Etıopathogenesıs of behcet's syndrome: recent developments and current controversıes

Review Article

ETIOPATHOGENESIS OF BEHCET'S SYNDROME:

RECENT DEVELOPMENTS AND CURRENT CONTROVERSIES

Invited Paper

(Received 22 Decem ber, 1998)

Haner Direşkendi, M.D.* / Emel Ekşioğlu-Demiralp, M.D. Ph.D.**

Tevfik Akoğlu, M.D.**

TÜBİTAK, Behcet's Disease Research Unit.

S u b -d e p a rtm e n t o f K h e u m a to lo g y , D e p a rtm e n t o f In te rn a l M e d ic in e , S c h o o l o f M e d ic in e , M arm a ra U n iv e rs ity , Is ta n b u l, Turkey.

S u b -d e p a rtm e n t o f H e m a to lo g y a n d Im m u n o lo g y , D e p a rtm e n t o f In te rn a l M e d ic in e , S c h o o l o f M ed icine , M a rm a ra U n iv e rs ity , Is ta n b u l, Turkey.

ABSTRACT

G enetic, infectious and im m une dysfunctions are im plicated in th e etio p ath o g en esis of B e h g et’s S yn d ro m e (B S ). Histopathological studies reveal mixed cellular infiltrations consisting of mostly T lym phocytes, m o n o c yte-m ac ro p h ag es and neutrophils. Although a viral etiology is also suggested, atypical streptoccocci (Strep Sanguis, Salivarius etc) is the most investigated. Increased pro- inflam matory and Th1 type cytokines such as T N F -a , IFN-y, IL-2, IL-6 and IL-8 are found to be increased in the se ra and in vitro culture su p ern atan ts. A controversial point is w hether neutrophils are primarily defective (hyper-reactive) or activated due to the cytokine profile. Streptoccocal proteins such as KTH-1 or 65 kD m ycobacterial heat shock protein (H S P ) and its cross-reactive hum an homologue are shown to cause T and B cell responses in patients with BS. Both C D 4+ and y8 T cells are activated with antigen-specific oligoclonal expansions and increased secretions of IFN-y, IL-8 and T N F -a . T he link with HLA-B51 which is present as a susceptibility or a severity marker of BS, is suggested to be related to neutrophil hyperreactivity with increased neutrophil burst responses also in FILA- B51 transgenic animals. T cell responses to an HLA- B51 d erived p ep tid e and its retin al-S antigen hom ologue in posterior uveitis patients suggest that auto-im m une responses might also be relevant. The sam e peptides are linked to uveitis also in rats and imply that different m anifestations of BS may be

related to various and possibly organ-specific antigens.

Key Words:

Behget’s Syndrom e (BS) is a multi-systemic disorder with muco-cutaneous, ocular, arthritic, vascular and central nervous system involvem ents. R ecent develop m ents in the etio patho g en esis of BS is discussed in this review.

Genetic Predisposition and HLA-B51

BS is mainly seen around M editerranean S ea in a belt of countries extending from the Atlantic O cean to Japan including Israel, Turkey, Iran, India, Korea and China (1). T he prevelance is reported to be between 1:250 to 1:10.000 in this region w hereas it is reported to be 0 .3 -1 :1 0 0 .0 0 0 in U S A and North Europe. The differences are not only reflected in prevelance but also in the severity of the cases. Most of the severe spectrum of BS such as uveitis, vascular and CNS involvement are mainly reported from countries where the disease is seen more frequently. Among various genetic markers, relationship to HLA class I antigens B5 and its split B51 is the most commonly reported (2,3). T he presence of this marker is reported to have

