1 Immunopathogenesis of SLE

1

1mmun0path09ene515 0f 5LE

Le51ey J. Ma50n 85c, M5c Re5earch A5515tant

Dav1d A. 15en6er9 MD, FRcP ARC Pr0fe550r 0f Rheumat0109y

Centre f0r Rheumat0109Y, 8100m56ury Rheumat0109y Un1t, Department 0f Med1c1ne, Un1ver51ty C011e9e L0nd0n, Arthur 5tan1ey H0u5e, 40-50 70ttenham 5treet, L0nd0n W1P 9P6, UK

5y5tem1c 1upu5 erythemat05u5 (5LE) 15 an aut01mmune rheumat1c d15ea5e character12ed 6y the dep051t10n 0f aut0ant160d1e5 and 1mmune c0mp1exe5, 1ead1n9 t0 t155ue dama9e. 7he 1mmun0path09ene515 0f 5LE 15 11ke a j195aw pu221e, 50me p1ece5 0f wh1ch are m1551n9 0r have n0t fa11en 1nt0 p1ace. 1n pred15p05ed 1nd1v1dua15, the 1n1t1a15t1mu1u5 15 11ke1yt0 6e 0ne 0r m0re 0f the env1r0nmenta1 a9ent5 1nteract1n9 w1th 5u5cept16111ty9ene5. 0nce the cr1t1ca1thre5h01d 15 6reached there 15 a fa11ure 0f the 1mmune 5y5tem t0 d0wnre9u1ate the en5u1n9 a6n0rma1 1mmune re5p0n5e, 1nv01v1n9 p01yc10na1 8 ce11 act1vat10n and hyperact1ve 7 ce11 he1p. Key 4ue5t10n5 1nc1ude, what are the pr0ce55e5 6eh1nd the ava11a6111ty0f aut0ant19en5 and the 6reakd0wn 0f t01erance that 91ve r15e t0 the path09en1c aut0ant160d1e5• Current area5 0f re5earch a150 1nv01ve the r01e5 p1ayed 6y cyt0k1ne5, adhe510n m01ecu1e5, c0-5t1mu1at0ry m01ecu1e5 and ap0pt0515.

Key w0rd5: 5y5tem1c 1upu5 erythemat05u5; aut0ant160d1e5; 1mmune c0mp1exe5; cyt0k1ne5; adhe510n m01ecu1e5; c0-5t1mu1at10n; ap0pt0515.

Aut0ant160d1e5

5pectrum 0f aut0ant160d1e5

A maj0r 5er01091ca1 feature 0f 5y5tem1c 1upu5 erythemat05u5 (5LE) 15 the pre5ence 0f c1rcu1at1n9 aut0ant160d1e5 a9a1n5t a mu1t1p11c1ty 0f nuc1ear, cyt0p1a5m1c and mem6rane ant19en5 (f0r rev1ew5, 5ee A1arc6n-5e90v1a and Ca6ra1, 1996; 15en6er9, 1997). 1ntr19u1n91y, a1th0u9h there are at 1ea5t 2000 p0tent1a1 1ntrace11u1ar tar9et5 the aut01mmune re5p0n5e 15 c0nf1ned t0 30-40 0f the5e. 7he5e ant160d1e5 are pred0m1nant1y tar9eted at 1ntrace11u1ar nuc1e0pr0te1n part1c1e5, w1th 98% 0f pat1ent5 hav1n9 ant1-nuc1ear ant160d1e5 (ANA). 7he5e 1nc1ude the 70% (appr0x1mate1y) 0f pat1ent5 wh0 8a1111~re~5C11n1ca1Rheumat0109y-V01. 12, N0. 3, Au9u5t 1998 158N 0-7020-2407-4 0950-3579/98/030385 + 19 $12.00/00

385 C0pyr19ht • 1998, 6y 8a1111~re71nda11 A11r19ht5 0f repr0duct10n 1n any f0rm re5erved

386

L.J. Ma50n and D. A. 15en6er9

have ant160d1e5 a9a1n5t d0u61e-5tranded DNA (d5DNA), h19h t1tre5 0f wh1ch are v1rtua11y c0nf1ned t0 5LE and have 6een e1uted fr0m affected k1dney and 5k1n 5amp1e5. Ant160d1e5 t0 60th nat1ve/d5DNA and denatured/ 51n91e-5tranded (55DNA) can 6e pre5ent 1n 5LE pat1ent5, 6ut the f0rmer are m0re 5tr0n91y a550c1ated w1th the rena1 path0109y. A1th0u9h attent10n ha5 f0cu5ed 0n ant1-DNA ant160d1e5, many 0ther aut0ant160d1e5 have 6een 1mp11cated 1n the path09ene515 0f 5LE, 50me 11nked t0 c11n1ca15u65et5 0f the d15ea5e (7a61e 1). 7a61e 1. Aut0ant160d1e5a550c1atedw1thc11n1ca15u65et5 0f 5LE. Ant160dy 5pec1f1c1ty

Percenta9e 0f pat1ent5(%)

d5DNA R0 La

=70. 35 15

5m

30 (Afr0-Car166ean5) 5-10 (Cauca51an5) 25

U1 RNP RA33 H5p 90 R16050ma1P Ph05ph011p1d5and card1011p1n Rheumat01dfact0r C0mp1ement(C14)

30 15-35 30 25 20-45

H15t0ne5 70 Red ce115and p1ate1et5 <10

C11n1ca1a550c1at10n Rena1 and card10va5cu1ar/re5p1rat0ryd15ea5e 5j(~9ren5 5yndr0me 1/20 1upu5pre9nanc1e5re5u1t1n ne0nata11upu5 5yndr0me: c0n9en1ta1heart 610ck/cutane0u5 erythemat05u5 Ph0t05en51t1v1ty(R0) 5LE 5pec1f1ca550c1at10nw1th ethn1c0r191n M11dd15ea5e Er051vearthr1t15(n0n-Cauca51an5) Card10va5cu1ar/re5p1rat0P/d15ea5e(5urface 0f P8MC5 fr0m pat1ent5) L1nk t0 1upu5 p5ych051515c0ntr0ver51a1 Ven0u5 and arter1a1thr0m605e5, m15carr1a9e,11ved0 ret1cu1ad5,thr0m60cyt0pen1a and cere6ra1 d15ea5e May 6e 11nkedt0 er051ved15ea5e R151n9t1tre51nd1cat1ve0f pr011ferat1ve910meru1ar nephr1t15 Dru9 1nduced 1upu5 Haem01yt1canaem1aand 1d10path1cthr0m60cyt0pen1c purpura re5pect1ve1y

d5DNA, d0u61e-5tranded DNA; U1 RNP, R160nuc1e0pr0te1n;H5p 90, heat 5h0ck pr0te1n 90; P8MC, per1phera16100d m0n0nuc1ear ce11.

0r191n 0f aut0ant160d1e5 7he 0r191n 0f ant1-DNA ant160d1e5 rema1n5 0ne 0f the 9reate5t en19ma5 0f 5LE, 51nce mamma11an DNA 15 p00r1y 1mmun09en1c (15en6er9 et a1, 1994). 7he 4ue5t10n 0f whether the ant160d1e5 t0 d5DNA pre5ent 1n pat1ent5 w1th 5LE are ant19en-dr1ven aut0ant160d1e5 0r der1ve fr0m a p001 0f 9erm11ne 9ene-enc0ded natura1 aut0ant160d1e5 15 5t111 a matter 0f de6ate. Mur1ne m0de15 0f 5LE have a 6ack9r0und 0f p01yc10na1 8 ce11 act1vat10n 6ut the aut0ant160d1e5 fr0m human 5LE pat1ent5 are th0u9ht t0 have pr06a61y ar15en a5 the re5u1t 0f an ant19en dr1ven 7 he1per ce11 dependent re5p0n5e, p055161y 1n c0m61nat10n w1th a 11m1ted and educated p01yc10na1 act1vat10n. 8acter1a1 DNA ha5 6een 5h0wn t0 6e much m0re ant19en1c than mamma11an DNA, wh1ch w0u1d 5upp0rt the 1dea 0f an ant19en dr1ven 0r191n f0r the aut0ant160d1e5; h0wever, re5earch exp10r1n9 the r01e 0f

1mmun0path09ene5150f 5LE

387

6acter1a a5 the 1nc1t1n9 5t1mu1u5 t0 d5DNA ant160dy pr0duct10n 1n human5 15 unc0nv1nc1n9. Recent w0rk ha5 5h0wn that p01y0mav1ru5 tran5cr1pt10n fact0r 7 ant19en can 1nduce ant1-DNA ant160d1e5 1n m1ce and that ant160d1e5 t0 d5DNA were f0und 1n pat1ent5 w1th fre4uent p01y0mav1ru5 react1vat10n5 (Rekv19 et a1, 1997). 1t 15 n0w th0u9ht 11ke1y that DNA 11nked t0 h15t0ne5, a5 f0und a6undant1y 1n ap0pt0t1ca11y re1ea5ed nuc1e050me5, may 6e the 5t1mu1at1n9 ant19en (f0r a rev1ew, 5ee 8erden, 1997). 0ne 5u99e5t10n 15 that act1vated pha90cyt1c ce115 can re1ea5e h19h1y react1ve 0xy9en 5pec1e5 that can penetrate ce11 mem6rane5 and a1ter nuc1ear DNA cau51n9 1t t0 6ec0me ant19en1c. 7he5e 1n1t1at1n9 mechan15m5 are n0t mutua11y exc1u51ve and the c0n5en5u5 appear5 t0 6e that ant160dy pr0duct10n 1n 5LE 15 ant19en dr1ven. 7h15 065ervat10n empha512e5 that 1mpa1red t01erance mu5t 6e the centra1 defect 1n 5LE and, 0nce tr199ered, a6n0rma1 1mmun0re9u1at10n 1ead5 t0 per515tence 0f the 1mmune re5p0n5e t0 DNA/h15t0ne5. Ep1t0pe 5pread1n9 15 a hyp0thet1ca1 mechan15m 6y wh1ch aut0ant160d1e5 t0 a w1de var1ety 0f 5pec1f1c1t1e5, a5 5een 1n 5LE, c0u1d deve10p. 7h15 hyp0the515 5u99e5t5 that 1f a 51n91e ep1t0pe 0n a 5e1f-pr0te1n 15 tar9eted the 1mmune re5p0n5e can 5pread t0 0ther ep1t0pe5 0n the 5ame m01ecu1e and 5u65e4uent1y t0 ep1t0pe5 0n 0ther c105e1y re1ated m01ecu1e5. 7h15 m0de1 re4u1re5 the maj0r h15t0c0mpata6111ty c0mp1ex (MHC) c1a55 11 re5tr1cted pre5entat10n 0f a 5e1f-pept1de fr0m a nat1ve part1c1e 6y a pr0fe5510na1 ant19en pre5ent1n9 ce11 (APC) 0r 8 ce11, t0 an aut0react1ve 7 ce11. 1t ha5 recent1y 6een rep0rted that an 0ctapept1de (PPP6MRPP), der1ved fr0m 5m8/8•, may 6e an ear1y tar9et 0f the aut01mmune re5p0n5e 1n 5LE. New 2ea1and Wh1te (N2W) ra661t5 1mmun12ed w1th th15 pept1de n0t 0n1y pr0duced ant160d1e5 5pec1f1c f0r the 1mmun121n9 pept1de 6ut deve10ped aut0ant160d1e5 t0 re1ated 5p11ce050ma1 ant19en5. U1t1mate1y,the ra661t5 a150 pr0duced aut0ant160d1e5 that 60und 0ther nuc1ear aut0ant19en5, e.9. d5DNA, and exh161ted c11n1ca1 feature5, 5u99e5t1ve 0f 1upu5, 5uch a5 pr0te1nur1a and 5e12ure5 (Jame5 et a1, 1995). A1th0u9h exper1menta1 ev1dence that th15 mechan15m app11e5 t0 human 1upu5 15 1ack1n9 1t ha5 f0und 9r0w1n9 5upp0rt fr0m 5tud1e5 1n exper1menta1 m0de15 (Craft and Fatenejad, 1997). 1n 0ur 0wn 5tud1e5 we have a150 f0und 50me ev1dence 0f ep1t0pe 5pread1n9 u51n9 th15 pept1de, 6ut d1d n0t f1nd ant1-d5DNA ant160d1e5 0r c11n1ca1 feature5 0f 1upu5 1n 0ur 1mmun12ed ra661t5 (Ma50n et a1, 1998). Path09en1c r01e 0f aut0ant160d1e5 7he path09en1c ant160d1e5 t0 d5DNA, wh1ch are a550c1ated w1th 910meru10nephr1t15 1n 5LE, are 9enera11y h19h aff1n1ty, 0ccur at h19h t1tre5 and are 0f the 196 150type. 7hey are a150 capa61e 0f f1x1n9 c0mp1ement, cu1m1nat1n9 1n 10ca1 1nf1ammat10n and t155ue dama9e. 7he5e path09en1c ant160d1e5 appear t0 dep051t preferent1a11y 1n the k1dney. 7hree hyp0thet1ca1 mechan15m5 may acc0unt f0r th15 10ca112at10n. 7he c1rcu1at1n9 1mmune c0mp1ex hyp0the515, the cr055-react1ve ant160dy hyp0the515 and the p1anted ant19en hyp0the515 (Dav15 et a1, 1996; Lefk0w1th

