Skip to main content

Advertisement

SpringerLink
Log in

Photosensitivity, Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

The underlying pathomechanisms of lupus erythematosus (LE), a multifactorial autoimmune disease, remain elusive. Due to the clinical evidence demonstrating a clear relationship between ultraviolet (UV) light exposure and skin lesions of LE, photosensitivity has been proven to be an important factor in the pathogenesis of the disease. Standardised photoprovocation with UVA and UVB irradiation has been shown to be a reliable model for evaluating photosensitivity in patients with cutaneous LE (CLE) and analysing the underlying medical conditions of the disease. In this respect, UV irradiation can cause aberrant induction of apoptosis in keratinocytes and contribute to the appearance of excessive apoptotic cells in the skin of CLE patients. Moreover, apoptotic cells that cannot be cleared by phagocytes may undergo secondary necrosis and release proinflammatory compounds and potential autoantigens, which may contribute to the inflammatory micromilieu that leads to formation of skin lesions in the disease. In addition to UV-mediated induction of apoptosis, the molecular and cellular factors that may cause the abnormal long-lasting photoreactivity in CLE include mediators of inflammation, such as cytokines and chemokines. In particular, interferons (IFNs) are important players in the early activation of the immune system and have a specific role in the immunological interface between the innate and the adaptive immune system. The fact that treatment with recombinant type I IFNs (α and β) can induce not only systemic organ manifestations but also LE-like skin lesions provides additional evidence for a pathogenetic role of these IFNs in the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gilliam JN, Sontheimer RD (1981) Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol 4:471–475

    CAS  PubMed  Google Scholar 

  2. Provost TT (2004) Nonspecific cutaneous manifestations of systemic lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka T (eds) Cutaneous lupus erythematosus. Springer, Heidelberg, pp 93–106

    Google Scholar 

  3. Schmitt V, Meuth AM, Amler S, Kuehn E, Haust M, Messer G et al (2010) Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus. Br J Dermatol 162:64–73

    CAS  PubMed  Google Scholar 

  4. Kuhn A, Bein D, Bonsmann G (2009) The 100th anniversary of lupus erythematosus tumidus. Autoimmun Rev 8:441–448

    CAS  PubMed  Google Scholar 

  5. Kuhn A, Ruzicka T (2004) Classification of cutaneous lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka T (eds) Cutaneous lupus erythematosus. Springer, Berlin, pp 53–58

    Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Kuhn A, Ruland V, Bonsmann G (2010) Photosensitivity, phototesting, and photoprotection in cutaneous lupus erythematosus. Lupus 19:1036–1046

    CAS  PubMed  Google Scholar 

  8. Foering K, Chang AY, Piette EW, Cucchiara A, Okawa J, Werth VP (2013) Characterization of clinical photosensitivity in cutaneous lupus erythematosus. J Am Acad Dermatol 69:205–213

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Schmidt E, Tony HP, Brocker EB, Kneitz C (2007) Sun-induced life-threatening lupus nephritis. Ann N Y Acad Sci 1108:35–40

    CAS  PubMed  Google Scholar 

  11. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277

    CAS  PubMed  Google Scholar 

  12. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    CAS  PubMed  Google Scholar 

  13. Nyberg F, Hasan T, Puska P, Stephansson E, Hakkinen M, Ranki A et al (1997) Occurrence of polymorphous light eruption in lupus erythematosus. Br J Dermatol 136:217–221

    CAS  PubMed  Google Scholar 

  14. Albrecht J, Berlin JA, Braverman IM, Callen JP, Connolly MK, Costner MI et al (2004) Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 13:839–849

    CAS  PubMed  Google Scholar 

  15. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR et al (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686

    PubMed Central  PubMed  Google Scholar 

  16. Kuhn A, Beissert S (2005) Photosensitivity in lupus erythematosus. Autoimmunity 38:519–529

    CAS  PubMed  Google Scholar 

  17. Epstein JH, Tuffanelli D, Dubois EL (1965) Light sensitivity and lupus erythematosus. Arch Dermatol 91:483–485

    CAS  PubMed  Google Scholar 

  18. Cripps DJ, Rankin J (1973) Action spectra of lupus erythematosus and experimental immunofluorescence. Arch Dermatol 107:563–567