Marmara Medical Journal Volume 12 No: 2 April 1999

a relative risk of 3-8 in different series. An important question is w hether B51 is a marker of susceptibility or severity in BS. HLA B51 is found in only 50 -6 0 % of the cases of BS suggesting that B51 is not required for the susceptibility to the disease. B51 may be related not to a gen eral susceptibility of BS but to certain manifestations such as uveitis or vascular involvement as reported from UK (4). In terms of disease severity, although a high prevelance is found in hospital based populations (5), a field study of BS prevelance from Turkey found HLA B5 in only 2 6 % of the cases (6). Most of these cases w ere not diagnosed as BS before and had a mild disease spectrum. But in contrast with these observations, a recent report from Japan did not find higher ocular severity linked to B 5 1(7 ). The spectrum of organ involvement in BS is studied mostly as the presence or absence of a certain manifestation such as uveitis or vascular involvement. As anterior and posterior uveitis have different ocular prognosis, with the latter generally causing irreversible vision loss, the role of B51 must be investigated with regard to posterior uveitis as a m arker of severity.

The role of HLA class I antigens such as B51 is the presentation of endogenous antigens synthesized within the cell to C D 8 + cytotoxic-suppressor T cells. The antigen specific region of B51 is analysed with the possible 8 -1 0 am ino acid length sequence of antigenic p eptides reported (8). Am ong th ese peptides autoantigens such as thymidylate synthase (aa .2 5 3 - 61) or a yeast protein U B C 5 (6 1 -6 8 ) is present. The role of these HLA-B51 specific peptides and w hether HLA B51 restricted C D 8 + T cells take a role in BS etiology is currently unknown. A recent animal model is also confusing as transgenic anim als with HLA B51 did not develop the disease but only have neutrophil hyperreactivity in response to neutrophil activating agents like fM LP or P M A (9). T he sam e group also observed an increased neutrophil burst activity in patients and healthy controls carrying HLA B51 which w e could not confirm in our studies (10).

In addition to being a primary risk factor itself, HLA B51 might be a marker of another gen e positioned closely to B51 and is found on the sam e haplotype. Ohno et al. from Japan reported recently a M IC A (M H C class I related-gene) betw een T N F -a gene and HLA B region on chrom osom e 6 with a higher risk factor com pared to HLA-B51 (11). But w hether this m arker which has a low heterogeneity is the real genetic predisposition to BS requires further studies in other ethnic groups.

Neutrophil hyperreactivity

As typical BS lesions such as pustular folliculitis, pathergy reactions and hypopyon has significant num bers of neutrophils, relationship of BS to neutrophil activation is pursued for a long time (1,3).

As neutrophils are a group of very m ature cells with a very short life in vitro, their research is difficult, technically, reflecting the controversy in the literature over which activity best reflects neutrophil functions and is deregulated in BS. V arious studies showed increased neutrophil c h em o ta xis, C

>2

C

>2

neutrophils (12), Pronai et al. observed increased C>2 both in stimulated or unstim ulated neutrophils (13), w hereas T aken o et al observed increased production only after fM L P stimulation (9). Neutrophil adhesion to endothelial cells is also reported to be both normal (14) or increased in BS with increased adhesion m olecule expressions such as C D 1 1 a and C D 1 8 (15 ). In addition, C D 1 0 and C D 1 4 two m arkers of neutrophil activation are also expressed higher on BS patients’ neutrophils (16). An interesting point is the occurrence of Behget's like sym ptom s in patients with chronic myeloid leukem ia (C M L ) w ho are given interferon-a (IF N -a ) treatm ent (17). In a controlled study, 2 4 % of these patients also d eveloped pathergy test positivity (18). As C M L is a disease with a large num ber of m ature neutrophils and their precursors in the blood, this effect of IF N -a m ay be linked to neutrophil hyperreactivity.

O ne of the main problem s in BS research is to distinguish b etw ee n w h e th e r BS neutrophils are primarily defective or w hether soluble agents in BS serum or in local milieu, such as pro-inflamm atory cytokines (IL-1, T N F -a , IL-6, IL-8 etc) released from activated m ononuclear cells, are responsible for the neutrophil hyperreactivity (3, 19-21). As neutrophils in the active phases of BS are already activated w hen they are taken in vitro, this question is hard to answer. A better approach is to study the cases in com plete remission but studies are very limited in this group and mostly negative.

