Pathogenesis of Skin Injury of Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus


Purpose of Review

The second most common clinical expression in lupus patients is skin damage that the pathogenesis remains unclear. We discuss the role of pathological factors in the development of skin damage in SLE.

Recent Findings

Skin deposited IgG is a crucial pathologic factor in the development of skin damage in SLE. Macrophages and signaling of TNFα/TNFR1 and IFN/IFNR play an important role in the skin injury of SLE. The intracellular molecules including Syk and calcium/calmodulin 4 and NFAT are involved in the manifestation of skin damage in lupus-prone mice. UV is the most typical environmental factor to trigger skin injury in areas of IgG deposition in SLE.


These evidences indicate that skin deposited IgG is a crucial pathological factor to trigger skin lesions in SLE and blockade of IgG signaling may be effective target against skin injury of SLE.


Systemic lupus erythematosus Skin injury IgG Immune cells Syk Ultraviolet light 


Compliance with Ethical Standards

Conflict of Interest

The author declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

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.
    Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2001;365:2110–21.CrossRefGoogle Scholar
  2. 2.
    Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929–39. Scholar
  3. 3.
    Cervera R, et al. The European working party on systemic lupus erythematosus. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine. 1993;72(2):113–24. Scholar
  4. 4.
    •• Deng GM, Tsokos GC. Pathogenesis and targeted treatment of skin injury in SLE. Nat Rev Rheumatol. 2015;11(11):663–9. This study provides a good discussion of pathological factors involved in pathogenesis of skin injury in SLE. CrossRefPubMedGoogle Scholar
  5. 5.
    Kuhn A, Landmann A. The classification and diagnosis of cutaneous lupus erythematosus. J Autoimmun. 2014;48-49:14–9. Scholar
  6. 6.
    Privette ED, Werth VP. Update on pathogenesis and treatment of CLE. Curr Opin Rheumatol. 2013;25(5):584–90. Scholar
  7. 7.
    Okon LG, Werth VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol. 2013;27(3):391–404. Scholar
  8. 8.
    Oke V, Wahren-Herlenius M. Cutaneous lupus erythematosus: clinical aspects and molecular pathogenesis. J Intern Med. 2013;273(6):544–54. Scholar
  9. 9.
    Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol. 1981;4(4):471–5. Scholar
  10. 10.
    Vera-Recabarren MA, García-Carrasco M, Ramos-Casals M, Herrero C. Comparative analysis of subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients. Br J Dermatol. 2010;162(1):91–101. Scholar
  11. 11.
    Kuhn A, Bein D, Bonsmann G. The 100th anniversary of lupus erythematosus tumidus. Autoimmun Rev. 2009;8(6):441–8. Scholar
  12. 12.
    Provost TT. Lupus band test. Int J Dermatol. 1981;20(7):475–81. Scholar
  13. 13.
    Dahl MV. Usefulness of direct immunofluorescence in patients with lupus erythematosus. Arch Dermatol. 1983;119(12):1010–7. Scholar
  14. 14.
    Furukawa F, Tanaka H, Sekita K, Nakamura T, Horiguchi Y, Hamashima Y. Dermatopathological studies on skin lesions of MRL mice. Arch Dermatol Res. 1984;276(3):186–94. Scholar
  15. 15.
    Deng GM, Tsokos GC. Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation. J Immunol. 2008;181(6):4019–26. Scholar
  16. 16.
    Kanauchi H, Furukawa F, Imamura S. Characterization of cutaneous infiltrates in MRL/lpr mice monitored from onset to the full development of lupus erythematosus-like skin lesions. J Invest Dermatol. 1991;96(4):478–83. Scholar
  17. 17.
    DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001;7(11):1189–93. Scholar
  18. 18.
