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Photosensitivity in Rheumatic Diseases

      There have been a number of recent advances in the genetic understanding of photosensitive rheumatic diseases, especially subacute cutaneous lupus erythematosus and dermatomyositis. These advances support the concept that increased numbers of ultraviolet light–induced apoptotic cells in skin lead to a suprathreshold concentration of antigenic peptides. The current genetic data suggest that increased keratinocyte apopotosis can result from increased amounts of TNF-α that induce apoptosis due to a ultraviolet light–sensitive TNF promoter polymorphism or to decreased clearance of apototic cells due to polymorphisms associated with decreased serum levels of collectins such as C1q and mannose-binding lectin. These diseases are frequently oligogenic, and other yet to be elucidated genes will, in individual patients, lead to increased numbers of apoptotic cells associated with these cutaneous autoimmune diseases. In the presence of specific MHC class I and II genes, antigen-presenting cells initiate a primary immune response that leads to cutaneous, and likely systemic, autoimmune disease.

      Keywords

      Abbreviations

      ADCC
      antibody-dependent cellulary cytotoxicity
      APC
      antigen-presenting cell
      CTL
      cytotoxic T lymphocyte
      DC
      dendritic cell
      DLE
      discoid lupus erythematosus
      DM
      dermatomyositis
      HLA
      human leukocyte antigen
      IF
      interferon
      LE
      lupus erythematosus
      MBL
      mannose-binding lectin
      MHC
      major histocompatibility
      NK
      natural killer
      SBC
      sunburn cell
      SCLE
      subacute cutaneous lupus erythematosus
      TNF-α
      tumor necrosis factor α
      UV
      ultraviolet

      Overview: Genetics and photosensitive rheumatic diseases (Figure 1)

      Ultraviolet (UV) light is a trigger of cutaneous lesions in several autoimmune diseases. These diseases include a number of subsets of cutaneous lupus erythematosus (LE) as well as dermatomyositis (DM). Recent studies suggest that the presence of increased numbers of apoptotic cells in SCLE (subacute cutaneous LE) and DM skin relate, at least in part, to the presence of genetic polymorphisms of genes that promote UV-induced apoptosis and delay clearance of apoptotic cells. In addition, studies show that individual HLA class II genes are important in the presentation of specific antigens to antigen-presenting cells (APC, see Table 1). Clearly, more genes will be defined over time for these two diseases, but the current evidence suggests that it is often combinations of pro-apoptotic and anticlearance genes in the correct HLA setting that determine the risk of developing SCLE or DM. UV is clearly a trigger for these diseases, but it remains to be determined whether other triggers, such as infections, also play a role in genetically predisposed individuals.
      Figure thumbnail gr1
      Figure 1Model for pathogenesis of photosensitive autoimmune disease. Apoptotic cells are normally cleared by noninflammatory pathways that involve macrophages. In the presence of a number of genetic polymorphisms that lead to overexpression or underexpression of proteins involved in promoting apoptosis or impairing clearance of apoptotic cells, marked with *, various immune effector pathways that increase apoptotic death are triggered, as outlined in the box.
      Table IPolymorphisms associated with photosensitive rheumatologic diseases:
      I.Overproduction of apoptotic cells
       –308A TNF promoter polymorphism (SCLE, DM)
      II.Decreased clearance of apoptotic cells
       C1q (SCLE)
       Mannose binding lectin (DM)
      III.Presentation of antigens from apoptotic cells
       Individual Class II HLA genes, e.g. HLA-DR3 (SCLE)
      A growing number of studies based on the genetics, phototesting, and serologic/pathologic testing of cutaneous photosensitive autoimmune disease patients are confirming differences between the various disease subsets. This review will focus on recent advances in our understanding of the genetics and pathogenesis of SCLE and DM, focusing on both similarities and differences between these diseases, and it will contrast these findings with those concerning other forms of photosensitive LE.

      Definition of Photosensitive Autoimmune Diseases

      The subsets of cutaneous LE that are commonly triggered by UV include subacute cutaneous LE, tumid (papulomucinous) LE, discoid LE (DLE), and systemic LE (SLE). SCLE and DLE are often clinically, histologically, and immunologically distinct (
      • David-Bajar K.M.
      • Bennion S.D.
      • DeSpain J.D.
      • Golitz L.E.
      • Lee L.A.
      Clinical, histologic, and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus.
      ;
      • Lee L.A.
      • Farris A.D.
      Photosensitivity diseases: cutaneous lupus erythematosus.
      ), as is tumid LE. SCLE and DM are similar in their histologic findings as well, but usually are distinct clinically and serologically, with anti-Ro (anti-SSA) antibodies strongly associated with SCLE (
      • Sontheimer R.D.
      • Maddison P.J.
      • Reichlin M.
      • Jordon R.E.
      • Stastny P.
      • Gilliam J.N.
      Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus.
      ).

      UV and phototesting

      Phototesting studies in cutaneous LE suggest that both UVA and UVB can trigger the photosensitive forms of LE with induction of LE lesions in 63% of SCLE cases, 72% of tumid LE cases, 60% of SLE cases, and 45% of DLE cases (
      • Lehmann P.
      • Holzle E.
      • Kind P.
      • Goerz G.
      • Plewig G.
      Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation.
      ;
      • Kuhn A.
      • Sonntag M.
      • Richter-Hintz D.
      • Oslislo C.
      • Megahed M.
      • Ruzicka T.
      • Lehmann P.
      Phototesting in lupus erythematosus tumidus-review of 60 patients.
      ). Most patients react to both UVA and UVB, although the doses of UVA used for most phototesting are well above the physiologic range. It is frequently observed that there is a delayed reaction between UV provocation and development of cutaneous LE lesions, thus making the correlation of UV exposure with exacerbation of the disease difficult to determine for many patients (
      • Kuhn A.
      • Sonntag M.
      • Richter-Hintz D.
      • Oslislo C.
      • Megahed M.
      • Ruzicka T.
      • Lehmann P.
      Phototesting in lupus erythematosus: A 15-year experience.
      ).