    CAS  PubMed  Google Scholar 

  19. Freeman RG, Knox JM, Owens DW (1969) Cutaneous lesions of lupus erythematosus induced by monochromatic light. Arch Dermatol 100:677–682

    CAS  PubMed  Google Scholar 

  20. Lehmann P, Hölzle E, von Kries R, Plewig G (1986) Lichtdiagnostische Verfahren bei Patienten mit Verdacht auf Photodermatosen. ZentrBl HuG 152:667–682

    Google Scholar 

  21. Lehmann P, Hölzle E, Kind P, Goerz G, Plewig G (1990) Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 22:181–187

    CAS  PubMed  Google Scholar 

  22. Klein RS, Werth VP, Dowdy JC, Sayre RM (2009) Analysis of compact fluorescent lights for use by patients with photosensitive conditions. Photochem Photobiol 85:1004–1010

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Klein RS, Sayre RM, Dowdy JC, Werth VP (2009) The risk of ultraviolet radiation exposure from indoor lamps in lupus erythematosus. Autoimmun Rev 8:320–324

    PubMed Central  PubMed  Google Scholar 

  24. Kuhn A, Wozniacka A, Szepietowski JC, Glaser R, Lehmann P, Haust M et al (2011) Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a standardized protocol. J Investig Dermatol 131:1622–1630

    Google Scholar 

  25. Ruland V, Haust M, Stilling RM, Amler S, Ruzicka T, Kuhn A (2013) Updated analysis of standardised photoprovocation in patients with cutaneous lupus erythematosus. Arthritis Care Res 65:767–776

    CAS  Google Scholar 

  26. Vaux DL, Korsmeyer SJ (1999) Cell death in development. Cell 96:245–254

    CAS  PubMed  Google Scholar 

  27. Henson PM, Hume DA (2006) Apoptotic cell removal in development and tissue homeostasis. Trends Immunol 27:244–250

    CAS  PubMed  Google Scholar 

  28. Orrenius S (2007) Reactive oxygen species in mitochondria-mediated cell death. Drug Metab Rev 39:443–455

    CAS  PubMed  Google Scholar 

  29. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    CAS  PubMed  Google Scholar 

  30. Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306

    CAS  PubMed  Google Scholar 

  31. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619–630

    CAS  PubMed  Google Scholar 

  32. Parnaik R, Raff MC, Scholes J (2000) Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Curr Biol 10:857–860

    Google Scholar 

  33. Franz S, Gaipl US, Munoz LE, Sheriff A, Beer A, Kalden JR et al (2006) Apoptosis and autoimmunity: when apoptotic cells break their silence. Curr Rheumatol Rep 8:245–247

    CAS  PubMed  Google Scholar 

  34. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345

    CAS  PubMed  Google Scholar 

  35. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50

    CAS  PubMed  Google Scholar 

  36. Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341:403–406

    CAS  PubMed  Google Scholar 

  37. Walczak H (2013) Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harb Perspect Biol 5:a008698

    PubMed  Google Scholar 

  38. Lavrik IN, Krammer PH (2012) Regulation of CD95/Fas signaling at the DISC. Cell Death Differ 19:36–41

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17:617–625

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

    CAS  PubMed  Google Scholar 

  41. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M et al (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188:2033–2045

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Hochreiter-Hufford A, Ravichandran KS (2013) Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol 5:a008748

    PubMed  Google Scholar 

  45. Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK et al (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–730

    CAS  PubMed  Google Scholar 

  46. Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE et al (2008) CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112:5026–5036

    CAS  PubMed  Google Scholar 

  47. Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R et al (2008) Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J 22:2629–2638

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF et al (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282–286

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Diaz C, Schroit AJ (1996) Role of translocases in the generation of phosphatidylserine asymmetry. J Membr Biol 151:1–9

    CAS  PubMed  Google Scholar 

  50. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439

    CAS  PubMed  Google Scholar 

  51. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z et al (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–434

    CAS  PubMed  Google Scholar 

  52. Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH et al (2008) Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ 15:192–201

    CAS  PubMed  Google Scholar 

  53. Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE et al (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M et al (2009) Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–3830