    Lee LA, Gaither KK, Coulter SN, Norris DA, Harley JB. Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice. J Clin Invest. 1989;83(5):1556–62. Scholar
  19. 19.
    Shi ZR, et al. Association of anti-acidic ribosomal protein p0 and anti-galectin 3 antibodies with the development of skin lesions in systemic lupus erythematosus. Arthritis Rheumatol. 2015;67(1):193–203. Scholar
  20. 20.
    Deng GM, Liu L, Kyttaris VC, Tsokos GC. Lupus serum IgG induces skin inflammation through the TNFR1 signaling pathway. J Immunol. 2010;184(12):7154–61. Scholar
  21. 21.
    •• Liu L, Xu G, Dou H, Deng GM. The features of skin inflammation induced by lupus serum. Clin Immunol. 2016;165:4–11. This study provides evidences that skin deposited lupus IgG induces skin inflammation and features of skin injury induced by skin deposited lupus IgG. CrossRefPubMedGoogle Scholar
  22. 22.
    Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature. 2012;483(7388):227–31. Scholar
  23. 23.
    Peng SL, et al. Murine lupus in the absence of alpha beta T cells. J Immunol. 1996;156:4041–9.PubMedGoogle Scholar
  24. 24.
    Peng SL, Madaio MP, Hayday AC, Craft J. Propagation and regulation of systemic autoimmunity by gammadelta T cells. J Immunol. 1996;157:5689–98.PubMedGoogle Scholar
  25. 25.
    Deng GM, Beltran J, Chen C, Terhorst C, Tsokos GC. T cell CD3ζ deficiency enables multiorgan tissue inflammation. J Immunol. 2013;191(7):3563–7. Scholar
  26. 26.
    Liossis SN, Ding XZ, Dennis GJ, Tsokos GC. Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain. J Clin Invest. 1998;101(7):1448–57. Scholar
  27. 27.
    Li Y, Harada T, Juang YT, Kyttaris VC, Wang Y, Zidanic M, et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J Immunol. 2007;178(3):1938–47. Scholar
  28. 28.
    Peng SL, et al. Alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. J Immunol. 1997;158:2464–70.PubMedGoogle Scholar
  29. 29.
    Kinoshita K, Tesch G, Schwarting A, Maron R, Sharpe AH, Kelley VR. Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice. J Immunol. 2000;164(11):6046–56. Scholar
  30. 30.
    Chan OT, Madaio MP, Shlomchik MJ. The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev. 1999;169(1):107–21. Scholar
  31. 31.
    Lu TY, et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum. 2009;61(4):482–7. Scholar
  32. 32.
    Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010;62(8):2458–66. Scholar
  33. 33.
    Hofmann SC, Leandro MJ, Morris SD, Isenberg DA. Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus—report of 17 cases and review of the literature. Lupus. 2013;22(9):932–9. Scholar
  34. 34.
    Lenda DM, Stanley ER, Kelley VR. Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice. J Immunol. 2004;173(7):4744–54. Scholar
  35. 35.
    Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity. 2010;33(6):967–78. Scholar
  36. 36.
    Blomberg S, Eloranta ML, Cederblad B, Nordlin K, Alm GV, Rönnblom L. Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. Lupus. 2001;10(7):484–90. Scholar
  37. 37.
    Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL. Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol. 2001;159(1):237–43. Scholar
  38. 38.
    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. Scholar
  39. 39.
    Sisirak V, Ganguly D, Lewis KL, Couillault C, Tanaka L, Bolland S, et al. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med. 2014;211(10):1969–76. Scholar
  40. 40.
    • Rowland SL, Riggs JM, Gilfillan S, Bugatti M, Vermi W, Kolbeck R, et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J Exp Med. 2014;211(10):1977–91. This study demonstrates that plasmocytoid dendritic cells plays important role in the expression of skin injury in SLE. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Eriksson AU, Singh RR. Cutting edge: migration of langerhans dendritic cells is impaired in autoimmune dermatitis. J Immunol. 2008;181(11):7468–72. Scholar
