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MECHANISMS OF INFLAMMATORY RESPONSE IN

SYMPATHETIC OPHHALMIA AND VKH

SYNDROME

.

Los Angeles, Califoia

Although the icitig events in the pathogenesis ofsympathetic ophtalmia and Vt-Kyanai-Harada(VH) syndrome are dierent, tese two forms ofbiateral granulomatous uveitis sare severa clinical, istopathological and immunoistocemical features,icludng their association it HL types and in teirin vitro Tcell response to retina antigens. Teseiical and immunopathological features indicate tattere is an underlying Tcellmedated atoimmuty tovearetina antigens in the development of tesrms of uveitis. Both forms exhiit presevation ofe coriocapillaris and retina despite extensive inam

atory cell inltration in the choroid. Recent experietal studies suggest that tis preservation ofriocapllaris could e te result of antiinammatoryroducts secreted y te retinal pigment epitelium,icldng transforming growt factoreta and a noveltein called retinal pigment epitelial protectivetein tat is known to suppress te pagocyteeeration of superoxide. Suc suppression of teidant release in te choroidal inammation could elp protect te uvea from necrotic change andeserve te coriocapillaris from inammatory cellltration.

Altoug sympathetic ophthalmia and Vogt-Koya i- Harada (VKH) syndrome are two distinct ical entities, they share virtually identical histotological features,  uorescein angiographic nd and asscatn wth HLA antgens f DR,DRw53 and Bw54.1 However, whereas VKH  syno as a predilection for darkly pigmented races sns, Hspancs, Natve Amercans and AsanIins 2  - no racial  predilection  is observed  in

Frm: A Ray Irvine, Jr, Ophthalic Pathology Laboratory.Dny Eye Institute, University of Southern California, School

of Medicine, Los Angeles, California, USArrespondence to: Narsing A Rao , oheny Eye

titte, 1450 San Pablo Street VRC-211, Los Angeles, CA933188, USA

sympathetc phthalma. rever, th ctgevent fr the tw enttes s dfferent the devpment f ntracular nammatn n sympathetphthalma requres a penetratng cular nury, butn traumatc event s requred fr the devlpmenf VKH syndme. The latter usually fllwsprdrmal symptms and sgns suggestve f asystemc vral nfectn. In addtn, altug tappears that extracular manfestatns such asvtlg, alpeca, plss, menngsmus and dysacuss are relatvely mre frequent n VKH syndrme,there are studes revealng the presnce f smlarmanfestatns n sympathetc phthalma 4

The typcal hstpathlgcal features sen n theearly phases f bth sympathetc pthalma andVKH syndrme nclude a granulmatus nammatn that prmarly nvlves the chrd, wth asmlar albet mlder nammatry nltrate thatnvlves the rs and clary bdy. Hwever, thechrd s te ste where several characterstfeatures are bserved, ncludng: 1 dffuse lympcytc nltratn nterrupted at multple stes wthcllectns f eptheld cells and few multnucleated gant cells; (2) the presence f pgment nthe eptheld cells and gant cells n the absence f

apparent chrdal necrss; sparng f thechrcapllars frm nammatry cell nltratn;and () preservatn f retnal pgment epthelum(RPE) and retna except at the stes f DalenFuchsndules and ther fc where RPE unctns aredsrupted. These dsrupted RPE cells are cmmnlydetected by urescen anggraphy as fcal leaks atthe level f RPE.

Sympathetc pthalma and VKH syndrme alsshare severa mmunpathlgcal features, suc asnltratn f prmarly T-lymphcytes n te crd. In bth nttes, mst f these nltrated cells

exhbt the arkers f helper and supprssr/cyttxc cells, alng wth class II HC mlecules. 5 6Smlar mlecules are als nted n the actvated

ye (997) , 3- © 1997 Ryl Cllg Ophhlmlgiss

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macrophages along with various adhesion molecules,including intercellular adhesion molecule-l. 6 Moreover, in both entities the choroidal inltratesgenerate various pro-inammatory cytokines? Overall, these immunohistological features suggest a

delayed type of hypersensitivity T-cell-mediatedmechanism in the inductio and/or perpetuation ofthe uveal inammation, possibly directd to the uveamelanocytes or other antigens in the uveal tract. 48Once initiated, an immune response against a tissuetarget, such as in the uvea, can lead to the furtherrelease of various sequestered self-antigens, againstwhich self-tolerance has never been established.Release of such antigens can lead to the perpetuationof uveitis, even though the initiating trigger may bedirected to a restricted response to a single specictarget.9