    CAS  PubMed  Google Scholar 

  55. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

    CAS  PubMed  Google Scholar 

  56. Nakano T, Ishimoto Y, Kishino J, Umeda M, Inoue K, Nagata K et al (1997) Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem 272:29411–29414

    CAS  PubMed  Google Scholar 

  57. Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E (2003) Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 4:87–91

    CAS  PubMed  Google Scholar 

  58. Savill J, Hogg N, Ren Y, Haslett C (1992) Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest 90:1513–1522

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Takizawa F, Tsuji S, Nagasawa S (1996) Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett 397:269–272

    CAS  PubMed  Google Scholar 

  60. Chen Y, Park YB, Patel E, Silverman GJ (2009) IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J Immunol 182:6031–6043

    CAS  PubMed  Google Scholar 

  61. Eda S, Yamanaka M, Beppu M (2004) Carbohydrate-mediated phagocytic recognition of early apoptotic cells undergoing transient capping of CD43 glycoprotein. J Biol Chem 279:5967–5974

    CAS  PubMed  Google Scholar 

  62. Chang MK, Bergmark C, Laurila A, Horkko S, Han KH, Friedman P et al (1999) Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A 96:6353–6358

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351

    CAS  PubMed  Google Scholar 

  65. Huynh ML, Fadok VA, Henson PM (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 109:41–50

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Stuart LM, Lucas M, Simpson C, Lamb J, Savill J, Lacy-Hulbert A (2002) Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation. J Immunol 168:1627–1635

    CAS  PubMed  Google Scholar 

  67. Weyd H, Abeler-Dorner L, Linke B, Mahr A, Jahndel V, Pfrang S et al (2013) Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLoS One 8:e62449

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Ferguson TA, Herndon J, Elzey B, Griffith TS, Schoenberger S, Green DR (2002) Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8(+) T cells produce active immune unresponsiveness. J Immunol 168:5589–5595

    CAS  PubMed  Google Scholar 

  69. Getts DR, Turley DM, Smith CE, Harp CT, McCarthy D, Feeney EM et al (2011) Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol 187:2405–2417

    Google Scholar 

  70. Hugues S, Mougneau E, Ferlin W, Jeske D, Hofman P, Homann D et al (2002) Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells. Immunity 16:169–181

    CAS  PubMed  Google Scholar 

  71. Tomimori Y, Ikawa Y, Oyaizu N (2000) Ultraviolet-irradiated apoptotic lymphocytes produce interleukin-10 by themselves. Immunol Lett 71:49–54

    CAS  PubMed  Google Scholar 

  72. Chen W, Frank ME, Jin W, Wahl SM (2001) TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14:715–725

    CAS  PubMed  Google Scholar 

  73. Kim S, Elkon KB, Ma X (2004) Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 21:643–653

    CAS  PubMed  Google Scholar 

  74. Skoberne M, Somersan S, Almodovar W, Truong T, Petrova K, Henson PM et al (2006) The apoptotic-cell receptor CR3, but not alphavbeta5, is a regulator of human dendritic-cell immunostimulatory function. Blood 108:947–955

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Wallet MA, Sen P, Flores RR, Wang Y, Yi Z, Huang Y et al (2008) MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med 205:219–232

    CAS  PubMed Central  PubMed  Google Scholar 

  76. AG N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N et al (2009) Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31:245–258

    Google Scholar 

  77. Perretti M, Ahluwalia A, Harris JG, Harris HJ, Wheller SK, Flower RJ (1996) Acute inflammatory response in the mouse: exacerbation by immunoneutralization of lipocortin 1. Br J Pharmacol 117:1145–1154

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Blume KE, Soeroes S, Waibel M, Keppeler H, Wesselborg S, Herrmann M et al (2009) Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis. J Immunol 183:8138–8147

    CAS  PubMed  Google Scholar 

  79. Pupjalis D, Goetsch J, Kottas DJ, Gerke V, Rescher U (2011) Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling. EMBO Mol Med 3:102–114

    CAS  PubMed Central  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  81. Kuhn A, Herrmann M, Kleber S, Beckmann-Welle M, Fehsel K, Martin-Villalba A et al (2006) Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum 54:939–950

