Immunogenetics and Clinical Phenotype of Sympathetic Ophthalmia in British and Irish Patients

8/10/2019 Immunogenetics and Clinical Phenotype of Sympathetic Ophthalmia in British and Irish Patients

http://slidepdf.com/reader/full/immunogenetics-and-clinical-phenotype-of-sympathetic-ophthalmia-in-british 1/7

Immunogenetics and clinical phenotype of sympathetic ophthalmia in British and Irishpatients

Dara J Kilmartin, David Wilson, Janet Liversidge, Andrew D Dick, Julia Bruce,Robert W Acheson, Stanislaw J Urbaniak, John V Forrester

Abstract

Background/aims —Sympathetic ophthal-mia (SO) is a classic example of autoim-mune disease where human leucocyte

antigen (HLA) genomic associations couldprovide further understanding of mecha-nisms of disease. This study sought to

assess HLA genetic polymorphism inBritish and Irish patients with SO, and toassess whether HLA gene variants are

associated with clinical phenotype ordisease severity.

Methods —High resolution DNA basedHLA typing using polymerase chain reac-tion sequence specific primers was per-formed in 27 patients with SO and 51

matched healthy controls. Clinical pheno-type and markers of disease severity weredetermined prospectively in 17 newly

diagnosed patients and from medicalrecord review and repeat clinical exam-ination in 10 previously diagnosed pa-

tients. Results —HLA-Cw*03 (p=0.008), DRB1*04(p=0.017), and DQA1*03 (p=0.014) weresignificantly associated with SO. For classII alleles at higher resolution, onlyHLA-DRB1*0404 (relative risk (RR) = 5.6,

p = 0.045) was significantly associatedwith SO. The highest relative risk for anyof the associated haplotypes was withHLA-DRB1*0404-DQA1*0301 (RR=10.9,p=0.019). Patients with the DRB1*04-DQA1*03 associated haplotype were sig-nificantly more likely to develop SO earlier,with fewer inciting ocular trauma events,and to require more systemic steroidtherapy to control inflammatory activity.Conclusions— Sympathetic ophthalmia isassociated with HLA-DRB1*04 andDQA1*03 genotypes in white patients,similar to Japanese patients. DiV erencesin DRB1*04 gene variant associations

(−0404 in Britain and Ireland and −0405 in Japan) may have implications for HLApeptide binding in disease initiation. TheDRB1*04–DQA1*03 haplotype is a markerof increased SO susceptibility and sever-ity, as in Vogt-Koyanagi-Harada disease,which also has similar clinicopathologicaland HLA associations.(Br J Ophthalmol 2001;85:281–286)

Sympathetic ophthalmia (SO) is an uncom-mon cause of bilateral granulomatous posterioruveitis which follows injury to one eye, from

ocular surgery or penetrating ocular trauma.Although rare, with a recent reported inci-dence of 0.03/100 000,1 it remains a seriouseye disease because of its potentially blindingeV ects on both the exciting injured eye and thecontralateral sympathising eye and usually thepatient is committed to receiving chronicimmunosuppressive therapy to preserve goodvision.1 2 SO is one of the most feared compli-cations of ocular surgery, and recent evidenceshows that the proportion of SO casesfollowing retinal surgery is increasing.1 2 SO is

also of particular interest to immunologists asit is regarded as the prototype for autoimmunedisease, where breaching of systemic ocularbarriers compromises the relative immuneprivilege of the eye, and causes sensitisation topreviously sequestered uveoretinal antigens.Although many candidate ocular antigens havebeen implicated,3–5 the precise autoantigen, ordisease inducing peptide, has yet to bedetermined.

Endogenous posterior uveitis (EPU) is aCD4+ T (helper) cell mediated disease3 and, inSO, both peripheral blood and vitreous T lym-phocytes have been shown to be reactive toretinal antigen stimulation.5 Immunohisto-

chemistry of enucleated exciting eyes in SO hasdemonstrated the pathogenic role of bothCD4+ T cells in the initial stages of disease,and CD8+ T (suppressor) cells in later stages.6

Human leucocyte antigen (HLA) associationswith autoimmune disease are central to under-standing disease mechanisms in ocular inflam-matory disease, including SO. HLA gene prod-ucts, through peptide-HLA binding aYnity,can uniquely influence the presentation of dis-ease inducing peptides, or adjust the develop-ment of the T cell repertoire in the thymus bydeleting autoreactive lymphocytes leading toself tolerance.7 8 Certain types of clinical andexperimental uveoretinal inflammatory dis-eases are HLA or major histocompatibilitycomplex (MHC) restricted—for example,birdshot retinochoroidopathy, Behçet’s dis-ease, Vogt-Koyanagi-Harada’s disease (VKH),and experimental autoimmune uveoretinitis,and individuals possessing the HLA/MHCsusceptibility gene have increased diseaseseverity in both human and animal disease.9–13

A precise HLA association with SO could pro-vide further understanding of mechanisms of disease pathogenesis, help reveal a diseaseinducing or tolerogenic peptide, and explainvariations in clinical phenotype seen in patientswith SO.