GRANULOMATOUS INFLAMMATIONS OFTHE UVEA

The cellular and molecular mechanisms leading todevelopment of granulomatous uveitis are poorlyunderstood. However, the role of macrophages, Tcells and their cytokines, melanocytes, vascularendothelial cells and arachidonic acid AA metabolites in the initiation, maintenance and resolution ofthe granulomatous inammation is becoming clear.In general the granulomatous uveits can be classied

as either hypersensitivity type or foreign body type.The latter is rarely observed and usualy resuts fromtraumatic events associated with retained foreignmaterial. The hypersensitivity granulomas usuayresult either from an infectious agent such asmycobacteria, or from a noninfectious aetiology,such as an autoimmune disorder, mediated by eitherTcels or immune compexes.

Hypersensitivi granulomas show three characteristic microscopic patterns: znal, sarcoidal ordiffuse. These three patterns may indicate an underying mechanism of granuloma formation. The zona

pattern of granulomatous uveitis consists of a centralarea of necrosis surrounded by zones of differentinltrating inammatory cells, such as epithelioidcell/histiocytes, lymphocytes and other inammatorycells, incuding broblasts. Such a zonal pattern isseen in tbercuosis and other infectious diseases.The sarcoidal pattern consists of a colection ofepithelioid cells without necrosis. Typicaly such apattern is observed in sarcoidosis. he diffuse patternreveals collections, primarily of lymphocytes,throughout the choroid and the anterior uvea withfocal collctions of epithelioid ces. his pattern is

commony seen in immune-mediated granulomassuch as sympathetic ophthalmia and VKH syndrome.In granuomatous uveitis, the epteioid ces

represent moied macrophages dispaying primarilythe morphologica features of secretory functions. It

appears that the formation of these epitheliod cellsrequires the presence of activated Tcells in theinammatory lesion. Moreover, the cytokines of Tcells, such as the interleukins IL-2, IL, IL, IL-and IL, interferon gamma and others, are also

known to modulate epithelioid cell formation and themaintenance and resolution of the granulomatousinammation 1 Granuoma formation is also modulated by the level of class II MHC moleculeexpression by he macrophages. Adhesion moleculesdisplayed on the macrophages and vascular endothelium may also contribute to the development ofgranulomatous inammation. 6

he metabolic products released at the site ofinammation are found either to accentuate granuloma development or to suppress formation ofepitheioid cel granuomas and the associated

chronic inammatory process Studies on experimental granulomatous uveitis have revealedenhancement of the granulomatous proces in thepresence of lip oxygenase metabolic products of AA.In contrast cyclo-oxgenase products are noted tosuppress granuloma formation. Such modulation ofgranulomatous inammation in the presence of AAmetaboites could be the result of altered macrophage expression of MHC class II molecules. Moreover, ipoxygenase products of AA are importantinammatory mediators with proinammatory funtions of chemotaxis, vasodilation and inductin of

lysosomal enzyme release.13T-cells cause pathological changes through thrability to produce cytokines, which can recruitadditional T-cells, macrophages and other phagocyticels, including eosinophilic leucocytes. All these cellsare present in the uveal tracts of patients withsympathetic ophthalmia and all may cause tissuedamage if not propery regulated. Additionally, asubset of T-ymphocytes, cytotoxic T-cells, may causethese pathological changes directly.