    PubMed  Google Scholar 

  82. Midgley A, McLaren Z, Moots RJ, Edwards SW, Beresford MW (2009) The role of neutrophil apoptosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 60:2390–2401

    CAS  PubMed  Google Scholar 

  83. Manea ME, Mueller RB, Dejica D, Sheriff A, Schett G, Herrmann M et al (2009) Increased expression of CD154 and FAS in SLE patients’ lymphocytes. Rheumatol Int 30:181–185

    CAS  PubMed  Google Scholar 

  84. Sahebari M, Rezaieyazdi Z, Nakhjavani MJ, Hatef M, Mahmoudi M, Akhlaghi S (2012) Correlation between serum concentrations of soluble Fas (CD95/Apo-1) and IL-18 in patients with systemic lupus erythematosus. Rheumatol Int 32:601–606

    CAS  PubMed  Google Scholar 

  85. Toberer F, Sykora J, Goettel D, Hartschuh W, Werchau S, Enk A et al (2013) Apoptotic signal molecules in skin biopsies of cutaneous lupus erythematosus: analysis using tissue microarray. Exp Dermatol 22:656–659

    Google Scholar 

  86. Viard-Leveugle I, Bullani RR, Meda P, Micheau O, Limat A, Saurat JH et al (2003) Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions. J Biol Chem 278:16183–16188

    CAS  PubMed  Google Scholar 

  87. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P (1998) Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 5387:290–293

    Google Scholar 

  88. Daniels F Jr, Brophy D, Lobitz WC Jr (1961) Histochemical responses of human skin following ultraviolet irradiation. J Invest Dermatol 37:351–357

    CAS  PubMed  Google Scholar 

  89. Matsunaga T, Hieda K, Nikaido O (1991) Wavelength dependent formation of thymine dimers and (6–4) photoproducts in DNA by monochromatic ultraviolet light ranging from 150 to 365 nm. Photochem Photobiol 54:403–410

    CAS  PubMed  Google Scholar 

  90. Bates S, Vousden KH (1999) Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci 55:28–37

    CAS  PubMed  Google Scholar 

  91. Rehemtulla A, Hamilton CA, Chinnaiyan AM, Dixit VM (1997) Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1). J Biol Chem 272:25783–25786

    CAS  PubMed  Google Scholar 

  92. Assefa Z, Garmyn M, Vantieghem A, Declercq W, Vandenabeele P, Vandenheede JR et al (2003) Ultraviolet B radiation-induced apoptosis in human keratinocytes: cytosolic activation of procaspase-8 and the role of Bcl-2. FEBS Lett 540:125–132

    CAS  PubMed  Google Scholar 

  93. Assefa Z, Vantieghem A, Garmyn M, Declercq W, Vandenabeele P, Vandenheede JR et al (2000) p38 mitogen-activated protein kinase regulates a novel, caspase-independent pathway for the mitochondrial cytochrome c release in ultraviolet B radiation-induced apoptosis. J Biol Chem 275:21416–21421

    CAS  PubMed  Google Scholar 

  94. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250

    CAS  PubMed  Google Scholar 

  95. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y et al (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150

    CAS  PubMed  Google Scholar 

  96. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76:227–324

    CAS  PubMed  Google Scholar 

  97. Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317–1330

    CAS  PubMed  Google Scholar 

  98. Ronnblom L, Eloranta ML, Alm GV (2006) The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 54:408–420

    PubMed  Google Scholar 

  99. Lauber K, Keppeler H, Munoz LE, Koppe U, Schroder K, Yamaguchi H et al (2013) Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids. Cell Death Differ 20:1230–1240

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Abeler-Dörner L, Rieger CC, Berger B, Weyd H, Gräf D, Pfrang S et al (2013) Interferon-α abrogates the suppressive effect of apoptotic cells on dendritic cells in an in vitro model of systemic lupus erythematosus pathogenesis. J Rheumatol 40:1683–1696

    Google Scholar 

  101. George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA (2012) Pharmacology and therapeutic potential of interferons. Pharmacol Ther 135:44–53

    CAS  PubMed  Google Scholar 

  102. Arur S, Uche UE, Rezaul K, Fong M, Scranton V, Cowan AE et al (2003) Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev Cell 4:587–598