Humoral immunity in BS

Although BS does not have the classical features of an auto-im m une disease such as Sjogren's syndrome, fe m a le d o m in an ce , h yp e rg a m a g lo b u lin e m ia and autoantibodies such as anti-nuclear antibodies, some B cell activity such as in c re a s e d sp o ntaneou s immunglobulin secretion is shown previously in BS (22). S o m e of the antibodies such as anti-endothelial cell or anti-cardiolipin antibodies are probably markers of endothelial d am a g e and activation in BS and not specific (23). Anti-65 kD m ycobacterial heat shock protein (H S P ) antibodies are more interesting as these are more frequently reported in linkage with infectious etiology (24, 25). In one study from Turkey, 4 8 % of n eu ro -B S patients co m p ared to 12% of multiple

sclerosis patients had increased levels of anti-65kD H S P antibodies in the cerebro-spinal fluid (26). B cells are recently studied also in detail in our Unit and although total B cell num ber was normal they w ere found to carry increased levels of activation markers such as C D 1 3 , C D 3 3 , C D 4 5 R O and C D 8 0 (27). The distinction of BS from auto-im m une disorders was also evident in this study in the low level of C D 5 + C D 1 9 + B cells which are thought to produce auto-antibodies. As the role of B cells are not limited to antibody production as previously suggested, but also include antigen- presentation, their role in BS requires further study.

T cells in BS

Various observations suggest a significant contribution of T cells in BS. Pathergy reactions are either T cell dom inated or have mixed infiltrates, as oral lesions, erythem a nodosum and late stages of uveitis such as enucleated eyes (28, 29). Both C D 4+ and C D 8+ T cells producing Th1 type pro-inflammatory cytokines such as IL -2 an d interferon -y are increased in peripheral blood (30 ). Recently C D 4 + C D 1 6 + and C D 4 + C D 5 6 + T cell subsets are also found to be increased in BS (31). An oligoclonal antigen-driven change in peripheral blood C D 4 and C D 8+ T C R V(i repertoire in patients with BS is also supportive of T cell participation (32 ). In addition to T C R a(3+ cells, T C R yô + cells are also increased in number in various studies {33, 34).

Antigenic stimulus in BS

Streptoccocal antigens

T cells respond to exogenous or endogenous antigens presented by HLA class I or class II molecules on antigen presenting cells. Among the few antigens studied in detail in BS, bacterial microorganisms such as streptococci are the most implicated. KTH-1 (a crude extract or Streptoccocus sanguis S S H -8 3) is shown to c a u s e increased IL-6 and interferon-y secretion from T cells of BS patients suggesting a role of this antigen in the pro-inflam m atory response (35). KTH-1 is also shown to cause an Increase of y8 T cells in BS patients after 9 day T cell cultures (36). Long term y5 T-cell lines produced by continuous stimulation with this antigen secrete pro-inflamm atory cytokines such as IL-6, IL-8 and T N F -a but no T-helper 2 type anti-inflam m atory cytokines IL-4 and IL-10, supported by the low levels of IL-4 and IL-10 in the serum (37).

65 kD Heal Shock Protein

Another important candidate antigen for BS is 65 kD H S P and its peptide dérivâtes. H S P s are proteins which have a scavenger role for other intracellular

proteins under denaturating stress conditions such as infections, hypoxia and toxic drugs. They are highly conserved during evolution (mycobacterial and human 65 kD H S P s have over 50 % homology). Although H S P s are part of the intra cellular protein transport mechanisms, 65 kD H S P is shown to be expressed on monocytes after interferon-y stimulation and also on T cells going apoptosis (3 8 ). T h e s e observations suggest that 60 /65 kD H S P s might be ubiquitous antigens for the im m une system . As significant sequence homology exists betw een mamalian and m icrobial H S P s , hum an H S P -res p o n s ive T cells stimulated by microbial counterparts (cross-reactivity) might trigger a longer T cell memory, responsible for the chronicity of certain autoim m une or vasculitic disorders.