Br J Ophthalmol 2001;85:281–286 281

Department of

Ophthalmology,

University of Aberdeen, Scotland,UK

D J Kilmartin J LiversidgeA D Dick

J V Forrester

Tissue TypingLaboratory, Aberdeenand Northeast

Scotland BloodTransfusion Service,Scotland, UK D Wilson

J BruceS J Urbaniak

Department of Ophthalmology, Mater

MisericordiaeHospital, Dublin,Ireland

R W Acheson

Correspondence to:Dara J Kilmartin,Department of Ophthalmology, Royal PerthHospital, Wellington Street,Perth WA 6000, [email protected]

Accepted for publication8 November 2000

www.bjophthalmol.com

group.bmj.comon October 22, 2014 - Published by bjo.bmj.comDownloaded from

http://group.bmj.com/



http://bjo.bmj.com/

http://bjo.bmj.com/


http://bjo.bmj.com/



Both SO and Vogt-Koyanagi-Harada(VKH) disease have been shown to have simi-lar clinical and immunohistopathological fea-tures, and identical associations with HLAclass II genes (HLA-DRB1*0405 andDQB1*0401) in Japanese patients.12 14–16 Inaddition, Japanese VKH patients with theHLA-DRB1*0405 subtype were shown tohave significantly increased disease severity.11 12

However, HLA-disease associations are de-

pendent on allelic frequency which varies dra-matically from one ethnic group to another.17 18

In western SO patients, no DNA based typinghas been performed but two older serologybased studies found an increase in frequency of HLA-DR419 20 and HLA-DQ3.20 In this study,we sought to assess HLA genetic polymor-phism and the development of SO, and toassess whether HLA gene variants were associ-ated with clinical phenotype or disease severity.

MethodsPATIENTS AND CONTROLS

Twenty seven patients (14 male and 13 female)with newly diagnosed and established SO were

recruited from throughout the UK and Ireland.Seventeen newly diagnosed patients were re-cruited in 1997 and 1998 through the BritishOphthalmological Surveillance Unit of theRoyal College of Ophthalmologists, as previ-ously reported.1 Ten established cases wererecruited from uveitis clinics at GrampianUniversity Hospitals, Aberdeen, and the MaterHospital, Dublin. All patients were white andwere native ethnic English (14 patients), Scot-tish (eight patients), Irish (four patients), andNorthern Irish (one patient). All patients hadbilateral posterior or panuveitis with a definitehistory of ocular trauma (accidental or surgical)followed by contralateral posterior uveitis withfeatures clinically consistent with SO. Nineteen

patients were diagnosed with SO by a uveitissubspecialist and eight had been diagnosed by aretina subspecialist. Although the diagnosis of SO was determined clinically, enucleated excit-ing eyes from five patients demonstrated histo-logical features consistent with SO. All referringophthalmologists returned questionnaire dataon clinical features, and 12 (two newly diag-nosed and 10 previously diagnosed) patientshad SO clinical features confirmed on examina-tion by three study investigators (DJK, ADD,

JVF). Clinical phenotype and markers of diseaseseverity assessed included visual acuity, timeinterval between SO onset and last ocular injury,number of preceding inciting injuries, ophthal-

moscopy features, such as degree of vitreouscellular infiltrate or haze (assessed by slit lampbiomicroscopy and binocular indirect ophthal-moscopy (BIO)),21 macular and disc oedema,Dalen-Fuchs nodules and choroidal neovascu-larisation, and therapeutic interventions such asenucleation and immunosuppressive therapy.Recurrence of uveitis was defined as an increasein disease activity, with worsening of visual acu-ity and/or BIO score, requiring an increase inimmunosuppressive therapy from previouslystable maintenance therapy. Median follow upwas 12 months (range 6–354 months). Controlsfor HLA typing were age, sex, and region

matched. Two controls were obtained for eachpatient and these were normal unrelated volun-teers without any history of uveitis or otherautoimmune disease attending the same hospi-tal or primary care clinic as the patient. Thisyielded 51 controls for HLA class I and class II(HLA-DRB1, HLA-DQB1) typing, as only onematching control could be obtained for threepatients, and 49 controls for HLA-DQA typingas insufficient DNA was available in two

controls. Informed consent was obtained fromboth patients and controls and the studyadhered to the tenets of the Declaration of Hel-sinki. Local institutional review board approvalwas obtained.