388

L.J. Ma50n and D. A. 15en6er9

and 611ke50n, 1996;Van 8ru99en et a1, 1996). 1t wa5 0r191na11yth0u9ht that c1rcu1at1n9 1mmune c0mp1exe5 0f DNA ant1-DNA ant160d1e5 6ec0me trapped 1n the 910meru1u5, 6ut the pre5ence 0f 5uch c0mp1exe5 1n human 1upu5 5era 15 c0ntr0ver51a1. 1t ha5 6een 5h0wn that 1njected c0mp1exe5 61nd p00r1y t0 910meru1ar 6a5ement mem6rane (68M) and that 5uch c0mp1exe5 w0u1d 6e rap1d1y c1eared 6y the 11ver. 7he prem15e 0f the cr055-react1ve ant19en hyp0the515 15 that ant1-DNA ant160d1e5 are 6r0ad1y react1ve, 61nd1n9 a w1de array 0f m01ecu1e5 5uch a5 6 8 M c0mp0nent5.7h15 the0ry 15 a var1ant 0n the m01ecu1ar m1m1cry theme, 6ut 1t 15 th0u9ht that the p01yreact1v1ty 0f ant160d1e5 15 1e55 11ke1yt0 0ccur than 61nd1n9 t0 the1r c09nate ant19en. Recent ev1dence 5upp0rt5 the •p1anted ant19en• mechan15m, wh1ch 5u99e5t5 that c1rcu1at1n9, n0n-c0mp1exed cat10n1c ant1-DNA ant160d1e5 61nd t0 c011a9en type 1V and the heparan 5u1phate 91yc05am1n091ycan c0mp0nent 0f the 6 8 M , v1a a c0mp1ex 0f h15t0ne5 and DNA, 1n the f0rm 0f nuc1e050me5. Nuc1e050me5 are chr0mat1n c0mp1exe5 9enerated dur1n9 ap0pt0515, wh1ch c0nta1n 180-200 6a5e-pa1r (6p) p1ece5 0f DNA ar0und h15t0ne pr0te1n5. 1t ha5 6een 5h0wn 1n v1tr0 that aut0react1ve 7 ce115 fr0m 1upu5 pat1ent5 rec09n12e nuc1e050me5 preferent1a11y t0 DNA 0r h15t0ne5 a10ne. 7he f0rmat10n 0f nuc1e050me-5pec1f1c ant160d1e5 may precede the deve10pment 0f 60th ant1-d5DNA and ant1-h15t0ne ant160d1e5.1f 50 the 1055 0f t01erance f0r nuc1e050me5 c0u1d 6e a pr1mary event dr1v1n9 the aut01mmune re5p0n5e 1n 5LE. 1t 15 a150 0f n0te that recent 5tud1e5 have 5h0wn that aut0ant160d1e5 are d1rected a9a1n5t mu1t1p1e ep1t0pe5 0n chr0mat1n 1nc1ud1n9, 6ut n0t 11m1ted t0, d5DNA. 1t 15 11ke1ythat, h0wever the aut0ant160d1e5 61nd t0 the k1dney, path0109y 15 ma1n1y cau5ed 6y the1r a6111tyt0 act1vate c0mp1ement cau51n9 1nf1ammat10n. Char9e and aff1n1ty f0r d5DNA may n0t 6e ade4uate pred1ct0r5 0f ant1-DNA ant160dy path09en1c1ty, wh1ch may 6e m0re re1ated t0 the1r f1ne 5pec1f1c1t1e5(Putterman et a1, 1996). A1th0u9h 0nce th0u9ht t0 6e h19h1y c0ntr0ver51a1 there are a num6er 0f 1n v1v0 5tud1e5 5u99e5t1n9 that ant1-DNA, ant1-U1 r160nuc1e0pr0te1n (RNP) and ant1-r16050ma1 P ant160d1e5 can penetrate 11v1n9 ce115 and p0tent1a11y 1nduce rena1 d15ea5e 6y 1ntrace11u1ar effect5, 5uch a5 1nduc1n9 1055 0f t01erance t0 5e1f 6y m0d1f1cat10n 0f ap0pt0t1c event5 (Ca6ra1 and A1arc6n5e90v1a, 1997). Recent 1n v1tr0 w0rk ha5 dem0n5trated that m0n0c10na1 ant1-d5DNA ant160d1e5 fr0m MRL/1pr/1prm1ce penetrate 11ve rena1 tu6u1ar ce115.51te-d1rected mutant5 5h0wed that 50me re51due5 0f the VH re910n are nece55ary f0r DNA 61nd1n9, 5u99e5t1n9 that ant160dy penetrat10n depend5 0n a mem6rane determ1nant re5em611n9 DNA (2ack et a1, 1996). Mur1ne m0n0c10na1 ant160d1e5 can penetrate ce115 and cau5e path01091ca1 a6n0rma11t1e5 (V1ahak05 et a1, 1992).

Ce11u1ara6n0rma11t1e5 and dy5re9u1at10n 5LE 15 character12ed 6y mu1t1p1e funct10na1 defect5 am0n9 the ce115 0f the 1mmune 5y5tem, 1nc1ud1n9 7 and 8 1ymph0cyte5, natura1 k111er (NK) ce115 and acce550ry ce115 (ant19en pre5ent1n9 ce115, APC5). 7he end re5u1t 15 a

1mmun0path09ene515 0f 5LE

389

6reakd0wn 0f 1mmun01091ca1 t01erance thr0u9h the rever5a1 0f c10na1 aner9y, act1vat10n 0f 5e1f-react1ve aut0a99re51ve 7 ce115 and defect1ve 7 ce11 5uppre5510n. 7he num6er5 0f c1rcu1at1n9 1ymph0cyte5, fr0m 60th 7 and 8 ce11 p0pu1at10n5, are extreme1y var1a61e and re1ate t0 d15ea5e act1v1ty and durat10n (Daya1 and Kammer, 1996; 750k05, 1996; 15en6er9 and H0r5faU, 1998). 7he m05t marked defect 1n 5LE 15 the 1ncrea5e 1n num6er5 0f act1vated 8 1ymph0cyte5 that c0ntr16ute5 t0 the hyper9amma9106u11naem1a a550c1ated w1th react1v1ty t0 5e1f-ant19en5. 7here 15 a150 an 1ncrea5e 1n 1nter1euk1n 2 (1L-2) recept0r 1eve15 0n c1rcu1at1n9 8 ce115 wh115t expre5510n 0f CR1, the C36 recept0r, 15 decrea5ed. 8 ce115 and CD4+ 7 ce115 a150 exh161t an 1ncrea5ed cyt0p1a5m1c expre5510n 0f h5p90, wh1ch 15 5e1d0m 5een 1n CD8+ ce115. 50me 0f the exce55 h5p90 15 10ca112ed 0n the ce11 5urface, and c0u1d exp1a1n the pre5ence 0f ant1-h5p90 ant160d1e5 1n pat1ent5.7he 1ncrea5e 1n 8 ce115 15 acc0mpan1ed 6y 7 1ymph0cyt0pen1a, e5pec1a11y 0f ce115 6ear1n9 the CD4•/CD45R+ phen0type. 7h15 p0pu1at10n 0f ce115 •he1p5• t0 1nduce 5uppre5510n 6y pr0v1d1n9 a 519na1 t0 the CD8+ ce115 and the reduct10n 1n th15 5u65et may c0ntr16ute t0 the fa11ure 0f the 7 ce115t0 5uppre55 the hyperact1ve 8 ce115. Ant1-1ymph0cyt1c ant160d1e5 may p1ay a r01e 1n the dep1et10n 0f th15 ce11u1ar 5u65et. 5he t1tre 0f ant1-7 ce11ant160d1e5 c0rre1ate5 w1th 60th d15ea5e act1v1ty and the 1eve1 0f 7 ce11 k1111n9, w1th f1are5 1n d15ea5e 6e1n9 a550c1ated w1th 1ncrea5ed CD4/CD8 k1111n9and rem15510n w1th a decrea5e (Yamada et a1, 1993). CD8+ ce115, and NK ce115 may 6ehave a6errant1y 6y pr0v1d1n9 he1p, rather than 5uppre5510n, t0 8 ce115 and hence 5t1mu1at1n9 pr0duct10n 0f aut0ant160d1e5. 7 ce115 fr0m 1upu5 pat1ent5 have 6een c10ned 1n v1tr0. 0n1y 15% 0f the5e 7 ce115 pr0v1ded he1p f0r 8 ce115t0 make path09en1c ant1-DNA ant160d1e5. 7he maj0r1ty (83%) 0f the5e ce115 were CD4+ w1th the c1a551ca1 0~ 7-ce11 recept0r (7CR) and were c1a55 11 re5tr1cted. 5e4uenc1n9 revea1ed h19h1y char9ed cat10n1c m0t1f5 1n the1r CDR3 100p5, nece55ary f0r pr0duct10n 0f ant1-DNA ant160d1e5 that w111 61nd the 6 8 M . 7he rema1n1n9 17% were •d0u61e ne9at1ve• and n0t c1a55 11 re5tr1cted. 7he pre5ence 0f 50 ca11ed d0u61e ne9at1ve 7 ce115 15 a feature 0f 5LE and 0f mur1ne m0de15. 7he5e a6errant ce1151ack the CD4 and CD8 marker5 and a5 d0u61e ne9at1ve5 they have pr06a61y e5caped thym1c de1et10n. 0~1y 30% 0f the5e ce115 have the c1a551ca1 0c[] 7CR cha1n5, 70% expre55 the a1ternat1ve 3•5 7CR. 5u65e4uent 5e4uenc1n9 0f the 7CR5 ha5 revea1ed V8 and V3• 9ene u5a9e n0t f0und 1n n0rma1 adu1t5 6ut re5em611n9 that 0f feta1 thym0cyte5 (Raja90pa1an et a1, 1992). 1n add1t10n t0 5t1mu1at1n9 8 ce11 hyperact1v1ty and aut0ant160dy pr0duct10n, d0u61e ne9at1ve 7 ce115 are 1mp11cated 1n the 1mpa1red ce11u1ar re5p0n5e t0 f0re19n ant19en5 and reca11 ant19en5 and hence may c0ntr16ute t0 the 1mpa1red a6111ty 0f pat1ent5 w1th 1upu5 t0 deter 1nfect10u5 a9ent5. 1ncrea5ed mutat10n5 have 6een f0und 1n the DNA 0f 7 ce1151n pat1ent5 w1th 1upu5, wh1ch may re5u1t 1n 7 ce11 death 6y necr0515 and the re1ea5e 0f n0nde9raded DNA c0ntr16ut1n9 t0 ant1-DNA ant160dy pr0duct10n. 1t may 6e that pat1ent5 w1th 1upu5 have a pr1mary 7 ce11519na111n9d150rder and that 7 ce11 dy5funct10n 15 a 6y-pr0duct 0f a6n0rma1 610chem1ca1 pathway5, re5u1t1n9 1n a1tered re9u1at10n 0f effect0r funct10n (Daya1 and