In a study by Ergun et al, in tissue specimens of pathergy reactions of BS patients, 65 kD H S P expression is found to be significantly higher compared to controls suggesting that it can also be a local antigen for BS (39). First in UK, then in Japan and in our Unit in Turkey, increased T cell responses to mycobacterial and hum an 60 /6 5 kD H S P are shown in the peripheral blood lym phocytes of BS patients compared to healthy controls (40 -43 ). Although they are reported to be specific to be BS in UK and Japan, we observed a 18% positivity in our diseased controls (43).

Although yS T cell subset is reported to respond mainly to 60 kD HS P in UK, an oligoclonal increase in certain C D 4+ T C R v p subsets is reported from Japan in patients with uveitis after stimulation with HS P derived peptides. These H S P responsive T cells are shown to release pro-inflamm atory cytokines such as IL-6 and IL-8 and thought to participate in the inflammatory stimulus (42). Recently, by Saruhan-Direskeneli et al, P P D and 65 kD H S P specific T cell lines are also found to be reactive to human 60 kD H S P derived peptides in both BS patients and healthy controls (44). An animal model in rats w here certain human HSP derived peptides ca u s e an uveitis but no other symptom of BS is also supportive of a role of HS P in BS (45).

Retinal>S Antigen and HLA-B51 -new

autoantigens?

Another candidate antigen in BS is retinal-S antigen. This protein found mainly in the retina is accepted to be im m u n e-p riviled ged and im m une responses against it are found mainly after tissue destruction due to uveitis. T cell responses against retinal-S antigen are found in various types of uveitis and are not specific to BS (46). Am ong various immuno-dominant epitopes of retinal-S antigen an epitope (aa 342-355) is found to share homology with a conserved region of

Marmara Medical Journal Volume 12 No: 2 April 1999

HLA B molecules (aa 12 5-1 3 8 ) such as HLA-B51 and B27 which are linked to uveitis (47). This epitope Is shown to be recognized by C D 4 + T cells. This observation provoked a challenging theory of class I HLA m o lecules b ecom ing an tigenic ep itopes themselves. Indeed, a significant portion of small peptides eluded from the surface of various HLA class II molecules are found to be HLA class I originated. As T cells recognizing class I antigens are a natural part of our immune repertoire but possibly tolerized in thymus, a break-dow n of tolerance is hypothesized to occur after uveal inflammation by cross-reactivity of retinal-S antigen reactive T cells with H LA-reactive T cells. Developm ent of uveitis in rats by both peptides is supportive of this observation. T cell responses to these peptides are shown in a small group of G erm an uveitis patients and recently confirmed in a larger group of BS patients in our Unit (48). Interestingly, only T cells from patients with posterior uveitis but not with non-uveitis BS patients are responsive. This suggests that serious uvea destruction and activation of retinal- S antigen reactive T cells is required for cross-reactive m em ory responses.

This theory provides another explanation for HLA B51 participation in BS. O ral feeding of HLA B27/51 derived peptide is shown to prevent retinal-S antigen uveitis in animal models and is now tried in refractory human uveitis patients as a w ay of treatm ent with oral tolerance (49).

Observations from the clinical trials:

different

antigenic

stimuli

for

different manifestations?

Different manifestations of BS occurring during the course of the disease unpredictably and unlinked to any previous risk factor suggests that various, possibly organ-specific antigens might be responsible for BS. Therapy studies support this observation as the effects of various popular treatm ents in BS seem s to be organ-specific. Colchicine is especially effective for erythem a-nodosum (E N ) like lesions but has a limited effect on uveitis. On the other hand, in a recently published double-blind controlled trial thalidomide was effective for oral and genital ulcers, but caused a significant increase in EN lesions in the first 8 w eeks (50). As an explanation for this suprising observation, Ham uryudan et al. suggest that “the cause of aphthous ulcers and EN may not have a comm on putative denom inator in B S ”.