      Apoptosis and its role in photosensitive autoimmune diseases

      One of the hallmarks of cutaneous SCLE, DLE, and DM is the presence of increased numbers of apoptotic cells in lesional skin (
      • Pablos J.L.
      • Santiago B.
      • Galindo M.
      • Carreira P.E.
      • Ballestin C.
      • Gomez-Reino J.J.
      Keratinocyte apoptosis and p53 expression in cutaneous lupus and dermatomyositis.
      ). Recent studies suggest that UV-induced apoptosis initiates or exacerbates autoimmunity. It is likely that abnormal production or abnormal clearance of UV-induced apoptotic cells may cause a suprathreshold concentration of nontolerized antigens that is inadequately cleared by the relatively anti-inflammatory macrophage pathway. Normally, apoptotic cells are cleared very efficiently, inhibiting inflammation and inducing tolerance, in part because of anti-inflammatory cytokines (
      • Huynh M.L.
      • Fadok V.A.
      • Henson P.M.
      Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.
      ). This then allows either the apoptotic or the necrotic cells access to the MHC class I and II pathway of a population of APCs that can then, in the presence of costimulatory signals and in susceptible hosts, initiate a primary immune response, leading to autoimmunity. The exact mechanism of development of autoimmunity is unclear, and it is possible that inefficient killing and removal of autoreactive T and B cells, in the setting of specific triggers that define the autoantigen, cause expansion of the population of autoreactive T cells (
      • Pollard K.M.
      Cell death, autoantigen cleavage, and autoimmunity.
      ).
      There is evidence that UV irradiation of cultured keratinocytes causes both translocation and apoptosis of various intracellular and intranuclear antigens to small surface blebs and apoptotic bodies on the keratinocyte cell surface. These blebs and bodies are enriched in 52-kDa Ro, ribosomes, calreticulin, and phospholipid complexes (
      • Casciola-Rosen L.A.
      • Anhalt G.
      • Rosen A.
      Autoantigens targets in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
      ;
      • Casciola-Rosen L.
      • Rosen L.
      Ultraviolet light-induced keratinocyte apoptosis. A potential mechanism for the induction of skin lesions and autoantibody production in LE.
      ), and these lupus autoantigens can be structurally modified during apoptosis (
      • Caciola-Rosen L.A.
      • Anhalt G.J.
      • Rosen A.
      DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis.
      ;
      • Casciola-Rosen L.
      • Andrade F.
      • Ulanet D.
      • Wong W.B.
      • Rosen A.
      Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity.
      ). Studies of T cells from cutaneous LE blood and skin suggest evidence of an antigen-driven response (
      • Furukawa F.
      • Tokura Y.
      • Matsushita K.
      • et al.
      Selective expansions of T cells expressing V beta 8 and V beta 13 in skin lesions of patients with chronic cutaneous lupus erythematosus.
      ;
      • Kita Y.
      • Kuroda K.
      • Mimori T.
      • et al.
      T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus.
      ). The subsequent generation of autoantibodies, such as anti-Ro/SSA and anti-LA/SSB, recognize the cell surface of the apoptotic cell, and this is enhanced with estrogen (
      • LeFeber W.P.
      • Norris D.A.
      • Ryan S.R.
      • et al.
      Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes.
      ;
      • Furukawa F.
      • Lyons M.B.
      • Lee L.A.
      • Coulter S.N.
      • Norris D.A.
      Estradiol enhances binding to cultured human keratinocytes of antibodies specific for SS-A/Ro and SS-B/La. Another possible mechanism for estradiol influence of lupus erythematosus.
      ;
      • Furukawa F.
      • Kashihara-Sawami M.
      • Lyons M.B.
      • Norris D.A.
      Binding of antibodies to the extractable nuclear antigens SS-A/Ro and SS-B/La is induced on the surface of human keratinocytes by ultraviolet light (UVL): Implications for the pathogenesis of photosensitive cutaneous lupus.
      ). Increased autoantibody binding to keratinocytes derived from SCLE and SLE patients has been reported (
      • Furukawa F.
      • Itoh T.
      • Wakita H.
      • Yagi H.
      • Tokura Y.
      • Norris D.A.
      • Takigawa M.
      Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity.
      ). IgG1 anti-Ro autoantibody, demonstrated in skin and blood in SCLE patients, can potentially activate both complement- and antibody-dependent cellular cytotoxicity (ADCC) (
      • Bennion S.D.
      • Ferris C.
      • Lieu T.S.
      • Reimer C.B.
      • Lee L.A.
      IgG subclasses in the serum and skin in subacute cutaneous lupus erythematosus and neonatal lupus erythematosus.
      ). Basal keratinocytes are more resistant to apoptosis and are targets of ADCC in SCLE (
      • Norris D.A.
      • Whang K.
      • David-Bajar K.
      • Bennion S.D.
      The influence of ultraviolet light on immunological cytotoxicity in the skin.
      ). It is likely that the interaction between these autoantibodies and irradiated keratinocytes leads to cytotoxic mechanisms through ADCC (
      • Norris D.A.
      • Whang K.
      • David-Bajar K.
      • Bennion S.D.
      The influence of ultraviolet light on immunological cytotoxicity in the skin.
      ;
      • Furukawa F.
      • Itoh T.
      • Wakita H.
      • Yagi H.
      • Tokura Y.
      • Norris D.A.
      • Takigawa M.
      Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity.
      ). In addition, cytotoxic T cells can induce apoptosis independently. The strongest evidence that these autoantibodies are pathogenic comes from the neonatal equivalent of SCLE, where the neonatal skin disease resolves at the time that maternal autoantibodies are cleared (
      • Lee L.A.
      • Farris A.D.
      Photosensitivity diseases: cutaneous lupus erythematosus.
      ).
      Less is known about the relevance of distinct autoantibodies in cutaneous DM, but there is evidence of activation of complement and deposition of C5b-9 in the skin of both SCLE and DM. It is likely that lymphocyte-mediated cytotoxicity plays a role in DM and, possibly, in SCLE.