390

L.J. Ma50n and D. A. 15en6er9

Kammer, 1996; 750k05, 1996; 750k05 et a1, 1997). 7 ce115fr0m 5LE pat1ent5 5h0wed 1mpa1red pr0te1n k1na5e A (PKA)-cata1y5ed pr0te1n ph05ph0ry1at10n, due t0 a def1c1ency 1n PKA-1 1502yme. PKA 15 re5p0n5161e f0r ph05ph0ry1at10n and act1vat10n 0f cAMP•5 5ec0nd me55en9er r01e. A1terat10n5 1n the ce11u1ar pr0te1n ph05ph0ry1at10n pattern may a1ter h0me05ta515 and d15tur6 the 1mmune funct10n 0f the ce11. 1mpa1red pr0te1n ph05ph0ry1at10n c0u1d affect 9ene tran5cr1pt10n re5u1t1n91n an 1m6a1ance 0f pr0te1n 5ynthe515 w1th1n ce115, f0r examp1e a1ter1n9 the pattern 0f cyt0k1ne pr0duct10n. 7here 15a150 a CD3 med1ated 1ncrea5e 1n free 1ntra-cyt0p1a5m1c ca1c1um that 0ccur5 5pec1f1ca11y1n 7 ce115fr0m pat1ent5 w1th 1upu5. 7h15 1ncrea5ed ca1c1um may acc0unt f0r a1terat10n5 1n PKA funct10n, a1tered ap0pt0515 0r decrea5ed 1L-2 pr0duct10n. 1n c0mpar1510n w1th 7 ce115fr0m n0rma11nd1v1dua15, th05e fr0m pat1ent5 w1th 1upu5 5h0w marked1y a6n0rma1 •capp1n9• 0f the ce11 5urface pr0te1n5, CD4 and CD8.7h15 pr0ce55 15 c0ntr011ed 6y the cAMP pathway, and 1n pat1ent5 w1th 1upu5 there 15 decrea5ed cAMP pr0duct10n, re5u1t1n9 1n an 1na6111ty t0 5w1tch phen0type and expre55 5uppre550r act1v1ty. Furtherm0re p0tent1a1 m01ecu1ar defect5 may 1nv01ve 9ene methy1at10n. 1nh161t10n 0f 7 ce119ene methy1at10n ha5 6een a550c1ated w1th aut0react1v1ty due t0 0verexpre5510n 0f 1ymph0cyte funct10n a550c1ated ant19en 1, 1ead1n9 t0 1ncrea5ed 7 ce11h0m1n9 t0 tar9et t155ue5. 7he 1nteract10n 6etween c0-5t1mu1at0ry m01ecu1e5 5uch a5 C7LA4-87 and CD28 15 e55ent1a1 f0r 7 ceU 5t1mu1at10n 6y APC5 and 15 cruc1a1 f0r 1L-2 pr0duct10n and t01erance 1nduct10n (750k05 et a1, 1997). 7he C7LA487/CD28 pathway ha5 6een 5h0wn t0 determ1ne act1vat10n 0f 7 ce115 fr0m 1upu5 pr0ne MRL-1pr/1prm1ce. 810ckade 0f 87-1 and 87-2 ha5 6een 5h0wn t0 1ncrea5e the rate 0f 5urv1va1 and t0 reduce ant1-DNA ant160dy t1tre5 and k1dney path0109y 1n the5e m1ce (750k05, 1996). Defect1ve re5p0n5e5 t0 reca11 ant19en5 have 6een rec09n12ed f0r 1upu5 1mmune ce115and the upre9u1at10n 0f 87-1 0n 1upu5 APC5 ha5 6een f0und t0 6e defect1ve (750k05 et a1, 1996). 7he pr0duct10n 0f path09en1c ant160d1e5 a150 re4u1re5 c09nate 1nteract10n 6etween CD40 119and (CD40L/9p39) 0n 7 ce115 and CD40 0n 8 ceU5. 1t 15 kn0wn that 519na111n9 thr0u9h the CD40 119and 15 nece55ary f0r expan510n 0f ant19en-5pec1f1c 7 he1per ce115 and theref0re ant19en-5pec1f1c ant160dy. Macr0pha9e and NK ce11 cyt0t0x1c1ty 15 a150 1mpa1red 1n pat1ent5 w1th 5LE, a5 15 the c1earance 0f 1mmune c0mp1exe5 6y the m0n0nuc1ear pha90cyt1c 5y5tem. 1n the5e pat1ent5 the num6er5 0f NK ce115 are reduced and th05e pre5ent are pr06a61y 5kewed t0ward5 8 ce11 he1p rather than 5uppre5510n. 7he dy5funct10n 0f the m0n0nuc1ear pha90cyte 5y5tem, 1n 1mmune-c0mp1ex c1ear1n9, 1n 5LE 15 part1y attr16uted t0 a6n0rma11t1e5 0f the 5urface recept0r5 f0r the Fc 0f 196 (FcyR).

Cyt0k1ne5 7he a6errant ce11u1ar effect0r mechan15m5 5een 1n 5LE are c105e1yc0nnected t0 the 1nteract10n 0f ce115 w1th the1r extrace11n1ar env1r0nment, wh1ch cr1t1ca11y 1nv01ve5 ce11u1ar me55en9er5, the cyt0k1ne5. 7 he1per ce115 are character12ed 1nt0 d1fferent 5u65et5 dependent 0n the1r cyt0k1ne pr0f11e. 1n

1mmun0path09ene515 0f 5 L E

391

9enera1 7h1 ce115 5upp0rt ce11-med1ated 1mmun1ty and pr0duce pr01nf1ammat0ry cyt0k1ne5, 5uch a5 1nterfer0n 9amma (1FNy), wherea5 7h2 ce115pr0v1de 8 ce11 he1p and 5uppre55 ce11-med1ated 1mmun1ty v1a cyt0k1ne5 1nc1ud1n9 1L-4, 1L-5 and 1L-10. W1th the caveat that a r191d d15t1nct10n 6etween 7h1 and 7h2 d15ea5e5 15 pr06a61y 1nc0rrect, 0ne m19ht pred1ct theref0re that 5LE w0u1d 6e a pred0m1nant1y 7h2 ce11-med1ated d15ea5e, re5u1t1n9 1n exce55 he1p f0r 8 ce115, p01yc10na1 8 ce11 act1vat10n and pr0duct10n 0f path09en1c aut0ant160d1e5 (750k05, 1995; 15en6er9 and H0r5fa11, 1998). 7he 5h1ft fr0m a pred0m1nant1y 7h0 p0pu1at10n 0f 7 ce115, pr0duc1n9 60th 7h1 and 7h2 cyt0k1ne5 t0ward5 a 7h2 pred0m1nance, m19ht ar15e a5 a re5u1t 0f a1tered re9u1at10n 0r expre5510n 0f 9ene5, due t0 a 610chem1ca1/519na111n9 defect. Recent exper1menta1 065ervat10n5 5u99e5t that 1L-10 p1ay5 a key r01e 1n the 1mmun0path09ene515 0f 5LE (f0r a rev1ew, 5ee 750k05 et a1, 1997). A 5ynthe515 0f the funct10n 0f the cyt0k1ne5 1n 5LE 15 5ummar15ed 1n 7a61e 2.

Ap0pt0515 Ap0pt0515 15 the term u5ed t0 de5cr16e pr09rammed ce11 death, the pr0ce55 wh1ch 15 1n1t1ated 6y 119and-recept0r 1nteract10n, a5 c0mpared w1th ce11 7a61e 2. R01e 0f cyt0k1ne5 1n 5y5tem1c 1upu5 erythemat08u8. Cyt0k1ne

C11n1ca1and exper1menta1065ervat10n5

1L-10

1• 1n 5era 0f pat1ent5 w1th 5LE, 5uppre55e5 7h1 ce115and 1mpa1r5ce11-med1ated1mmun1ty 1• pr0duct10n 6y macr0pha9e5 and 8 ce115--->defect1ve 87-1 expre5510n -4, $ APC funct10n 1• 8 ce11funct10n and 1• pr0duct10n 0f path09en1c aut0ant160d1e5, 6y aut0cdne pathway Ant1-1L-10 610ck5 ant1-DNA A6 pr0duct10n 6y P8MC5 fr0m 1upu5 pat1ent5 1n 5C1D m1ce Ant1-1L-10 de1ayed d15ea5e 0n5et and 1• 7NFc2 pr0duct10n 1n the N28/W mur1ne m0de1 D15ea5e 5evedty c0rre1ate5 w1th 1• rat10 0f 1L-10: 1FNy5ecret10n 1n 1upu5 P8MC5 1• 5ecret10n 6y ant19en-pr1med 7 ce115 $ pr0duct10n 1n pat1ent5 w1th 1upu5 --> 1mpa1redmacr0Pha9e and NK ce11-med1ated cyt0t0x1c1ty Rec0m61nant 1FNytherapy 51de effect: aut0ant19en expre5510n and ant1-55DNA and ant1-d5DNA pr0duct10n. Pr0tect1ve r01e 1n 1upu5. Pr0duced 6y 7h1 ce115,8 ce115, NK ce115and m0n0nuc1ear pha90cyte5 MHC 11nkedpr0duct10n: 1• 7NF(2 5een 1n hap10type5, DR3 and DR4, a550c1ated w1th 10w 1nc1dence 0f 1upu5 nephdt15. 4. 7NF~ 5een 1n hap10type5, DR2 and D4W1, a550c1ated w1th 1upu5 nephr1t15 $ pr0duct10n 1n pat1ent5 w1th 1upu5. 7 ce115unre5p0n51ve, p055161ydue t0 defect1ve 1L-1 recept0r 1• 1eve151n 5era and cere6ra1 5p1na1f1u1d0f pat1ent5 w1th 1upu5. L0ca112ed1n nephr1t1c k1dney5 1• mRNA 1n P8MC5 fr0m pat1ent5. 8 ce115have 1• 1L-6R and 5p0ntane0u51y pr0duce 1L-6 (aut0cdne) and 1" A6 pr0duct10n $1n v1tr0 CD4 and CD8 pr011ferat1vere5p0n5e t0 m1t09en5/f0re19n ant19en5 $ 7 ce11maturat10n and $ CD8 5uppre550r funct10n. CD4 ce115have 10w aff1n1ty 1L-2 recept0r5

1L-4 1FN7

7NFc~

1L-1 1L-6

1L-2

1L, 1nter1euk1n; 1FNy, 1nterfer0n-y; 7NFc~, tum0r necr0515 fact0r-c~; 7h1, 7 he1per 1; APC, ant19en pre5ent1n9 ce115; A6, ant160dy; P8MC, per1phera1 6100d m0n0nuc1ear ce11; 5C1D, 5evere c0m61ned 1mmun0def1c1ent m1ce; N28/W, New 2ea1and 61ack/wh1te; NK, natura1 k111er; 55DNA, 51n91e-5tranded DNA; d5DNA, d0u61e-5tranded DNA; MHC, maj0r h15t0c0mpata6111tyc0mp1ex.