T cell responses to HLA-B and retinal-S antigen derived peptides only in posterior uveitis patients mentioned above may also support this hypothesis. Im m une responses to local antigens such as derm al keratins in psoriasis or synovial antigens such as

collagen type II in rheum atoid arthritis w ere reported previously. Similarly, local antigens might be relevant for patient subgroups with m uco-cutaneous or articular organ involvements in BS. Better characterization and im muno-m odulation of these local antigens m ay help to d eve lo p m o re specific an d less toxic im m u n o th erap eu tic a p p ro a c h e s to this still unsatisfactorily treated disease.

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2 5 . D ir e ş k e n d i H, H a s a n A, S h in n ic k T, e t al. R e c o g n itio n o f B c e ll e p ito p e s o f th e 6 5 KDa HSP in B e h ç e t's D ise a se . S can J Im m u n o l 1 9 9 6 /4 3 :4 6 4 - 4 7 1 . 2 6 . Taşçı B, D ir e ş k e n d i ft, S e rd a ro ğ lu P, e t al. H u m o ra l im m u n e r e s p o n s e a g a in s t m - h s p 6 5 in th e c e re b r o s p in a l f lu id o f n e u ro -B e h ç e t's p a tie n ts . C lin E x p Im m u n o l 1 9 9 8 /1 1 3 :1 0 0 - 1 0 4 . 2 7 . E k ş io ğ lu -D e m ira lp E, K ib a ro ğ lu A, D ire s k e n e li H, e t al. P h e n o ty p ic c h a ra c te ris tic s o f B c e lls in B e h ç e t 's D ise a se : In c re a s e d a c tiv ity in B c e ll s u b s e ts . J R h e u m a to lo g y 1 9 9 9 /2 6 :8 2 6 -8 3 2 .

2 8 . E rg u n T, G ü r b ü z O, H a r v e ll J, e t at. The h is to p a th o lo g y o f P a th e rg y: c h ro n o lo g ic a l s tu d y o f s k in h y p e r r e a c tiv ity in B e h ç e t’s d is e a s e . In t J D e rm a to lo g y 1 9 9 8 /3 7 :9 2 9 -9 3 3 .

2 9 . G ü l A, E sin S, D ü şe n H, e t al. Im m u n o h is to lo g y o f s k in p a th e rg y re a c tio n in B e h ç e t 's d ise a se , B ritis h J D e rm a to lo g y 1 9 9 5 /1 3 2 :9 0 1 -9 0 7 . 3 0 . S u g i-lk a i H, H a kazaw a M, N a k a m u ra S, O h n o S, M in a m i M. In c re a s e d fre q u e n c ie s o f in te rle u k in -2 a n d in te rfe ro n -g a m m a p ro d u c in g T c e lls in p a tie n ts w ith B e h ç e t’s d is e a s e In v e s t O p h th a lm o l Vis S c i 1 9 9 8 /3 6 :6 :9 9 6 -1 0 0 4 .

3 1. D e m ira lp -E E , D ire s k e n e li H, Karsh P, e t al. In c re a s e d T ly m p h o c y te s C D 4 + C D 16 + , C D4 + C D 5 6 + a n d C D 8+ C D 1 l b s u b s e ts in B e h ç e t’s D is e a s e . In : H am za M, eds. B e h ç e t's D ise a se : P ro c e e d in g s o f th e 7 th In te rn a tio n a l C o n fe re n c e . T unis: Pub A d h o u a , 1 9 9 7 :4 4 -4 7 .