HLA TYPING

Ten ml of peripheral blood was obtained fromeach patient and control and DNA wasextracted using the salt extraction method.22

HLA class I (A, B, and C) and II (DRB1,DRQA1, and DRQB1) typing was performedusing polymerase chain reaction sequence spe-cific primer sets (PCR-SSP) (AllSet and Clas-sic PCR-SSP, Dynal Ltd, Liverpool) based on

the method of Olerup.23 Initially low resolutiontyping was performed for class I and II, andthen higher resolution typing was repeated forclass II subtypes. HLA-DPB1 typing was notperformed as the only previous DNA basedHLA study of sympathetic ophthalmia foundno HLA-DPB1 association.16 Briefly, DNAsamples were amplified by PCR with 0.38units per µl of Taq polymerase (AppligeneOncor Lifescreen Ltd, Watford) and nucle-otides (final concentration 0.2 mM of each)(Amersham Pharmacia Biotech Ltd, Bucks).All other reagents for PCR were provided inthe PCR-SSP sets and used according tomanufacturer recommendations. The reaction

mixture was processed in an automatedthermocycler (Perkin Elmer 9600, Warrington,UK) and subjected to 94°C for 2 minutes fol-lowed by 10 cycles at 94°C for 10 seconds and65°C for 60 seconds, 20 cycles at 94°C and61°C for 50 seconds, and 72°C for 30 secondsfor denaturation, annealing, and extension toallow DNA amplification. After amplification,10 µl of PCR products were electrophoresed ina 2% agarose gel containing ethidium bromidewith 0.5% TRIS-borate-EDTA buV er. HLAtypes were assigned on the basis of PCR-SSPpatterns using WHO nomenclature.24

STATISTICS

The

2

test with the continuity correction orFisher exact test were used to compare patientand control groups. Significance was attributedwhen the p value was less than 0.05. The pvalue was not corrected by the number of com-parisons made to correct for the number of alleles. Relative risk (RR) was calculated usingthe Woolf formula (a × d)/(b × c) where a, b, c,and d represented the numbers of patients withthe marker, patients without the marker,controls with the marker and controls withoutthe marker, respectively.25 When a value was 0,the Haldane modification was used by adding0.5 to every number.

282 Kilmartin,Wilson,Liversidge,et al






http://bjo.bmj.com/

http://bjo.bmj.com/


http://bjo.bmj.com/



disease severity in SO patients with theCw*03-DRB1*04-DQA1*03 haplotype, orwith the individual genotypes Cw*03,DRB1*0404 or DQA1*0301 (data not shown)compared with SO patients without these HLAgene variants.

DiscussionThe most important finding of this DNAtyping study of sympathetic ophthalmia is that

there is a similar association with HLA-DRB1*04 and DQA1*03 genotypes in whitepatients and Japanese patients with SO. Of equal importance is the finding that theDRB1*04-DQA1*03 haplotype is a marker of more severe clinical phenotype in SO, withincreased disease susceptibility and severity,similar to VKH, which has identical HLAassociations and increased disease severityassociated with DRB1*04 gene variants.11 12

Previous serological HLA studies of SO havereported an increase in both HLA-DR4 andDQ3 in non-Japanese and Japanese pa-tients.16 19 20 Previous studies outside of Japanhave been small and control groups were inap-propriate as they were too large, falselyincreasing the power of statistical analysis,8 20

did not have racial matching, or were not typedin the same laboratory at the same time as thepatients.20 26 Our SO patient (n=27) andcontrol (n=51) groups are relatively small instatistical terms, and interpretation of the datamust be more cautious with the smaller SOpatient subgroups in phenotypic analysis.However, this is the largest population based

(UK and Ireland) cohort of SO patients yetdescribed, with rigorous matching of controlsto each patient, and all DNA based typing wasperformed in the same laboratory at the sametime. With the greater accuracy and resolutionof DNA based typing compared to serology,greatly reducing the chance of a type 1 error,we have not performed Bonferroni’s correctionfor multiple comparison procedures, similar toother recent DNA based HLA studies.7 12 16