    CAS  PubMed  Google Scholar 

  103. Scannell M, Flanagan MB, deStefani A, Wynne KJ, Cagney G, Godson C et al (2007) Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages. J Immunol 178:4595–4605

    CAS  PubMed  Google Scholar 

  104. Szodoray P, Tarr T, Tumpek J, Kappelmayer J, Lakos G, Poor G et al (2009) Identification of rare anti-phospholipid/protein co-factor autoantibodies in patients with systemic lupus erythematosus. Autoimmunity 42:497–506

    Google Scholar 

  105. Kretz CC, Norpo M, Abeler-Dorner L, Linke B, Haust M, Edler L et al (2010) Anti-annexin 1 antibodies: a new diagnostic marker in the serum of patients with discoid lupus erythematosus. Exp Dermatol 19:919–921

    CAS  PubMed  Google Scholar 

  106. Lindenmann J (2007) Interferon and before. J Interferon Cytokine Res 27:2–5

    CAS  PubMed  Google Scholar 

  107. Agmon-Levin N, Blank M, Paz Z, Shoenfeld Y (2009) Molecular mimicry in systemic lupus erythematosus. Lupus 18:1181–1185

    CAS  PubMed  Google Scholar 

  108. Elkon KB, Wiedeman A (2012) Type I IFN system in the development and manifestations of SLE. Curr Opin Rheumatol 24:499–505

    CAS  PubMed  Google Scholar 

  109. Hagberg N, Berggren O, Leonard D, Weber G, Bryceson YT, Alm GV et al (2011) IFN-alpha production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes is promoted by NK cells via MIP-1beta and LFA-1. J Immunol 186:5085–5094

    CAS  PubMed  Google Scholar 

  110. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S et al (2013) Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39:482–495

    CAS  PubMed  Google Scholar 

  111. Ronnblom LE, Alm GV, Oberg KE (1990) Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med 227:207–210

    CAS  PubMed  Google Scholar 

  112. Ronnblom L, Alm GV, Eloranta ML (2011) The type I interferon system in the development of lupus. Semin Immunol 23:113–121

    PubMed  Google Scholar 

  113. Dall’era MC, Cardarelli PM, Preston BT, Witte A, Davis JC Jr (2005) Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis 64:1692–1697

    PubMed Central  PubMed  Google Scholar 

  114. Ronnblom L, Alm GV (2001) An etiopathogenic role for the type I IFN system in SLE. Trends Immunol 22:427–431

    CAS  PubMed  Google Scholar 

  115. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J et al (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197:711–723

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Fah J, Pavlovic J, Burg G (1995) Expression of MxA protein in inflammatory dermatoses. J Histochem Cytochem 43:47–52

    CAS  PubMed  Google Scholar 

  118. Freutel S, Gaffal E, Zahn S, Bieber T, Tuting T, Wenzel J (2011) Enhanced CCR5+/CCR3+ T helper cell ratio in patients with active cutaneous lupus erythematosus. Lupus 20:1300–1304

    CAS  PubMed  Google Scholar 

  119. Wenzel J, Tuting T (2008) An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in “interface dermatitis”. J Invest Dermatol 128:2392–2402

    CAS  PubMed  Google Scholar 

  120. Guiducci C, Tripodo C, Gong M, Sangaletti S, Colombo MP, Coffman RL et al (2010) Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med 207:2931–2942

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Arrue I, Saiz A, Ortiz-Romero PL, Rodriguez-Peralto JL (2007) Lupus-like reaction to interferon at the injection site: report of five cases. J Cutan Pathol 34(Suppl 1):18–21

    PubMed  Google Scholar 

  122. Wenzel J, Zahn S, Mikus S, Wiechert A, Bieber T, Tuting T (2007) The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets. Br J Dermatol 157:752–757

    CAS  PubMed  Google Scholar 

  123. Tomasini D, Mentzel T, Hantschke M, Cerri A, Paredes B, Rutten A et al (2010) Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner’s lymphocytic infiltrate of the skin and cutaneous lupus erythematosus. J Cutan Pathol 37:1132–1139