      Apoptosis and UV light

      UV light triggers apoptosis through several mechanisms, and UVA and UVB have distinct modes of induction of the DNA damage that lead to apoptosis. Apoptosis of keratinocytes (KC), or sunburn cells, are recognized by the presence of pyknotic nuclei and shrunken and eosinophilic cytoplasm. In particular, UVB causes DNA damage through formation of thymidine dimers. It induces TNF-α via a mechanism related to DNA damage (
      • Kock A.
      • Schwarz T.
      • Kirnbauer R.
      • Urbanski A.
      • Perry P.
      • Ansel J.C.
      • Luger T.A.
      Human keratinocytes are a source for tumor necrosis factor alpha. Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light.
      ;
      • Skov L.
      • Hansen H.
      • Barker J.N.
      • Simon J.C.
      • Baadsgaard O.
      Contrasting effects of ultraviolet-A and ultraviolet-B exposure on induction of contact sensitivity in human skin.
      ;
      • Kibitel J.
      • Hejmadi V.
      • Alas L.
      • O'Connor A.
      • Sutherland B.M.
      • Yarosh D.
      UV-DNA damage in mouse and human cells induces the expression of tumor necrosis factor alpha.
      ;
      • Werth V.P.
      • Zhang W.
      Wavelength-specific synergy between ultraviolet radiation and interleukin-1 alpha in the regulation of matrix-related genes: mechanistic role for tumor necrosis factor-alpha.
      ). TNF-α has been shown to play an important role in UV-induced apoptosis (
      • Schwarz A.
      • Bhardwaj R.
      • Aragane Y.
      • Mahnke K.
      • Riemann H.
      • Metze D.
      • Schwarz T.
      Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells.
      ;
      • Zhuang L.
      • Wang B.
      • Shinder G.A.
      • Shivji G.M.
      • Mak T.W.
      • Sauder D.N.
      TNF receptor p55 plays a pivotal role in murine keratinocyte apoptosis induced by ultraviolet B irradiation.
      ). UVB, through DNA damage and possibly immunomodulatory factors such as prostaglandins and TNF-α, induces IL-10 (
      • Nishigori C.
      • Yarosh D.B.
      • Ullrich S.E.
      • Vink A.A.
      • Bucana C.D.
      • Roza L.
      • Kripke M.L.
      Evidence that DNA damage triggers interleukin 10 cytokine production in UV-irradiated murine keratinocytes.
      ). It also has effects on membrane and cytoplasmic targets. One example of this is UVB activation of death receptors, with direct activation of FAS (
      • Takahashi H.
      • Ishida-Yamamoto A.
      • Iizuka H.
      Ultraviolet B irradiation induces apoptosis of keratinocytes by direct activation of Fas antigen.
      ). UVA effects are complex and involve both early and late mechanisms, some of which are mediated through reactive oxygen species and induction of pro-apoptotic FasL. There is also some activation of pyrimidine dimers with UVA, but UVA-1–induced apoptosis is not inhibited by DNA repair enzymes, suggesting potential mechanistic differences between UVA and UVA-1 (
      • Godar D.E.
      UVA1 radiation triggers two different final apoptotic pathways.
      ;
      • Nishigaki R.
      • Mitani H.
      • Tsuchida N.
      • Shima A.
      Effect of cyclobutane pyrimidine dimers on apoptosis induced by different wavelengths of UV.
      ;
      • Murphy G.
      • Young A.R.
      • Wulf H.C.
      • Kulms D.
      • Schwartz T.
      The molecular determinants of sunburn cell formation.
      ;
      • Nghiem D.X.
      • Kazimi N.
      • Mitchell D.L.
      • Vink A.A.
      • Ananthaswamy H.N.
      • Kripke M.L.
      • Ullrich S.E.
      Mechanisms underlying the suppression of established immune responses by ultraviolet radiation.
      ). Both UVA and UVB induce IL-1 and IL-12, but UVB appears to selectively increase keratinocyte production of TNF-α and IL-10 (
      • Kondo S.
      • Jimbow K.
      Dose-dependent induction of IL-12 but not IL-10 from human keratinocytes after exposure to ultraviolet light A.
      ;
      • Skov L.
      • Hansen H.
      • Allen M.
      • et al.
      Contrasting effects of ultraviolet A1 and ultraviolet B exposure on the induction of tumour necrosis factor-alpha in human skin.
      ;
      • Werth V.P.
      • Zhang W.
      Wavelength-specific synergy between ultraviolet radiation and interleukin-1 alpha in the regulation of matrix-related genes: mechanistic role for tumor necrosis factor-alpha.
      ;
      • Werth V.P.
      • Bashir M.
      • Zhang W.
      IL-12 completely blocks the secretion of TNFα from cultured skin fibroblasts and keratinocytes.
      ). Thus, there are specific cytokines and mechanisms that account for some of the differential effects of UVA and UVB (
      • O'Garra A.
      • Murphy K.
      T-cell subsets in autoimmunity.
      ). Additional mechanisms important in determining UV-induced apoptosis involve the Bcl-2 regulatory family, with control pro- and anti-apoptotic proteins located in the mitochondrial membranes. Nitric oxide protects against keratinocyte and endothelial cell UVA-induced apoptosis, possibly by induction of Bcl-2 (Suschek et al, 2001), but it is decreased with UVB irradiation (
      • Yamaoka J.
      • Sasaki M.
      • Miyachi Y.
      Ultraviolet B radiation downregulates inducible nitric oxide synthase expression induced by interferon-gamma or tumor necrosis factor-alpha in murine keratinocyte Pam 212 cells.
      ).
      Because UVA and UVB can induce apoptosis, it is not surprising that both have been implicated in the induction of LE and DM skin lesions in systematic phototesting (
      • Lehmann P.
      • Holzle E.
      • Kind P.
      • Goerz G.
      • Plewig G.
      Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation.
      ), although the UVA doses utilized for such testing (100 J/cm2) tend to be higher than physiologic exposures, which are about 5 J/cm2 per hour. Clearly, irradiation of human skin with 20 J/cm2 is sufficient to induce significant amounts of apoptosis (Figure 2), and primidine dimers are induced by UVA in mice at doses of 8 J/cm2 (
      • Nghiem D.X.
      • Kazimi N.
      • Mitchell D.L.
      • Vink A.A.
      • Ananthaswamy H.N.
      • Kripke M.L.
      • Ullrich S.E.
      Mechanisms underlying the suppression of established immune responses by ultraviolet radiation.
      ).
      Figure thumbnail gr2
      Figure 2Skin biopsy showing TUNEL + apoptotic keratinocytes in (a) UVA-irradiated skin 48 hours after irradiation (20 J/cm2), but not in (b) sham-irradiated normal skin.
      Fas and FasL are increased in lesional CLE skin, and Bcl-2 is decreased in the basal layer of the epidermis (
      • Baima B.
      • Sticherling M.
      Apoptosis in different cutaneous manifestations of lupus erythematosus.
      ). Thus, suppression of protective Bcl-2 may be necessary prior to the Fas-induced apoptosis of basal KCs in LE skin lesions.
      Although there are several pathways for apoptosis of KCs, as well as numerous anti-inflammatory regulatory molecules, studies have shown that TNF-α is a significant factor in UVB-induced apoptosis (
      • Schwarz A.
      • Bhardwaj R.
      • Aragane Y.
      • Mahnke K.
      • Riemann H.
      • Metze D.
      • Schwarz T.
      Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells.
      ).