There has been only one previous DNAbased HLA study of SO, on 16 Japanesepatients, which found significant associationswith HLA-DRB1*0405, DQA1*03, andDQB1*0401.16

HLA disease associations are dependent onthe prevalence of a specific HLA allele in thepopulation and the evolution of particular link-age disequilibria—for example, betweenHLA-DR and HLA-DQ, is also dependent onethnic background. Japan has a relativelyhomogeneous ethnic genetic island populationand HLA disease associations with particulargenotypes may not be as relevant outside of

Japan. Owing to strong linkage disequilibriumbetween DRB1*0405 and DQB1*0401 in

Japan only,17 18 and lack of serological SOassociation with DQ4 in North Americanpatients,20 the authors of the Japanese studysuggested that DQB1*0401 was unlikely tocontrol the development of SO but wereunable make a definite conclusion. Our studysupports this finding as DQB1*0401 was notassociated with SO, nor was DRB1*0405,probably because the prevalence of DRB1*0405 is low outside the Far East.17 18

The subtypes of DRB1*04 are invariablylinked with DQA1*03 across all races.18 How-ever, DQA1*03 is linked with other types, suchas subtypes of DRB1*08, DRB1*09, andDRB1*12, and these other types were notincreased in the patients with SO in our studywhere only DRB1*04 (0404) was significantlyincreased. Our data support the finding that

Table 3 Frequencies of higher resolution subtypes of HLA-DRB1 and DQ alleles in patients with SO

Alleles

Controls (n=51)* Patients (n=27)

Relative risk p Value No (%) No (%)

DRB1*0103 1 (2.0) 3 (11.1)DRB1*0401 8 (15.7) 9 (33.3)DRB1*0403 1 (2.0) 0DRB1*0404 2 (3.9) 5 (18.5) 5.6 0.045DRB1*0405 0 1 (3.7)DRB1*0407 0 1 (3.7)

DRB1*0408 2 (3.9) 1 (3.7)DRB1*0413 1 (2.0) 0

DQA1*0101 12 (24.5) 4 (14.8)DQA1*0102 8 (16.3) 5 (18.5)DQA1*0201 17 (34.7) 6 (11.8)DQA1*0301 7 (14.3) 8 (15.7)DQA1*0302 0 1 (3.7)DQA1*0303 6 (12.2) 8 (29.6)DQA1*0401 2 (4.1) 1 (3.7)DQA1*0501 20 (40.8) 11 (40.7)

DQB1*0301 16 (31.3) 10 (37.0)DQB1*0302/08 8 (15.7) 9 (33.3)DQB1*0303 7 (13.7) 0

*n=49 for DQA1* alleles due to insuYcient DNA.

Table 4 Frequencies of associated haplotypes in patients with SO

Alleles

Controls (n=51)* Patients (n=27)Relativer isk p Value No (%) No (%)

Cw*03-DRB1*04-DQA1*03 3 (6.1) 8 (29.6) 6.7 0.013DRB1*04-DQA1*03 13 (26.5) 15 (55.5) 3.5 0.024DRB1*0404-DQA1*0301 1 (2.0) 5 (18.5) 10.9 0.019Cw*03-DRB1*04 3 (5.9) 8 (29.6) 6.7 0.007Cw*03-DQA1*03 2 (4.1) 8 (29.6) 9.9 0.003

*n=49 for DQA1* alleles due to insuYcient DNA.

Table 5 Influence of HLA-DRB1*04-DQA1*03 haplotype on clinical phenotype in patients with SO

Ocular signs*

DRB1*04-DQA1*03 positive (n=15)†

DRB1*04-DQA1*03negative (n=12)‡

p Value No (%) No (%)

VA <0.5§ 10 (67) 9 (75)

Onset <3 months\ 13 (87) 3 (25) 0.001Onset >12 months\ 2 (13) 5 (42)>2 inciting events# 4 (27) 8 (67) 0.038Surgical cause of SO 5 (33) 7 (58)Moderate/severe vitritis** 11 (73) 5 (42)Persistent macular oedema >3

months 7 (47) 5 (42)Disc oedema 2 (13) 4 (33)Dalen-Fuchs nodules 10 (67) 8 (67)Choroidal neovascularisation 1 (7) 1 (8)Enucleation 5 (33) 3 (25)Prednisolone >10 mg/day†† 10 (67) 3 (25) 0.031>1 immunosuppressive drug 12 (80) 8 (67)Recurrence uveitis on therapy 12 (80) 6 (50)

*Ocular signs during follow up in sympathising eyes only, where applicable.†HLA-DRB1*04-DQA1*03 positive patients possessed both alleles.‡HLA-DRB1*04-DQA1*03 negative patients did not possess either allele.§Worst level of best corrected visual acuity.\ Onset of SO from last ocular injury.#Inciting event defined as penetrating eye trauma or surgery.

