Key words: cytokines, Fuchs’ heterochromic cyclitis,interleukin-10,T cells, uveitis.

INTRODUCTION

The term uveitis covers a wide variety of disorders recog-nized by their clinical phenotype. Some are fairly benign intheir effects on the eye (e.g. Fuchs’ heterochromic cyclitis)whereas others (e.g. Behcet’s disease) can be visually devas-tating. In some patients it is associated with a systemicdisease (e.g. sarcoidosis or Behcet’s disease) whereas inothers it appears to be confined to the eye alone, such as inpars planitis and sympathetic ophthalmia. A wide variety ofcomplications can occur and treatment, with topical andsystemic drugs particularly steroids, is often required.Despite treatment, there are a significant number of patientswho suffer permanent serious loss of vision; it is calculatedthat 10% of the population under the age of 65 years whoare registered blind are blind due to uveitis and its sequelae.1

Posterior uveitis encompasses a wide variety of clinicalphenotypes with the retinal vessels, retina, choroid andoptic nerve involved in some disorders and not others.Toxoplasmosis remains the commonest cause of posterioruveitis worldwide2 but in many of the rest of the disorders,the cause is unknown and the disease is thought to be per-petuated by autoimmune mechanisms.3,4 Treatment withsteroids and often other immunosuppressive agents is aimedat controlling the sight-threatening sequelae of the inflam-matory process and may be required for many years.5

HISTOLOGY AND IMMUNOPATHOLOGY OF

ENUCLEATED EYES

Few eyes become available for examination during the acutephase except in sympathetic ophthalmia where they mayhave been removed for diagnostic purposes.6 The other eyesthat are available are when the eye has been removedbecause it is blind and painful, often due to intractable glau-coma or hypotony due to inoperable retinal detachment.

Where there are active foci of inflammation, it is notice-able that the appearance is very similar, whatever the

original clinical phenotype. The predominate cell type is thelymphocyte with many macrophages and few plasma cellswhich may be in either the retina or choroid or both7

(Fig. 1). Immunophenotyping of these lymphocytes showsthem to be of the CD4 type with only a few CD8 type T cells8 (Fig. 2). The macrophages are activated as shown by their increased expression of MHC class II antigens ontheir surface and the T cells are also activated and expressinterleukin (IL)-2 receptors on their cell surface.9 Aberrantexpression of MHC class II antigens is also seen on cellssuch as the retinal pigment epithelium and retinal vascularendothelium, suggesting that autoimmune mechanisms areinvolved at least in the perpetuation of the inflammatoryresponse.10 Immunoglobulin deposition and neutrophil infil-tration characteristic of immune complex formation are notseen.

EXPERIMENTAL MODELS

Many different types of animal models have been used to tryand reproduce human disease.11 The best characterized isthat in the Lewis rat in which retinal S-antigen is given inadjuvant and bilateral uveitis ensues around 12 days later12

(Fig. 3). The uveitis can also be induced by intravenousadministration of activated T-cell lines specific for retinal S-antigen demonstrating the important role of the T cell.13

During the course of the disease, cytokine messenger RNAsuch as for interleukin-2 (IL-2), interferon-γ (IFN-γ) andinterleukin-4 (IL-4) can be detected in areas of the retinaand choroid infiltrated by T cells14,15 (Fig. 4). Further under-standing of the role of different cytokines has been achievedusing mouse models as well as the genetics involved indisease susceptibility.16

STUDIES ON AQUEOUS HUMOUR

When iris biopsies from patients with different types ofuveitis are taken at the time of cataract surgery, there is verylittle apparent difference between those taken from patientswith mild disease and those taken from patients with severedisease. The biopsy specimens are full of lymphocytes

Clinical and Experimental Ophthalmology (2001) 29, 48–51

Norman Gregg Lecture

Uveitis: what do we know and how does it help?Susan Lightman PhD FRCOphthInstitute of Ophthalmology and Moorfields Eye Hospital, London, UK

� Correspondence: Professor Susan Lightman, Institute of Ophthalmology and Moorfields Eye Hospital, City Road, London, EC1V 2PD, UK.