      The role of pro-apoptotic genes in SCLE and DM

      Variant alleles associated with increased amounts of TNF-α, given the known UV induction of TNF-α and the role of TNF-α in inducing apoptosis, are prime candidates in the genetic pathogenesis of SCLE and DM. TNF-α induces Ro and La antigen on cultured KCs, causing increased translocation or apoptosis of these cells (
      • Dorner T.
      • Hucko M.
      • Mayet W.J.
      • Trefzer U.
      • Burmester G.R.
      • Hiepe F.
      Enhanced membrane expression of the 52 kDa Ro (SS-A) and La (SS-B) antigens by human keratinocytes induced by TNF alpha.
      ). The first TNF variant described within the human TNF locus was a biallelic polymorphism located at position –308 of the TNF promoter region. There is a very strong association between the uncommon TNF allele (–308 A) and the HLA-A1, -B8, and -DR3 alleles, and early studies could not demonstrate an independent association between the –308 A TNF promoter polymorphism and SLE (
      • Wilson A.G.
      • de Vries N.
      • Pociot F.
      • di Giovine F.S.
      • van der Putte L.B.
      An allelic polymorphism within the human tumor necrosis, factor alpha promoter region is strongly associated with, HLA, A1, B8, and, DR3 alleles.
      ), probably because of the strong linkage dysequilibrium seen in Caucasians between –308 A and HLA-DR3 (
      • Wilson A.G.
      • de Vries N.
      • Pociot F.
      • di Giovine F.S.
      • van der Putte L.B.
      An allelic polymorphism within the human tumor necrosis, factor alpha promoter region is strongly associated with, HLA, A1, B8, and, DR3 alleles.
      ). There is a strong association of HLA-DR3 and the presence of anti-SSA and anti-SSB autoantibodies in SLE patients not seen with the –308 A polymorphism alone (
      • Wilson A.G.
      • Gordon C.
      • di Giovine F.S.
      • de Vries N.
      • van de Putte L.B.
      • Emery P.
      • Duff G.W.
      A genetic association between systemic lupus erythematosus and tumor necrosis factor alpha.
      ). Studies in African Americans with SLE, who do not exhibit linkage dysequilibrium between –308 A and HLA-DR3, determined the independent association of the –308 A promoter polymorphism with SLE (
      • Sullivan K.E.
      • Wooten C.
      • Schmeckpeper B.J.
      • Goldman D.
      • Petri M.A.
      A promoter polymorphism of tumor necrosis factor alpha associated with systemic lupus erythematosus in African-Americans.
      ), which has subsequently been confirmed (
      • Rood M.J.
      • van Krugten M.V.
      • Zanelli E.
      • et al.
      TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.
      ). Reporter genes under the control of the two allelic TNF promoters demonstrated that –308 A is a much stronger transcriptional activator than the –308G wild-type promoter in a human B cell line (
      • Wilson A.G.
      • Symons J.A.
      • McDowell T.L.
      • McDevitt H.O.
      • Duff G.W.
      Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.
      ). More recent studies demonstrated a large increase in the –308 A promoter polymorphism in SCLE and a more modest but significant increase in both juvenile and adult DM (
      • Pachman L.M.
      • Liotta-Davis M.R.
      • Hong D.K.
      • Kinsella T.R.
      • Mendez E.P.
      • Kinder J.M.
      • Chen E.H.
      TNFalpha-308A allele in juvenile dermatomyositis. Association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications.
      ;
      • Werth V.P.
      • Zhang W.
      • Dortzbach K.
      • Sullivan K.
      Association of a promoter polymorphism of TNFalpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.
      ;
      • Werth V.
      • Callen J.P.
      • Ang G.
      • Sullivan K.E.
      Associations of, tumor necrosis factor-α (TNFα) and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis.
      ). Reporter genes under the control of the two allelic TNF promoters demonstrated that –308 A is a much stronger transcriptional activator than the –308G wild-type promoter in UVB-irradiated, but not UVA-irradiated, keratinocytes, and the –308 A variant is associated with increased TNF-α production in keratinocytes (
      • Silverberg N.B.
      • Liotta M.
      • Paller A.S.
      • Pachman I.M.
      TNR-alpha-308 polymorphisms (AA,GA) is associated with increased UVB induced keratinocyte TNF-alpha production in-vitro (Abstract).
      ;
      • Werth V.P.
      • Zhang W.
      • Dortzbach K.
      • Sullivan K.
      Association of a promoter polymorphism of TNFalpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.
      ). The initial reported association with SCLE has been subsequently confirmed in a separate cohort of SCLE patients (
      • Millard T.P.
      • Koneatis E.
      • Cox A.
      • et al.
      A candidate gene analysis of three related photosensitivity disorders: Cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo.
      ). With atotal of 52 SCLE patients in our cohort to date (51 Caucasian, 1African American), 63% are either homozygous (15%) or heterozygous (48%) for the –308 A TNF promoter polymorphism. In the Caucasian control group, 27.7% are either homozygous (1.3%) or heterozygous (26.4%) for the –308 A TNF promoter polymorphism. No statistical difference between DLE and controls could be demonstrated, suggesting genetic differences between SCLE and DLE (
      • Werth V.P.
      • Zhang W.
      • Dortzbach K.
      • Sullivan K.
      Association of a promoter polymorphism of TNFalpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.
      ) and a role for increased TNF-α in the more photosensitive SCLE.
      With a total of 60 DM patients in our cohort to date (55 Caucasian, 4 African American, 1 Hispanic), 45% are either homozygous (6.7%) or heterozygous (38.3%) for the –308 A TNF promoter polymorphism (
      • Werth V.
      • Callen J.P.
      • Ang G.
      • Sullivan K.E.
      Associations of, tumor necrosis factor-α (TNFα) and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis.
      ). In the juvenile DM group, 48% are homozygous (26%) or heterozygous (22%), demonstrating a higher incidence of homozygosity for the overproducing polymorphism than in the adult DM group (
      • Pachman L.M.
      • Liotta-Davis M.R.
      • Hong D.K.
      • Kinsella T.R.
      • Mendez E.P.
      • Kinder J.M.
      • Chen E.H.
      TNFalpha-308A allele in juvenile dermatomyositis. Association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications.
      ). In addition, the disease course was longer in both TNFα promoter -308A heterozygous and homozygous juvenile DM patients and more severe and therapeutically resistant in only the -308A homozygous adult DM patients (