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L.J. Ma50n and D. A. 15en6er9

necr0515 cau5ed 6y t0x1c 1n5u1t5.7he 5tr1ct re9u1at10n 0f ce11 death 15 0f v1ta1 1~p0rtance 1n en5ur1n9 a c0mpetent, 6ut n0t aut0react1ve, 1ymph0cyte repert01re. Dy5funct10n 0f ap0pt0515 may under11e many 0f the 1mmun01091ca1 a6n0rma11t1e5 5een 1n 5LE, 5uch a5 the fa11ure t0 e11m1nate 5e1freact1ve 7 ce115 and 8 ce115 dur1n9 t01erance 1nduct10n (f0r rev1ew5, 5ee E1k0n, 1994; M0unt2 et a1, 1994; R05e et a1, 1997). 7he pr0ce55 0f ap0pt0515 1nv01ve5 c0mp1ex 610chem1ca1 pathway5, wh05e f1na1 5ta9e5 pr06a61y 1nv01ve a DNa5e and a pr0tea5e. 7he act1vat10n 0f DNa5e cau5e5 c1eava9e 0f 1nternuc1e050ma1 DNA re1ea51n9 nuc1e050me5. C1rcu1at1n9 nuc1e050me5 have 6een detected 1n pat1ent5 w1th 1upu5 wh05e d15ea5e 15 act1ve and may 6e an 1mp0rtant 1mmun09en f0r the pr0duct10n 0f aut0ant160d1e5 t0 DNA. 7he pr0duct10n 0f 5uch ant160d1e5 depend5 up0n pat1ent5 hav1n9 a 5u5cept161e 9enet1c 6ack9r0und. 1ndeed, the remarka61e d1ver51ty 0f d15ea5e man1fe5tat10n5 5een 1n d1fferent Fa5-def1c1ent 1n6red m1ce under11ne5 the 1mp0rtant 1nf1uence 0f 9enet1c 6ack9r0und 0n d15ea5e expre5510n. Ap0pt0t1c defect5 1nv01v1n9 at 1ea5t tw0 9ene5, 6c1-2 and fa5, have 6een 1nve5t19ated 1n the path09ene515 0f 5LE. 8c1-2 15 a pr0t0-0nc09ene 10cated 0n the 1nner m1t0ch0ndr1a1 mem6rane. 8c1-2 15 un14ue am0n9 0nc09ene5 1n that 1t pr0m0te5 1ymph01d ce115urv1va1 6y 1nterfer1n9 w1th ap0pt0515 rather than 6y 1nduc1n9 ce11pr011ferat10n. 7he 6c1-2 9ene pr0duct exert5 a re9u1at0ry funct10n 0n adu1t t155ue5 6y prevent1n9 ap0pt0515 0f 5pec1f1c ce11 type5. 1t 15 1nv01ved 1n 7 ce11 deve10pment and thym1c 5e1ect10n and 15 a150 f0und 1n 10n9-11ved 8 ce115w1th1n the f0111cu1ar mant1e 20ne. 8c1-2 pr0te1n 15 10ca112ed 1n t155ue5 character12ed 6y ap0pt0t1c ce11 death, f0r examp1e 1t 15 c0nf1ned t0 20ne5 0f 5urv1v1n9 8 ce115 1n 9erm1na1 centre5 and t0 the thym1c medu11a c0nta1n1n9 mature 7 1ymph0cyte5.7here 15 n0w c0n51dera61e ev1dence that 8c1-2 expre5510n 15 enhanced 1n a pr0p0rt10n 0f per1phera1 7 ce115, 6ut n0t 1n 8 ce115 0f 5LE pat1ent5 and that 8c1-2 1eve15c0rre1ate w1th 0vera11 d15ea5e act1v1ty (Ar1n9er et a1, 1994). N0rma1 c1rcu1at1n9 1ymph0cyte5 5h0w a6undant expre5510n 0f 8c1-2, 5u99e5t1n9 that th15 pr0te1n a1d5 5urv1va1 1n the per1phery; h0wever 7 ce115, 6ut n0t 8 ce115, fr0m the per1phera1 6100d 0f 5LE pat1ent5 0verexpre55 8c1-2. 7h15 0verexpre5510n 0f 8c1-2 0n 7 ce115 c0rre1ate5 w1th 0vera11 d15ea5e act1v1ty 1n pat1ent5 w1th 5LE (rev1ewed 6y R05e et a1, 1997). A1th0u9h there 15 1ncrea5ed 8c1-2 1n 50me 1ymph0cyte5 fr0m pat1ent5 w1th 5LE, 1n 0ne 5tudy the rate 0f 1n v1tr0 ap0pt0515 wa5 1ncrea5ed 1n 1ymph0cyte5 (Em1en et a1, 1993). 1f th15 1ncrea5ed ap0pt0515 a150 0ccur5 1n v1v0 1t w0u1d re5u1t 1n the re1ea5e 0f exce55 nuc1e050me5 that c0u1d pr0v1de a 50urce 0f ant19en1c DNA f0r aut0ant160dy pr0duct10n. 7ran59en1c m1ce w1th 8 ce115expre551n9 8c1-2 5h0w pr010n9ed 8 ce115urv1va1, pr0duct10n 0f aut0ant160d1e5, pr010n9ed 8 ce11 mem0ry and c10na1 de1et10n 0f 5e1freact1ve 8 ce115 15 1nh161ted. 7he5e m1ce, 0n an appr0pr1ate 9enet1c 6ack9r0und, can deve10p ant1-DNA, ant1-5m ant160d1e5 and 910meru10nephr1t15 (5tra55er et a1, 1991). Fa5 (Ap0-1/CD95) 15 the ce11 5urface pr0te1n re5p0n5161e f0r 1nduct10n 0f ap0pt0515 1n 1ymph0cyte5 thr0u9h 1nduct10n 0f 5evera1 519na111n9pathway5. Fa5 recept0r (Fa5R) 15 f0und at very 10w 1eve150n n0rma1 re5t1n9 per1phera1

1mmun0path09ene5150f 5LE

393

7 and 8 ce115,6ut 15marked1y upre9u1ated 0n act1vated ce115,wh1ch under90 ap0pt0515 1f they are n0t re5t1mu1ated 6y ant19en. 7hree 1ndependent mutat10n5 0f the Fa5R 0r 1t5 119and have ar15en 1n three d1fferent m0u5e 5tra1n5. Mutat10n5 1n e1ther the fa5 9ene (1pr) 0r the 9ene f0r Fa5 119and (C3H 91d) re5u1t 1n Fa5 119and expre551n9 cyt0t0x1c 7 ce115, wh1ch fa11 t0 rem0ve aut0react1ve 8 ce115, re5u1t1n9 1n 0verpr0duct10n 0f aut0ant160d1e5. MRL-1pr/1pr m1ce have an end09en0u5 retr0v1ra1 DNA 5e4uence 1nte9rated 1nt0 the1r fa5 9ene wh1ch re5u1t5 1n 1055 0f ap0pt0515 due t0 1nc0rrect mem6rane expre5510n 0f Fa5. 7h15 a6n0rma11ty may acc0unt f0r the accumu1at10n 0f 5e1f-react1ve d0u61e-ne9at1ve 7 ce115(CD4- CD8-) 1n the5e m1ce. 1n c0ntra5t t0 MRL-1pr/1pr m1ce Fa5 expre5510n 1n 5LE pat1ent5 15 519n1f1cant1y 1ncrea5ed 0n per1phera1 6100d m0n0nuc1ear ce115 (P8MC5) c0mpared w1th n0rma1 c0ntr015 (My51er et a1, 1994). 1ncrea5ed Fa5R wa5 5een 0n 60th 8 ce115 and 7 ce115, e5pec1a11y CD8+ ce115. 7he5e pat1ent5 have 1ymph0pen1a and an 1ncrea5ed rate 0f ap0pt0515, 1n v1tr0 (f0r a rev1ew, 5ee E1k0n, 1994). Recent 1n v1tr0 5tud1e5 have 5h0wn that 8 ce115 act1vated 6y CD40 119and are 5en51t1ve t0 Fa5-med1ated ap0pt0515 wh115t 1L-4 and/0r 5urface 19M recept0r en9a9ement pr0tect5 8 ce115 fr0m Fa5 119and cyt01y515. Un11ke the f1nd1n95 1n mur1ne m0de15, there are 0n1y 5p0rad1c ca5e5 0f 5LE pat1ent5 wh0 have mutat10n5 1n the 9ene5 f0r Fa5 0r Fa5 119and. H0wever, recent rep0rt5 de5cr16e e19ht ch11dren w1th mutat10n5 1n fa5 wh0 have a 1ymph0pr011ferat1ve 5yndr0me 51m11ar t0 that 5een 1n 1pr m1ce. A 1ar9e pr0p0rt10n 0f the per1phera1 and 5p1en1c 7 ce115 fr0m the5e ch11dren expre55ed ne1ther CD4 n0r CD8 and Fa5-med1ated ap0pt0515 wa5 defect1ve 1n 7 ce115 fr0m a11 0f the5e ch11dren (f0r a rev1ew, 5ee R05e et a1, 1997). 0n1y 0ne pat1ent w1th a Fa5 119and mutat10n and 1ymph0pr011ferat1ve d15ea5e wa5 f0und 1n a 5tudy 0f 100 1upu5 pat1ent5, and an0ther pat1ent w1th treatment re515tant 1upu5 had per515tent expre5510n 6y act1vated 7 ce115 0f a 501u61e f0rm 0f Fa5 (750k05 et a1, 1997). Mur1ne m0de15 and 1n v1tr0 5tud1e5 0n P8MC5 had exc1ted 1ntere5t 1n a 501u61e f0rm 0f Fa5 that 1ack5 the tran5mem6rane re910n (5Fa5), wh1ch 1t wa5 th0u9ht c0u1d 6e re5p0n5161e f0r decrea5ed ap0pt0515 and accumu1at10n 0f 1ymph0cyte5. 5u65e4uent1y 5Fa5/Ap0-1 ha5 6een f0und t0 0ccur 0n1y 1nfre4uent1y 1n the 5era 0f pat1ent5 w1th 5LE, and 1eve15 have fa11ed t0 c0rre1ate w1th 1nd1ce5 0f d15ea5e act1v1ty. C0n5e4uent1y, 5Fa5 15 un11ke1y t0 6e 0f maj0r path09en1c 1mp0rtance (60e1 et a1, 1995; Kn1pp1n9 et a1, 1995). 7he5e c0nf11ct1n9 re5u1t5 6etween m1ce and human5 1nd1cate that further re5earch 15 nece55ary t0 1nve5t19ate the r01e 0f ap0pt0515 1n the path09ene515 0f 5LE. Ce11adhe510n m01ecu1e5

Adhe510n m01ecu1e5 are c1a551f1ed 1nt0 5e1ect1n, 1nte9r1n and 1mmun09106u11n 5uper9ene fam11y 9r0up5. Leuk0cyte adhe510n 15 re9u1ated 6y chan9e5 1n adhe510n m01ecu1e expre5510n and av1d1ty, dependent 0n the 1eve1 0f ce11u1ar act1vat10n. Dur1n9 the 1nf1ammat0ry 0r aut01mmune re5p0n5e,