3 2 . D ire s k e n e li H, E k ş io ğ lu D e m ira lp E, K ib a ro ğ lu A, e t al. G lig o c lo n a l T c e ll e x p a n s io n s in p a tie n ts w ith B e h ç e t's d ise a se . C lin E xp Im m u n o l (1 9 9 9 , in p re s s ) 3 3 . F o rtu n e F, W a lk e r J, L e h n e r T. The e x p re s s io n o f g d T c e ll r e c e p to r a n d th e p re v a la n c e o f p rim e d , a c tiv a te d a n d Ig A -b o u n d T c e lls in B e h ç e t's s y n d ro m e . C lin E xp Im m u n o l 1 9 9 0 /8 2 :3 2 6 -3 3 2 . 3 4 . S u z u k i Y, H o s h i K, M a ts u d a T, e t at. In c re a s e d p e rip h e r a l b lo o d g d + T c e lls a n d n a tu r a l k ille r c e lls in B e h ç e t's d ise a se . J R h e u m a to l 19 9 2 / 19 :5 8 8 - 5 9 2 . 3 5 . H iro h a ta S, O k a H, M iz u s h im a Y. S tre p to c o c c a l re la te d a n tig e n s s tim u la te p ro d u c tio n o f IL-6 a n d in te rfe ro n -g b y T c e lls fr o m p a tie n ts w ith B e h ç e t ’s D isease. C e ll Im m u n o lo g y 1 9 9 2 /1 4 0 :4 1 0 -4 1 9 . > 3 6 . M o c h iz u k i N, S u z u k i N- T a k e n o M, e t al. F ine a n tig e n

s p e c ific ity o f h u m a n g d T c e ll lin e s e s ta b lis h e d b y re p e titiv e s tim u la tio n w ith a s e ro ty p e (KTH-1) o f a g r a m - p o s itiv e b a c te r iu m , S tr S a n g u is . E u r J

Im m u n o l 19 9 4 /2 7 :1 5 3 6 -1 5 4 3 .

3 7 . M a n ta ş C, D ir e s k e n e li II, E k ş io ğ lu -D e m ira lp E, A k o ğ lu T, S e ru m le v e ls o f IL-4 a n d IL 10 in B e h ç e t’s D isease. J R h e u m a to l 1 9 9 9 (in p re s s )

3 8 . P o ccia F, P is e lli P, V e n d e tti S, e t al. H e a t s h o c k p ro te in e x p re s s io n o n th e m e m b ra n e o f T c e lls u n d e rg o in g a p o p to s is . Im m u n o lo g y 1 9 9 6 /8 8 :6 -1 2 . 3 9 . E rgun T, Ü m it I, D e m ira lp E, e t al. E x p re s s io n o f 6 0

k D h e a t s h o c k p ro te in in m u c o c u ta n e o u s le s io n s in B e h ç e t's D ise a se 8 th In te rn a tio n a l C o n g re ss o n B e h ç e t's D isease. 7-9 O c to b e r 1 9 9 8 , R e g g io -E m ilia, İtalya. P52 (1 5 1 ).

4 0 . P e rvin K, C h ild e rs to n e A, S h in n ic k T, e t al. T c e ll e p ito p e e x p re s s io n o f m y c o b a c te r ia l a n d h o m o lo g o u s h u m a n 6 5 - k ilo d a lt o n H e a t S h o c k p ro te in p e p tid e s in s h o rt te rm c e ll lin e s fro m p a t ie n t s w ith B e h ç e t's D is e a s e . J I m m u n o l

1 9 9 3 /1 5 1 :2 2 7 3 - 2 2 8 2 .

4 1. Hasan A, F o rtu n e F, W ilso n A, e t al. R ole o f yS T c e ll in p a th o g e n e s is a n d d ia g n o s is o f B e h ç e t's d ise a se L a n c e t 1 9 9 6 /3 4 7 :7 8 9 - 7 9 4 .

