Photosensitivity in Rheumatic Diseases
2004; Elsevier BV; Volume: 9; Issue: 1 Linguagem: Inglês
10.1111/j.1087-0024.2004.00839.x
ISSN1529-1774
AutoresVictoria P. Werth, Muhammad M. Bashir, Wei Zhang,
Tópico(s)T-cell and B-cell Immunology
ResumoThere 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. 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. antibody-dependent cellulary cytotoxicity antigen-presenting cell cytotoxic T lymphocyte dendritic cell discoid lupus erythematosus dermatomyositis human leukocyte antigen interferon lupus erythematosus mannose-binding lectin major histocompatibility natural killer sunburn cell subacute cutaneous lupus erythematosus tumor necrosis factor α ultraviolet 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.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) Open table in a new tab 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. 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 et al., 1992David-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.J Invest Dermatol. 1992; 99: 251-257Crossref PubMed Scopus (95) Google Scholar;Lee and Farris, 1999Lee L.A. Farris A.D. Photosensitivity diseases: cutaneous lupus erythematosus.J Investig Dermatol Symp Proc. 1999; 4: 73-78Abstract Full Text PDF PubMed Scopus (22) Google Scholar), 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 et al., 1982Sontheimer 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.Ann Intern Med. 1982; 97: 664-671Crossref PubMed Scopus (331) Google Scholar). 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 et al., 1990Lehmann P. Holzle E. Kind P. Goerz G. Plewig G. Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation.J Am Acad Dermatol. 1990; 22: 181-187Abstract Full Text PDF PubMed Scopus (235) Google Scholar;Kuhn et al., 2001bKuhn A. Sonntag M. Richter-Hintz D. Oslislo C. Megahed M. Ruzicka T. Lehmann P. Phototesting in lupus erythematosus tumidus-review of 60 patients.Photochem Photobiol. 2001; 73: 532-536Crossref PubMed Google Scholar). 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 et al., 2001aKuhn A. Sonntag M. Richter-Hintz D. Oslislo C. Megahed M. Ruzicka T. Lehmann P. Phototesting in lupus erythematosus: A 15-year experience.J Am Acad Dermatol. 2001; 45: 86-95Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). One of the hallmarks of cutaneous SCLE, DLE, and DM is the presence of increased numbers of apoptotic cells in lesional skin (Pablos et al., 1999Pablos 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.J Path. 1999; 188: 63-68Crossref PubMed Scopus (67) Google Scholar). 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 et al., 2002Huynh M.L. Fadok V.A. Henson P.M. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.J Clin Invest. 2002; 109: 41-50Crossref PubMed Scopus (959) Google Scholar). 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, 2002Pollard K.M. Cell death, autoantigen cleavage, and autoimmunity.Arthr Rheum. 2002; 46: 1699-1702Crossref PubMed Scopus (11) Google Scholar). 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 et al., 1994Casciola-Rosen L.A. Anhalt G. Rosen A. Autoantigens targets in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.J Exp Med. 1994; 179: 1317-1330Crossref PubMed Scopus (1489) Google Scholar;Casciola-Rosen and Rosen, 1997Casciola-Rosen L. Rosen L. Ultraviolet light-induced keratinocyte apoptosis. A potential mechanism for the induction of skin lesions and autoantibody production in LE.Lupus. 1997; 6: 175-180Crossref PubMed Scopus (144) Google Scholar), and these lupus autoantigens can be structurally modified during apoptosis (Caciola-Rosen et al., 1995Caciola-Rosen L.A. Anhalt G.J. Rosen A. DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis.J Exp Med. 1995; 182: 1625-1634Crossref PubMed Scopus (395) Google Scholar;Casciola-Rosen et al., 1999Casciola-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.J Exp Med. 1999; 190: 815-826Crossref PubMed Scopus (413) Google Scholar). Studies of T cells from cutaneous LE blood and skin suggest evidence of an antigen-driven response (Furukawa et al., 1996Furukawa 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.J Dermatol. 1996; 23: 670-676Crossref PubMed Scopus (25) Google Scholar;Kita et al., 1998Kita Y. Kuroda K. Mimori T. et al.T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus.J Invest Dermatol. 1998; 110: 41-46Crossref PubMed Scopus (20) Google Scholar). 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 et al., 1984LeFeber W.P. Norris D.A. Ryan S.R. et al.Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes.J Clin Invest. 1984; 74: 1545-1551Crossref PubMed Scopus (280) Google Scholar;Furukawa et al., 1988Furukawa 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.J Immunol. 1988; 141: 1480-1488PubMed Google Scholar;Furukawa et al., 1990Furukawa 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.J Invest Dermatol. 