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Photodermatol Photoimmunol Photomed 2001; 17: 95-113

Hak Cipta
C
Munksgaard 2001
Dicetak di Denmark All rights reserved
Munksgaard Copenhagen
ISSN 0905-4383
Artikel Ulasan
Patofisiologi fotosensitifitas di lupus erythematosus
Catherine H. Orteu
1
, Richard D. Sontheimer
2
, Jan P. Dutz
1
1
Divisi Dermatologi, Fakultas Kedokteran, Universitas British Columbia, Vancouver
dan Rumah Sakit dan Pusat Ilmu Kesehatan, Vancouver
BC, Canada;
2
Departemen Dermatologi, Universitas Iowa Rumah Sakit dan Klinik / University of
Iowa Kesehatan, Iowa City, Iowa, USA
Hubungan yang kuat antara fotosensitifitas dan
lupus erythematosus telah menyebabkan saran bahwa ABphotoreactivity biasa berpartisipasi dalam patogenesis yang
usul lesi kulit. Dalam ulasan ini kita membahas
bukti reaktivitas kulit normal untuk mataharicahaya dalam lupus dan berspekulasi mengenai seluler, molekul
Bukti fotosensitifitas klinis pada lupus
erythematosus
Lesi kulit yang ditemukan pada sampai dengan 90% dari pasien dengan sistem
pendokumentasian
andil lupus erythematosus (SLE) (1), dan adalah yang pertama
manifestasi penyakit pada 23-28% (2). Dalam satu co- besar
hort, temuan kulit-lupus tertentu seperti ruam malar
(Akut lupus erythematosus kulit - ACLE) dan dis
lupus coid (kronis eritematosus lupus kulit CCLE) ditemukan pada 64% dan 31% dari pasien, masing-masing (1). Ada hubungan yang jelas antara sinar matahari
eksposur dan manifestasi kulit lupus ery-

thematosus, dan lesi cenderung terjadi pada kulit yang terpapar sinar matahari
(3, 4). Sampai dengan 73% dari pasien dengan laporan LE sistemik
photosensitivity (5), meskipun hal ini berkorelasi buruk dengan
Hasil foto-testing menggunakan protokol standar (6).
Mengulangi pengamatan pasien tunggal menunjukkan sinar matahari yang
dapat memicu penyakit sistemik de novo atau memperburuk
penyakit yang ada. Fototerapi untuk dianggap psoriasis memiliki
menyebabkan kejengkelan lesi lupus (7). Tanning bed digunakan
juga telah dilaporkan memperburuk SLE (8). Tambahan Pula,
pasien melaporkan bahwa beberapa gejala penyakit (termasuk
kelemahan, kelelahan dan nyeri sendi) yang meningkat sebesar matahari mantan
posure (5). Variasi aktivitas penyakit yang berhubungan dengan matahari mantan
posure menggunakan variabel obyektif belum ditunjukkan dalam
penelitian kohort besar; Namun, dua penelitian terbaru menunjukkan bahwa
meskipun manifestasi kulit lebih sering terjadi pada
musim panas, aktivitas penyakit sistemik meningkat
dalam 3-6 bulan setelah maksimal potensi mantan matahari
posure. Hal ini telah menyebabkan para penulis ini menyarankan bahwa musim panas
Paparan sinar UV dapat menyebabkan flare sistemik beberapa
bulan kemudian (9, 10).
Kedua tunggal dan berulang eksposur ultraviolet (UV)
95
dan faktor genetik yang mungkin mendasari ini abnormalitas
mality.
Kata kunci: erythematosus lupus; fotosensitifitas;
apoptosis; TNF a, protein heat shock.
radiasi dapat memicu lesi kulit pada pasien dengan LE
(11-13). Selain induksi lesi, yang mungkin
tertunda hingga 2 minggu, batas penurunan untuk
induksi eritema dan eritema berkepanjangan setelah UV
iradiasi telah dijelaskan (14, 15). Dengan demikian, pasien
dengan baik lupus sistemik atau kulit mengembangkan berkepanjangan
kulit kemerahan pada dosis rendah sinar UV daripada con yang normal
controls.
Sinar ultraviolet terdiri dari berbagai disebabkan oleh gelombang yang berbeda
panjang dan umumnya dibagi menjadi UV kuman
cahaya (UVC, 100-280 nm), sinar UV midrange atau terbakar sinar matahari
Sinar UV (UVB, 280-320 nm) dan gelombang panjang sinar UV
(UVA, 320-400 nm), juga disebut dekat UV atau cahaya hitam.
UVC tidak mungkin relevansi patofisiologis,
karena benar-benar diblokir oleh atmosfer bumi.

Spektrum UV matahari terdiri dari sekitar 510% UVB dan UVA 90-95%. Panjang gelombang yang berbeda
memiliki tingkat energi yang berbeda dan penetrasi karakteristics, dan akibatnya memiliki berbagai efek biologis dalam
kulit (16). Penurunan tingkat energi dan kedalaman
penetrasi meningkat dengan meningkatnya panjang gelombang. Itu
Efek dari UVB dengan demikian sebagian besar diarahkan
epidermis dan dermis papillary, sedangkan UVA penaetrates lebih dalam dermis retikular. Sebuah alamiah lainnya tindakan
trum di kisaran UVB telah ditetapkan untuk kulit yang
bentuk LE (11-13, 17, 18). Baru-baru ini, penelitian telah
menunjukkan baik eritema normal berkepanjangan, dan
induksi lesi kulit berikut paparan UVA
(19, 20). Lehmann dan rekan melakukan ekstensif
Studi photoprovocation pada tahun 1990 (20). Mereka mampu
menginduksi lesi pada 64% pasien dengan subakut kulit
lupus erythematosus (SCLE), yang paling fotosensitif
Halaman 2

Orteu et al.
bentuk lupus kulit, dan di 42% dan 25% dari pasien
dengan CCLE dan SLE masing-masing. Dari mereka dengan UV-in
Lesi diproduksi, 53% yang disebabkan oleh UVB atau UVA, 14%
oleh UVA sendiri dan 33% oleh UVB saja. Meskipun UVAdiinduksi eritema pada kulit normal membutuhkan 1000 kali
lebih banyak energi daripada dari UVB (18), paparan setiap hari untuk UVA
jauh lebih besar daripada UVB, dan pada tingkat dermatofita yang
kapiler mal, efek UVA - karena lebih besar penaetrance - jauh lebih kuat bahwa UVB. Dengan demikian, sinar UV dari
berbagai panjang gelombang dapat memprovokasi respon kulit normal
pada pasien lupus dan dapat menyebabkan lesi kulit. Col
lectively, pengamatan ini telah digunakan untuk membenarkan con
fotoproteksi terus berlanjutnya untuk pasien dengan baik kulit
dan lupus sistemik (21, 22).
Fitur histopatologis lupus kulit
Perubahan pada epidermis
Patologi lupus kulit merupakan salah satu lichenoid sebuah
reaksi jaringan di mana kerusakan sel basal epidermis adalah
dimanifestasikan oleh perubahan vacuolar dan adanya keratinocytes dengan inti pyknotic dan eosinophilic menyusut
sitoplasma (23, 24). Meskipun karakter-morfologis