**Vitritis where vitreal haze/binocular indirect ophthalmoscopy score or cellular infiltrate was 2+or worse. †† Maintenance systemic prednisolone dose.

284 Kilmartin,Wilson,Liversidge,et al






http://bjo.bmj.com/

http://bjo.bmj.com/


http://bjo.bmj.com/



HLA-DRB1*04, and not its subtypes, controlsSO susceptibility in diV erent ethnic groups.

Although SO and VKH in Japan arereported to have identical HLA associationswith DRB1*0405 and DQB1*0401,15 16

another Japanese VKH study has discountedthe importance of the DRB1*0405 orDQB1*0401 genotype, due to strong Japaneselinkage disequilibrium for this haplotype, andsuggested that DQA1*0301 is the primary

genotype for VKH susceptibility with assist-ance by the DRB1*04 gene variant.12 A morerecent Japanese SO study also found an associ-ation with DQA1*03 but no DQA1*03subtyping was performed.16 Our study inpatients with SO did not find an associationwith the HLA-DQA1*0301 genotype, whichoccurred only when in the haplotypeDRB1*0404-DQA1*0301, whereas theDRB1*0404 genotype alone was associated,which suggests that a DRB1*04 gene variant,rather than DQA1*0301, controls SO suscep-tibility. However, the theory of combinedallelic predisposition is supported by thefinding that the HLA DRB1*04-DQA1*03

haplotype confers increased SO disease sus-ceptibility, through earlier disease onset andthe need for fewer inciting events to initiatedisease, and increased disease severity but theDQA1*03 genotype may be of secondaryimportance. The possession of DRB1*04 genevariants has also been found to increase diseaseseverity in rheumatoid arthritis, another au-toimmune disease.27 The higher resolutionDRB1*0404-DQA1*0301 haplotype, al-though significantly associated, was present inonly five patients which did not allow meaning-ful comparison of clinical phenotype in pa-tients with and without this haplotype.

Our study diV ers from previous Japanesedata in that DRB1*0404, and not DRB1*0405,

which diV er by two amino acids (AA) insequence, was associated with SO. This associ-ation was also weaker as the relative risk forDRB1*0404 was 5.6 in our study comparedwith 13.7 for DRB1*0405 in Japan.16 The twoAA diV erence comparing DRB1*0404 andDRB1*0405, where asparagine is replaced byserine at position 57 and valine is replaced byglycine at position 86, occurs in the hypervari-able extracellular domains of these class II mol-ecules where the peptide binding groove isformed. This can significantly alter the chemi-cospatial relations that determine peptide bind-ing aYnity. Altered peptide binding aYnity, inturn, influences peptide presentation to CD4+

T cells, central to disease initiation in EPU.Defining a particular HLA class II association,such as DRB1*0404 or DRB1*0405, andknowing its AA sequence and three dimen-sional structure, could allow identification of certain disease inducing peptides through pep-tide binding aYnity. It has been observed thatHLA alleles associated with autoimmunity areusually poor peptide binders28 and this ap-proach could be used in SO to identifycandidate autoantigens through predicted ortested peptide binding aYnity. Certain peptidescontain anchor residues that define allelespecific motifs common to all peptides capable

of binding to a specific HLA molecule. Tolero-genic peptides could be identified through allelespecific motifs allowing high aYnity competi-tive binding of either inert peptides, stabilisingthe HLA complex and preventing access to thepeptide binding groove, or immunomodulatorypeptides with anti-inflammatory or regulatorycytokine responses.29

The association with HLA-Cw*03 in pa-tients with SO has not been reported previ-

ously, nor has this allele been previously foundto be associated with other categories of uveitisor autoimmune disease. However, increasedcytotoxic T cell lytic activity has been observedin HLA-Cw*03 positive patients againstmelanoma cell lines30 and this may support arole for melanin associated antigens in thepathogenesis of Cw*03 restricted SO.