4 2 . K a n e k o S, S u z u k i N, Y a m a s h ita N, e t al. C h a ra c te riz a tio n o f T c e lls s p e c ific f o r an e p ito p e o f h u m a n 6 0 k D h e a t s h o c k p ro te in (hsp) in p a tie n ts w ith B e h ç e t's d is e a s e in J a p a n . C lin E xp Im m u n o l

1 9 9 7 /1 0 8 :2 0 4 -2 1 1 .

4 3 . D ir e s k e n e li H, E k ş io ğ lu -D e m ira lp E, E rgun T, e t al. T c e ll re s p o n s e s to 6 0 / 6 5 k D HSP d e riv e d p e p tid e s in T u rk is h B e h ç e t's D is e a s e p a tie n ts . Im m u n o lo g y L e tte rs 1 9 9 7 /3 7 9 :P. 1 .0 7 .0 8 .

Marmara Medical Journal Volume 12 No: 2 April 1999 4 4 . S a ru h a n -D ire s k e n e li O, C e le t B, D ir e s k e n e li H. The re s p o n s e o f th e H S P 65 s p e c ific T c e ll lin e s to h u m a n H S P 60 p e p tid e s in B e h ç e t's D ise a se . 8 tfl In te rn a tio n a l C o n g re s s o n B e h ç e t’s D isease. 7-9 O c to b e r 1 9 9 8 , R e g g io -E m ilia Ita ly . P 4 9 (1 4 8 ) 4 5 . S ta n fo rd MR, R asp E, W h is to n R, e t al. H e a t s h o c k

p ro te in p e p tid e s re a c tiv e in p a tie n ts w ith B e h ç e t’s d is e a s e a re u v e ito g e n ic in L e w is rats. C lin E xp Im m u n o l 1 9 9 4 ;9 7 :2 2 6 -2 3 1 .

4 6 . D e S m e t MD, Y a m a m a to JH , M o c h iz u k i M, e t al. C e llu la r im m u n e re s p o n s e s o f p a tie n ts w ith u v e itis to r e tin a l a n tig e n s a n d t h e ir fra g m e n ts . A m J O p h th a lm o l 19 9 0 ; ! 10 : 13 5 -1 4 2 .

4 7 . W ild n e r O, T h u ra u SR. C ro s s -re a c tiv ity b e tw e e n an H L A -B 2 7 -d e riv e d p e p tid e a n d a r e tin a l a u to a n tig e n p e p tid e : a c lu e to m a jo r h is to c o m p a tib ility c o m p le x

a s s o c ia tio n w ith a u t o - im m u n e d is e a s e . E u r J Im m u n o l 1 9 9 4 ;2 4 :2 5 7 9 - 2 5 8 5 .

4 8 . Y avuz $. D ir e s k e n e li H, B o z k u r t H, e t al. T c e ll re s p o n s e s to a re tin a l-S a n tig e n a n d a n HLA-B d e riv e d c ro s s -re a c tiv e p e p tid e in u v e itis p a tie n ts w ith B e h c e t's d is e a s e . A r th r itis R h e u m 1 9 9 8 ;9 :5 3 8 . 4 9 . T h u ra u SR, D ie d ric h s -M o h rin g M, F ric k e 11, A rb o g a s t S, W ild n e r G. M o le c u la r m im ic r y as a th e ra p e u tic a p p r o a c h f o r a n a u t o im m u n e d is e a s e : o r a l tr e a tm e n t o f u v e itis p a tie n ts w ith a n M H C -p e p tid e c r o s s r e a c tiv e w ith a u t o a n t ig e n - fir s t r e s u lts . Im m u n o lo g y L e tte rs 19 9 7 , 5 7 : ! 9 3 -2 0 1 . 5 0 . H a m u ry u d a n V, M at C, S a ip S, e t a l. T h a lid o m id e in th e tr e a tm e n t o f th e m u c o -c u ta n e o u s le s io n s o f th e B e h c e t’s S y n d ro m e . A n n In te rn M e d 19 9 8 ; 12 8 :4 4 3 - 4 5 0 . 10 6