Distler, O.

Gay, S.

Huber, L. C.

Pisetsky, D. S.

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Rheumatology 2006;45:500–501 doi:10.1093/rheumatology/kel036Advance Access publication 8 February 2006EditorialThe effect of UVB on lupus skin: new light on therole of apoptosis in the pathogenesis of autoimmunityApoptosis is a major form of programmed cell death and occursin both physiological and pathological conditions. With apoptosis,cells display distinct morphological and biochemical features thatallow their identiﬁcation and enumeration both in vivo and in vitro.Prominent changes in cells undergoing this process are chromatincondensation, DNA fragmentation, membrane blebbing andexternalization of phosphatidylserine of the cell membrane [1].Once apoptosis is initiated, alterations in membrane structuremark a cell for recognition by macrophages that can engulf thedying cell for safe disposal. Indeed, the phagocytosis of dead cellsis one of the critical functions of the immune system in preventinginadvertent immune activation by proinﬂammatory cellularmaterial arising during death. Given the potential impact ofdying cells and their products on the immune system, disturbancesof the cell death and clearance processes have been postulated tooccur in a variety of human diseases, including autoimmunesyndromes such as systemic lupus erythematosus (SLE).In this issue of Rheumatology, Reefman and co-workers explorepossible abnormalities of cell death in SLE by investigatingthe frequency of apoptotic cells in the skin resulting from exposureof deﬁned areas to UVB light. Ultraviolet radiation, in particularUVB with a short wavelength range (between 290 and 320 nm),represents an important environmental factor that can triggera variety of deleterious responses in humans. The intracellularprocesses induced by UVB are complex, cell injury and death beingmediated by various mechanisms, including DNA damage,the production of reactive oxygen species and the activation ofcell death receptors [2]. In the skin, UVB is well characterized asan inducer of cutaneous damage, causing the accumulationof apoptotic keratinocytes at the dermo-epidermal junction.Given the toxic products induced by UVB exposure, apoptosismay represent part of a protective mechanism to remove damagedcells and reduce the potential risk to the system from spillage oftheir contents.In SLE, the outcome of exposure to UVB radiation isphotosensitivity and the development of photolesions in the skin,as observed typically in cutaneous lupus. The amount of energyneeded for UVB to provoke cutaneous changes is usually referredto as the minimal erythemal dose (MED). Since photosensitivityis one of the clinical hallmarks of lupus, it may not be surprisingthat the SLE patients in the study of Reefman et al. had a lowerthreshold than normal subjects for the development of an UVB-induced erythema. This observation conﬁrms data from otherstudies [3], although the ﬁnding that UVB-induced erythema canbe associated with an increased frequency of apoptotic cells(detected by light microscopy or immunochemical staining forcleaved caspase 3) is novel. Importantly, in the context of modelsfor the pathogenesis of SLE, it is notable that the number ofapoptotic cells and the amount of pycnotic nuclear debris observedhistologically in the skin of patients and healthy volunteerswere similar after 24 h. The development of erythema thus appearsto be directly linked to the number of apoptotic cells, butthe extent to which cells die appears to be independent of thepresence of underlying autoimmunity. These data thus suggestthat keratinocytes of SLE patients have normal sensitivity toUVB-mediated apoptosis, at least under the conditions of thepresent study.Studies of several mouse models of SLE have suggested adirect link between apoptosis and the development of lupus.For example, defects involving the induction of apoptosis throughthe Fas/FasL system [4], overexpression of the anti-apoptoticmolecule Bcl-2 [5] or heterozygosity for Pten (a tumour-suppressorgene involved in the induction of apoptosis) [6] are all associatedwith an increased number of autoreactive cells leading tolymphoproliferation and autoimmunity. T and B lymphocytesfrom these mice showed highly increased populations positive forseveral activation markers as well as hypergammaglobulinaemiawith autoantibodies against nuclear antigens. Moreover, thekidneys of these mice showed glomerular abnormalities dueto deposition of immune complexes. However, the effects ofUVB irradiation have not been extensively investigated in lupusmouse models with respect to the induction of apoptosis [7] or thepotentiation of autoimmunity.The evidence for disturbed apoptosis in human lupus, on theother hand, is less clear. Increased levels of circulating apoptoticcells have been found in SLE patients [8–10], although