394

L.J. Ma50n and D. A. 15en6er9

adhe510n m01ecu1e5 med1ate the 1nteract10n5 6etween 1ymph0cyte5 and va5cu1ar end0the11a1 ce115dur1n9 extrava5at10n and h0m1n9 a5 we11 a5 a110w1n9 10ca1 retent10n 0f ce115 1n the extrace11u1ar matr1x. Adhe510n m01ecu1e5 a150 p1ay an 1mp0rtant r01e 1n the 1nteract10n 6etween APC5 and 7 ce115, en5ur1n9 effect1ve 7 ce11he1p 0r cyt0t0x1c 7 ce11funct10n. 1n 5LE E-5e1ect1n, 1ymph0cyte funct10n-a550c1ated ant19en-1/1nterce11u1ar adhe510n m01ecu1e-1 (LFA-1/1CAM-1) and very 1ate ant19en-4/va5cu1ar ce11 adhe510n m01ecu1e-1 (VLA-4/VCAM-1) appear t0 pr0v1de the pred0m1nant adhe51ve 1nteract10n5 at 1nf1ammat0ry 51te5 (f0r rev1ew5, 5ee 5f1kak15 and 750k05, 1995; McMurray, 1996). 5k1n 610p51e5 fr0m 1upu5 pat1ent5 5h0w upre9u1at10n 0f 5urface expre5510n 0f E-5e1ect1n, VCAM-1 and 1CAM-1 0n derma1 ve55e1end0the11a1 ce115. Leve15 0f adhe510n m01ecu1e5 d1rect1y c0rre1ated w1th d15ea5e act1v1ty and, 1n 5evera1 ca5e5, decrea5ed w1th c11n1ca1 1mpr0vement. 7he5e adhe510n m01ecu1e5 are a150 f0und t0 6e e1evated 1n 5ke1eta1 mu5c1e w1th per1va5cu1ar 1nf11trate5 when c0mpared w1th c0ntr015. E-5e1ect1n 15 1ncrea5ed even 1n the a65ence 0f per1va5cu1ar 1nf11trat10n. 1ncrea5ed 910meru1ar expre5510n 0f 1CAM-1, and a150 very 1ate ant19en-3 (VLA-3), ha5 6een f0und 1n pat1ent5 w1th 5LE wh0 had rap1d1y pr09re551ve 910meru1arnephr1t15. 7he5e pat1ent5 a150 expre55 e1evated 1eve15 0f E-5e1ect1n 0n 910meru1ar and tu6u1ar ep1the11um, and VCAM-1 15 upre9u1ated 0n the end0the11um 0f 1nter5t1t1a1 ve55e15. Per1phera1 6100d 1ymph0cyte5 fr0m pat1ent5 w1th 5LE 5h0w 1ncrea5ed expre5510n 0f LFA-1 c0mpared w1th c0ntr015, and LFA-1 and VLA-4 are 1ncrea5ed 1n 5LE pat1ent5 w1th va5cu11t15. Leuk0cyte-end0the11a1 ce11 adhe510n may 6e 1nduced 6y exce551ve c0mp1ement act1vat10n. 1CAM-1 expre5510n ha5 6een 5h0wn t0 6e 1ncrea5ed 6y u1trav101et 1rrad1at10n 0f kerat1n0cyte5 1n v1tr0, m0du1ated 6y cyt0k1ne re1ea5e wh1ch 1n v1v0 c0u1d cu1m1nate 1n ph0t05en51t1ve 1upu5. A9ent5 5uch a5 pr0ca1nam1de 0r hydra1a21ne, wh1ch can cau5e dru9-1nduced 1upu5, have 6een 5h0wn 1n v1tr0 t0 1nduce LFA-1 0verexpre5510n and 5u65e4uent aut0react1v1ty due t0 the1r a6111ty t0 1nh161t 7 ce11DNA methy1at10n. Ad0pt1ve tran5fer 0f 7 ce115 made aut0react1ve 6y th15 mechan15m cau5e5 a 1upu5-11ke d15ea5e 1n 5yn9ene1c rec1p1ent m1ce (Yun9 et a1, 1996). Pat1ent5 w1th act1ve 1upu5 have a150 6een 5h0wn t0 have e1evated 1eve15 0f the 501u61e adhe510n m01ecu1e5, 501u61e E-5e1ect1n, 51CAM-1 and 5VCAM-1 1n the1r 5era, c0mpared w1th n0rma1 c0ntr015, 1eve15 0f wh1ch 1n 50me 5tud1e5 c0rre1ated w1th d15ea5e act1v1ty. 7he5e f1nd1n95 f1t w1th 065ervat10n5 1n mur1ne 1upu5, where upre9u1at10n 0f 60th 1CAM-1 and VCAM-1 have 6een f0und 1n nephr1t1c k1dney5 fr0m MRL-1pr/1prm1ce. K1dney 5ect10n5 fr0m the5e m1ce 5h0w 1ncrea5ed adhe510n 0f 7 ce11and macr0pha9e ce1111ne5.7h15 adhe510n 15 610cked 6y m0n0c10na1 ant160d1e5 t0 1CAM-1 and VCAM-1.1n v1tr0 5tud1e5 have 5h0wn that 1L-1, tum0ur necr0515 fact0r-1x (7NF1x) and 1FN~/ 5t1mu1ate upre9u1at10n 0f adhe510n m01ecu1e expre5510n 0n 910meru1ar me5an91a1 ce115. 7-ce11 c10ne5 der1ved fr0m k1dney-1nf11trat1n9 1ymph0cyte5 0f MRL-1pr/1prm1ce, 1nduced 1CAM-1 expre5510n 1n v1tr0, wh1ch wa5 610cked 6y an ant1-1FN7 m0n0c10na1 ant160dy. 7he effect 0f ant1-adhe510n m01ecu1e therapy 1n pat1ent5 w1th 5LE

1mmun0path09ene5150f 5LE

395

15 n0t yet kn0wn. 7ar9et1n9 1ymph0cyte adhe510n m01ecu1e5 0r the1r 119and5 15 11ke1yt0 6e u5ed t0 1nduce t01erance 1n pat1ent5.

6enet1c and env1r0nmenta1 c0mp0nent5 6enet1c fact0r5 c0ntr16ute 1nd15puta61y t0 the path09ene515 0f 5LE (750k05 et a1, 1997). 7here 15 a h19her rate 0f c0nc0rdance f0r th15 d15ea5e 1n m0n02y90t1c tw1n5 (25%) c0mpared t0 d12y90t1ctw1n5 (3%). 7he fre4uency 0f 1upu5 and 1mmun01091ca1 a6n0rma11t1e5 15 h19her 1n re1at1ve5 0f 1upu5 pat1ent5 c0mpared t0 hea1thy c0ntr015 (M11e5 and 15en6er9, 1993) and 1upu5 a150 0ccur5 m0re fre4uent1y 1n certa1n ethn1c 9r0up5. At pre5ent n0 51n91e 9ene 0r env1r0nmenta1 a9ent ha5 6een 5h0wn t0 6e the 501e cau5e 0f 1d10path1c 5LE, and 1t 15 11ke1ythat the tr199er1n9 event5 vary 6etween 1nd1v1dua15, a5 d0e5 the f1na1 c11n1ca1man1fe5tat10n 0f the d15ea5e. A recent 5tudy ha5 1dent1f1ed a re910n 0n chr0m050me 1441-442 that 15 11nked t0 human 5LE; th15 re910n 15 5ynten1c t0 a mur1ne 5u5cept16111ty re910n. 7he 10cu5 appear5 t0 pred15p05e t0 5LE 1n a11 ethn1c 9r0up5 exam1ned and 15 c0n5erved acr055 5pec1e5 (75a0 et a1, 1997). 0ther pred15p051n9 9ene5 are 11ke1y t0 emer9e a5 a re5u1t 0f 1ar9e fam11y5tud1e5 current1y underway 1n the U5A. Many ce11u1ar a6n0rma11t1e5 are due t0 9enet1c defect5, an examp1e 6e1n9 the FcyR11A-H131 a11e1e. 7he FcyR11A recept0r, 0n pha90cyte5, rec09n12e5 and a1d5 c1earance 0f path09en1c 1962 ant160d1e5/c0mp1exe5, and the 1ack 0f th15 a11e1e 15 a550c1ated w1th 1upu5 nephr1t15 1n th05e 0f 61ack race (5a1m0n et a1, 1996). Recent1y FcyR111Aa11e1e5w1th d1fferent1a1 aff1n1ty f0r 1961 and 1963 have a150 6een 5h0wn t0 6e a550c1ated w1th 5LE, w1th a 519n1f1cant1y 1ncrea5ed fre4uency 0f the 10w-aff1n1ty a11e1e 1n 5LE pat1ent5 fr0m d1ver5e ethn1c 9r0up5 (Wu et a1, 1997). 7he 9enet1c 6a515 0f 5LE 15 de5cr16ed 1n 9reater deta11 1n a c0mprehen51ve rev1ew 6y 5chur (1995).

Maj0r h15t0c0mpat16111tyc0mp1ex Certa1n MHC c1a55 11 a11e1e5 are a550c1ated w1th 1upu5 (15en6er9 and H0r5fa11, 1998). Am0n9 Cauca51an5 the hap10type A1 88 DR3 15 a550c1ated w1th an appr0x1mate1y tenf01d 1ncrea5e 1n r15k 0f deve10p1n9 1upu5; h0wever the pr1mary 11nkhere may 6e the c0mp1ement C4 nu11 a11e1e;1ndeed tw0 nu11 a11e1e5 1ncrea5e the re1at1ve r15k t0 17. Certa1n MHC 9ene5 5eem t0 6e a550c1ated w1th part1cu1ar 5u65et5 0f 1upu5 0r ant160dy pr0f11e5, and 5evera1 5tud1e5 5upp0rt the 1dea that d1fferent aut0ant160dy 5pec1f1c1t1e5 are a550c1ated w1th HLA type5 that can 6e d15t1n9u15hed at the nuc1e0t1de 1eve1 (E1k0n, 1995). 1n Afr1can-Amer1can pe0p1e DRw52[3 15p051t1ve1ya550c1ated w1th rena1 d15ea5e and ne9at1ve1y a550c1ated w1th ant1nuc1ear RNP ant160d1e5. DR3 and D4w2 are h19h1y a550c1ated w1th the a6111ty t0 pr0duce ant1-R0/ant1-La ant160d1e5, and hence w1th 5u6acute cutane0u5 1upu5, 1ymph0cyt0pen1a and ne0nata1 1upu5 5yndr0me. DR4 15 a550c1ated w1th the a6111ty t0 make ant1-RNP and w1th a reduced r15k 0f 1upu5 nephr1t15. DR2

396

L.J. Ma50n and D. A. 15en6er9

c0nfer5 5u5cept16111ty t0 nephr1t15 and 15 a550c1ated w1th ant1-5m ant160d1e5 1n Afr0-Car166ean pat1ent5. DRw8 15 a550c1ated w1th ear1y-0n5et 0f d15ea5e. 7 ce11recept0r 9ene5