      • Pachman L.M.
      • Liotta-Davis M.R.
      • Hong D.K.
      • Kinsella T.R.
      • Mendez E.P.
      • Kinder J.M.
      • Chen E.H.
      TNFalpha-308A allele in juvenile dermatomyositis. Association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications.
      ;
      • Werth V.
      • Callen J.P.
      • Ang G.
      • Sullivan K.E.
      Associations of, tumor necrosis factor-α (TNFα) and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis.
      ). Overall, these data demonstrate a highly significant statistical association of the overproducing –308A TNF promoter polymorphisms in SCLE and juvenile and adult DM.
      The role of other pro-apoptotic cytokines remains to be defined in photosensitive rheumatic diseases. There is an association of three IL-10 SNPs with production of anti-Ro antibodies in SLE, as well as reports of the association of overproducing IL-10 polymorphisms with SLE (
      • Lazarus M.
      • Hajeer A.H.
      • Turner D.
      • Sinnott P.
      • Worthington J.
      • Ollier W.E.
      • Hutchinson I.V.
      Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus.
      ;
      • Gibson A.W.
      • Edberg J.C.
      • Wu J.
      • Westendorp R.G.
      • Huizinga T.W.
      • Kimberly R.P.
      Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus.
      ); however, increases in IL-10 production were not found in cutaneous LE (
      • van der Linden M.W.
      • Westendorp R.G.
      • Sturk A.
      • Bergman W.
      • Huizinga T.W.
      High interleukin-10 production in first-degree relatives of patients with generalized but not cutaneous lupus erythematosus.
      ).
      It is of interest that UV-induced immunosuppression and tolerance induction are reversed by recombinant interleukin (IL)-12 (
      • Schmitt D.A.
      • Owen-Schaub L.
      • Ullrich S.E.
      Effect of IL-12 on immune suppression and suppressor cell induction by ultraviolet radiation.
      ;
      • Schwarz A.
      • Grabbe S.
      • Aragane Y.
      • et al.
      Interleukin-12 prevents ultraviolet B-induced local immunosuppression and overcomes UVB-induced tolerance.
      ). IL-12 suppresses IL-10 secretion from irradiated KCs and blunts the rise of plasma TNF-α that typically occurs after UV irradiation (
      • Schmitt D.A.
      • Walterscheid J.P.
      • Ullrich S.E.
      Reversal of ultraviolet radiation-induced immune suppression by recombinant interleukin-12: suppression of cytokine production.
      ). Recent studies suggest that IL-12 is induced in a dose-responsive fashion by both UVA and UVB (
      • Werth V.P.
      • Bashir M.
      • Zhang W.
      IL-12 completely blocks the secretion of TNFα from cultured skin fibroblasts and keratinocytes.
      ). In addition, IL-12 blocks TNF-α secretion from irradiated KCs, and this effect is mediated mostly at the level of the TNF promoter (
      • Werth V.P.
      • Bashir M.
      • Zhang W.
      IL-12 completely blocks the secretion of TNFα from cultured skin fibroblasts and keratinocytes.
      ). IL-12 induces DNA repair enzymes and inhibits KC apoptosis (
      • Schwarz A.
      • Stander S.
      • Berneburg M.
      • et al.
      Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.
      ). It is thus tempting to speculate that UVA-1–induced IL-12 may be responsible for inhibition of TNF-α, possibly working through DNA repair enzymes, and so accounts for the therapeutic effects of UVA-1 seen in particular with anti-Ro/SSA positive photosensitive LE patients (
      • McGrath Jr., H.
      Ultraviolet-A1 irradiation decreases clinical disease activity and autoantibodies in patients with systemic lupus erythematosus.
      ).
      Increased UV-induced epidermal cytokines, such as TNF-α, have other ramifications in terms of potential contributions to the pathogenesis of SCLE and DM. First, UV-induced cytokines such as IL-1α and TNF-α increase keratinocyte expression of adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1), which enhances the adhesion of T cells. Increases in keratinocyte and endothelial cell ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1) are seen in DLE, SCLE, tumid LE, and DM (
      • Hausmann G.
      • Mascaro Jr., J.M.
      • Herrero C.
      • Cid M.C.
      • Palou J.
      • Mascaro J.M.
      Cell adhesion molecule expression in cutaneous lesions of dermatomyositis.
      ;
      • Kuhn A.
      • Sonntag M.
      • Sunderkotter C.
      • Lehmann P.
      • Vestweber D.
      • Ruizicka T.
      Upregulation of epidermal surface molecule expression in primary and ultraviolet-induced lesions of lupus erythematosus tumidus.
      ). Soluble E-selectin is increased in cutaneous LE and DM (
      • Nyberg F.
      • Stephansson E.
      Elevated soluble E-selectin in cutaneous lupus erythematosus.
      ;
      • Nyberg F.
      • Hasan T.
      • Skoglund C.
      • Stephansson E.
      Early events in ultraviolet light-induced skin lesions in lupus erythematosus. Expression patterns of adhesion molecules ICAM-1, VCAM-1, and E-selectin.
      ;
      • Kubo M.
      • Ihn H.
      • Yamane K.
      • Yazawa N.
      • Kikuchi K.
      • Soma Y.
      • Tamaki K.
      Increased serum levels of soluble vascular cell adhesion molecule-1 and soluble E-selectin in patients with polymyositis/dermatomyositis.
      ;
      • Kuhn A.
      • Sonntag M.
      • Sunderkotter C.
      • Lehmann P.
      • Vestweber D.
      • Ruizicka T.
      Upregulation of epidermal surface molecule expression in primary and ultraviolet-induced lesions of lupus erythematosus tumidus.
      ), as is soluble ICAM-1 (
      • Kumamoto T.
      • Abe T.
      • Ueyama H.
      • Sugihara R.
      • Shigenaga T.
      • Tsuda T.
      Elevated soluble intercellular adhesion molecules-1 in inflammatory myopathy.
      ) and soluble VCAM-1.
      CXCR3-activating chemokines (CXCL9, CXCL10, and CXCL11) are secreted by macrophages and activated keratinocytes, and likely bring inflammatory cells to the dermal–epidermal junction and periadnexal areas in cutaneous LE. IFN-γ, secreted by activated T cells, macrophages, and UVA-irradiated KCs, induces not only these activating chemokines but also ICAM-1 and HLA-DR3, which are present on keratinocytes, endothelial cells, macrophages, and most infiltrating T cells (
      • Flier J.
      • Boorsma D.M.
      • van Beek P.J.
      • Nieboer C.
      • Stoof T.J.
      • Willemze R.
      • Tensen C.P.
      Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation.
      ). CXCR3 is expressed by both CD4+ and CD8+ dermal T cells in areas where the CXCR3-activating chemokines are present in cutaneous LE.