    PubMed  Google Scholar 

  124. Wenzel J, Tuting T (2007) Identification of type I interferon-associated inflammation in the pathogenesis of cutaneous lupus erythematosus opens up options for novel therapeutic approaches. Exp Dermatol 16:454–463

    CAS  PubMed  Google Scholar 

  125. Zahn S, Rehkamper C, Kummerer BM, Ferring-Schmidt S, Bieber T, Tuting T et al (2011) Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNlambda) in cutaneous lupus erythematosus. J Invest Dermatol 131:133–140

    CAS  PubMed  Google Scholar 

  126. Bose A, Baral R (2007) IFNalpha2b stimulated release of IFNgamma differentially regulates T cell and NK cell mediated tumor cell cytotoxicity. Immunol Lett 108:68–77

    CAS  PubMed  Google Scholar 

  127. Zella D, Barabitskaja O, Casareto L, Romerio F, Secchiero P, Reitz MS Jr et al (1999) Recombinant IFN-alpha (2b) increases the expression of apoptosis receptor CD95 and chemokine receptors CCR1 and CCR3 in monocytoid cells. J Immunol 163:3169–3175

    CAS  PubMed  Google Scholar 

  128. Zahn S, Rehkamper C, Ferring-Schmitt S, Bieber T, Tuting T, Wenzel J (2011) Interferon-alpha stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus. Br J Dermatol 165:1118–1123

    CAS  PubMed  Google Scholar 

  129. Zampieri S, Alaibac M, Iaccarino L, Rondinone R, Ghirardello A, Sarzi-Puttini P et al (2006) Tumour necrosis factor alpha is expressed in refractory skin lesions from patients with subacute cutaneous lupus erythematosus. Ann Rheum Dis 65:545–548

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Norman R, Greenberg RG, Jackson JM (2006) Case reports of etanercept in inflammatory dermatoses. J Am Acad Dermatol 54:S139–S142

    PubMed  Google Scholar 

  131. Vedove CD, Del Giglio M, Schena D, Girolomoni G (2009) Drug-induced lupus erythematosus. Arch Dermatol Res 301:99–105

    PubMed  Google Scholar 

  132. Fiorentino DF (2007) The Yin and Yang of TNF-{alpha} inhibition. Arch Dermatol 143:233–236

    CAS  PubMed  Google Scholar 

  133. Aringer M, Burkhardt H, Burmester GR, Fischer-Betz R, Fleck M, Graninger W et al (2012) Current state of evidence on ‘off-label’ therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland—a consensus report. Lupus 21:386–401

    CAS  PubMed  Google Scholar 

  134. Kuhn A, Ochsendorf F, Bonsmann G (2010) Treatment of cutaneous lupus erythematosus. Lupus 19:1125–1136

    CAS  PubMed  Google Scholar 

  135. Ochsendorf FR (2010) Use of antimalarials in dermatology. J Dtsch Dermatol Ges 8:829–844, quiz 45

    PubMed  Google Scholar 

  136. Kuhn A, Ruland V, Bonsmann G (2011) Cutaneous lupus erythematosus: update of therapeutic options. Part I. J Am Acad Dermatol 65:e179–e193

    PubMed  Google Scholar 

  137. Patsinakidis N, Wenzel J, Landmann A, Koch R, Gerss J, Luger TA et al (2012) Suppression of UV-induced damage by a liposomal sunscreen: a prospective, open-label study in patients with cutaneous lupus erythematosus and healthy controls. Exp Dermatol 21:958–961

    CAS  PubMed  Google Scholar 

  138. Baker VS, Imade GE, Molta NB, Tawde P, Pam SD, Obadofin MO et al (2008) Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age. Malar J 7:41

    PubMed Central  PubMed  Google Scholar 

  139. Sharma S, DeOliveira RB, Kalantari P, Parroche P, Goutagny N, Jiang Z et al (2011) Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35:194–207

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186:4794–4804

    CAS  PubMed  Google Scholar 

  141. Chang AY, Piette EW, Foering KP, Tenhave TR, Okawa J, Werth VP (2011) Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Arch Dermatol 147:1261–1267

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Baima B, Sticherling M (2001) Apoptosis in different cutaneous manifestations of lupus erythematosus. Br J Dermatol 144:958–966