7here 15 very 11tt1e pu6115hed data 11nk1n9 7CR 9ene u5a9e t0 1upu5 1n human5 0r 1n 1upu5 pr0ne m1ce 5tra1n5. 5e4uenc1n9 0f the 7CR-0c and [3 cha1n 9ene5 fr0m 42 CD4+ 11ne5fr0m f1ve 1upu5 pat1ent5 revea1ed recurrent m0t1f5 0f h19h1y char9ed re51due5 1n the1r CDR3 100p5. Cat10n1c char9e 15 1mp0rtant 1n the pr0duct10n 0f ant1-DNA ant160d1e5 that can 61nd t0 the 910meru1ar 6a5ement mem6rane. F0ur 0f the f1ve pat1ent5 d15p1ayed the V~8 9ene fam11y (De5a1-Mehta et a1, 1995; f0r a rev1ew, 5ee 750k05 et a1, 1997). 1nd15cr1m1nate 5e4uenc1n9 0f 7 and 5 cha1n5 0f the 7CR fr0m per1phera1 6100d 0f pat1ent5 w1th 1upu5 5h0wed 01190c10na1 expan510n 0f y5 7 ce1151n 1upu5 (A1arc6n-5e90v1a and Ca6ra1, 1996). 7here 15 ev1dence that the ant1-R0 re5p0n5e 5een 1n 50me 5LE pat1ent5 15 re1ated t0 a 7CR-~ 9ene pr0duct. 7h15 a550c1at10n 15, h0wever, re1ated t0 ant160dy 5pec1f1c1ty pr0duced rather than a5 a r15k fact0r f0r the d15ea5e 1t5e1f. 8 ce11 V 9ene5

7he expre5510n 0f 9erm11ne V. 9ene5 1n un5t1mu1ated CD19+ 8 ce115 0f n0rma1 adu1t5 ha5 6een c0mpared w1th th05e VH 9ene5 u5ed 1n m0n0c10na1 ant1-DNA ant160d1e5 der1ved fr0m pat1ent5 w1th 5LE. 1n 60th ca5e5 certa1n 9ene5 are much m0re c0mm0n1y expre55ed than 0ther5, 6ut there 15 n0 c1ear ev1dence 0f preferent1a1 9ene u5a9e 1n the enc0d1n9 0f ant1-DNA ant160d1e5. H0wever, the maj0r1ty 0f the human m0n0c10na1 ant1-DNA ant160d1e5 that have 6een 5e4uenced are 10w aff1n1ty 19M ant160d1e5. Many 0f the m0re 5pec1f1c human 196 m0n0c10na1 ant1-DNA ant160d1e5 have 6een f0und t0 u5e 9ene5 0f the VH3 0r V~4 fam11y. 8ut few 5uch 196 m0n0c10na15 have 6een 5e4uenced, and the maj0r1ty 0f human V~ 9ene5 are mem6er5 0f the VH1, VH3 0r VH4 fam111e5. 1ntere5t1n91y many human m0n0c10na1 ant1DNA ant160d1e5 0f 60th 150type5 u5e V. 9ene5 that are mem6er5 0f the feta11y expre55ed repert01re. 7he 5e4uent1a1 accumu1at10n 0f 50mat1c mutat10n5 may 1ead t0 a 9radua1 1ncrea5e 1n the 5pec1f1c1tyand 61nd1n9 aff1n1ty0f the ant160dy pr0duced 6y a part1cu1ar c10ne 0f ce115. A num6er 0f rep0rt5 have 5h0wn that there 15 a 9reater fre4uency 0f 50mat1c mutat10n51n 196 rather than 19M human m0n0c10na1 ant1-DNA ant160d1e5.7he 0ccurrence 0f p051t1ve1ychar9ed re51due5 1n the c0mp1ementar1ty determ1n1n9 re910n (CDR) 15 a recurr1n9 feature 0f human m0n0c10na1 ant1-DNA ant160d1e5. 1t 15 p05tu1ated that mutat10n5 re5u1t1n9 1n 5uch p051t1ve re51due5 m19ht enhance 61nd1n9 t0 the ne9at1ve1y char9ed DNA m01ecu1e. 1t 15 n0w 6e11eved that 60th the pre5ence and the actua1 p051t10n 0f mutat10n5 and 0f 9erm11ne enc0ded p051t1ve re51due5, 1n 60th the V~ and VLre910n5, may 6e 1mp0rtant 1n creat1n9 5e4uence m0t1f5 that enhance 61nd1n9 0f DNA (f0r a rev1ew, 5ee 15en6er9 et a1, 1997).

1mrnun0path09ene5150f 5LE

397

Ethn1c6ack9r0und 5LE 5h0w5 an ethn1c 61a5 w1th m0re Afr0-Car166ean5 (1/250) 6e1n9 affected than 0r1enta15 (1/1000), wh0 1n turn are m0re affected than Cauca51an5(1/4300). 81ack race 15an 1ndependent r15k fact0r f0r deve10p1n9 5LE. Afr1can-Amer1can5 and Afr0-Car166ean5, 11v1n91n the U~U5A, are at 9reate5t r15k 0f deve10p1n9 5LE, deve10p the d15ea5e ear11er 1n 11fe, and have an 1ncrea5ed fre4uency and 5ever1ty 0f rena1 path0109y. A150 0f n0te and n0t 5at15fact0r11y exp1a1ned, 5LE 15 rare 1n nat1ve Afr1can5 (N1ved and 5turfe1t, 1997). A 5tudy 1n 81rm1n9ham dem0n5trated maj0r d1fference5 1n the 1nc1dence and preva1ence rate5 0f 5LE 1n the UK depend1n9 0n ethn1c 9r0up. 7he 065erved preva1ence 1n fema1e5 wa5 206/100000 am0n9 Afr0Car166ean5, 91/100 000 am0n9 A51an5 and 36/100 000 am0n9 Cauca51an5. 7he5e re5u1t5 were 1rre5pect1ve 0f p1ace 0f 61rth (J0hn50n et a1, 1995).

C0mp1ement C0mp1ement pr0te1n5 p1ay a v1ta1 r01e 1n the pr0ce551n9 and c1ear1n9 0f 1mmune c0mp1exe5 (1C5) (Dav1e5, 1996; 15en6er9 and H0r5fa11, 1998). 1nher1ted c0mp1ement def1c1enc1e5 are rare 6ut 0ccur w1th 1ncrea5ed fre4uency 1n 5LE, w1th the fre4uency 0f 5LE 6e1n9 at 1ea5t 50% 1n pat1ent5 w1th h0m02y90u5 def1c1enc1e50f the ear1y c1a551ca1c0mp1ement pathway. 1n c0ntra5t 5LE 15 very 5e1d0m a550c1ated w1th 1ate c0mp1ement c0mp0nent def1c1enc1e5. 7he 1ncrea5ed 5u5cept16111ty t0 5LE a550c1ated n0ta61y w1th C14, C1r, C15 and C2 def1c1ency,15 th0u9ht t0 6e due t0 1mpa1rment 0f 1mmune c0mp1ex c1earance and 501u61112at10n, 1ead1n9 t0 1C dep051t10n and the a550c1ated 1nf1ammat0ry re5p0n5e 1n the 1un95 and k1dney5. 7he defect1ve ear1y c0mp1ement c0mp0nent5 C1, C2 and C4 may 6e part1a1, heter02y90u5 0r c0mp1ete, h0m02y90u5 def1c1enc1e5. C0n9en1ta1 defect5 1n C2 and C4 are 0ften f0und 1n pat1ent5 w1th MHC hap10type5 DR3 and DR2. 7he C4 pr0te1n5, C4A and C48 61nd 1mmune c0mp1exe5 prevent1n9 the1r 1mmun0prec1p1tat10n. H0m02y90u5 C4A def1c1ency0ccur5 1n 10-15% 0f Cauca51an 1upu5 pat1ent5 de5p1te 6e1n9 rare 1n the hea1thy p0pu1at10n. Part1a1 C4A def1c1ency 0ccur5 1n 50-80% 0f 5LE pat1ent5 6ut 0n1y 10-20% 0f c0ntr015. 7he 1eve15 0f c0mp1ement recept0r5, CR1 and CR2 are a150 a1tered 1n 5LE. CR1 61nd5 act1vated c0mp1ement c0mp0nent5 C36 and C46 w1th a550c1ated 1C5. CR1 expre5510n 0n erythr0cyte5 and per1phera1 6100d 1euk0cyte5 ha5 6een f0und t0 6e decrea5ed 1n pat1ent5, c0mpared w1th c0ntr015, and 1eve15c0rre1ate w1th d15ea5e act1v1ty. N0rma1 erythr0cyte5 1nfu5ed 1nt0 pat1ent5 w1th 1upu5 a150 5h0w an act1ve reduct10n 1n CR1 recept0r5. CR2 15 f0und 0n 10-40% 0f per1phera1 6100d 7 ce115, 8 ce115 and f0111cu1ar dendr1t1c ce115 and 61nd5 C3d, C39 and Ep5te1n-8arr v1ru5. 1n pat1ent5 w1th act1ve 1upu5, CR2 expre5510n 15 reduced 0n 8 ce115, wh1ch may ref1ect the h19h1y act1vated 5tate 0f the5e ce115. CR2 expre5510n 15 1ncrea5ed 0n 7 ce115 fr0m pat1ent5 w1th act1ve 1upu5 6ut 15 n0rma1 0n th05e w1th 1nact1ve d15ea5e. CR2 15 1mp0rtant 1n 519na111n9 and 1ncrea5ed expre5510n 0f th15 recept0r may p1ay a r01e 1n ce11 adhe510n 0r cyt0t0x1c1ty.

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L.J. Ma50n and D. A. 15en6er9