      The role of genes related to decreased clearance of apoptotic cells in SCLE and DM

      The mechanisms for phagocytosis of apoptotic cells (ACs) are enormously complex, with several receptors implicated in the uptake of ACs by phagocytes. These receptors interact with their ligands on the AC either directly or through bridging proteins (
      • Somersan S.
      • Bhardwaj N.
      Tethering and tickling: a new role for the phosphatidylserine receptor.
      ). In apoptosis, there is exposure of phosphatidylserine on the outer leaflet of the plasma membrane (
      • Hoffmann P.R.
      • deCathelineau A.M.
      • Ogden C.A.
      • et al.
      Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells.
      ). Recent data suggest that a common pathway for apoptosis involves tethering through engagement of receptors on the phagocyte, such as CD36, αvβ3, and αvβ5 integrins, CD14, and CD68 combined with ligation of the phosphatidylserine receptor (
      • Hoffmann P.R.
      • deCathelineau A.M.
      • Ogden C.A.
      • et al.
      Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells.
      ). There are phosphatidylserine-independent pathways for phagocytosis, and these involve the collectins. Under noninflammatory conditions, uptake of ACs by macrophages is thought to suppress autoimmune responses through production of IL-10, TGF-β, PAF, and PGE and inhibition of proinflammatory cytokines such as TNF-α, GM-CSF, IL-12, IL-1β, and IL-8 (
      • Somersan S.
      • Bhardwaj N.
      Tethering and tickling: a new role for the phosphatidylserine receptor.
      ).
      Under inflammatory conditions or when phosphatidylserine or its receptor levels are decreased, it has been proposed that other forms of clearance, such as the collectins, dominate. C1q and mannose-binding lectin (MBL) belong to a family of collectins, otherwise known as defense collagens. Collectins contain a collagen-like tail and a globular head with lectin domains. They play a role in innate immunity, and deficiences of them are associated with an increased susceptibility to infections and autoimmunity (
      • Hansen S.
      • Holmskov U.
      Structural aspects of collectins and receptors for collectins.
      ;
      • Ogden C.A.
      • deCathelineau A.
      • Hoffman P.R.
      • Bratton D.
      • Ghebrehiwet B.
      • Fadok V.A.
      • Henson P.M.
      C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.
      ). The absence of collectins could predispose to a redirection of apototic material away from noninflammatory macrophage clearance to more proinflammatory immature dendritic cells (DC).
      C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes (
      • Korb L.C.
      • Ahearn J.M.
      C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited.
      ). The globular head of C1q binds to apoptotic endothelial cells, and MBL binds to apoptotic Jurkat T cells (
      • Navratil J.S.
      • Watkins S.C.
      • Wisnieski J.J.
      • Ahearn J.M.
      The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells.
      ). Recent data suggest that the collagenous tail of C1q and MBL bind to macrophages through calreticulin (CRT) and CD91 on the macrophage cell surface (
      • Ogden C.A.
      • deCathelineau A.
      • Hoffman P.R.
      • Bratton D.
      • Ghebrehiwet B.
      • Fadok V.A.
      • Henson P.M.
      C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.
      ). C1q and MBL enhance macrophage uptake of apoptotic cells, debris, and infectious organisms through this CRT/CD91 receptor, which in turn initiates macropinocytosis and engulfment of apoptotic cells (
      • Guan E.
      • Robinson S.L.
      • Goodman E.B.
      • Tenner A.J.
      Cell-surface protein identified on phagocytic cells modulates the C1q-mediated enhancement of phagocytosis.
      ;
      • Nepomuceno R.R.
      • Henschen-Edman A.H.
      • Burgess W.H.
      • Tenner A.J.
      cDNA cloning and primary structure analysis of C1qR (P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.
      ;
      • Navratil J.S.
      • Watkins S.C.
      • Wisnieski J.J.
      • Ahearn J.M.
      The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells.
      ;
      • Ogden C.A.
      • deCathelineau A.
      • Hoffman P.R.
      • Bratton D.
      • Ghebrehiwet B.
      • Fadok V.A.
      • Henson P.M.
      C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.
      ).
      Growing evidence in SLE patients and autoimmune mouse models indicates that defects in the clearance of apoptotic cells may also be important in triggering autoimmune responses. There is abnormal clearance of apoptotic lymphocytes and fragments by macrophages in SLE (
      • Herrmann M.
      • Voll R.E.
      • Zoller O.M.
      • Hagenhofer M.
      • Ponner B.B.
      • Kalden J.R.
      Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus.
      ). There is impaired uptake of apoptotic cells in macrophages in germinal centers of some SLE patients (
      • Baumann I.
      • Kolowos W.
      • Voss R.E.
      • et al.
      Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus.
      ). It has been noted that C1q-deficient humans have a nearly 100% chance of developing SLE. These patients develop photosensitive eruptions (
      • Bowness P.
      • Davies K.A.
      • Norsworthy P.J.
      • et al.
      Hereditary C1q deficiency and systemic lupus erythematosus.
      ). In addition, targeted disruption of the receptor tyrosine kinase MER results in uningested apoptotic cells in the thymus, which is associated with induction of antinuclear antibodies (Scott, 2001).
      Animal models with homozygous C1q deficiency develop high titers of antinuclear antibodies and glomerulonephritis, coupled with the accumulation of apoptotic bodies in the glomeruli (
      • Botto M.
      • Dell'Agnola C.
      • Bygrave A.E.
      • et al.
      Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.
      ;
      • Taylor P.R.
      • Carugati A.
      • Fadok V.A.
      • et al.
      A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo.
      ;
      • Mitchell D.A.
      • Pickering M.C.
      • Warren J.
      • et al.
      C1q deficiency and autoimmunity: The effects of genetic background on disease expression.
      ). UV irradiation studies utilizing C57BL/6, 129/Sv, and C57BL/6×129/Sv did not demonstrate an alteration in rate of clearance of sunburn cells after acute UV exposure, and chronic exposure did not alter the systemic disease (
      • Pickering M.C.
      • Fischer S.
      • Lewis M.R.
      • Walport M.J.
      • Botto M.
      • Cook H.T.
      Ultraviolet-radiation-induced keratinocyte apoptosis in C1q-deficient mice.
      ). More recent studies crossed these mice onto various genetic backgrounds, and it was determined that only C1q-deficient MRL/MpJ mice, but not C57BL/6-lpr/lpr or MRL/Mp-lpr/lpr strains, had acceleration of the onset and severity of renal disease and autoantibodies associated with an impairment in the phagocytic clearance of apoptotic cells (
      • Mitchell D.A.
      • Pickering M.C.
      • Warren J.
      • et al.
      C1q deficiency and autoimmunity: The effects of genetic background on disease expression.
      ). UV irradiation studies have not been reported in these mice.
      SCLE was recently linked to a low-producing variant of the C1qA gene, and it is likely that low C1q levels permit delayed clearance of UV-induced apoptotic KCs (
      • Racila D.M.
      • Sontheimer C.J.
      • Sheffield A.
      • Racila E.V.
      • Sontheimer R.D.
      Homozygous variant of complement C1qA gene associated with subacute cutaneous lupus erythematosus (Abstract).
      ). Probably, persistence of apoptotic and necrotic KCs leads to phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for MHC class I and class II presentation (
      • Rovere P.
      • Sabbadini M.G.
      • Fazzini F.
      • Bondanza A.
      • Zimmermann V.S.
      • Rugarli C.
      • Manfredi A.A.
      Remnants of suicidal cells fostering systemic autoaggression. Apoptosis in the origin and maintenance of autoimmunity.
      ).
      There is a parallel story developing with the role of MBL in SLE. MBL has been recognized as a basis for opsonic defects in children with immunodeficiency (
      • Sumiya M.
      • Super M.
      • Tabona P.
      • Levinsky R.J.
      • Arai T.
      • Turner M.W.
      • Summerfield J.A.
      Molecular basis of opsonic defect in immunodeficient children.
      ). Recent data suggest that it plays a role in increased susceptibility to infections in SLE as well as in disease activity (
      • Sullivan K.E.
      • Wooten C.
      • Goldman D.
      • Petri M.
      Mannose binding protein genetic polymorphisms in black patients with systemic lupus erythematosus.
      ;
      • Ip W.K.
      • Chan S.Y.
      • Lau C.S.
      • Lau Y.L.
      Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene.
      ;
      • Garred P.
      • Voss A.
      • Madsen H.O.
      • Junker P.
      Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients.
      ;
      • Tsutsumi A.
      • Sasaki K.
      • Wakamiya N.
      • et al.
      Mannose-binding lectin gene. Polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.
      ), although this has not been a uniform finding (Horiuchi et al, 2001).
      Recent studies find low-producing MBL polymorphisms highly enriched in photosensitive DM patients, but not in SCLE patients, and 53% of DM patients had more than one low-producing MBL polymorphism relative to 17% of controls (p=0.0002) (
      • Werth V.P.
      • Ang G.C.
      • Sullivan K.E.
      Genetic polymorphisms of mannose-binding lectin associated with delayed clearance of apoptotic cells are strongly enriched in leading to subacute cutaneous lupus erythematosus (SCLE) and adult dermatomyositis (Abstract).
      ). Our data show MBL-binding to apoptotic keratinocytes from UV-irradiated human skin (Rosenbaum et al, 2003). It is likely that deficiencies in MBL alter the ability of macrophages to clear apoptotic keratinocytes, thus allowing for persistence of apoptotic cells and debris. Suprathreshold concentrations of nontolerized antigens, in the presence of costimulatory signals, can then gain access to the MHC class I and II pathways of a population of antigen-presenting cells that initiate a primary response, leading to DM. It is unclear why MBL deficiency is associated with DM and not SCLE, but this difference probably relates to different requirements for antigen presentation in DM relative to SCLE.
      C3 has been shown on sunburn cells in C1q-deficient mice, and it is likely that C3 opsonic fragments play a role in the recognition and removal of sunburn cells (SBCs) in skin (
      • Pickering M.C.
      • Fischer S.
      • Lewis M.R.
      • Walport M.J.
      • Botto M.
      • Cook H.T.
      Ultraviolet-radiation-induced keratinocyte apoptosis in C1q-deficient mice.
      ). C2 and C4 complement deficiencies, also associated with SCLE and DM, may play a role in decreased clearance of apoptotic cells.