istics dari sel-sel ini menyarankan mereka apoptosis, itu tidak

sampai saat ini bahwa terminal deoxynucleotidyl transferasedimediasi UTP nick akhir pelabelan (TUNEL) pewarnaan adalah
digunakan untuk mengkonfirmasi kehadiran peningkatan jumlah
keratinosit apoptosis pada lesi LE (25, 26). In ini
lipatan kini telah ditunjukkan di zona basal
Lesi CCLE dan di zona suprabasal lesi SCLE
(25) dan telah dikaitkan dengan peningkatan protein p53
ekspresi yang ditentukan oleh imunohistokimia (26,
27). Perubahan atas ditemukan dalam hubungan dengan
keratinosit hyperproliferation, dengan berbeda- awal yang normal
entiation dan diferensiasi terminal dini (28). Di
lesi spontan dan akhir lesi foto-diinduksi, keratinocyte MHC kelas II dan intraseluler adhesi mol
ecule I (ICAM-1) ekspresi meningkat dan jumlah
epidermal sel Langerhans berkurang (29-33). De- ini
lipatan jumlah sel Langerhans mungkin mencerminkan DC mengaktivasi
elevasi dan migrasi ke kelenjar getah bening regional (lihat
bawah).
Perubahan di persimpangan dermo-epidermal
Penebalan membran basal merupakan temuan yang sering
di LE. Penyebabnya tidak diketahui, tetapi tampaknya disebabkan terutama
dengan reduplikasi dari lamina densa (34). ImmunofluStudi orescence dari kulit lesi LE menunjukkan de- lesi
posisi imunoglobulin. Pada 80-90% dari CCLE atau
ACLE, dan 50-60% dari SCLE, sebuah band tebal imun
globulin dan melengkapi komponen disimpan bersama
persimpangan dermo-epidermal (35). Kompleks ini memiliki
telah terlokalisasi pada serat kolagen dermal atas dan
sepanjang lamina densa dari ruang bawah tanah epidermal gota
96
Zona brane (36). Sebagai deposito ini juga ditemukan dalam clinKulit turun tajam normal pasien dengan SLE, peran mereka dalam lo- tersebut
cal induksi cedera jaringan kulit masih belum jelas (37).
Selanjutnya, kekhususan basement kulit ini membran dan
antibodi disimpan belum ditetapkan.
Perubahan dalam dermis
Sebuah infiltrasi sel radang kulit hadir untuk berbagai
derajat dalam segala bentuk kulit LE, dan ditandai
oleh sel mononuklear di persimpangan dermo-epidermal
(DEJ) serta sekitar pembuluh darah dan kulit append-

usia. Ini cenderung lebih dangkal di ACLE dan

SCLE, dengan lebih menonjol dermatofita peri-adneksa dan mendalam
komponen mal di DLE (38). Sejumlah penelitian telah
menyelidiki karakteristik fenotipik infiltrasi
sel. Dalam didirikan kulit lesi LE, CD3 positif
sel mendominasi, dengan sel CD4 positif hadir di
angka lebih tinggi dari sel-sel CD8 (ditinjau dalam (35)). Itu
Studi lesi foto-diinduksi telah memungkinkan analisis
perubahan histologis awal dan evolusi mereka. Pada awal
lesi, analisis ini telah menunjukkan CD4

Sel T pradominan di DEJ tersebut. Dalam lesi spontan dan akhir

lesi foto-diinduksi, peningkatan jumlah CD8

T
Sel yang diamati (29-32). Jenis dominan T
sel dalam membentuk infiltrat inflamasi tetap kontroversial
versial. Volc-Platzer et al. telah menyarankan bahwa sel-sel T dari
fenotipe reseptor sel T gd spesifik istimewa
diperluas dalam infiltrat (39). Mereka mengusulkan agar
Sel-sel ini dapat mengenali protein heat shock induksi atau
translokasi dalam keratinosit oleh UV atau stres. Fivenson et
al., bagaimanapun, melaporkan bahwa sel gd T yang hampir tidak ada
dalam infiltrate (40). Penggunaan V b infiltrasi sel T
pada lesi kulit LE baru-baru ini dibandingkan dengan
dalam darah perifer dan con kulit inflamasi lainnya
ditions (41). Persentase V b 8.1 sel CD3 adalah elevated pada lesi kulit dari kedua CCLE dan ACLE saat
dibandingkan dengan pasien dengan kulit inflamasi lainnya dis
kemudahan. Ada condong signifikan untuk V ini jenis b saat
dibandingkan dengan darah perifer. Ekspansi selektif ini
konsisten dengan respon antigen didorong. Urutan
Reseptor sel T (TCR) clonotypes berasal dari in the
flammatory infiltrat lanjut menunjukkan antigen-induced
akumulasi klonal (42). Ekspresi kelas II MHC
molekul dan CD28 dengan infiltrasi sel T dan ekspresi
dari B7-1 (CD80) dan B7-2 (CD86) costimulatory mol
ecules oleh sel antigen-presenting di lesi tetapi tidak
kulit non-lesi menunjukkan berlangsung aktif dan produktif
presentasi antigen ke sel T dalam kulit LE (43).

Efek biologis dari sinar UV pada epidermis

Sinar ultraviolet memiliki beberapa efek pada jaringan hidup. Po
target molekul bangkan sinar ultraviolet termasuk DNA,
RNA, protein dan lipid.
Halaman 3

Fotosensitifitas pada lupus eritematosus

Kerusakan DNA
Kemungkinan bahwa sinar UV yang terlibat dalam patogenesis yang
genesis lupus eritematosus sistemik dan kulit lupus
Penyakit ini didukung oleh studi mekanistik. Autoantitubuh untuk DNA dan protein DNA terkait karakterize sistemik LE. Penyakit lupus seperti Extracutaneous dapat
diinduksi pada hewan dengan pengenalan anti-DNA anti
tubuh baik transgenik (44) atau dengan injec- intravena
tion (45). Dalam penelitian awal, DNA-iradiasi UV tapi tidak
DNA asli ditunjukkan untuk mendorong kembali imun humoral
tanggapan pada hewan. Suntikan berulang dari UV-iradiasi
DNA (UV-DNA) menjadi kelinci mengakibatkan penyakit ginjal
ditandai dengan proteinuria dan imunoglobulin ginjal
deposisi (46). Hasil yang sama diperoleh pada tikus dan
beberapa immunopathological dan histopatologis
perubahan yang berhubungan dengan kulit LE kemudian reprodiproduksi dengan mengekspos kulit tikus UV-DNA diimunisasi
radiasi UV (47).
Panjang gelombang yang berbeda dari radiasi UV menyebabkan berbeda
jenis kerusakan DNA. Meskipun ada beberapa derajat
tumpang tindih (16), UVB terutama menghasilkan pirimidin
dimer oleh eksitasi langsung dari molekul DNA, sedangkan
UVA merusak DNA secara tidak langsung melalui photosensi- sebuah
Reaksi tized dimediasi terutama oleh oksigen singlet, yang
menghasilkan modifikasi basa purin (48-50). Timidin
dimer ditemukan pada kulit tikus-iradiasi UV dan
Antibodi UV-DNA bereaksi terhadap ini dimer timidin (51,
52). Lebih data hewan baru-baru ini menunjukkan bahwa DNA yang rusak
oleh spesies oksigen reaktif (ROS-DNA) juga bisa
imunogenik, mendorong antibodi yang mengenali baik native dan ROS-DNA (53, 54). Respon imun seperti untuk
DNA-UV diubah juga telah ditemukan pada pasien LE
(55).
Translokasi autoantigens nuklir untuk

permukaan keratinosit
Radiasi UV tidak hanya mengubah DNA, menyebabkan cytoskeletal
reorganisasi dalam keratinosit (56). Sebuah studi awal oleh
LeFeber mengungkapkan bahwa sinar UV dapat menyebabkan pengikatan
antibodi terhadap antigen nuklir dipilih pada manusia berbudaya
keratinosit (57). Kekhasan antibodi ini adalah
tidak didefinisikan tetapi sekarang diketahui bahwa mereka umumnya
diarahkan terhadap Ro / SSA, La / SSB, ribonucleoprotein
(RNP) dan Smith (Sm) antigen dan antibodi adalah
terkait dengan LE dan fotosensitifitas. Penelitian lebih lanjut
telah mengkonfirmasikan adanya peningkatan autoantibodi
mengikat antigen ini pada normal dan LE keratinosit
Berikut UVA dan UVB iradiasi in vitro dan in vivo
(58, 59). Relocalization dari Ro60, Ro52, Sm dan La anti
gens ke permukaan sel telah dibuktikan secara in vitro
Berikut paparan keratinosit manusia untuk UVA dan
UVB (60, 61), dan ekspresi mereka lebih tinggi pada lupus-pasien
pasien-dengan didokumentasikan photosensitivity (62). Hasilnya97
Peningkatan semut di autoantibodi yang mengikat bisa membuat UV
Sel-sel iradiasi lebih rentan terhadap antibodi-bergantung
diperantarai sel sitotoksisitas (ADCC). Dominan IgG
subclass yang disimpan pada lesi adalah IgG
1
, Bentuk yang
dikenal untuk mengaktifkan komplemen dan memulai ADCC (63).
Serangan membran pelengkap kompleks (C5b-9) memiliki
telah diidentifikasi dalam lesi tapi tidak di kulit tidak terlibat dari
pasien dengan SLE, SCLE, atau CCLE (64, 65). Obser- ini
vations telah menyebabkan saran bahwa interaksi menjadiantibodi tween (terutama anti-SS-A / Ro) dan UVBkeratinosit iradiasi dapat menyebabkan lesi kulit
SLE dan SCLE melalui mekanisme sitotoksik (66-69).
Meskipun bukti ini, anti-Ro / SSA, La / SSB dan lainnya
autoantibodi mungkin tidak memiliki peran dalam memulai clin- yang
Lesi ical lupus kulit sejak deposisi immunoglobulin dan melengkapi komponen yang terdeteksi
dengan mikroskop fluoresensi umumnya mengikuti penampilannya yang
Ance peradangan perivaskular di photoprovoked
lesi (13, 20). Meskipun antibodi anti-Ro / SSA dapat potentiate ADCC in vitro (69, 70), pembunuh alami (NK) sel