1990; 94: 77-85Abstract Full Text PDF PubMed Google Scholar). Increased autoantibody binding to keratinocytes derived from SCLE and SLE patients has been reported (Furukawa et al., 1999Furukawa 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.Clin Exp Immunol. 1999; 118: 164-170Crossref PubMed Scopus (65) Google Scholar). IgG1 anti-Ro autoantibody, demonstrated in skin and blood in SCLE patients, can potentially activate both complement- and antibody-dependent cellular cytotoxicity (ADCC) (Bennion et al., 1990Bennion 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.J Investig Dermatol Symp Proc. 1990; 95: 643-646Abstract Full Text PDF Google Scholar). Basal keratinocytes are more resistant to apoptosis and are targets of ADCC in SCLE (Norris et al., 1997Norris D.A. Whang K. David-Bajar K. Bennion S.D. The influence of ultraviolet light on immunological cytotoxicity in the skin.Photochem Photobiol. 1997; 65: 636-646Crossref PubMed Scopus (37) Google Scholar). It is likely that the interaction between these autoantibodies and irradiated keratinocytes leads to cytotoxic mechanisms through ADCC (Norris et al., 1997Norris D.A. Whang K. David-Bajar K. Bennion S.D. The influence of ultraviolet light on immunological cytotoxicity in the skin.Photochem Photobiol. 1997; 65: 636-646Crossref PubMed Scopus (37) Google Scholar;Furukawa et al., 1999Furukawa 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.Clin Exp Immunol. 1999; 118: 164-170Crossref PubMed Scopus (65) Google Scholar). 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 and Farris, 1999Lee L.A. Farris A.D. Photosensitivity diseases: cutaneous lupus erythematosus.J Investig Dermatol Symp Proc. 1999; 4: 73-78Abstract Full Text PDF PubMed Scopus (22) Google Scholar). 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. 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 et al., 1990Kock 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.J Exp Med. 1990; 172: 1609-1614Crossref PubMed Scopus (611) Google Scholar;Skov et al., 1997Skov 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.Clin Exp Immunol. 1997; 107: 585-588Crossref PubMed Scopus (55) Google Scholar;Kibitel et al., 1998Kibitel 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.Photochem Photobiol. 1998; 67: 541-546Crossref PubMed Scopus (67) Google Scholar;Werth and Zhang, 1999Werth 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.J Invest Dermatol. 1999; 113: 196-201Crossref PubMed Scopus (24) Google Scholar). TNF-α has been shown to play an important role in UV-induced apoptosis (Schwarz et al., 1995Schwarz 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.J Invest Dermatol. 1995; 104: 922-927Crossref PubMed Scopus (245) Google Scholar;Zhuang et al., 1999Zhuang 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.J Immunol. 1999; 162: 1440-1447PubMed Google Scholar). UVB, through DNA damage and possibly immunomodulatory factors such as prostaglandins and TNF-α, induces IL-10 (Nishigori et al., 1996Nishigori 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.Proc Natl Acad Sci U S A. 1996; 93: 10354-10359Crossref PubMed Scopus (215) Google Scholar). 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 et al., 2002Takahashi H. Ishida-Yamamoto A. Iizuka H. Ultraviolet B irradiation induces apoptosis of keratinocytes by direct activation of Fas antigen.J. Invest Dermatol Symp Proc The. 2002: 64-68Google Scholar). 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, 1999Godar D.E. UVA1 radiation triggers two different final apoptotic pathways.J Invest Dermatol. 1999; 112: 3-12Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar;Nishigaki et al., 1999Nishigaki R. Mitani H. Tsuchida N. Shima A. Effect of cyclobutane pyrimidine dimers on apoptosis induced by different wavelengths of UV.Photochem Photobiol. 1999; 70: 228-235Crossref PubMed Scopus (14) Google Scholar;Murphy et al., 2001Murphy G. Young A.R. Wulf H.C. Kulms D. Schwartz T. The molecular determinants of sunburn cell formation.Exp Dermatol. 2001; 10: 155-160Crossref PubMed Scopus (107) Google Scholar;Nghiem et al., 2002Nghiem 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.J Invest Dermatol. 2002; 119: 600-608Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). 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 and Jimbow, 2001Kondo S. Jimbow K. Dose-dependent induction of IL-12 but not IL-10 from human keratinocytes after exposure to ultraviolet light A.J Cell Physiol. 2001; 177: 493-498Crossref Scopus (38) Google Scholar;Skov et al., 1998Skov 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.Br J Dermatol. 1998; 138: 216-220Crossref PubMed Scopus (91) Google Scholar;Werth and Zhang, 1999Werth 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.J Invest Dermatol. 