TISSUE INJURY IN UVEITIS

Several kinds of experimentally induced uveitis inanimals have revealed the importance of macrophages and other phagocytic inammatory cells iinducing tissue daage, although Tces are requirefor the induction of uveitis. These phagocytes causenecrosis of the tissue and amplify the inammationby releasing various secretory products, includinproteases, AA metabolites and free radicals. Thefree radicas are potent cytotoxic agents thatprimarily cause peroxidation of lipid cell membranesat the site o ther release. he free radicals that

cause such tissue amage are mostly derived frothe oxygen metablite superoxide and its deriveagents such as hydrogen peroxide, hypochlorous aciand hydroxy radicals.4 Nitric oxide, another molecule released by the activated macrophages, may as

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induce tissue damage in the presence of superoxideby formation of peroxynitrites Reease or formationof a these oxidants at the site of inammation canead to uvea necrosis and mpication of theinammatory process4 15 However tissue necrosis

is minima or is not apparent in sympatheticophthamia and VKH syndrome thus suggestingthe presence of protective mechanisms in the uveand/or in the granuomas that may minimise tissueecrosis

PVTO OF COOCPLLAD RETA

constant feature of sympathetic ophthamia andKH syndrome is the preservation of choriocapiaris and retina despite extensive uvea intration by

ononucear ces and other phagocytes Athougho preise reason for such preservation is knownausibe expanations incude one or a combinationf the foowing mechanisms: 1 RPE ces mayeease soube and diffusibe factors that downeguate the uvea inammation; (2) endotheia cesf the choriocapiaris coud produce anti-inammatry cytokines that coud downreguate the inamation; (3) the choriocapiaris endotheia ces mayt express adhesion moecues required for attachent and migration of eucocytes; and/or () immunempexes may not deposit in the capiaries We

ecenty made an attempt to investigate the roe ofPE in the down-reguation of inammation partiary with regard to its roe in the preservation ofhoriocapiaris and retina in severe uveitis as seen inympathetic ophthamia and VKH syndrome

Our current i vitro studies on RPE have reveaedthat these ces synthesise and reease a protein thatuppresses phagocyte generation of superoxide 6 andat is known to dismutate into hydrogen peroxidefrming highy reactive hydroxy radicas In inamtory conditions these highy reactive oxidants areriariy formed at the extraceuar sites Such

idants can induce tissue damage at the site of theiration by various mechanisms incuding peroxition of ipid ce membranes Such oxidised ipids ampify the inammatory process by theirotactic property1 5

though the RPE is endowed with mutipetioidant enzymes incuding superoxide dismue such enzymes have at most a imited signice in scavenging the phagocyte-generatederoxide in the extraceuar sites because theye ocaised to the cytoso of the RPE7 Moreovevenging of phagocyte-derived extraceuar super

ide by these antioxidants has never been demonted It is possibe that the newy discovered RPEtein may offer protection against such extracer superoxide formation in uveitis since thistein is secreted into extraceuar sites6 Primariy

because of the pausibiity of suc a roe for thisnove RPE protein we caed the protein 'retinapigment epitheia protective protein

1 618 There are

other anti-inammatory factors produced by theRPE such as transforming growth factorbea;

these factors coud aso downreguate uvea inammation by atering ongoing inammatory eventssuch as antigen presentation

In sympathetic ophthamia and VKH syndromethe histoogica nding of preserved choriocapiarisand retina may suggest that the RPE coud offerprotection aains exension of ammaor cesinto te choriocapiaris and retina However RPEces in cuture are known to generate various proinammatory cytokines such as IL- IL ILpateetderived growth factorike protein granuocyte macrophage-coony stimuating factor and var

ious adhesion moecues190 A these moecues ifoperative i vivo coud enhance uveitis and ead toextension of inammation into the choriocapiarisand the adjacent retina Paradoxicay the enuceated eyes of patients with sympathetic ophthamiaand VKH show preservation of the retina andchoriocapiaris at the site of intact RPE eventhough the choroid is heaviy intrated by macrophages and other inammatory ces Such contradictory ndings suggest that simiar to macrophagesRPE ces can moduate uvea inammation ieeither enhance it by reeasing various pro-inamma

tory cytokines or suppress the inammation byreeasing transforming growth factorbeta and othersoube factors incuding the nove retina pigmentepitheia protective protein8 However further ivivo studies are reuired on spathetic ophtamiaand VKH syndrome to deineate the importance ofRPE and its products in the moduation of uveitis

Supported in part by NIH grant EY022 and by an unrestricted grant from Research to Prevent BlindnessInc.,New York

Key words: Sypathetic ophthalia, VogtKoyanagiHaradasyndroe Granuloatous uveitis, Oxygen free radicals, Retinalpigent epitheliu, Protective protein

RFEEC

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