adalah mediator yang paling umum dari ADCC dan ini

jarang terlihat di infiltrat lupus kulit (71, 72). Ini ulang
induk kemungkinan bahwa jenis sel lain, termasuk monosit
atau limfosit, yang berpartisipasi dalam ADCC tetapi ini
belum dikonfirmasi secara in vivo.
Ada mekanisme lain dimana keratinosit mantan
posure sinar UV dapat menyebabkan translokasi autoantigens ke permukaan sel. Penelitian terbaru telah menyarankan
yang kelainan dalam proses kematian sel apoptosis
mungkin memainkan peran penting dalam inisiasi dan propagation LE dengan mengubah generasi dan pembelahan
antigen (73).
Peningkatan apoptosis keratinosit, pembentukan
neo-antigen
Apoptosis merupakan cara memerintahkan sel non-inflamasi
penghapusan di mana inisiat Program biokimia pusat
pembongkaran sel dengan fragmentasi nuklir, formation amplop apoptosis dan menyusutnya sel
menjadi fragmen yang mengarah ke fagositosis oleh parenkim
sel serta fagosit (74-76). Apoptosis dapat
lebih dikategorikan ke dalam '' langsung '' apoptosis atau pra
diprogram kematian sel, dan '' menengah '' dan '' delayed '' apoptosis atau sel mati terprogram (ditinjau oleh
(77)). Apoptosis langsung adalah protein sintesis kemerdekaanpenyok, terjadi dengan cepat setelah memicu (78) dan hasilnya
kerusakan singlet oksigen ke membran mitokondria.
Menengah apoptosis umumnya hasil mengaktivasi
elevasi dari reseptor membran dengan domain kematian tersebut
sebagai Fas (ditinjau dalam (79)). Tertunda apoptosis membutuhkan sevjam eral untuk eksekusi dan protein sintesis dependent. Hal ini dapat menjadi hasil dari kerusakan DNA (80) atau karena
kurangnya sinyal survival penting (81-84).
Page 4

Orteu et al.
Peningkatan jumlah keratinosit apoptosis yang tekanan
ent di basal dan suprabasal lapisan kulit LE
lesi (25-27). Meskipun apoptosis pada sel granular
lapisan epidermis terjadi sebagai bagian dari keratino- yang normal
diferensiasi monosit (38, 85, 86), keratino- basilar yang normal
cytes relatif tahan terhadap kematian sel yang disebabkan oleh var- sebuah

iety rangsangan (25). Hal ini mungkin sebagai akibat dari mantan mereka
pression protein, seperti bcl-2, survivin (87) dan lainnya
IAP (inhibitor apoptosis - Ulasan dalam (88)), yang
khusus menghambat apoptosis. Kemampuan ultraviolet
cahaya untuk menginduksi apoptosis kematian di suprabasal keratinocytes telah diakui selama bertahun-tahun dan sel-sel ini
yang disebut '' sel kulit terbakar '' oleh ahli morfologi (89). Bagai Manapernah, keratinosit berbudaya dari pasien dengan SLE dan
SCLE menunjukkan sitotoksisitas secara signifikan lebih besar berikut
Paparan UV dari keratinosit dari orang dewasa normal concontrols (67, 69). Ada sejumlah cara yang berbeda dari mana memulainya?
oleh sinar UV dapat menginduksi kematian sel pada keratinosit. Panjang
sinar ultraviolet gelombang (UVA1; 380-400 nm) dapat menginduksi
'' Kematian apoptosis 'langsung' melalui singlet oksigen
kerusakan membran mitokondria (90). Paparan
panjang gelombang yang lebih luas UVA dapat mengaktifkan gen-gen yang mengkode
protein pro-apoptosis FasL (Fas ligand) dan Bax (61).
UVB dapat menginduksi langsung, ligan independen, aktivasi
reseptor membran kematian seperti Fas (91) serta
FasL upregulation dan selanjutnya Fas-FasL mengikat (92).
Tumor necrosis factor-a (TNF a) rilis dan konsekuen
ligasi p55 reseptor TNF (TNFR1) juga telah
terbukti menjadi mediator penting dari imbas UVB
keratinosit apoptosis (93, 94). Akhirnya, UVB dapat menginduksi
apoptosis keratinosit sekunder terhadap kerusakan DNA (95),
dan peningkatan regulasi dari phosphoprotein nuklir dan tumor penekan p53 (96, 97).
Pada tahun 1994, Casciola-Rosen dan rekan menunjukkan
bahwa ketika keratinosit tumbuh di kultur sel yang IR
terpancar dengan UVB, mereka secara aktif memotong DNA mereka dan
mati oleh apoptosis (98). Selama proses ini, antigen
diakui oleh autoantibodi seperti Ro / SSA dan calreticulin terkonsentrasi dalam struktur disebut blebs atau
badan apoptosis ditemukan pada permukaan sel. Blebs lebih besar
timbul dari inti dan pelabuhan Ro / SSA, La / SSB dan
bahan nuklir lainnya. Peneliti ini (73) dan lain-lain
(99, 100) telah mengusulkan bahwa antigen bleb terkait
kemudian dapat phagocytosed, dikemas dan disajikan untuk
limfosit, sehingga memberikan pemicu untuk prakarsa
tion dari respon imun utama untuk molekul-molekul ini.
Sekarang ada bukti bahwa proses biokimia

dari apoptosis sendiri menghasilkan antigen baru yang

unik ditargetkan oleh autoantibodi. Para caspases mengaktivasi
vated selama apoptosis membelah protein intraseluler ke
fragmen yang terikat oleh autoantibodi dari beberapa
pasien dengan LE (101, 102). Selanjutnya, protein khusus
terfosforilasi selama stres akibat apoptosis yang tar98
geted oleh antibodi dari serum pasien LE (103-106).
Granzyme B, protease serin ditemukan terutama di
butiran sitotoksik CTL dan sel NK, juga dapat membelah
autoantigens seluler menjadi fragmen unik yang tidak terdeteksi
dalam bentuk lain dari apoptosis. Produk pemecahan ini
khusus untuk kematian sitotoksik-granul diinduksi, dan juga
terikat oleh antibodi hadir di LE sera (107). Menariknya
ingly, ekspresi granzim B telah terdeteksi di keratinocytes, menunjukkan bahwa molekul-molekul ini dapat berpartisipasi
dalam mekanisme pertahanan kulit (108) dan mungkin di
kematian keratinosit. Enzim khusus untuk pro kematian sel
gram sehingga dapat membelah dan memodifikasi autoantigen di LE,
yang dapat mengungkapkan sebelumnya '' samar '' epitop. Sekarang Ini,
telah menunjukkan bahwa pasien dengan penyakit kulit LE memiliki
autoantibodi yang istimewa mengakui apoptoticdimodifikasi antigen U1-70- kDa RNP bila dibandingkan dengan
pasien tanpa penyakit kulit (109). Ini menyediakan lanjut
bukti vivo bahwa pengakuan kekebalan dimodifikasi
bentuk antigen diri terjadi pada kulit LE dan menyarankan
bahwa pengakuan kekebalan dan pengolahan apopantigen totic yang diturunkan dapat berpartisipasi dalam patogenesis
penyakit.
Sarana yang antigen apoptosis yang diturunkan seperti
dapat diproses disarankan oleh penelitian in vitro yang
menunjukkan bahwa dengan adanya tingginya jumlah apoptosis
sel, sel dendritik belum matang (DC) dapat phagocytopuing-puing apoptosis se. Proses ini disertai dengan
sekresi IL-1 b dan TNF a yang memicu DC maturansum, dan memungkinkan mereka untuk menyajikan antigen yang berasal dari
sel apoptosis baik MHC kelas I- dan kelas II-ulang
Sel T stricted (100, 110, 111). Interaksi tersebut dapat ulang
sult tidak hanya dalam generasi-antigen spesifik CD4
Sel-sel yang mampu berinteraksi dengan sel B untuk mempromosikan otomatis
sintesis antibodi, tetapi juga pada generasi tertentu