levelsdid not correlate with disease activity in these studies. Data onapoptotic keratinocytes in the skin lesions of SLE patients arecontroversial with respect to both the induction of apoptosisand correlation with autoantibodies [11–13]. These differencescould be due to the inﬂuence of various medication schemes ordifferences in the patient population studied.While Reefman et al. have shown a similarity in the frequencyof apoptotic cells in patients with SLE and normal subjects treatedwith UVB, these ﬁndings do not exclude an important role ofdefective apoptosis in the pathogenesis of lupus. Apoptosis isa highly heterogeneous process that may vary in time-courseand biochemical features depending on cell type, location andtrigger. In the context of the current experiments, it is possible thatthe number of apoptotic cells or the amount of nuclear debriswould differ between patients and controls at later time-points ofinvestigation. Similarly, it is possible that differences betweenpatients and normal subjects would be more pronounced if UVBwere applied repeatedly or in different concentrations over acertain period instead of in one or two single doses. Moreover,the duration of disease and activity of cutaneous lesions mightalso inﬂuence the extent of apoptosis following UVB exposure.The ﬁndings, while intriguing in terms of existing models for SLE,must nevertheless be interpreted with caution, given the hetero-geneity in the dynamics and mechanisms of cell death processes.In addition to altered induction of apoptosis, the removal ofapoptotic cells has attracted interest in SLE as an importantelement in the pathogenesis of the disease [14–17]. The clearanceof potentially autoantigenic material or debris created by dyingcells is a highly regulated process that may actively inhibit theinitiation of inﬂammation and immune responses. Cells under-going apoptosis are removed rapidly through non-inﬂammatoryengulfment by macrophages or even non-professional phagocytessuch as ﬁbroblasts, endothelial cells, or vascular smooth musclecells [18]. The clearance process involves a host of cellular andhumoral elements to promote phagocytosis prior to the transitionof dying cells to secondary necrosis, a proinﬂammatory state,or access of apoptotic cells to dendritic cells, where uptake wouldlead to antigen presentation. The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org500Several defects are known in humans with respect to theclearance of dying cells and cellular material. In the contextof SLE, in particular, relative failure of the acute-phase CRPresponse [19], reduced activity of DNase I [20, 21] and complementdefects [22] could all contribute to impaired clearance of apoptoticcells and the accumulation of cells in late apoptosis, a phase alsotermed ‘secondary necrosis’. While the cellular events in thelate stages of the death processes are not well deﬁned, they mayinvolve leakage of proinﬂammatory molecules into the externalmilieu; the generation of new moieties from proteolytic digestionor the action of reactive oxygen species may also occur. A furtherbuild-up of secondarily necrotic cells may occur when theapoptotic load exceeds the local capacity for phagocytes to mediateclearance, a situation that could reﬂect either increased death orfailed clearance. The time-course for these events is speculativeand it is possible that the experiments of Reefman et al. werenot long enough to detect defects in the phagocytosis ofapoptotic keratinocytes, a phenomenon that might explainthe increased rate of apoptotic cells in established skin lesions inSLE patients.More than 10 years ago, in seminal experiments Casciola-Rosenet al. [23] showed that keratinocytes undergoing apoptosis afterexposure to UV light cluster a variety of macromolecules in blebson the cell surface. Importantly, these small blebs contained themajor autoantigens recognized by lupus sera. From these studies,it can be hypothesized that the persistence of these blebs due toimpaired removal of apoptotic cells could lead to the release ofantigenic structures into the surrounding tissue or circulation.Once released, these structures might induce an immune responseculminating in the production of autoantibodies. In their study,Reefman and co-workers did not ﬁnd a correlation between MEDvalues and the presence of autoantibodies in the serum. Otherinvestigators, however, have shown such a correlation [13],in particular by showing a positive association between anti-Ro(SS-A)/anti-La (SS-B) autoantibodies and a pathological photo-provocation. This issue awaits further experimentation under otherconditions.While the study of Reefman et al. did not show increasedapoptosis following UVB exposure in patients with SLE, it isnevertheless important in providing an in vivo test for animportant hypothesis. However, these ﬁndings must be viewedtentatively, given