      Presentation of antigen from apoptotic cells

      Antigens must be taken up by antigen-presenting cells via some form of endocytic process prior to presentation to the T lymphocyte sytem. Generally MHC class I and II molecules capture peptides in the endoplasmic reticulum and endosome/lysosome system, respectively. The assembly of peptides with MHC class I is chaperoned by a number of membrane-bound (calnexin, tapsin) and soluble (calreticulin, Erp57) endoplasmic reticulum proteins. Phagocytosis of apoptotic cells by DCs usually triggers responses associated with DC maturation and antigen presentation. DCs then secrete inflammatory and immunoregulatory cytokines and chemokines; there is increased surface MHC, adhesion, and costimulatory molecules, followed by the loss of phagocytic activity and efficient antigen presentation to CD4+ T cells. TheT cell clonal response to antigen can also trigger B cell autoantibody responses. Antigen uptake and MHC class I–restricted presentation is facilitated by heat shock proteins, which are upregulated by heat and UV light (reviewed in
      • Orteu C.H.
      • Sontheimer R.D.
      • Dutz J.P.
      The pathophysiology of photosensitivity in lupus erythematosus.
      ).

      Dendritic cells and photosensitive autoimmune disease

      There is reason to believe that DCs are involved in the pathogenesis of photosensitive LE. Plasmacytoid DCs found in lesional LE skin may be an important source of the increased IFN-α/β found in cutaneous LE lesions (
      • Toro J.R.
      • Finlay D.
      • Dou X.
      • Zheng S.C.
      • LeBoit P.E.
      • Connolly M.K.
      Detection of type 1 cytokines in discoid lupus erythematosus.
      ). In murine models, these type I IFNs can act in an autocrine manner to activate DCs, and neutralizing antibodies inhibit upregulation of costimulatory molecules, secretion of IFN-γ, and T cell stimulatory activity (
      • Montoya M.
      • Schiavoni G.
      • Mattei F.
      • Gresser I.
      • Belardelli F.
      • Borrow P.
      • Tough D.F.
      Type I interferons produced by dendritic cells promote their phenotypic and functional activation.
      ).
      IL-1α and TNF-α, stimulated by UVB irradiation of keratinocytes, promotes DC maturation and efficient antigen presentation (
      • Cumberbatch M.
      • Dearman R.J.
      • Groves R.W.
      • Antonopoulos C.
      • Kimber I.
      Differential regulation of epidermal langerhans cell migration by interleukins (IL)-1alpha and IL-1beta during irritant- and allergen-induced cutaneous immune responses.
      ). Of interest, IL-10 is inhibitory of DC maturation and is in general anti-inflammatory (
      • Moore K.W.
      • de Waal Malefyt R.
      • Coffman R.A.
      • O'Garra A.
      Interleukin-10 and the interleukin-10 receptor.
      ).