Sel T sitotoksik (CTL) (112, 113) dapat menginduksi

apoptosis pada target keratinosit mereka melalui beberapa
Mekanisme (Ulasan di (114)). Ini termasuk trig- yang
gering dari Fas oleh FasL (115); pelepasan sitokin
(IFN- g, TNF a, b TNF, IL-1) (116); dan pelepasan
perforin dan granzyme (117). Identifikasi
Sel CD8 T dalam lesi SLE (67); kehadiran leukocytes di dekat dengan sel apoptosis (25); dan kehadiran
limfosit positif FasL dan makrofag dalam lesi
kulit (118) semua mendukung peran apoptosis seluler seperti
Mekanisme pada lesi didirikan.
Secara kolektif, data ini menunjukkan bahwa peningkatan '' burden '' keratinosit apoptosis hadir dalam kulit
di LE dan autoantigen baru dapat dihasilkan oleh
apoptosis yang baik stres akibat (sinar UV, di- virus
fection, atau pemicu lainnya) atau sekunder imun seluler
mekanisme. Generasi dan konsentrasi seperti
neo-antigen dapat menimbulkan tantangan untuk diri toleransi
(119). Apakah peningkatan apoptosis keratinosit mencatat
Halaman 5

Fotosensitifitas pada lupus eritematosus

di kulit LE mengarah langsung ke pembentukan otomatis
antibodi spesifik untuk produk sampingan apoptosis diturunkan masih
spekulasi. Namun, saran ini didukung oleh
studi di mana tikus normal disuntik dengan angka tinggi
dari syngeneic thymocytes apoptosis dikembangkan antinuclear,
anticardiolipin dan anti-ssDNA antibodi dan setandidemonstrasikan IgG deposisi dalam glomeruli ginjal beberapa
bulan kemudian (120).
Kontribusi autoantibodi
Konsekuensi dari anti-Ro, anti-La dan anti-RNP pengikat
ing pada permukaan keratinosit belum sepenuhnya
dijelaskan. Namun, dalam neonatal LE, yang juga
sangat terkait dengan dengan respon anti-Ro (121),
bayi dari ibu yang memperoleh antibodi IgG Ro / SSA
dan mengembangkan lesi kulit SCLE seperti. Lesi ini menyelesaikan
sebagai antibodi Ro / SSA maternal yang diturunkan akan dihapus
dari peredaran bayi (122). Anti-Ro antibodi
spesifisitas telah terlibat sebagai penyebab langsung hati
blok, manifestasi lain dari neonatal LE (123-126).

Telah diusulkan bahwa Ro / SSA dan La / SSB antibodi

cardiocytes manusia mengikat hanya setelah pembangunan sesuai
apoptosis mental dan bahwa in vivo opsonized apoptosis
cardiocytes kemudian mempromosikan respon inflamasi kerusakan y
penuaan jaringan (127) sekitarnya. Potensi signifikansi
dari opsonisasi lebih lanjut ditunjukkan oleh studi investigasi
gating peran antibodi anti-fosfolipid. Mengikat
antibodi anti-fosfolipid pada membran permukaan
blebs sel apoptosis telah terbukti menghasilkan mereka
opsonisasi dan fagositosis ditingkatkan berikutnya oleh
makrofag dan DC bantalan reseptor Fc. Di bawah ini
kondisi, fagosit, bukan upregulating mantan mereka
pression sitokin non-inflamasi seperti TGF b,
menghasilkan sejumlah besar TNF a, menghasilkan en- lokal
lingkungannya di mana representasi apoptosis yang diturunkan
antigen ke sel T dipromosikan (128-130).
Pembersihan abnormal sel-sel apoptosis
Peningkatan diamati pada jumlah sel apoptosis pada LE epidermis bisa disebabkan baik peningkatan tingkat sel
kematian atau penurunan tingkat clearance apoptosis
puing-puing. Fagositosis oleh makrofag atau sel parenkim
adalah acara terakhir dalam kliring sel yang mengalami
apoptosis (75, 76, 131). Sejumlah observasi menyarankan
bahwa pembersihan puing-puing apoptosis mungkin terganggu di LE.
Menariknya, para blebs permukaan keratinosit apoptosis
mengikat C1q, komponen awal dari kaskade komplemen
(132). Satu-satunya protein yang mengikat C1q yang telah mengidentifikai
tified di blebs apoptosis sampai saat ini adalah calreticulin (98) dan
autoantibodi untuk calreticulin dapat mengganggu pengikat ini
ing (133). Pengikatan C1q ke sel apoptosis telah
mendalilkan untuk memfasilitasi pembersihan sel ini dengan
makrofag, yang mengekspresikan reseptor permukaan sel C1q
99
(134, 135). Sebuah peran potensial untuk C1q di clearance
puing-puing apoptosis dan asal-usul kulit LE adalah
disarankan oleh pengamatan berikut. Pasien dengan
Kekurangan C1q mengembangkan letusan fotosensitif LE-seperti
(136). Tikus dengan defisiensi C1q mengembangkan dis SLE seperti
kemudahan yang berhubungan dengan akumulasi sel apoptosis di
ginjal (137). Makrofag dari C1q tikus kekurangan
menunjukkan cacat dalam penyerapan fagositik sel apoptosis

in vivo (135). Dalam studi yang sama, Taylor et al. ditunjukkan

bahwa makrofag C1q-kekurangan dari tiga C1q-kekurangan
pasien dengan SLE menunjukkan cacat dalam penyerapan apopSel totic in vitro, yang dikoreksi, dalam dosis-dependcara ent, dengan menggunakan protein C1q dimurnikan. Selain itu,
studi manusia lebih lanjut juga menunjukkan bahwa jelasAnce limfosit apoptosis oleh makrofag adalah imdipasangkan pada pasien dengan SLE (138). Apa masih belum jelas
adalah apakah izin gangguan ini adalah sekunder untuk cacat
pengakuan dan mengikat partikel apoptosis
(Seperti yang terjadi pada defisiensi C1q) atau cacat dalam makro
fag fagositosis. Hal ini juga diketahui apakah cacat ini mantan
cenderung untuk fagositosis tipe sel lainnya seperti keratinocytes. Sel Sunburn biasanya dibersihkan dengan cepat dan
hilang dalam waktu 24-48 jam dalam kulit murine (139, 140).
Apakah ini karena shedding, atau fagositosis oleh salah
tetangga keratinosit atau makrofag tidak jelas. DeStudi ekor clearance sel sengatan matahari pada manusia memiliki
belum diterbitkan namun mekanisme yang seperti
sel apoptosis diakui dan dibersihkan in vivo adalah daerah
penyelidikan aktif.
Makrofag adalah remover utama organisme dari
puing-puing selular. Serapan mereka sel apoptosis adalah sayadiated, setidaknya sebagian, oleh fosfat reseptor mengakui
phatidylserine (PS) residu terpapar pada permukaan
sel apoptosis (141). Makrofag yang telah tertelan
sel apoptosis in vitro mengeluarkan mengubah factor pertumbuhan
b (TGF b) dan prostaglandin E-2 (PGE-2) (142, 143).
Umpan balik inhibisi oleh TGF b kemudian menghambat makrofag
sintesis dan pelepasan TNF dan kemokin (143).
Makrofag sinyal melalui PS-reseptor juga menghasilkan
upregulation makrofag produksi TGF b (141). Di
Selain untuk menghilangkan debris seluler, makrofag mungkin
Oleh karena itu secara aktif mempromosikan toleransi dan menghambat pro-in
produksi sitokin flammatory (142). Pada tikus, blokade
penghapusan makrofag-dimediasi tumor apoptosis
garis sel menyebabkan respon CTL meningkat ketika tikus
yang rechallenged dengan sel-sel tumor hidup (144). Pesatnya
fagositosis sel apoptosis oleh makrofag atau parenOleh karena itu, sel-sel chymal tampaknya menjadi langkah penting dalam
resolusi peradangan. Saat ini sudah meningkat-bukti

dence menunjukkan bahwa jika makrofag gagal untuk membersihkan apoptotsel ic normal, yang terakhir dikeluarkan melalui alternatif
pro-inflamasi rute. Sel dendritik (DC) yang proSel-sel antigen-presenting fessional hadir dalam kulit yang
Halaman 6