the complexity of the death process and themultitude of ways in which cells can succumb. Sunlightremains hazardous to patients and it is still too early to concludethat UVB-induced apoptosis in SLE is intact and that UVB doesnot play a role in inducing cell death and injury that provokesautoreactivity.The skin is a unique system for study since it is a very accessiblesite and allows experiments not possible with other organs. It willbe a challenge to investigators to devise experimental systems toassess death processes in tissues that cannot be readily biopsied orfollowed after exposure to agents that are too toxic for systemicadministration. While the studies of Reefman et al. shed some lighton an important subject, they provide a reminder that, like life,death is a complicated process and its role in SLE still appears to benot well understood.The authors have declared no conﬂicts of interest.L. C. Huber, S. GAY, O. DISTLER and D. S. PISETSKY1Center of Experimental Rheumatology and Department ofRheumatology, University Hospital, Zurich, Switzerland and1Medical Research Service, Durham Veterans AdministrationHospital and Departments of Medicine and Immunology, DukeUniversity Medical Center, Durham, NC, USACorrespondence to: O. Distler. E-mail: oliver.distler@usz.chReferences1. Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770–6.2. Kulms D, Schwarz T. Independent contribution of three differentpathways to ultraviolet-B-induced apoptosis. Biochem Pharmacol2002;64:837–41.3. Doria A, Biasinutto C, Ghirardello A et al. Photosensitivity insystemic lupus erythematosus: laboratory testing of ARA/ACRdeﬁnition. Lupus 1996;5:263–8.4. Nagata S, Suda T. Fas and Fas ligand: lpr and gld mutations.Immunol Today 1995;16:39–43.5. Strasser A, Harris AW, Cory S. bcl-2 transgene inhibits T cell deathand perturbs thymic self-censorship. Cell 1991;67:889–99.6. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB,Pandolﬁ PP. Impaired Fas response and autoimmunity in Ptenþ/–mice. Science 1999;285:2122–5.7. Chung JH, Kwon OS, Eun HC et al. Apoptosis in the pathogenesis ofcutaneous lupus erythematosus. Am JDermatopathol 1998;20:233–41.8. Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ,Bell AL. Increased apoptotic peripheral blood neutrophils in systemiclupus erythematosus: relations with disease activity, antibodies todouble stranded DNA, and neutropenia. Ann Rheum Dis1999;58:309–14.9. Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. Highlevels of circulating early apoptic peripheral blood mononuclear cellsin systemic lupus erythematosus. Lupus 1998;7:113–8.10. Bengtsson AA, Sturfelt G, Gullstrand B, Truedsson L. Inductionof apoptosis in monocytes and lymphocytes by serum from patientswith systemic lupus erythematosus – an additional mechanism toincreased autoantigen load? Clin Exp Immunol 2004;135:535–43.11. Furukawa F. Photosensitivity in cutaneous lupus erythematosus:lessons from mice and men. J Dermatol Sci 2003;33:81–9.12. Wolska H, Blaszczyk M, Jablonska S. Phototests in patients withvarious forms of lupus erythematosus. Int J Dermatol 1989;28:98–103.13. Hasan T, Nyberg F, Stephansson E et al. Photosensitivity in lupuserythematosus, UV photoprovocation results compared with historyof photosensitivity and clinical ﬁndings. Br J Dermatol 1997;136:699–705.14. Pablos JL, Gomez-Reino JJ. Defective phagocytosis in systemic lupuserythematosus. Eur J Clin Invest 1998;28:864–5.15. Dieker JW, van der Vlag J, Berden JH. Deranged removal ofapoptotic cells: its role in the genesis of lupus. Nephrol DialTransplant 2004;19:282–5.16. Gaipl US, Voll RE, Sheriff A, Franz S, Kalden JR, Herrmann M.Impaired clearance of dying cells in systemic lupus erythematosus.Autoimmun Rev 2005;4:189–94.17. Kaplan MJ. Apoptosis in systemic lupus erythematosus. ClinImmunol 2004;112:210–8.18. Ren Y, Savill J. Apoptosis: the importance of being eaten. Cell DeathDiffer 1998;5:563–8.19. Russell AI, Cunninghame Graham DS et al. Polymorphism at theC-reactive protein locus inﬂuences gene expression and predisposes tosystemic lupus erythematosus. Hum Mol Genet 2004;13:137–47.20. Bodano A, Amarelo J, Gonzalez A, Gomez-Reino JJ, Conde C.Novel DNASE I mutations related to systemic lupus erythematosus.Arthritis Rheum 2004;50:4070–1.21. Chitrabamrung S, Rubin RL, Tan EM. Serum deoxyribonuclease Iand clinical activity in systemic lupus erythematosus. Rheumatol Int1981;1:55–60.22. Botto M, Walport MJ. C1q, autoimmunity and apoptosis.Immunobiology 2002;205:395–406.23. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted insystemic lupus erythematosus are clustered in two populationsof surface structures on apoptotic keratinocytes. J Exp Med 1994;179:1317–30.Editorial 501

The effect of UVB on lupus skin: new light on the role of apoptosis in the pathogenesis of autoimmunity

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