      Inflammatory cells in photosensitive autoimmune disease: The link to antigen presentation

      The inflammatory cells in cutaneous LE are predominantly CD3+, with CD4+ more prevalent than CD8+ cells. There is selective expansion of Vβ8.1 CD3+ cells in skin compared to peripheral blood, consistent with an antigen-driven response (
      • Furukawa F.
      • Tokura Y.
      • Matsushita K.
      • et al.
      Selective expansions of T cells expressing V beta 8 and V beta 13 in skin lesions of patients with chronic cutaneous lupus erythematosus.
      ). Sequencing of TCR clonotypes from skin also suggests an antigen-driven response (
      • Kita Y.
      • Kuroda K.
      • Mimori T.
      • et al.
      T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus.
      ). Additionally, there is evidence of active and productive antigen presentation, with the presence of B7.1 and B7.2 on antigen-presenting cells and expression of MHC class II and CD28 by infiltrating T cells in the cutaneous skin lesions of LE (
      • Denfeld R.W.
      • Kind P.
      • Sontheimer R.D.
      • Schopf E.
      • Simon J.C.
      In situ expression of B7 and CD28 receptor families in skin lesions of patients with lupus erythematosus.
      ). This suggests costimulation of T cells by the B7-1 or B7-2 on APCs that interact with CD28 on T cells. T cells in cutaneous skin lesions of DM are predominantly CD4+, in contrast to the predominant CD8+ T cells found in the blood and muscle of myositis but not DM patients (
      • Benveniste O.
      • Cherin P.
      • Maisonobe T.
      • et al.
      Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients.
      ).
      CXCR3 is expressed by a majority of both CD4+ and CD8+ infiltrating T cells in cutaneous LE, suggesting a functional interaction between locally produced keratinocyte and endothelial chemokines and CXCR3-expressing T cells. Other adhesion molecules such as ICAM-1 and E-selectin are likely also important.
      IL-10 stimulates immunoglobulin production by B cells, and plays a major role in the pathogenesis of SLE. The role of IL-10 is less clear in photosensitive autoimmune disease, since it is known to inhibit activation and effector function of T cells, monocytes, and macrophages (
      • Moore K.W.
      • de Waal Malefyt R.
      • Coffman R.A.
      • O'Garra A.
      Interleukin-10 and the interleukin-10 receptor.
      ).

      Genetics of antigen presentation

      The anti-Ro/SSA antibody production present in SCLE sera is influenced by the presence of specific HLA class II genes (
      • Sontheimer R.D.
      • Maddison P.J.
      • Reichlin M.
      • Jordon R.E.
      • Stastny P.
      • Gilliam J.N.
      Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus.
      ;
      • Provost T.T.
      • Watson R.
      Anti-Ro (SS-A) HLA-DR3-positive women. The interrelationship between some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients.
      ). In particular, HLA-DR3 is associated with both SCLE and DM. Given the importance of TNF-α in photoinduction of autoimmunity, it is likely that the linkage dysequilibrium between the –308 A TNF promoter polymorphism and HLA-DR3 can explain some of this association. Recently it was determined that the association of the –308A TNF promoter polymorphism with HLA-DR3 is much stronger in SCLE (100%) versus DM (60%) or control (56%) (see Table 2) (
      • Werth V.
      • Callen J.P.
      • Ang G.
      • Sullivan K.E.
      Associations of, tumor necrosis factor-α (TNFα) and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis.
      ). This would suggest that Ro antigen presention, enhanced because of increased apoptosis due to TNF-α, can, in the context of HLA-DR3, stimulate an autoantibody response and trigger SCLE. HLA-DR3 is seen to a lesser extent in DM patients, who show the same linkage dyequilibrium that was exhibited in Caucasian controls, thus suggesting that antigen presentation in DM is not enhanced with HLA-DR3. Recent animal experiments support the importance of HLA class II genes in terms of T cell response to autoantigens. Mice transgenic for DR2, DR3, and DQ8 showed stronger T and B cell reponses to human Ro antigen than did DQ6 mice (
      • Paisansinsup T.
      • Deshmukh U.S.
      • Chowdhary V.R.
      • Luthra H.S.
      • Fu S.M.
      • David C.S.
      HLA class II influences the immune response and antibody diversification to Ro60/Sjogren's syndrome-A: heightened antibody responses and epitope spreading in mice expressing HLA-DR molecules.
      ). In addition, there is growing evidence that tissue damage during an immune response primes T and/or B lymphocytes, regardless of the specificity of the orginal insult, leading to epitope spreading. This is also determined by HLA class II genes (
      • Paisansinsup T.
      • Deshmukh U.S.
      • Chowdhary V.R.
      • Luthra H.S.
      • Fu S.M.
      • David C.S.
      HLA class II influences the immune response and antibody diversification to Ro60/Sjogren's syndrome-A: heightened antibody responses and epitope spreading in mice expressing HLA-DR molecules.
      ).
      Table IIAssociation of HLA-DR3 and –308A TNF promoter polymorphism
      TNF-308A++% TNF-308A+ patients
      DR3+who are also DR3+
      Controls16%12%57%
      Dermatomyositis31%20%60%
      SCLE47%0%100%
      It is likely that combinations of polymorphisms are at least in part responsible for the majority of SCLE and DM. Individuals who are homozygous for the –308A TNF promoter polymorphism may have enough residual antigen from apoptotic cells to trigger an immunologic response without having a clearance defect. For many patients who are heterozygous for pro-apoptotic polymorphisms, it is likely that combinations of pro-apoptotic defects with apoptotic clearance defects predispose to autoimmunity. Similarly, as seen with the MBL polymorphisms, patients often have combinations of low-producing variants that probably increase the likelihood of low MBL serum levels and decreased clearance of apoptotic cells (
      • Werth V.P.
      • Ang G.C.
      • Sullivan K.E.
      Genetic polymorphisms of mannose-binding lectin associated with delayed clearance of apoptotic cells are strongly enriched in leading to subacute cutaneous lupus erythematosus (SCLE) and adult dermatomyositis (Abstract).
      ). Clearly, HLA genes will also play a role in antigen presentation and in determining the autoantibody response to nontolerized apoptotic antigen.
      The candidate gene approach has expanded the understanding of the pathogenesis and genetic risk factors of both subacute cutaneous lupus erythematosus and dermatomyositis. The significantly increased incidence of specific genes that correlate with overproduction or decreased clearance of apototic cells, along with HLA genes involved with antigen presentation, support the concept of the relationship between genetic and environmental influences that trigger cutaneous autoimmune disease.
      We thank Dr. Michele Rosenbaum for her help with Figure 2. This work is supported in part by grants from the Lupus research Instititue, National Institutes of Health (K24AR002207) and a V.A. Merit Review Grant.

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