Orteu et al.
telah terbukti baik untuk mendapatkan antigen dari apoptosis
sel dan kemudian ke sel T naif utama di antigen-spesifik
mode (100, 111, 145). Proses ini mengharuskan DC menjadi
terkena pematangan rangsangan, yaitu saya- inflamasi
diators seperti TNF dan CD40 ligan (145). Dengan demikian, detertunda pada lingkungan mikro lokal dan sifat
sel fagositik dengan yang sel apoptosis berinteraksi,
autoimunitas atau toleransi mungkin terjadi. Kelimpahan
sel apoptosis, baik karena jumlah berlebihan kematian
induksi oleh UV atau mekanisme lainnya, atau karena cacat
clearance bisa mengizinkan toleransi terhadap antigen apoptosis
menjadi rusak. Peran potensial mekanisme apoptosis
dalam inisiasi dan pelestarian fotosensitif LE adalah
diringkas dalam Gambar. 1.
Peningkatan panas ekspresi shock protein
Heat shock protein (Hsp) adalah keluarga di mana-mana
protein, dengan fungsi homeostatis dalam regulasi
perakitan protein normal, lipat dan transportasi dalam
Gambar. 1. Potensi peran keratinosit apoptosis di
patogenesis lupus fotosensitif. Apoptosis adalah atau-tanya berarti kematian sel. Apoptosis dapat dimulai pada
keratinosit oleh UVR (UVB serta UVA), oleh virus,
oleh sitokin (TNF), dengan faktor pertumbuhan penarikan, dengan
diferensiasi dan dengan sitotoksik serangan seluler.
Apoptosis menyebabkan pembentukan lepuh kecil di mana Ro anti
gen (60 kDa dan 52 kDa), dan calreticulin yang konsentrasi
basisnya. Badan apoptosis yang lebih besar mengandung potensi lainnya
autoantigens termasuk Ro antigen (60 kDa), La, nucleoprotein
somes, dan 70 kDa RNP antigen. Apoptosis mengarah ke
eksposur phosphatidylserine dan pengikatan C1q.
Kehadiran peningkatan jumlah sel apoptosis pada
lingkungan pro-inflamasi dapat menyebabkan berkurangnya jelasAnce puing apoptosis melalui makrofag-dimediasi, non
jalur inflamasi, dan peningkatan penyerapan dan pro

pemrosesan oleh sel dendritik, yang mengakibatkan priming dan

meningkatkan sel T dan sel B untuk apoptosis diturunkan diri
antigen.
100
sel. Mereka diregulasi selama respon stres dan
melindungi sel dari kerusakan akibat fisiologis
tekanan seperti panas dan sinar UV berdasarkan kemampuan mereka
untuk mendeteksi dan mengikat rantai polipeptida terdenaturasi (146,
147). Data yang lebih baru menunjukkan bahwa Hsp juga mampu
untuk memodulasi respon imun seluler. Hsp dari
sitosol (hsp70, Hsp90) dan retikulum endoplasma
(Gp96, calreticulin) telah terlibat dalam transportasi
dan pemuatan peptida imunogenik dari sitosol
ke MHC kelas I molekul (148-151). Hsp sehingga fungsi
tion sebagai kendaraan untuk peptida antigenik, dan peningkatan intra
seluler HSP (hsp72, hsp65) ekspresi dapat meningkatkan
kepadatan kompleks I-peptida MHC kelas pada sel surwajah, menunjukkan peningkatan pengolahan anti endogen
gens (152, 153).
Imunisasi dengan Hsp (hsp 70, Hsp90, gp96 dan kalreticulin) dapat menyebabkan priming sel T naif CD8
spesifik untuk antigen tumor, antigen virus, histo- kecil
antigen kompatibilitas dan antigen model yang diungkapkan oleh
sel-sel dari mana Hsp terisolasi (148, 154-156).
Imunisasi dengan kanker yang diturunkan HSP-peptida complexes telah lebih jarang ditampilkan untuk memperoleh sel CD4 T dan
Tanggapan NK cell (154, 157, 158), dan gd sel T recognizing permukaan terikat Hsp juga telah dijelaskan (reviewed di (156)). Persiapan HSP diisolasi dari sel yang diberikan
berhubungan dengan berbagai peptida termasuk diri dan
peptida antigenik yang dihasilkan dalam sel itu. Spesimen yang
ficity respon kebal terhadap Hsp berasal dari peptida yang
pasang yang mereka terikat (159, 160). Data terbaru memiliki
menjelaskan mekanisme yang terlibat dalam elisitasi
respon CTL spesifik oleh Hsp: peptida dikomplekskan
untuk gp96, Hsp90 dan hsp70 dilepaskan dari sel-sel yang diambil
oleh endositosis reseptor-mediated pada APC termasuk DC
dan makrofag dan re-disajikan kepada sel T dalam con yang
teks MHC kelas I (161-166). Menariknya, CD91, sekarang
diidentifikasi sebagai reseptor untuk peptida dimuat-gp96 pada
makrofag, juga hadir pada keratinosit (162). Gp96

juga menginduksi DC untuk mengekspresikan MHC kelas II, co-stimulasi

molekul seperti B7 dan menghasilkan IL-12 dan TNF a,
dan dengan demikian telah terlibat dalam pematangan DC (167).
Hsp70 dapat memiliki efek yang sama, mengaktifkan factor nuklir
k B, dan upregulating ekspresi TNF a, IL-1 b dan
IL-6 dalam monosit manusia (168). The importance of this
''cytokine-like'' function of HSPs is underscored by a recent in vitro study, which showed that mature rather than
naive human DCs were required for the generation of tumor-specific CTL responses (169).
The ability of HSPs to promote cellular immune responses both by chaperoning peptides into cellular antigen processing compartments and by directly activating
antigen-presenting cells suggests that they could also have
a role in the induction of autoimmune responses. Sebuah num
ber of observations in LE support this view. Intracellular
Halaman 7