  42. 42.
    Yang JQ, Chun T, Liu H, Hong S, Bui H, van Kaer L, et al. CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Eur J Immunol. 2004;34(6):1723–32. Scholar
  43. 43.
    Deng GM, Nilsson M, Verdrengh M, Collins LV, Tarkowski A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med. 1999;5(6):702–5. Scholar
  44. 44.
    Deng GM, Liu ZQ, Tarkowski A. Intracisternally localized bacterial DNA containing CpG motifs induces meningitis. J Immunol. 2001;167(8):4616–26. Scholar
  45. 45.
    Deng GM, Verdrengh M, Liu ZQ, Tarkowski A. The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs. Arthritis Rheum. 2000;43(10):2283–9.<2283::AID-ANR16>3.0.CO;2-9.CrossRefPubMedGoogle Scholar
  46. 46.
    Hochrein H, O’Keeffe M, Wagner H. Human and mouse plasma-cytoid dendritic cells. Hum Immunol. 2002;63(12):1103–10. Scholar
  47. 47.
    Haas C, Ryffel B, Le Hir M. IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW)F1 mice. J Immunol. 1998;160:3713–8.PubMedGoogle Scholar
  48. 48.
    Schwarting A, Wada T, Kinoshita K, Tesch G, Kelley VR. IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas (lpr) mice. J Immunol. 1998;161:494–503.PubMedGoogle Scholar
  49. 49.
    Kikawada E, Lenda DM, Kelley VR. IL-12 deficiency in MRL-Fas (lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol. 2003;170(7):3915–25. Scholar
  50. 50.
    Wenzel J, Zahn S, Bieber T, Tüting T. Type I interferon-associated cytotoxic inflammation in cutaneous lupus erythematosus. Arch Dermatol Res. 2009;301(1):83–6. Scholar
  51. 51.
    Zampieri S, Alaibac M, Iaccarino L, Rondinone R, Ghirardello A, Sarzi-Puttini P, et al. Tumour necrosis factor alpha is expressed in refractory skin lesions from patients with subacute cutaneous lupus erythematosus. Ann Rheum Dis. 2006;65(4):545–8. Scholar
  52. 52.
    Aringer M, Smolen JS. Therapeutic blockade of TNF in patients with SLE-promising or crazy? Autoimmun Rev. 2012;11(5):321–5. Scholar
  53. 53.
    Postal M, Appenzeller S. The role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of systemic lupus erythematosus. Cytokine. 2011;56(3):537–43. Scholar
  54. 54.
    Deng GM, Zheng L, Chan FK, Lenardo M. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat Med. 2005;11(10):1066–72. Scholar
  55. 55.
    Deng GM, Liu L, Tsokos GC. Targeted tumor necrosis factor receptor I preligand assembly domain improves skin lesions in MRL/lpr mice. Arthritis Rheum. 2010;62(8):2424–31. Scholar
  56. 56.
    •• Li X, Guo X, Liu H, Gao G, Xu G, Fei X, et al. Skin inflammation induced by lupus serum was inhibited in IL-1R deficient mice. Clin Immunol. 2017;180:63–8. This study provides evidence that IL-1 is involved in pathogenesis of skin injury in SLE and IL-1 is a therapeutic target against skin injury in SLE. CrossRefPubMedGoogle Scholar
  57. 57.
    Kurosaki T, Takata M, Yamanashi Y, Inazu T, Taniguchi T, Yamamoto T, et al. Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling. J Exp Med. 1994;179(5):1725–9. Scholar
  58. 58.
    Pamuk ON, Tsokos GC. Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases. Arthritis Res Ther. 2010;12(6):222. Scholar
  59. 59.
    Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 2010;62(7):2086–92. Scholar
  60. 60.
    Nazareth M, Fanti P, Schwach C, Poppenberg K, Janis K, Aronica SM. Altered Bax expression and decreased apoptosis in bone marrow cells of lupus-susceptible NZB/W mice. Lupus. 2001;10(11):785–93. Scholar
  61. 61.
    Takeuchi O, Fisher J, Suh H, Harada H, Malynn BA, Korsmeyer SJ. Essential role of BAX, BAK in B cell homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci U S A. 2005;102(32):11272–7. Scholar