Genetic susceptibility to SO may not residewith DRB1*0404 or DRB1*0405, or otherDRB1*04 variants, with varying heuristiceV ects on HLA class II peptide binding aYnityand T cell activation or selection. TheDRB1*0404-DQA1*0301 haplotype associ-ation, and weaker association with

DRB1*0404 compared to DRB1*0405 in Japan, may point to primary susceptibility witha gene involved in the immune response in theHLA class II region tightly linked to HLA-DR and HLA-DQ genes, such as HLA-DM, HLA-DO, TAP, LMP, and tapasin.7 8 HLA-DMgenes are closely involved in peptide editing,regulate peptide binding to HLA class II mol-ecules by facilitating low aYnity peptideexchange, and may allow selection of immuno-dominant epitopes.31 32 Recent work has foundthat HLA-DM gene variants are associatedwith rheumatoid arthritis33 and type 1 diabetesmellitus,34 where class II antigen processing isimportant. MHC restriction and both geneticsusceptibility and disease severity association

have been demonstrated in very well definedanimal models of uveitis,13 but it has beenmuch more diYcult to show this in the geneti-cally diverse human clinical situation. Furthergene mapping and analysis of genetic polymor-phisms in patients with SO may determine theprecise genes responsible for susceptibility anddisease severity in SO.

Presented in part at the Annual Meeting for Research andVision in Ophthalmology, Florida, May 2000.

This study was funded by the Wellcome Trust whichsupported DJK with a Vision Research training fellowship. Theauthors also wish to gratefully acknowledge the data contribu-tion of 20 ophthalmologists throughout the United Kingdomand Republic of Ireland, the technical assistance of Joanne Har-ris, Tissue Typing Laboratory, and the statistical advice of DrGordon Prescott, Department of Public Health Medicine, Uni-versity of Aberdeen.

1 Kilmartin DJ, Dick AD, Forrester JV. Prospective surveil-lance of sympathetic ophthalmia in the United Kingdomand Republic of Ireland. Br J Ophthalmol 2000;84:259–63.

2 Chan CC, Roberge FG,Whitcup SM,et al. Thirty-two casesof sympathetic ophthalmia: a retrospective study at theNational Eye Institute, USA from 1982–1992. ArchOphthalmol 1995;113:597–600.

3 Forrester JV. New concepts on the role of autoimmunity inthe pathogenesis of uveitis. Eye 1992;6:433–46.

4 Chan CC, Roberge FG. Sympathetic ophthalmia. In:Pepose JS, Holland GN, Wilhelmus FR, eds. Ocular infection and immunity. St Louis: Mosby; 1996:724.

5 Liversidge J, Dick A, Cheng Y-F, et al. Retinal antigen spe-cific lymphocytes, TCR-gamma delta T cells and CD5+ Bcells cultured from the vitreous in acute sympatheticophthalmitis. Autoimmunity 1993;15:257–66.

Immunogenetics and clinical phenotype of sympathetic ophthalmia in British and Irish patients 285






http://bjo.bmj.com/

http://bjo.bmj.com/


http://bjo.bmj.com/



doi: 10.1136/bjo.85.3.281 2001 85: 281-286Br J Ophthalmol

Dara J Kilmartin, David Wilson, Janet Liversidge, et al. patientssympathetic ophthalmia in British and IrishImmunogenetics and clinical phenotype of

http://bjo.bmj.com/content/85/3/281.full.html

Updated information and services can be found at:

These include:

References

http://bjo.bmj.com/content/85/3/281.full.html#related-urls

Article cited in:

http://bjo.bmj.com/content/85/3/281.full.html#ref-list-1

This article cites 27 articles, 9 of which can be accessed free at:

serviceEmail alerting

box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up in the

CollectionsTopic

(1209 articles)Neurology (500 articles)Choroid

Articles on similar topics can be found in the following collections

Notes

http://group.bmj.com/group/rights-licensing/permissions

To request permissions go to:

http://journals.bmj.com/cgi/reprintform

To order reprints go to:

http://group.bmj.com/subscribe/

To subscribe to BMJ go to:







http://bjo.bmj.com/cgi/collection/neurology












http://bjo.bmj.com/

http://bjo.bmj.com/


http://bjo.bmj.com/





http://bjo.bmj.com/cgi/collection/choroid




Immunogenetics and Clinical Phenotype of Sympathetic Ophthalmia in British and Irish Patients

Documents

Transcript of Immunogenetics and Clinical Phenotype of Sympathetic Ophthalmia in British and Irish Patients