Photosensitivity in lupus erythematosus

and surface hsp90 and hsp70 are increased in peripheral
blood mononuclear cells (PBMCs), predominantly B cells
and CD4 T cells of patients with SLE (170, 171). Ini
increased level of hsp90 (but not hsp70) in PBMCs is associated with increased IL-6-mediated transcription of the
hsp90 beta gene (172, 173). The relevance of increased intracellular and surface expression of hsp90 is uncertain,
but, as discussed, it could result in the increased translocation of both HSP-peptide (eg HSP-Ro/ HSP-La) complexes and MHC class I-associated peptides to the cell
surface, thereby rendering cells more susceptible to lysis
by gd and/or CD8 T cells, and promoting autoantigen
presentasi.
Approximately 30% of SLE patients have IgM and
IgG autoantibodies to hsp90, and their presence correlates with low C3 and renal disease (174, 175). Ini
findings are paralleled in lupus prone MRL/lpr mice,
which show elevated levels of hsp90 in splenocytes and
the development of autoantibodies to hsp90 soon before
the onset of disease (176, 177). A possible mechanism
for the induction of autoantibodies to HSPs in lupus patients is suggested by a study in C3H/HeJ mice immun-

ized with either 52 kDa or 60 kDa isoforms of the Ro/

SSA antigen (178). In addition to antibodies to the initial Ro immunogens, these mice developed autoantibodies to inducible members of the hsp70 family (grp78
and hsp70), and to calreticulin. These authors suggested
that the response to cytoplasmic hsp70 represented
cross-reactivity to grp78-driven autoantibodies, and that
the spread of immunity from Ro epitopes to HSPs
(termed epitope spreading) could be due either to the
formation of Ro-HSP complexes or to the colocalization
of Ro and HSP, either within cells or on the surface
membrane blebs of apoptotic cells. Identifikasi
a dominant grp78 binding motif on Ro52 (178) and the
coexistence of grp78, Ro52 and Ro60 in the surface
membrane blebs of apoptotic cells (98) support this view.
Interestingly, autoantibodies directed towards grp94/gp96
and calreticulin have also been detected in the sera of
patients with SLE (133, 179, 180) and could perhaps be
generated via a similar mechanism.
In the skin, Hsp70 expression is increased in both sunexposed and sun-protected sites in SLE patients (181). Induction of hsp70 by UVB has been correlated to the increased binding of antibodies to Ro/SSA, La/SSB and
U1-RNP from LE patients' serum in keratinocytes in vitro
(182). Heat shock and UV irradiation, which both upregulate HSP expression, result in increased expression of
the 52 kDa form of the Ro antigen and binding of antiRo antibodies from patient sera on human peripheral
lymphocytes (183). Upregulation of HSPs could therefore
be an important event in UVB-mediated translocation of
these nuclear antigens to the cell surface.
101
It has been argued that the mechanism by which cells
die and the level of HSP expression induced by the process
of cell death can influence the potency of the resultant
immune response (163, 184). In necrosis, cells are passive
targets of extensive membrane damage leading to cell lysis
and release of contents, including HSPs. Necrotic cell
death thus induces immunological activation signals
which recruit, load, activate and mature appropriate subsets of antigen-presenting cells. In contrast, for apoptotic

cell death to be immunogenic, signals additional to cell

death alone must be provided within the milieu of the dying cells (185). Such additional signals may be provided
by necrotic cells. In a recent study, Sauter et al. demonstrated that optimal cross-presentation of antigens from
tumor cells required two steps: phagocytosis of apoptotic
cells by immature DCs, which provides antigenic peptides
for major histocompatibility complex class I and class II
presentation, and a maturation signal delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli (186). It is tempting to speculate
that this maturation signal may be provided to some degree by HSPs.
What is the relevance of this data to cutaneous LE?
Exposure to UV light can induce both increased keratinocyte HSP expression and keratinocyte apoptosis. Delayed
clearance of apoptotic cells can result in their secondary
necrosis (138), and keratinocyte necrosis can also occur
following exposure to UVA (60). UV irradiation causes
upregulated expression of epidermal cytokines, including
IL-1 a and TNF- a (see below) promoting DC maturation
and efficient antigen presentation. Collectively, these effects of UV light may generate a cutaneous microenvironment containing a mix of apoptotic and necrotic cells
(and their released HSPs) and pro-inflammatory cytokines which favors cross-presentation of autoantigens
derived from dying keratinocytes, and the elicitation of
specific T cell responses.
Epidermal cytokine expression
An appropriate cytokine milieu can facilitate and modulate immune responses. UV light can promote cutaneous
inflammation by inducing the release of inflammatory mediators and cytokines, by inducing adhesion molecule display and by releasing chemokines to attract inflammatory
cells into the skin (reviewed by Bennion & Norris (187)).
Both UVB and UVA can participate in lesion induction
and act by differing mechanisms. UVB-induced primary
cytokine production and release is likely the result of
UVB-induced DNA damage: thymidine dimer formation
induces DNA repair enzymes that also regulate cytokine
transcriptional activity (188). In contrast, UVA affects

gene transcription directly via the production of oxygen

free-radicals (189).
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Orteu et al.
UVB-mediated cytokine expression
Primary cytokines: TNF-a and IL-1
TNF- a release can be induced in keratinocytes (190) by
UVB and possibly UVA (191, 192). This may be partly
dependent on the photoisomerization of trans to cis urocanoic acid in the differentiated epidermis (193), and is
greatest in terminally differentiated keratinocytes in culture (194). TNF- a has numerous effector functions and
has been termed a master regulator of leukocyte movement (195). It can induce activation of Langerhans cells
(LC) via binding of their TNF p75 receptor (TNFR2)
(196). This results in LC migration to the regional lymph
nodes where they can participate in immune responses
(197). Abnormal TNF- a expression can promote autoimTengoklah. Prolonged overexpression of TNF- a in the pancreas of mice has been shown to initiate organ-specific
autoimmune disease (198). In the skin, TNF- a can induce
rapid Ro/SSA and La/SSB antigen translocation and surface expression in keratinocytes (199). It can also induce
keratinocyte apoptosis via binding of its TNF p55
(TNFR1) receptor (93). In mice, transgenic overproduction of TNF- a by the epidermis results in:
O
epidermal basal cell degeneration;
O
a pleomorphic dermal leukocyte infiltrate with macrophage engulfment of degenerating cells;
O
hyperkeratosis;
O
ultimately, a graft-versus-host like histology (200).
Some of these features are reminiscent of cutaneous lupus. Unfortunately, these mice also have high levels of
TNF- a in the serum and soon die of cachexia, which has
presumably prevented further analysis for features of autoimmunity. Raised circulating levels of TNF- a may cor-

relate with disease activity in human systemic lupus (201).

Direct involvement of TNF- a in the pathogenesis of cutaneous LE inflammation could explain the clinical benefit of thalidomide in this setting (202204). Thalidomide
is known to decrease TNF- a production, possibly via an
increase in the rate of TNF- a mRNA degradation (205,
206).
UVB also induces IL-1 a gene transcription in keratinocytes (207) and elevates circulating levels of IL-1 a bioactivity (208). Like TNF- a , IL-1 has broad pro-inflammatory activities (209). IL-1 a predominates in keratinocytes,
while IL-1 b is the predominant form in monocytes,
macrophages and dendritic cells. Transgenic overexpression of IL-1 a by basal keratinocytes in mice results in hair
loss, scaling, and focal inflammatory lesions (210).
IL-1 a and TNF- a are ''primary cytokines'' which induce the release of a number of other pro-inflammatory
cytokines from the epidermis (reviewed in (211)). Untuk mantan
ample, IL-1 a and TNF- a induce the secondary release of
IL-6, prostaglandin E-2, IL-8, and granulocyte-monocyte
colony-stimulating factor (GM-CSF) by keratinocytes
102
(212, 213). These molecules are costimulatory factors for
lymphocyte activation by antigens or superantigens. Ta Men
stimulate Langerhans cell function, collagenase production, and act as pyrogens and stimulators of acute phase
reaktan. In addition, IL-8 and GM-CSF are chemotactic
and induce inflammatory cell migration into the skin
(214). Both IL-1 a and TNF- a also induce the expression
of adhesion molecules such as intracellular adhesion molecule1 (ICAM-1) on keratinocytes, which facilitates T cell
adhesion (215, 216).
IL-10 and IL-6
UVB can also stimulate the release of IL-10 (217220) and
IL-6 directly (221). Both these cytokines have been shown
to induce local heat-shock protein synthesis (222, 223).
Transgenic overexpression of IL-6 in murine keratinocytes
has been associated with an increase in the thickness of
the stratum corneum but not with significant cutaneous
inflammation when expressed alone (224). IL-10 can mediate local (220) as well as systemic UV-induced immuno-

suppression (225) and has been postulated to have an inhibitory role in Langerhans cell migration, possibly via
the downregulation of IL-1 and TNF- a (226). Akan Tetapi,
IL-10 can also promote B cell activation and autoantibody production (227, 228). Although its mechanisms of
action remain unclear, administration of an anti-IL-10
monoclonal antibody produced beneficial effects in 5/6
patients with active and steroid dependent SLE (229).
UVA mediated cytokine expression
UVA shares some of the effects of UVB, it upregulates
IL-8, and IL-10 production and ICAM-1 expression in
keratinocytes (230). Acute low-dose UVA administration,
but not UVB, also results in IL-12 production by keratinocytes (231, 232). IL-12 is a potent immunostimulant
that can abrogate tolerance induced by low dose UVB
(233).
UVA exposure also results in a rapid increase in interferon- g (IFN- g ) levels in the skin, the source of which may
be resident epidermal T cells (232). Elevated IFN- g
mRNA levels are noted in lesions of cutaneous LE (234).
This cytokine has recently been shown to be pivotal in the
induction of keratinocyte apoptosis in two skin inflammatory conditions: allergic contact dermatitis and atopic
dermatitis (235). In these conditions, T cell derived IFNg promotes keratinocyte apoptosis by enhancing their expression of Fas (235). In vitro , IFN- g mediated keratinocyte cell death has been correlated with upregulation of
both Fas (236, 237) and p53 (117). Berlebih dari
IFN- g alone in the suprabasal skin of transgenic mice, by
the use of the involucrin promoter (a protein restricted to
suprabasal keratinizing epithelium) results in a model
of systemic lupus with the production of anti-nuclear
Halaman 9