  62. 62.
    Hook SS, Means AR. Ca(2+)/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol. 2001;41(1):471–505. Scholar
  63. 63.
    Soderling TR. The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem Sci. 1999;24(6):232–6. Scholar
  64. 64.
    Juang YT, Wang Y, Solomou EE, Li Y, Mawrin C, Tenbrock K, et al. Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest. 2005;115(4):996–1005. Scholar
  65. 65.
    Ichinose K, Juang YT, Crispín JC, Kis-Toth K, Tsokos GC. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. Arthritis Rheum. 2011;63(2):523–9. Scholar
  66. 66.
    Müller MR, Rao A. FAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010;10(9):645–56. Scholar
  67. 67.
    Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science. 1988;241(4862):202–5. Scholar
  68. 68.
    Jain J, McCafffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993;365(6444):352–5. Scholar
  69. 69.
    McCaffrey PG, et al. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science. 1993;262(5134):750–4. Scholar
  70. 70.
    Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J Immunol. 2007;178(3):1960–6. Scholar
  71. 71.
    Kyttaris VC, Zhang Z, Kampagianni O, Tsokos GC. Calcium signaling in systemic lupus erythematosus T cells: a treatment target. Arthritis Rheum. 2011;63(7):2058–66. Scholar
  72. 72.
    Mulero MC, Aubareda A, Orzáez M, Messeguer J, Serrano-Candelas E, Martínez-Hoyer S, et al. Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem. 2009;284(14):9394–401. Scholar
  73. 73.
    • Zahn S, Graef M, Patsinakidis N, Landmann A, Surber C, Wenzel J, et al. Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus. Exp Dermatol. 2014;23(7):516–8. This study provides evidence that UV enhances skin injury in SLE through interferon. CrossRefPubMedGoogle Scholar
  74. 74.
    Kuhn A, Wenzel J, Weyd H. Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clin Rev Allergy Immunol. 2014;47(2):148–62. Scholar
  75. 75.
    Yu C, Chang C, Zhang J. Immunologic and genetic considerations of cutaneous lupus erythematosus: a comprehensive review. J Autoimmun. 2013;41:34–45. Scholar
  76. 76.
    Menke J, Hsu MY, Byrne KT, Lucas JA, Rabacal WA, Croker BP, et al. Sunlight triggers cutaneous lupus through a CSF-1- dependent mechanism in MRL-Fas(lpr) mice. J Immunol. 2008;181(10):7367–79. Scholar
  77. 77.
    • Yin Q, Xu X, Lin Y, Lv J, Zhao L, He R, et al. Irradiation induces skin accumulation of plasmacytoid dendritic cells: a possible role for chemerin. Autoimmunity. 2014;47(3):185–92. This study demonstrates that UV induces skin inflammation in lupus-prone mice through plasmacytoid dendritic cells. CrossRefPubMedGoogle Scholar
  78. 78.
    Kirou KA, Gkrouzman E. Anti-interferon alpha treatment in SLE. Clin Immunol. 2013;148(3):303–12. Scholar
  79. 79.
    Kreuter A, Lehmann P. Relevant new insights into the effects of photoprotection in cutaneous lupus erythematosus. Exp Dermatol. 2014;23(10):712–3. Scholar
  80. 80.
    Sigges J, Biazar C, Landmann A, Ruland V, Patsinakidis N, Amler S, et al. Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus. Autoimmun Rev. 2013;12(7):694–702. Scholar
  81. 81.
    • Kuhn A, Sigges J, Biazar C, Ruland V, Patsinakidis N, Landmann A, et al. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus: analysis of 1002 patients from the EUSCLE database. Br J Dermatol. 2014;171(3):571–9. This study demonstrates that smoking influences skin injury in SLE. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Key Laboratory of antibody techniques of ministry of healthNanjing Medical UniversityNanjingChina

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