoid lupus erythematosus with other clinical manifestations among patients with systemic lupus erythematosus. J Am Acad Dermatol. 2013;69(1):19–24.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Chong BF, Tseng LC, Lee T, Vasquez R, Li QZ, Zhang S, et al. IgG and IgM autoantibody differences in discoid and systemic lupus patients. J Invest Dermatol. 2012;132(12):2770–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Luo YJ, Tan GZ, Yu M, Li KW, Liu YY, Guo Q, et al. Correlation of cutaneous immunoreactants in lesional skin with the serological disorders and disease activity of systemic lupus erythematosus. PLoS One. 2013;8(8):e70983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Deocharan B, Qing X, Beger E, Putterman C. Antigenic triggers and molecular targets for anti-double-stranded DNA antibodies. Lupus. 2002;11(12):865–71.

    Article  CAS  PubMed  Google Scholar 

  101. Zieve GW, Khusial PR. The anti-Sm immune response in autoimmunity and cell biology. Autoimmun Rev. 2003;2(5):235–40.

    Article  CAS  PubMed  Google Scholar 

  102. Riemekasten G, Hahn BH. Key autoantigens in SLE. Rheumatology (Oxford). 2005;44(8):975–82.

    Article  CAS  Google Scholar 

  103. Koutouzov S, et al. Nucleosomes in the pathogenesis of systemic lupus erythematosus. Rheum Dis Clin N Am. 2004;30(3):529–58 ix.

    Article  Google Scholar 

  104. Burlingame RW, Boey ML, Starkebaum G, Rubin RL. The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest. 1994;94(1):184–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jovelin F, Mostoslavsky G, Amoura Z, Chabre H, Gilbert D, Eilat D, et al. Early anti-nucleosome autoantibodies from a single MRL+/+ mouse: fine specificity, V gene structure and pathogenicity. Eur J Immunol. 1998;28(11):3411–22.

    Article  CAS  PubMed  Google Scholar 

  106. Arbuckle MR, McClain M, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–33.

    Article  CAS  PubMed  Google Scholar 

  107. Merola JF, et al. Is chronic cutaneous discoid lupus protective against severe renal disease in patients with systemic lupus erythematosus? J Drugs Dermatol. 2011;10(12):1413–20.

    CAS  PubMed  Google Scholar 

  108. Li QZ, Zhou J, Wandstrat AE, Carr-Johnson F, Branch V, Karp DR, et al. Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin Exp Immunol. 2007;147(1):60–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Li QZ, et al. Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J Clin Invest. 2005;115(12):3428–39.

    Article  PubMed  CAS  Google Scholar 

  110. Liu L, et al. The features of skin inflammation induced by lupus serum. Clin Immunol. 2016;165:4–11.

    Article  CAS  PubMed  Google Scholar 

  111. Li J, et al. Chinese SLE treatment and research group registry: III. association of autoantibodies with clinical manifestations in Chinese patients with systemic lupus erythematosus. J Immunol Res. 2014;2014:809389.

    PubMed  PubMed Central  Google Scholar 

  112. Deng GM, et al. Lupus serum IgG induces skin inflammation through the TNFR1 signaling pathway. J Immunol. 2010;184(12):7154–61.

    Article  CAS  PubMed  Google Scholar 

  113. Zhang J, Jiang J, Guo L. Different prognoses of two types of subacute cutaneous lupus erythematosus: a follow-up of 40 cases. Chin J Dermatol. 2001.

  114. Haber JS, Merola JF, Werth VP. Classifying discoid lupus erythematosus: background, gaps, and difficulties. Int J Womens Dermatol. 2017;3(1 Suppl):S62–6.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Dey-Rao R, Smith JR, Chow S, Sinha AA. Differential gene expression analysis in CCLE lesions provides new insights regarding the genetics basis of skin vs. systemic disease. Genomics. 2014;104(2):144–55.

    Article  CAS  PubMed  Google Scholar 

  116. Ehrenstein MR, McSweeney E, Swane M, Worman CP, Goldstone AH, Isenberg DA. Appearance of anti-DNA antibodies in patients treated with interferon-alpha. Arthritis Rheum. 1993;36(2):279–80.

    Article  CAS  PubMed  Google Scholar 

  117. Ronnblom LE, Alm GV, Oberg KE. Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med. 1990;227(3):207–10.

    Article  CAS  PubMed  Google Scholar 

  118. Meller S. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment. Arthritis & Rheumatism. 2005;52:1504–16.

    Article  CAS  Google Scholar 

  119. Meller S, Winterberg F, Gilliet M, Müller A, Lauceviciute I, Rieker J, et al. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum. 2005;52(5):1504–16.