Photosensitivity in lupus erythematosus

antibodies and immune complex glomerulonephritis (238,
239). The mice also develop scaly skin, alopecia and cutaneous inflammation suggestive but not characteristic
of cutaneous LE. This murine model demonstrates increased keratinocyte apoptosis and requires the presence
of ab T cells (240). This is currently the most provocative

experimental evidence that the upregulation of cutaneous

immune responses through cytokine overexpression can
promote T cell mediated local and systemic lupus-like diskemudahan.
Overall, exposure to UVB radiation correlates with a
predominance of cytokines that promote T helper 2 (Th2)
immune responses at the expense of T helper 1 (Th1) immune responses and that may result in photoimmunosuppression (241). While potentially suppressing cellular immune responses, Th2 responses generally promote antibody production (242). Exposure to physiologic levels of
UVA radiation alone, or in together with UVB (like natural sunlight), results in the local predominance of cytokines that promote Th1 immune responses. These Th1 responses are ''immunopotentiating'' and result in strong
cellular immune responses including CD8

cytotoxic T
cell responses (242). Thus, both UVB and UVA modulate
the epidermal cytokine milieu. Whether patients with cutaneous LE have a unique primary or secondary sensitivity to UV light-induced cytokine changes is not yet
clear.
Biologic effects of UV light on the dermis
UVB, by virtue of its penetration characteristics, has little
effect on dermal structures lying beyond the subpapillary
plexus. The dermal effects of UV radiation are thus largely mediated by UVA and predominantly affect the vasculature.
Vascular activation and adhesion molecule
ekspresi
Dermal blood vessels are involved in all forms of cutaneous lupus as targets for the cytokines and other mediators released from keratinocytes. These vessels are also
affected directly by UV light. The potential importance
of UV light in contributing to dermal and perivascular
inflammation is underscored by the exquisite photosensitivity of lupus tumidus, a dermal variant of cutaneous LE
without epidermal or interface changes (29, 243). Di sebuah
model of UV-induced erythema in the guinea pig, infusion
of sera from patients with SCLE greatly enhanced UV-

induced blood flow and this was greatest with sera containing high titers of anti-Ro/SSA (244). Passive transfer
of serum from patients with vesiculobullous lupus erythematosus into guinea pigs followed by UV irradiation
also results in lesion induction (245). These observations
highlight the potential interactions of the various soluble
103
factors present in circulation of patients with cutaneous
LE with the vasculature.
Enhanced expression of adhesion molecules on the surface of endothelial cells is an essential point of control for
leukocyte attachment and migration through the endothelial barrier into cutaneous tissues (reviewed by (246,
247)). A subpopulation of human memory T cells preferentially recirculates to the skin. These cells interact via
cutaneous lymphocyte associated antigen (CLA) on their
surface with E-selectin molecules on dermal microvascular endothelial cells. Levels of soluble E-selectin correlate with active disease and levels of dsDNA antibodies in
patients with SLE (248). E-selectin can be upregulated by
UVB (249) and its expression is increased in CCLE and
SLE photoinduced lesions (250). Elevated levels of soluble
E-selectin in LE patients with widespread and active cutaneous disease further suggests an important role for endothelial cell activation in the pathogenesis of disease
(251). Intracellular adhesion molecule 1 (ICAM-1) expression by endothelial cells is a crucial step in the initiation of endothelial-T cell binding which occurs via LFA1 (216). ICAM-1 is expressed by the endothelial cells in
lesional skin of most patients with CCLE or SCLE (33).
Endothelial ICAM-1 is also upregulated following UV irradiation, and this is stimulated by TNF- a and IFN- g
(252). In the MRL/lpr mouse model of SLE, systemic
TNF- a (and IL-1) levels are elevated and these cytokines
sequentially induce endothelial ICAM-1 in vivo with disease evolution (253). Vascular cell adhesion molecule
(VCAM)-1 is necessary for leukocyte emigration from the
microvasculature and is the ligand for VLA-4 on leukocytes. Serum concentrations of soluble VCAM1 are elevated in patients with SLE and correlate negatively with
serum C4 levels (254). Immunohistochemical studies have

confirmed that VCAM-1 is expressed both in lesional and

non-lesional cutaneous endothelium in active systemic lupus (255) and levels of VCAM-1 are increased in lesional
skin (250, 256). Chemokines doubtless also have a key role
in the recruitment of inflammatory cells to lesional skin
but their specific expression and regulation in cutaneous
LE has not yet been studied.
Nitric oxide and inducible nitric oxide synthase
Nitric oxide (NO) is a pleiotropic molecule synthesized
by a family of nitric oxide synthases (NOSs) which are
constitutively expressed in endothelial cells (cNOS), and
inducible (iNOS) in a wide variety of cell types, including
endothelial cells and keratinocytes. The short-lived expression of low levels of NO generated by cNOS activation appears to have physiologic regulatory and antiinflammatory effects. In contrast, increased iNOS expression results in the more sustained production of larger
quantities of NO, which can promote apoptosis and have
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Orteu et al.
multiple pro-inflammatory effects (reviewed in (257)). In
vitro , NO and peroxynitrite, one of its highly toxic byproducts, can induce apoptosis in macrophages, and this occurs in part via upregulation of Hsp70 (258, 259). Dalam con
trast, T cells appear to be relatively resistant to NO-mediated apoptosis (260). NO appears to have differential
effects upon different cell types within the skin. Mengalami Peningkatan
NO production by human keratinocytes following UVB
irradiation has been implicated in the generation of erythema (261, 262). NO can protect against UVA-induced
endothelial cell damage and apoptosis by increasing Bcl2 expression and inhibiting UVA-induced overexpression
of Bax protein (263). When applied to normal, unirradiated human skin, NO induced accumulation of CD4

dan CD8

T cells, expression of ICAM-1 and VCAM-1,

and accumulation of p53, followed by keratinocyte
apoptosis (264). Altered expression of this molecule may

therefore provide a further link between dysregulated

keratinocyte apoptosis and inflammation. It remains uncertain whether NO has a role in the pathogenesis of LE.
Increased levels could merely reflect underlying inflammation. Nevertheless, there is increased production of NO
during the course of the murine MRL/lpr and NZB/W
models of lupus and in human SLE (265267). Tambahan Pula,
elevated levels of endothelial cell iNOS, serum nitrite and
peroxynitrite levels correlate with measures of disease activity and titers of dsDNA antibodies (267, 268). Increased levels of iNOS have been found in epidermal keratinocytes and adjacent vascular endothelium in the clinically normal appearing skin of patients with active SLE
(267). Aberrant regulation of iNOS expression has also
been noted in photoinduced lesions of cutaneous lupus
(262). Healthy controls were shown to have short-term expression (Days 12) of iNOS after either UVA or UVB
irradiation. Patients with cutaneous LE were noted to
have significantly delayed but prolonged expression (days
324) of iNOS. Both IL-1 and TNF- a promote the expression of iNOS (269) and this abnormal expression in
cutaneous LE could be secondary to a genetic dysregulation of these cytokines (see below).
Genetics potential involvement in human
penyakit
Abnormalities in either constitutive or UV-induced cytokine expression and the genes governing these factors may
be important in the cutaneous lupus phenotype. The associations of cytokine gene polymorphisms with disease
described below so far remain preliminary in nature and
will need to be confirmed in multiple populations.
IL-1
Keratinocytes normally contain an excess of interleukin1 receptor antagonist, which binds to the IL-1 receptor
104
and inhibits IL-1-induced activation (270). This molecule
is particularly polymorphic and a significant increase of
a null allele has been reported in SLE patients (271),
especially those with photosensitivity (272). A correlation
with CCLE has also been published in abstract form
(273).