5ex h0rm0ne5 5LE 0ccur5 n1ne t1me5 m0re 0ften 1n fema1e5 than 1n ma1e5 (9:1 rat10). Andr09en5 are kn0wn t0 6e 1mmun05uppre551ve and 0e5tr09en5 are 1mmun0enhanc1n9. Pr10r t0 pu6erty the rat10 0f fema1e5:ma1e5 15 10wer at appr0x1mate1y 3:1 and after men0pau5e the rat10 a150 fa115. A6n0rma1 0e5tr09en meta60115m ha5 6een de5cr16ed 1n w0men w1th 5LE, wh1ch re5u1t5 1n an exce55 0f 16-a-hydr0xye5tr0ne and 0e5tr01 meta6011te5, w1th chr0n1c hyper0e5tr09en15m. 5ex h0rm0ne5 m19ht 5t1mu1ate the CN5 t0 re1ea5e 1mmun0re9u1at0ry pept1de5, affect m0n0cyte/macr0pha9e 5y5tem5 and thu5 the1r cyt0k1ne5, 0r cau5e re1ea5e 0f 0ther 1mmun0m0du1at0ry h0rm0ne5. 7he anter10r p1tu1tary h0rm0ne, pr01act1n, ha5 6een f0und t0 6e 1mmun05t1mu1at0ry 1n 5LE and ha5 6een rep0rted t0 6e e1evated 1n 5evera1 5tud1e5 0f 60th ma1e and fema1e pat1ent5 (f0r a rev1ew, 5ee F0x et a1, 1996). 0e5tr09en5 have a150 6een 5h0wn t0 1ncrea5e the 5p0ntane0u5 pr0duct10n 0f ant160d1e5 1n m1ce, wh115t te5t05ter0ne treatment reduce5 1upu5 5ympt0m5. 1n pat1ent5 w1th 5LE when a pre9nancy 0ccur5 dur1n9 act1ve d15ea5e, r151n9 0e5tr09en 1eve15 may p055161y cau5e exacer6at10n 0f the c11n1ca1 d15ea5e, a1th0u9h the data are c0nf11ct1n9. 0e5tr09en ha5 6een 5h0wn t0 decrea5e 1n v1tr0 ap0pt0515 0f P8MC fr0m w0men w1th 5LE and th15 may 6e a mechan15m a110w1n9 1ncrea5ed ce115urv1va11n pat1ent5. Leve15 0f 7 N F a were a150 decrea5ed 1n 0e5tr09en treated cu1ture5 (Evan5 et a1, 1997). Recent re5earch ha5 5u99e5ted that there 15 an 1nterdependence 0f the neur0end0cr1ne and 1mmune 5y5tem5, 1nv01v1n9 many d1fferent h0rm0ne5 (F0x et a1, 1996). A1th0u9h the5e data may 6e 1nterpreted a5 1nd1cat1n9 the p055161e r01e 0f 5ex h0rm0ne5 1n the aet10path0109y 0f 1upu5 they d0 n0t pr0ve 1t. Much rema1n5 t0 6e d0ne 6ef0re 0ur under5tand1n9 0f why w0men 1n part1cu1ar 9et 1upu5 15 tru1y c1ar1f1ed. 1nfect10u5 a9ent5 A c0mm0n, 6ut 5t111t0 6e pr0ven, hyp0the515 15 that 5LE, and 0ther aut01mmune d15ea5e5, are tr199ered 6y 1nfect10u5 a9ent5 1nc1ud1n9 v1ru5e5 (E1k0n, 1995). C0-1mmun15at10n w1th v1ru5-5e1fc0mp1exe5 ha5 6een 5h0wn t0 6e a p055161e mechan15m capa61e 0f 6reak1n9 t01erance and 9enerat1n9 aut01mmun1ty (D0n9 et a1, 1994). 8a16/c m1ce were 1mmun12ed w1th c0mp1exe5 0f mur1ne 1ntrace11u1ar pr0te1n, p53 and 51m1an v1ru5 1ar9e 7 ant19en (5V7) and ant1-p53 aut0ant160d1e5 were 9enerated, wh1ch c0u1d 5u65e4uent1y 6e e11c1ted u51n9 p53 a10ne. 7h15 15 c0n515tent w1th the 1dea that 0nce t01erance 15 6r0ken, 5e1f ant19en can perpetuate the aut01mmune re5p0n5e. 1t 15 hyp0the512ed that crypt1c ep1t0pe5 0f 5e1f ant19en, a9a1n5t wh1ch the h05t 15 n0t t01er12ed, are exp05ed due t0 a1tered pr0ce551n9 0f the p53 due t0 1t5 a550c1at10n w1th 5V7 0r ant1-p53 ant160dy. U51n9 the techn14ue 0f ep1t0pe mapp1n9 ant19en1c ep1t0pe5 0f 5m and nRNP aut0ant19en5 have 6een 1dent1f1ed, and re5earcher5 have f0und a 5tr1k1n9 51m11ar1ty 6etween the5e re910n5 and ant19en1c pept1de5 der1ved fr0m E8NA-1

1mmun0path09ene5150f 5LE

399

(Ep5te1n-8arr v1ru5 nuc1ear ant19en), 5u99e5t1n9 a p055161e r01e f0r the5e a9ent5 1n the aet10109y 0f 1upu5 (Har1ey and Jame5, 1995). Ant1-d5DNA ant160d1e5 have 6een 5h0wn t0 6e 1nduc161e 6y p01y0ma v1ru5 8K 1n 1upu5 pr0ne m1ce. Recent1y Jame5 et a1 (1997) have 5h0wn a h19h1y 519n1f1cant 1ncrea5ed preva1ence 0f Ep5te1n-8arr v1ru5 1nfect10n 1n y0un9 pat1ent5 w1th 1upu5 c0mpared t0 c0ntr015. 7h15 may thu5 pr0ve t0 6e an 1mp0rtant tr199er.

0ther env1r0nmenta1 tr199er5 U1trav101et (UV) rad1at10n ha5 6een 5h0wn t0 tr199er and exacer6ate the ph0t05en51t1ve 1upu5 ra5h, 6ut there 15 a150 ev1dence that UV 119ht may actua11y 6e capa61e 0f a1ter1n9 the 5tructure 0f DNA 1ead1n9 t0 the 9ene515 0f aut0ant160d1e5. UV 119ht ha5 a150 6een 5h0wn t0 1nduce ap0pt0515 1n human kerat1n0cyte5 re5u1t1n9 1n 61e65 0f nuc1ear and cyt0p1a5m1c aut0ant19en5 0n the ce11 5urface. 7h15 pr0v1de5 a mechan15m where6y nuc1ear ant19en5, wh1ch are fre4uent aut0ant160dy tar9et5, can reach the ce11 5urface. Ant1-hyperten51ve dru95, am0n9 0ther5, have 6een 5h0wn t0 91ve r15e t0 dru9-1nduced 1upu5; h0wever th15 d15ea5e 15 a550c1ated w1th ant160d1e5 t0 55DNA and h15t0ne5 rather than d5DNA. A1th0u9h 5k1n and j01nt d15ea5e are c0mm0n, rena1 0r CN5 path0109y 15 v1rtua11y unkn0wn and the d15ea5e 15 rever5ed 0n curta11ment 0f the dru9 1nv01ved.

5ummary 1nteract10n 0f 9enet1c and env1r0nmenta1 fact0r5 unden1a61y pr0v1de the 1n1t1at1n9 5t1mu1u5 f0r the path09ene515 0f 5LE, a1th0u9h the1r re1at1ve c0ntr16ut10n c1ear1y var1e5 1n 1nd1v1dua1 pat1ent5. Recent w0rk ha5 dem0n5trated n0ve1 5u5cept16111ty 9ene5 and mechan15m5 f0r aut0ant160dy pr0duct10n 1n the c0ntext 0f v1ra1 1nfect10n5. 7he 5er01091ca1 ha11mark 0f 5LE 15 the pre5ence 0f a 5pectrum 0f aut0ant160d1e5, n0ta61y th05e a9a1n5t d5DNA. 7he1r pr0duct10n 15 5kewed t0ward5 h19h aff1n1ty, cat10n1c ant160d1e5 0f the 196 150type, wh1ch have 6een 5h0wn t0 6e capa61e 0f 61nd1n9 v1a nuc1e050me5 t0 the hepar1n 5u1phate 0f the 910meru1ar 6a5ement mem6rane, re5u1t1n9 1n act1vat10n 0f c0mp1ement and t155ue 1nf1ammat10n. Aut0ant160d1e5 ar15e due t0 a6n0rma1 1mmune funct10n, c0mpr151n9 p01yc10na1 8-ce11 act1vat10n and dy5re9u1ated ce11-med1ated 1mmun1ty. L055 0f 1mmun01091ca1 t01erance re5u1t5 1n the pr0duct10n 0f aut0react1ve 7-ce11 c10ne5, 60th CD4 and CD8 5u65et5, wh1ch pr0v1de exce55 he1p t0 8 ce115. 7he pr0duct10n 0f aut0ant160d1e5 per515t5 due t0 def1c1ent 5upre550r ce11 act1v1ty. 7here are c0nf11ct5 6etween the f1nd1n95 1n mur1ne m0de15 and human pat1ent5, re9ard1n9 a6n0rma11t1e5 0f ap0pt0515 1n 5LE. H0wever, 1ncrea5ed ap0pt0515 1n pat1ent5 may re5u1t 1n the re1ea5e 0f aut0ant19en5 1n the f0rm 0f nuc1e050me5.7here appear5 t0 6e a re1at1ve d0m1nance 0f 7h2 ce115 and the1r cyt0k1ne5, n0ta61y 1nter1euk1n-10.7 ce11 dy5funct10n 15 a 6ypr0duct 0f a pr1mary 7 ce11 519na111n9 d150rder re5u1t1n9 fr0m a6n0rma1

400 L.J. Ma50nand D. A. 15en6er9 610chem1ca1 pathway5. Recent re5earch ha5 f0cu5ed 0n 519na111n9 a6n0rma11t1e5 1n ce115fr0m pat1ent5 w1th 1upu5, wh1ch re5u1t fr0m defect5 1n c05t1mu1at0ry pathway5 1nv01v1n9C7LA4-87/CD28 and CD40 119and (9p39)/ CD40 m01ecu1e5 0n the 5urface 0f 1ymph0cyte5. De5p1te 519n1f1cant advance5 1n 0ur under5tand1n9 0f the aet10path09ene515 0f 1upu5 much rema1n5 t0 6e d0ne 6ef0re we fu11y under5tand 1t5 deve10pment (F19ure 1).

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Reference5 A1arc6n-5e90v1a D • Ca6ra1 AR (1996) Aut0ant160d1e5 1n 5y5tem1c 1upu5 erythemat05u5. Current 0p1n10n 1n Rheumat0109y 8: 403-407. Ar1n9er M, W1nter56er9er W, 5te1ner CW et a1 (1994) H19h 1eve150f 6c1-2 pr0te1n 1n c1rcu1at1n9 7 1ymph0cyte5, 0f pat1ent5 w1th 5y5tem1c 1upu5 erythemat05u5. Arthr1t15 and Rheumat15m 17(10): 1423-1430. 8erden JHM (1997) Lupu5 nephr1t15. K1dney 1nternat10na152: 538-558. Van 8ru99en MC, Kramer5 C • 8erden JH (1996) Aut01mmun1ty a9a1n5t nuc1e050me5 and 1upu5 nephr1t15. Anna1e5 de Medec1ne 1nterne (Par15) 147(7): 485-489. *Ca6ra1 AR • A1arc6n-5e90v1a D (1997) Aut0ant160d1e5 1n 5y5tem1c 1upu5 erythemat05u5. Current 0p1n10n 1n Rheumat0109y 9: 387-392. *Craft J • Fatenejad 5 (1997) 5e1f ant19en5 and ep1t0pe 5pread1n9 1n 5y5tem1c aut01mmun1ty. Arthr1t15 and Rheumat15m 40(8): 1374-1382. Dav1e5 KA (1996) C0mp1ement, 1mmune c0mp1exe5 and 5y5tem1c1upu5 erythemat05u5.8r1t15h J0urna1 0f Rheumat0109y 35: 5-23. *Dav15 JC, 7a551u1a5 L0 • 80umpa5 D7 (1996) Lupu5 nephr1t15. Current 0p1n10n 1n Rheumat0109y 8: 415-423. Daya1 AK • Kammer 6M (1996) 7he 7 ce11 en19ma 1n 1upu5. Arthr1t15 and Rheumat15m 39(1): 23-33. De5a1-Mehta A, Ma0 C, Raja90pa1an 5 et a1 (1995) 5tructure and 5pec1f1c1ty0f 7 ce11recept0r5 expre55ed 6y p0tent1a11y path09en1c ant1-DNA aut0ant160dy-1nduc1n9 7 ce115 1n human 1upu5. J0urna1 0f C11n1ca11nve5t19at10n 95:531-541. D0n9 X, Ham11t0n KJ, 5at0h M e t a1 (1994) 1n1t1at10n 0f aut01mmun1ty t0 the p53 tum0ur 5uppre550r pr0te1n 6y c0mp1exe5 0f p53 and 5V40 1ar9e 7 ant19en. J0urna1 0f Exper1menta1 Med1c1ne 179: 1243-1252. E1k0n K8 (1994) Ap0pt0515 1n 5LE--t00 11tt1e 0r t00 much• C11n1ca1and Exper1menta1 Rheumat0109y 12: 553-559. *E1k0n K8 (1995) Aut0ant160d1e5 1n 5y5tem1c 1upu5 erythemat05u5. Current 0p1n10n 1n Rheumat0109y 7: 384-388. Em1en W, N1e6ur J • Kadera R (1993) Acce1erated 1n v1tr0 ap0pt0515 0f 1ymph0cyte5 fr0m pat1ent5 w1th 5y5tem1c 1upu5 erythemat05u5. J0urna1 0f 1mmun0109y 152: 3685-3692. Evan5 MJ, MacLau9h11n 5, Marv1n RD • A6d0u N1 (1997) E5tr09en decrea5e5 1n v1tr0 ap0pt0515 0f per1phera1 6100d m0n0nuc1ear ce115 fr0m w0men w1th n0rma1 men5trua1 cyc1e5 and decrea5e5 7NF-a1pha pr0duct10n 1n 5LE 6ut n0t 1n n0rma1 cu1ture5. C11n1ca1 1mmun0109y and 1mmun0path0109y 82(3): 258-262. F0x RA, M00re PM • 15en6er9 DA (1996) Neur0end0cr1ne chan9e5 1n 5y5tem1c 1upu5 erythemat05u5 and 5j69ren•5 5yndr0me. 8a1111~re~5C11n1ca1Rheumat0109y 10(2): 333347. 60e1 N, U1r1ch D7, 5t C1a1r EW et a1 (1995) Lack 0f c0rre1at10n 6etween 5erum 501u61e fa5/AP0-1 1eve15and aut01mmune d15ea5e.Arthr1t15 and Rheumat15m 38: 1738-1743. Har1ey J8 • Jame5 JA (1995) Aut0ep1t0pe5 1n 1upu5. J0urna1 0f La60rat0ry and C11n1ca1 Med1c1ne 126: 509-516. *15en6er9 DA (1997) 5y5tem1c Lupu5 erythemat05u5:1mmun0path09ene515 and the card 9ame ana109y. J0urna1 0f Rheumat0109y 24(548): 562-566. *15en6er9 DA • H0r5fa11 AC (1998) 5y5tem1c 1upu5 erythemat05u5. 1n Madd150n PJ, 15en6er9 DA, W00 P • 61a55 DN (ed5) 0xf0rd 7ext600k 0f Rheumat0109y, 2nd edn, pp 1145-1180. 0xf0rd: 0xf0rd Un1ver51tyPre55. 15en6er9 DA, Ehren5te1n MR, L0n9hur5t C • Ka151JK (1994) 7he 0r191n, 5e4uence, 5tructure and c0n5e4uence5 0f deve10p1n9 ant1-DNA ant160d1e5. Arthr1t15 and Rheumat15m 37(2): 169-180.