    Article  CAS  PubMed  Google Scholar 

  120. Sommereyns C, Paul S, Staeheli P, Michiels T. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4(3):e1000017.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Sheshachalam A, et al. Granule protein processing and regulated secretion in neutrophils. Front Immunol. 2014;5:448.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012;30:459–89.

    Article  CAS  PubMed  Google Scholar 

  123. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75.

    Article  CAS  PubMed  Google Scholar 

  124. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.

    Article  CAS  PubMed  Google Scholar 

  125. Denny MF, et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. 2010;184(6):3284–97.

    Article  CAS  PubMed  Google Scholar 

  126. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564–9.

    Article  CAS  PubMed  Google Scholar 

  127. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206(9):1983–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mauri C, Menon M. The many faces of type I interferon in systemic lupus erythematosus. J Clin Invest. 2015;125(7):2562–4.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, et al. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001;108(9):1331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Heine G, et al. A shift in the Th(1)/Th(2) ratio accompanies the clinical remission of systemic lupus erythematosus in patients with end-stage renal disease. Nephrol Dial Transplant. 2002;17(10):1790–4.

    Article  CAS  PubMed  Google Scholar 

  131. Mok MY, Wu HJ, Lo Y, Lau CS. The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus. J Rheumatol. 2010;37(10):2046–52.

    Article  PubMed  Google Scholar 

  132. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127(3):385–93.

    Article  CAS  PubMed  Google Scholar 

  133. Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, et al. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 2010;12(2):R53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Alunno A, et al. Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new. Clin Dev Immunol. 2012;2012:823085.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Biswas PS, Aggarwal R, Levesque MC, Maers K, Ramani K. Type I interferon and T helper 17 cells co-exist and co-regulate disease pathogenesis in lupus patients. Int J Rheum Dis. 2015;18(6):646–53.

    Article  CAS  PubMed  Google Scholar 

  136. Ali N, Rosenblum MD. Regulatory T cells in skin. Immunology. 2017;152(3):372–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wenzel J, Uerlich M, Wörrenkämper E, Freutel S, Bieber T, Tüting T. Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA. Br J Dermatol. 2005;153(5):1011–5.

    Article  CAS  PubMed  Google Scholar 

  138. Kind P, Lipsky PE, Sontheimer RD. Circulating T- and B-cell abnormalities in cutaneous lupus erythematosus. J Invest Dermatol. 1986;86(3):235–9.

    Article  CAS  PubMed  Google Scholar 

  139. Mori M, Pimpinelli N, Romagnoli P, Bernacchi E, Fabbri P, Giannotti B. Dendritic cells in cutaneous lupus erythematosus: a clue to the pathogenesis of lesions. Histopathology. 1994;24(4):311–21.

    Article  PubMed  Google Scholar 

  140. Ortaldo JR, Mason AT, O'Shea JJ. Receptor-induced death in human natural killer cells: involvement of CD16. J Exp Med. 1995;181(1):339–44.

    Article  CAS  PubMed  Google Scholar 

  141. Yin S, et al. Hyperactivation and in situ recruitment of inflammatory Vδ2 T cells contributes to disease pathogenesis in systemic lupus erythematosus. Sci Rep. 2015;5(1).

  142. Paul S, Singh AK, Shilpi, Lal G. Phenotypic and functional plasticity of gamma-delta (gammadelta) T cells in inflammation and tolerance. Int Rev Immunol. 2014;33(6):537–58.

    Article  CAS  PubMed  Google Scholar 

  143. Li X, et al. Generation of human regulatory gammadelta T cells by TCRgammadelta stimulation in the presence of TGF-beta and their involvement in the pathogenesis of systemic lupus erythematosus. J Immunol. 2011;186(12):6693–700.

    Article  CAS  PubMed  Google Scholar 

  144. Lu Z, et al. Elevated apoptosis and impaired proliferation contribute to downregulated peripheralγδT cells in patients with systemic lupus erythematosus. Clin Dev Immunol. 2013;2013:1–9.

    Google Scholar 

  145. Volc-Platzer B, Anegg B, Milota S, Pickl W, Fischer G. Accumulation of gamma delta T cells in chronic cutaneous lupus erythematosus. J Invest Dermatol. 1993;100(1):84S–91S.