    CAS  PubMed  Google Scholar 

  143. Petri M, Wallace DJ, Spindler A, Chindalore V, Kalunian K, Mysler E et al (2013) Sifalimumab, a human anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum 65:1011–1021

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Wang B, Higgs BW, Chang L, Vainshtein I, Liu Z, Streicher K et al (2013) Pharmacogenomics and translational simulations to bridge indications for an anti-interferon-alpha receptor antibody. Clin Pharmacol Ther 93:483–492

    CAS  PubMed  Google Scholar 

  145. Meyer O (2012) Interferon-alpha as a treatment target in systemic lupus erythematosus. Jt Bone Spine 79:113–116

    Google Scholar 

  146. Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S et al (2013) The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-203756

  147. Wolska H, Blaszczyk M, Jablonska S (1989) Phototests in patients with various forms of lupus erythematosus. Int J Dermatol 28:98–103

    CAS  PubMed  Google Scholar 

  148. van Weelden H, Velthuis PJ, Baart de la Faille H (1989) Light-induced skin lesions in lupus erythematosus: photobiological studies. Arch Dermatol 281:470–474

    Google Scholar 

  149. Beutner EH, Blaszczyk M, Jablonska S, Chorzelski TP, Vijay K, Wolska H (1991) Studies on criteria of the European Academy of Dermatology and Venereology for the classification of cutaneous lupus erythematosus. Int J Dermatol 30:411–417

    CAS  PubMed  Google Scholar 

  150. Kind P, Lehmann P, Plewig G (1993) Phototesting in lupus erythematosus. J Invest Dermatol 100:53S–57S

    CAS  PubMed  Google Scholar 

  151. Nived O, Johansen PB, Sturfelt G (1993) Standardized ultraviolet-A exposure provoces skin reaction in systemic lupus erythematosus. Lupus 2:247–250

    CAS  PubMed  Google Scholar 

  152. Bensaid P, Vaillant L, Esteve E, Machet MC, Machet L, Lorette G (1995) Photobiological study of lupus erythematosus. Ann Dermatol Venereol 122:84–89

    CAS  PubMed  Google Scholar 

  153. Walchner M, Messer G, Kind P (1997) Phototesting and photoprotection in LE. Lupus 6:167–174

    CAS  PubMed  Google Scholar 

  154. Hasan T, Nyberg F, Stephansson E, Puska P, Hakkinen M, Sarna S et al (1997) Photosensitivity in lupus erythematosus, UV photoprovocation results compared with history of photosensitivity and clinical findings. Br J Dermatol 136:699–705

    CAS  PubMed  Google Scholar 

  155. Leenutaphong V, Boonchai W (1999) Phototesting in oriental patients with lupus erythematosus. Photodermatol Photoimmunol Photomed 15:7–12

    CAS  PubMed  Google Scholar 

  156. Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed M, Ruzicka T et al (2001) Phototesting in lupus erythematosus tumidus—review of 60 patients. Photochem Photobiol 73:532–536

    CAS  PubMed  Google Scholar 

  157. Sanders CJ, Van Weelden H, Kazzaz GA, Sigurdsson V, Toonstra J, Bruijnzeel-Koomen CA (2003) Photosensitivity in patients with lupus erythematosus: a clinical and photobiological study of 100 patients using a prolonged phototest protocol. Br J Dermatol 149:131–137

    CAS  PubMed  Google Scholar 

  158. Choonhakarn C, Poonsriaram A, Chaivoramukul J (2004) Lupus erythematosus tumidus. Int J Dermatol 43:815–818

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University of Muenster, Von-Esmarch-Strasse 58, 48149, Muenster, Germany

    Annegret Kuhn

  2. Department of Dermatology, University of Bonn, Bonn, Germany

    Jörg Wenzel

  3. Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany

    Annegret Kuhn & Heiko Weyd

Authors
  1. Annegret Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörg Wenzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heiko Weyd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annegret Kuhn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuhn, A., Wenzel, J. & Weyd, H. Photosensitivity, Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review. Clinic Rev Allerg Immunol 47, 148–162 (2014). https://doi.org/10.1007/s12016-013-8403-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-013-8403-x

Keywords

Search

Navigation