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*15en6er9 DA, Rav1rajan C7, Rahman A • Ka151J (1997) 7he r01e 0f ant160d1e5 t0 DNA 1n 5LE--A rev1ew and 1ntr0duct10nt0 an 1nternat10na1w0rk5h0p 0n DNA ant160d1e5he1d 1n L0nd0n, May 1996. Lupu5 6: 290-304. Jame5 JA, Kaufman KM • Farr15 AD (1997) An 1ncrea5ed preva1ence 0f Ep5te1n-8arr v1ru5 1nfect10n1n y0un9 pat1ent5 5u99e5t5 a p055161eet10109y f0r 5y5tem1c1upu5erythemat05u5. J0urna1 0f C11n1ca11nve5t19at10n 100(12): 3019-3026 Jame5 JA, 6r055 7, 5ch0f1e1dRH • Har1eyJ8 (1995) 1mmun09106u11nep1t0pe 5pread1n9 and aut01mmune d15ea5e after pept1de 1mmun15at10n: 5m 8/8•--der1ved PPP6MRPP and PPP61R6P 1nduce 5p11ce050me aut01mmun1ty:J0urna1 0f Exper1menta1 Med1c1ne 181: 453-462. J0hn50n AE, 60rd0n C, Pa1mer R6 • 8ac0n PA (1995) 7he preva1ence and 1nc1dence0f 5y5tem1c 1upu5 erythemat05u5 1n 81rm1n9ham, En91and. Re1at10n5h1p t0 ethn1c1ty and c0untry 0f 61rth. Arthr1t15 and Rheumat15m 38(4): 551-558. Kn1pp1n9E, Krammer PH, 0ne1 K8 et a1 (1995) Leve150f 501u61efa51Ap0-1/CD95 1n 5y5tem1c 1upu5 erythemat05u5 and juven11e rheumat01d arthr1t15. Arthr1t15 and Rheumat15m 38: 1735-1737. Lefk0w1th J8 • 611ke50n65 (1996) Nephr1t09en1caut0ant160d1e51n 1upu5: current c0ncept5 and c0nt1nu1n9c0ntr0ver51e5.Arthr1t15 and Rheumat15m 39(6): 894-903. Ma50n LJ, 15en6er9DA • Ka151JK (1998) D0e5 1mmun15at10nw1th a pept1de 0f 5m8/8• cau5e ep1t0pe 5pread1n9and aut01mmun1ty1nn0rma1 an1ma15• 8r1t15hJ0urna10fRheumat0109y 37(81): 69. McMurray RW (1996) Adhe510nm01ecu1e51n aut01mmune d15ea5e.5em1nar5 1n Arthr1t15 and Rheumat15m 25(4): 215-233. M11e5 5 • 15en6er9 DA (1993) 5er01091ca1 a6n0rma11t1e5 1n 5LE fam11ymem6er5. Lupu5 2: 145-153. M0unt2 JD, J1an9u0 WU, J1anhua C • 2h0u 7 (1994) Aut01mmune d15ea5e: a pr061em 0f defect1ve ap0pt0515. Arthr1t15and Rheumat15m 37(10): 1415-1420. My51er E, 81n1P, Drappa Jet a1 (1994) 7he ap0pt0515-1/fa5 pr0te1n 1n human 5LE. J0urna1 0f C11n1ca11nve5t19at10n 93(3): 1029-1034. N1ved 0 • 5turfe1t 6 (1997) D0e5 the 61ack p0pu1at10n 1n Afr1ca 9et 5LE. 1f n0t, why n0t• 1n 15en6er9 DA • 7ucker L8 (ed5) C0ntr0ver51e5 1n Rheumat0109y, pp 65-74. L0nd0n: Mart1n Dun1t2Ltd. Putterman C, L1mpana51thku1W, Ede1manM • D1am0nd 8 (1996) 7he d0u61e ed9e 5w0rd 0f the 1mmunere5p0n5e:mutat10na1ana1y5150f a mur1ne ant1-pneum0c0cca1ant1-DNA ant160dy. J0urna1 0f C11n1ca11nve5t19at10n 97: 2251-2259. Raja90pa1an 5, Ma0 C • Datta 5K (1992) Path09en1caut0ant160dy-1nduc1n93•/8 7 he1per ce115 fr0m pat1ent5 w1th act1ve 1upu5 nephr1t15 expre55 unu5ua1 7 ce11 recept0r5. C11n1ca1 1mmun0109y and 1mmun0path0109y 62: 344-350. Rekv19 0P, M0en5 U, 5und5fj0rd Aet a1 (1997) Exper1menta1expre5510n 1n m1ce and 5p0ntane0u5 expre5510n 1n human 5LE 0f p01y0mav1ru5 7-ant19en. J0urna1 0f C11n1ca1 1nve5t19at10n 99(8): 2045-2054. *R05e LM, Latchman D5 • 15en6er9 DA (1997) Ap0pt0515 1n per1phera1 1ymph0cte5 1n 5y5tem1c 1upu5erythemat05u5: a rev1ew.8r1t15hJ0urna1 0f Rheumat0109y 36: 158-163. 5a1m0n JE, M111ard 5, 5chachter LA et a1 (1996) FcyR11Aa11e1e5are her1ta61e r15k fact0r5 f0r 1upu5 nephr1t151n Afr1can Amer1can5.J0urna1 0f C11n1ca11nve5t19at10n 97: 1348-1354. 5chur PH (1995) 6enet1c5 0f 5y5tem1c1upu5erythemat05u5. Lupu5 4: 425-437. (Rev1ew). 8f1kak15 PP • 750k05 6C (1995) Lymph0cyte adhe510n m01ecu1e51n aut01mmune rheumat1c d15ea5e5: 6a51c 155ue5and c11n1ca1expectat10n5. C11n1ca1and Exper1menta1 Rheumat0109y 13: 763-777. 5tra55er A, Wh1tt1n9ham5, Vaux DL et a1 (1991) Enf0rced 6c1-2 expre5510n1n 8 1ymph01dce11 pr010n95 ant160dy re5p0n5e5 and e11c1t5aut01mmune d15ea5e. Pr0ceed1n950fthe Nat10na1 Academy 0f 5c1ence5 0f the U5A 88: 8661-8665. *75a0 8P, Cant0 RM, Ka1un1anKC et a1 (1997) Ev1dence f0r 11nka9e0f a cand1date chr0m050me 1 re910n t0 human 5y5tem1c1upu5erythemat05u5.J0urna1 0f C11n1ca11nve5t19at10n 99(4): 725-731. 750k05 6C (1995) Lymph0cyte5, cyt0k1ne5, 1nf1ammat10n,and 1mmune traff1ck1n9. Current 0p1n10n 1n Rheumat0109y 7: 376-383. *750k05 6C (1996) Lymph0cyte5, cyt0k1ne5, 1nf1ammat10n,and 1mmune traff1ck1n9. Current 0p1n10n 1n Rheumat0109y 8: 395-402.

1mmun0path09ene5150f 5LE

403

750k05 6C, K0vac5 8 • L105515 5-NC (1997) Lymph0cyte5, cyt0k1ne5, 1nf1ammat10n, and 1mmune traff1ck1n9. Current 0p1n10n 1n Rheumat0109y 9: 380-386. 750k05 6C, K0vac5 8, 5f1kak15PP et a1 (1996) Defect1ve ant19en pre5ent1n9 ce11 funct10n 1n pat1ent5 w1th 5y5tem1c 1upu5 erythemat05u5: r01e 0f the 87-1 (CD80) c05t1mu1at0ry m01ecu1e. Arthr1t15 and Rheumat15m 39: 600-609. V1ahak05 D, F05ter MH • Ucc1 AA (1992) Mur1ne m0n0c10na1 ant1-DNA ant160d1e5 penetrate ce115, 61nd t0 nuc1e1, and 1nduce 910meru1ar pr011ferat10n and pr0te1nur1a 1n v1v0. J0urna1 0f the Amer1can 50c1ety 0f Nephr0109y 2: 1345-1354. Wu J, 8an5a1 V, Redecha P e t a1 (1997) A n0ve1 p01ym0rph15m 0f FcyR111A, wh1ch a1ter5 funct10n, a550c1ated w1th the 5LE phen0type. J0urna1 0f1nve5t19at1ve Med1c1ne45: 200A. YamadaA, M1n0ta 5, N0j1ma Y • Ya2ak1Y (1993) Chan9e51n 5u65et 5pec1f1c1ty0f ant1-7 ce11 aut0ant160d1e5 1n 5y5tem1c1upu5 erythemat05u5. Aut01mmun1ty 14: 269-273. Yun9 R, P0wer5 D, J0hn50n K et a1 (1996) Mechan15m5 0f dru9 1nduced 1upu5.11.7 ce1150verexpre551n9 1ymph0cyte funct10n-a550c1ated ant19en 1 6ec0me aut0react1ve and cau5e a 1upu511ke d15ea5e 1n 5yner9ene1c m1ce. J0urna1 0f C11n1ca1 1nve5t19at10n 97(12): 2866-2871. 2ack DJ, 5trempn1ak M, W0n9 AL et a1 (1996) Mechan15m5 0f ce11u1ar penetrat10n and nuc1ear 10ca112at10n 0f an ant1-d0u61e 5trand DNA ant160dy. J0urna1 0f1mmun0109y 15 7: 2082-2088.