Email: s.lightman@ucl.ac.uk

Uveitis 49

and macrophages, and the lymphocytes are predominatelyT cells.17 Yet the differing clinical behaviour means thatthere must be a difference somewhere; maybe the type ofcell is the same but their effect is different. T cells haveeffector functions determined by the type of cytokines theysecrete and can be subdivided on this basis.18

In a study comparing different types of uveitis, patientswith active uveitis were asked (with informed consent andethics approval) to give a blood and aqueous sample. Thesewere analysed for type of cell present as well as cytokinespresent.19 Significant increases in the presence of CD4 andactivated CD4 T cells were present in all patients withuveitis when compared to peripheral blood, further confirm-ing the difficulties in making assumptions of the situation inthe eye when only peripheral blood analyses are done.

When comparing Fuch’s heterochromic cyclitis (FHC) tomore severe forms of uveitis, there was a marked differencein the number of CD8 cells (Fig. 5) which were greatlyincreased in FHC as was the concentration of IL-10 (Fig. 6).Interleukin-10 is a cytokine which is able to downregulatethe inflammatory response and is one of the ways in whichcorticosteroids dampen inflammation. This may also explainwhy steroids are ineffective in FHC as these patients alreadyhave high IL-10 levels.

To see if IL-10 was being produced by the T cells them-selves, intracellular cytokine staining techniques were usedto identify which ones were being secreted by the T cells

Figure 1. Lymphocytic infiltration in the choroid, typical ofmany different clinical phenotypes of uveitis.

Figure 2. CD4 and T cells infiltrating in ocular sarcoidosis.

Figure 3. Histology of S-antigen-induced uveoretinitis showinglymphocytic infiltrate and retinal destruction.

Figure 4. Cytokine mRNA in the retina in uveitis, shown by in situ hybridization.

Figure 5. Cell phenotypes in the aqueous in (�) Fuchs’ hetero-chromic cyclitis (FHC) and (�) idiopathic anterior uveitis. Thereare more CD8+ T cells in FHC.

into aqueous.20 Certainly some of these T cells contain IL-10 in their cytoplasm (Fig. 7) and whether this correlateswell with clinical severity is not yet known.

STUDIES ON VITREOUS HUMOUR

The most serious sequelae of uveitis occur in the posteriorsegment and it would therefore be ideal to see if the changespresent in the aqueous are also found in the vitreous. Twodisorders were compared: patients with FHC and vitritis;and patients with intermediate uveitis and vitritis, which hasfar more sight-threatening sequelae. T-cell lines were gener-ated from the vitreous and blood samples from eachpatient.21 Again IL-10 production was significantly higherby the T cells derived from patients with FHC confirmingthe findings in the aqueous humour (Fig. 8).

CURRENT HYPOTHESIS

It is likely that the difference in the clinical severity ofuveitis depends upon the cytokine secretion patterns by the

T cells infiltrating the involved tissues. This gives no infor-mation on the initiation mechanisms but suggests thatpatients who have benign uveitis such as FHC secrete down-regulatory cytokines such as IL-10, as compared to the moreaggressive active disease. Current immunosuppressiveagents act to reduce all cytokines secreted and may also suppress IL-10 secretion in some patients, perhaps explain-ing why some patients do not respond to this type oftherapy, that is those who have refractory disease.

HOW DOES IT HELP?

Many patients with uveitis face years of systemic immuno-suppressive medication with all its side-effects. At present,local therapy, which usually comprises depot steroids,involves repeated injections and is not successful in at leasthalf of the patients. Intraocular drug delivery devices forganciclovir have been used extensively in AIDS patientswith cytomegalovirus retinitis and are a safe way for chronicdrug administration.22 At present, they can also containdrugs such as triamcinolone and 5-fluorouracil,23 and otherscontain cyclosporin. These devices are now in early clinicaltrials. If IL-10 is as effective a downregulator in the eye as it appears to be to date, then it could be given in thesedevices without the need for systemic administration or forsteroids at all. This is an exciting possibility for patients withsevere uveitis and the results on larger studies on patients areawaited.

REFERENCES

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3. Lightman S, Towler H. Immunopathology and altered immu-nity in posterior uveitis in man. Curr. Eye Res. 1992; 11: 11–15.

50 Lightman

Figure 6. Cytokines in the aqueous in (�) Fuchs’ heterochromiccyclitis (FHC) and (�) idiopathic anterior uveitis. More interleukin(IL)-10 is present in the aqueous in FHC.

Figure 7. T cell stained for intracellular interleukin-10.

Figure 8. Cytokines in the vitreous in (�) Fuchs’ heterochromiccyclitis (FHC) and (�) idiopathic anterior uveitis. T cells from thevitreous in FHC also produce more interleukin (IL)-10.

Uveitis 51

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