IL-10
Polymorphisms within the IL-10 gene promoter associated with high levels of expression of this cytokine have
been associated with anti-Ro/SSA sero-positivity (274).
Increased production of IL-10 by monocytes and B cells
has been documented both in patients with SLE and in
their unaffected relatives (275). More recently, high innate
IL-10 production was also found in family members of
patients with SLE, but not CCLE (276).
TNF-a
Raised circulating levels of TNF- a may correlate with disease activity in human systemic lupus (201). A polymorphic variant in the TNF- a promoter in humans (TNF- a
308A) is associated with increased production of TNF- a
(277). The presence of this promoter is associated with an
increased risk of SLE in African-Americans (277) and it
is an independent susceptibility factor for systemic lupus
in Dutch Caucasians (278). TNF- a production in keratinocytes shows inter-individual variability and it has been
proposed that this variability may underlie a predisposition to cutaneous lupus (194, 279). Recently, this concept has found support in that the TNF- a 308A promoter
polymorphism associated with increased TNF- a production has been shown to be highly associated with photosensitive cutaneous LE in Caucasians (280). Menariknya,
this polymorphism is strongly associated with HLA A1,
B8 and DR3 (281).
Komplemen
Homozygous deficiencies of the complement components
C2, and C4 have been associated with both SCLE and
systemic LE (282-284), and more rarely with DLE (285).
Most patients with homozygous C2 or C4 complement
deficiency possess anti-Ro/SSA antibodies (282, 286).
Likewise, most individuals with a complete deficiency of
C1q or C1r/C1s develop systemic LE (reviewed by (287)).
These patients also have prominent photosensitive cutaneous involvement. Such deficiencies may enhance the
lupus phenotype by decreasing the clearance of apoptotic
cells, thereby allowing immune cell activation.
It is of interest that TNF- a , complement components,
and heat shock proteins are all encoded by genes within

the Class III region of the human major histocompatibility complex (MHC) on chromosome 6. Although a
number of polymorphisms for HSP genes have been idenHalaman 11

Photosensitivity in lupus erythematosus

tified (288, 289), their possible association with LE has
not yet been investigated.
Class II MHC genes
Anti-Ro/SSA antibody responses have been linked to susceptibility loci associated with Class II MHC alleles.
There is a strong association between SCLE, Anti-Ro/
SSA antibodies and the HLA-B8, DR-3, DRw52 phenotypes (290, 291). Associations between Ro antibody responses and DQA1 alleles, DQ2 alleles and HLA-DR3 in
different populations suggest that specific MHC class II
Gambar. 2. A model of the pathogenesis of photosensitive lupus erythematosus. Recent studies of photosensitive lupus
patients have demonstrated an increased number of apoptotic keratinocytes in established lesions and after photoprovokasi. Either increased apoptosis or delayed clearance of apoptotic debris could result in increased autoantigen packaging and processing in a form accessible to the
immune system. Reduced clearance by macrophages may
lead to increased uptake and processing by dendritic cells
resulting in the presentation of apoptosis-derived autoantigens (eg Ro, La and calreticulin) to T cells and subsequently B cells. Uncleared apoptotic cells may also undergo secondary necrosis, with release of cell contents, including HSPs and HSP-peptide complexes. The latter may
promote both the release of pro-inflammatory cytokines,
and autoantigen processing by antigen presenting cells.
Opsonization of apoptotic debris by autoantibodies may
enhance macrophage uptake, but contribute further to the
pro-inflammatory cytokine milieu by stimulating their
production of TNF- a . UV irradiation itself stimulates local cytokine release, resulting in increased expression of
inflammatory mediators including adhesion molecules
and prostanoids, and facilitating leukocyte migration into
kulit. The end result would be to promote further inflammation and tissue damage by cellular cytotoxic mech-

anisms mediated by T cells and monocyte-macrophages;

and by processes such as epitope spreading, mediated by
antibodies and B cells.
105
molecules participate in the anti-Ro response (292294).
Diversification of the Ro/SSA and LA/SSB antibody response has also been linked to specific HLA class II
phenotypes (295).
Since there is potential overlap between the pathophysiologic mechanisms involved, it is possible that combinations of genetic polymorphisms function jointly to predispose patients to photosensitivity and to generate the
varied clinical manifestations of cutaneous and systemic
LE.
A model of pathogenesis of photosensitive
cutaneous lupus
A number of significant advances have been made in our
understanding of the pathogenesis of cutaneous LE and
the impact of UV irradiation, both on initial triggering
and on perpetuation of cutaneous disease. Clinical and
experimental data now suggest that apoptosis may be an
important mechanism leading to autoantigen display in
cutaneous LE and that UV light is an important initiator
of apoptosis. Proteolysis and phosphorylation of intracellular proteins (autoantigens) by pathways selectively activated during apoptosis can produce modified self-peptides. These novel self-antigens are exposed on the surface
membrane blebs of apoptotic keratinocytes. Abnormalities may exist in either apoptosis induction or apoptotic
cell clearance. Reduced clearance of apoptotic debris via
macrophage-mediated, non-inflammatory pathways may
cause increased channeling through the pro-inflammatory
dendritic cell pathway, resulting in the generation of
CD8 and CD4 T cells specific to apoptosis-derived
antigens. High load or reduced clearance of apoptotic
cells could also result in secondary necrosis and release of
cell constituents, including HSPs and HSP-peptide complexes, further promoting TNF- a release, activation/
maturation of antigen-presenting cells and CTL generation. In addition to cell death and neoantigen generation,
UV light induces and modulates release of inflammatory

mediators including IL-1, TNF- a and IL-10, and upregulates adhesion molecule expression on dermal endothelial
cells, facilitating leukocyte migration into the skin. TNFa , in particular, not only induces keratinocyte apoptosis,
but also promotes DC maturation and migration to local
lymph nodes, and T cell chemotaxis and migration into
kulit. The recirculation of autoantigen-specific CD8
CTLs to the skin may cause local tissue damage and
further keratinocyte apoptosis via cytotoxic mechanisms.
CD4 cells, in addition to participating in cutaneous inflammation, provide B cell help for autoantibody production. The latter may serve as opsonins, enhancing phagocytosis of apoptotic debris, but paradoxically promoting
the release of pro-inflammatory cytokines by APCs. AutoHalaman 12

Orteu et al.
antibody production and directed T cell responses may
thus perpetuate and amplify autoantigen recognition as
well as keratinocyte toxicity, leading to the clinical hallmarks of cutaneous LE disease. The salient points of this
model are shown in Fig. 2. Ongoing research will no
doubt shed light on the in vivo role of cellular apoptosis
in disease induction and perpetuation, the primary or secondary pathophysiologic role of specific autoantibodies,
and the nature of the underlying genetic makeup that predisposes to disease.
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Ucapan Terima Kasih
CH Orteu is supported by a Geoffrey Dowling Fellowship from the British Association of Dermatologists, JP
Dutz is supported by the Arthritis Society of Canada, and
RD Sontheimer by NIH grant AR-19101. Dr. Sontheimer also holds the John S. Strauss Endowed Chair in Dermatology.
Accepted for publication October 9, 2000
Penulis yang sesuai:
Dr. Jan Dutz
Division of Dermatology
Faculty of Medicine
University of British Columbia
835 West 10
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Avenue
Vancouver BC V5Z 4E8
Kanada

Tel: 1 604 875 4747

Fax: 1 604 873 9919
e-mail: dutz
/
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