    Article  CAS  PubMed  Google Scholar 

  146. •• Quelhas da Costa R, et al. Assessment of response to B-Cell depletion using rituximab in cutaneous lupus erythematosus. JAMA Dermatol. 2018;154(12):1432–40. This is one of the largest long-term follow-up (>6 months) studies comparing and assessing the response of SLE patients with or without CLE lesions to rituximab treatment. There is a significant absence of response to rituximab treatment in the SLE patients with DLE lesions, indicating potentially different pathogenesis in DLE subtype.

    Article  PubMed  PubMed Central  Google Scholar 

  147. O'Brien JC, Hosler GA, Chong BF. Changes in T cell and B cell composition in discoid lupus erythematosus skin at different stages. J Dermatol Sci. 2017;85(3):247–9.

    Article  CAS  PubMed  Google Scholar 

  148. Chong BF, et al. Differential expression of BAFF and its receptors in discoid lupus erythematosus patients. J Dermatol Sci. 2014;73(3):216–24.

    Article  CAS  PubMed  Google Scholar 

  149. Reich A, Marcinow K, Bialynicki-Birula R. The lupus band test in systemic lupus erythematosus patients. Ther Clin Risk Manag. 2011;7:27–32.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Zecevic RD, Pavlovic MD, Stefanovic D. Lupus band test and disease activity in systemic lupus erythematosus: does it still matter? Clin Exp Dermatol. 2006;31(3):358–60.

    Article  CAS  PubMed  Google Scholar 

  151. Beutner EH, Blaszczyk M, Jablonska S, Chorzelski TP, Kumar V, Wolska H. Studies on criteria of the European Academy of Dermatology and Venerology for the classification of cutaneous lupus erythematosus. I. Selection of clinical groups and study factors. Int J Dermatol. 1991;30(6):411–7.

    Article  CAS  PubMed  Google Scholar 

  152. Fabre VC, et al. Twenty percent of biopsy specimens from sun-exposed skin of normal young adults demonstrate positive immunofluorescence. Arch Dermatol. 1991;127(7):1006–11.

    Article  CAS  PubMed  Google Scholar 

  153. Kulthanan K, et al. Chronic discoid lupus erythematosus in Thailand: direct immunofluorescence study. Int J Dermatol. 1996;35(10):711–4.

    Article  CAS  PubMed  Google Scholar 

  154. Jordon RE. Cutaneous immunofluorescence. Clin Rheum Dis. 1982;8(2):479–91.

    CAS  PubMed  Google Scholar 

  155. Yu M, Li KW, Tan GZ, Luo T, Xu DQ, Wang L. The gender disparity of immunoreactants in lesional skin of lupus erythematosus patients. Clin Exp Rheumatol. 2012;30(1):103–5.

    CAS  PubMed  Google Scholar 

  156. Gronhagen CM, et al. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden. Br J Dermatol. 2011;164(6):1335–41.

    Article  CAS  PubMed  Google Scholar 

  157. Ohata C, et al. Comparative study of direct immunofluorescence in discoid lupus erythematosus and bullous pemphigoid. Am J Dermatopathol. 2016;38(2):121–3.

    Article  PubMed  Google Scholar 

  158. Baek YS, et al. Cutaneous lupus erythematosus and its association with systemic lupus erythematosus: a nationwide population-based cohort study in Korea. J Dermatol. 2019.

  159. Arkin LM, Ansell L, Rademaker A, Curran ML, Miller ML, Wagner A, et al. The natural history of pediatric-onset discoid lupus erythematosus. J Am Acad Dermatol. 2015;72(4):628–33.

    Article  PubMed  Google Scholar 

  160. Das NK, Dutta RN, Sengupta SR. Skin lesions in lupus erythematosus: a marker of systemic involvement. Indian J Dermatol. 2011;56(5):537–40.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Chong BF, Song J, Olsen NJ. Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus. Br J Dermatol. 2012;166(1):29–35.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (no. 81972943, no.81830097) and Hunan Talent Young Investigator (no. 2019RS2012).

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Qianwen Li and Haijing Wu wrote the manuscript. Suqing Zhou and Ming Zhao edited the manuscript. Qianjin Lu revised the manuscript.

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Correspondence to Qianjin Lu.

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Qianwen Li and Haijing Wu contribute equally to this article and should be considered co-first authors.

This article is part of the Topical Collection on Systemic Lupus Erythematosus

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Li, Q., Wu, H., Zhou, S. et al. An Update on the Pathogenesis of Skin Damage in Lupus. Curr Rheumatol Rep 22, 16 (2020). https://doi.org/10.1007/s11926-020-00893-9

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