1999; 113: 196-201Crossref PubMed Scopus (24) Google Scholar;Werth et al., 2003Werth V.P. Bashir M. Zhang W. IL-12 completely blocks the secretion of TNFα from cultured skin fibroblasts and keratinocytes.J Invest Dermatol. 2003Google Scholar). Thus, there are specific cytokines and mechanisms that account for some of the differential effects of UVA and UVB (O'Garra and Murphy, 1993O'Garra A. Murphy K. T-cell subsets in autoimmunity.Curr Opin Immunol. 1993; 5: 880-886Crossref PubMed Scopus (121) Google Scholar). 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 et al., 2000Yamaoka 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.Arch Dermatol Res. 2000; 292: 312-319Crossref PubMed Scopus (21) Google Scholar). 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 et al., 1990Lehmann P. Holzle E. Kind P. Goerz G. Plewig G. Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation.J Am Acad Dermatol. 1990; 22: 181-187Abstract Full Text PDF PubMed Scopus (235) Google Scholar), 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 et al., 2002Nghiem 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.J Invest Dermatol. 2002; 119: 600-608Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Fas and FasL are increased in lesional CLE skin, and Bcl-2 is decreased in the basal layer of the epidermis (Baima and Sticherling, 2001Baima B. Sticherling M. Apoptosis in different cutaneous manifestations of lupus erythematosus.Br J Dermatol. 2001; 144: 958-966Crossref PubMed Scopus (87) Google Scholar). 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 et al., 1995Schwarz 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.J Invest Dermatol. 1995; 104: 922-927Crossref PubMed Scopus (245) Google Scholar). 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 et al., 1995Dorner 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.Ann Rheum Dis. 1995; 54: 904-909Crossref PubMed Scopus (59) Google Scholar). 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 et al., 1993Wilson 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.J Exp Med. 1993; 177: 557-560Crossref PubMed Scopus (670) Google Scholar), probably because of the strong linkage dysequilibrium seen in Caucasians between –308 A and HLA-DR3 (Wilson et al., 1993Wilson 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.J Exp Med. 1993; 177: 557-560Crossref PubMed Scopus (670) Google Scholar). 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 et al., 1994Wilson 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.Eur J Immunol. 1994; 24: 191-195Crossref PubMed Scopus (211) Google Scholar). 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 et al., 1997Sullivan 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.Arthr Rheum. 1997; 40: 2207-2211Crossref PubMed Scopus (153) Google Scholar), which has subsequently been confirmed (Rood et al., 2000Rood M.J. van Krugten M.V. Zanelli E. et al.TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.Arthr Rheum. 2000; 43: 129-134Crossref PubMed Scopus (168) Google Scholar). 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 et al., 1997Wilson 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.Proc Natl Acad Sci U S A. 1997; 94: 3195-3199Crossref PubMed Scopus (2046) Google Scholar). 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 et al., 2000Pachman 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.Arthr Rheum. 2000; 43: 2368-2377Crossref PubMed Scopus (180) Google Scholar;Werth et al., 2000Werth 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.J Invest Dermatol. 2000; 115: 726-730Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar;Werth et al., 2002bWerth 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.J Invest Dermatol. 2002; 119: 617-620Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). 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 et al., 1999Silverberg 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).Arthr Rheum. 1999; 42: 93Google Scholar;Werth et al., 2000Werth 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.J Invest Dermatol. 2000; 115: 726-730Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). The initial reported association with SCLE has been subsequently confirmed in a separate cohort of SCLE patients (Millard et al., 2001Millard 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.Br J Dermatol. 2001; 145: 229-236Crossref PubMed Scopus (46) Google Scholar). 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 et al., 2000Werth 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.J Invest Dermatol. 2000; 115: 726-730Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) 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 et al., 2002bWerth 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 uniqu
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