WHAT DETERMINES THE SITE OF INFLAMMATION IN AND ?

2 JOHN V. FORRESTER\ JANET LIVERSIDGE\ ANDREW DICK\ PAUL McMENAMIN , l l l MARIA KUPPNER , ISOBEL CRANE and PARWEZ HOSSAIN Aberdeen

Uveitis is a relatively confusing term since it implies CLASSIFICATION OF INTRAOCULAR primary inflammation of the uveal tract. However, it INFLAMMATION has become clear during the last few decades of In essence, the answer to this question lies in the research into the causes of uveitis that the uveal tract cause of the 101. For instance, acts primarily as the conduit for the inflammatory (CMV) with choroiditis is clearly localised cells and the increased blood flow that accompany to the and pars planitis is localised to the pars inflammation targeted to other sites in the eye such plana. However, further analysis leads to blurring of as the retina and . Uveitis is, therefore, better these distinctions in many of the conditions. Pars referred to as intraocular inflammation (l01). planitis is a subset of what is termed 'intermediate A major problem in understanding the pathophy­ uveitis' according to the International Uveitis Study 4 siology of 101 is that clinically there is a great variety Group Classification and is caused by or associated with several conditions of presentations of apparently different conditions. including and . How­ However, a significant unifying concept, at least from ever, sarcoidosis can also cause retinitis and/or the viewpoint of pathogenetic mechanisms, is that choroiditis in isolation, so what constitutes sarcoido­ many of the clinical manifestations of 101 can be sis-related 101? Furthermore, pars planitis is essen­ mimicked with models of experimental autoimmune tially a clinical diagnosis which can be confused, uveoretinitis (EAU) which utilise a single antigen.1 albeit rarely, with other conditions such as Toxocara This is not to say that autoimmune mechanisms uveitis. account for most causes of 101 since the opposite is Accordingly, while it is important to make specific probably true; rather, that the intraocular tissues, diagnoses where possible, it is also necessary to particularly the retina and , can respond to retain a pathogenetic view of the inflammatory challenge by foreign or autoantigen in only a limited condition and to consider that any particular set of ways and that it should not be surprising that presentation of 101 represents a stage in the there is considerable overlap in the clinical manifes­ spectrum of clinical severity that may accompany tations of many of these conditions. These concepts any form of 10L have been discussed previously?.3 In order to keep this perspective, a simple This paper aims to address a separate but related classification of 101 is required. 101 may therefore problem: if the eye and its component tissues can be categorised according to site as anterior or posterior, and according to cause as infective or respond in only a limited set of clinical manifesta­ non-infective. tions, why is there preferential localisation of Anterior 101 refers to all intraocular inflammatory inflammation and tissue damage to discrete sites in conditions in which the primary site of inflammation certain conditions? is located anterior to the - diaphragm and I From: Department of , University of Aber­ essentially represents all types of iritis and iridocy­ 2 deen, Aberdeen, UK; Department of Anatomy and Human clitis; posterior 101 refers to all intraocular inflam­ Biology, University of Western Australia. matory conditions occurring posterior to the iris-lens Correspondence to: Professor J. V. Forrester, Department of Ophthalmology, University of Aberdeen, Medical School, diaphragm and includes pars planitis, intermediate Foresterhill, Aberdeen AB9 2ZD, UK. uveitis, vitritis, all forms of chorioretinitis and

Eye (1997) 11, 162-166 © 1997 Royal College of Ophthalmologists THE SITE OF INFLAMMATION IN UVEITIS AND CHORIORETINITIS 163 choroiditis, retinitis and . This that a retinal inflammation only develops when the classification has been described before and relates cysts rupture. In contrast, it is rare to find this to the general pathogenetic mechanisms involved in organism in the choroid or indeed at any site in the each category of 101? and are not uveal tract, and if present it sets up a marked normally included in this classification, even if they inflammation. are associated with secondary uveitis.5 Several viral organisms also have a clear neuro­ Anterior 101 may be acute recurrent or chronic tropism, such as HSV and CMV, while mycobacteria and direct infective causes are uncommon. In non­ primarily locate in the uveal tract or . The 5 infective anterior uveitis MHC class I mediated location of autoantigens in the photoreceptors1 or in mechanisms appear to be important since approxi­ the iris pigment epithelium16 clearly determines the mately 50% of cases of acute anterior uveitis are site of inflammation, characterised for instance by linked to HLA-B27 and its associated conditions.6 the Dalen-Fuchs' nodule in sympathetic ophthal­ Interestingly, a tenuous link to Gram-negative mia17 (see below). Conditions such as serpiginous bacteria in both the ocular and non-ocular HLA­ choroiditis are clearly located to the retinal pigment B27 disease has been suggested by several groups but epithelium (RPE), but it is not known whether the not firmly established?-9 antigen is an RPE-specific autoantigen or a foreign Posterior 101 takes many forms some of which are antigen in virus-infected RPE cells. However, some clearly infective, such as Toxoplasma chorioretinitis ophthalmologists have treated this condition empiri­ and herpes simplex (HSV) retinitis, while others are cally with anti-viral agents on the basis that HSV may apparently non-infective such as idiopathic retinal be the infective agent. vasculitis, and sympathetic ophthalmia. Some non­ Each of these antigens will have a different effect infective conditions may be part of a wider systemic based, in the case of foreign antigens, on its virulence disorder such as Beh<;et's disease or multiple and strain, and, in the case of autoantigens, sclerosis, but this may apply equally to infective determined by its immunogenicity. conditions such as leprosy, and miliary . Others may be considered THE DEGREE OF SYSTEMIC IMMUNE CELL infective in certain circumstances, e.g. presumed ACTIVATION ocular , but have striking phenotypic similarity to non-infective causes of multifocal Uveitis or 101 can be regarded as a systemic illness in choroiditis with subretinal neovascular membrane which the eye is the target tissue, in much the same formation.lO On the basis of their clinical and way as many arthritides or other organ-specific (immuno)h istological resemblance to models of diseases are, such as thyroiditis. This concept fits EAU, many of these conditions are assumed to be well with many infective causes of uveitis in which an MHC class II mediated.1 However, in some cases initial exposure to antigen such as Toxoplasma or MHC class I mechanisms may be important also, Epstein-Barr (EB) virus leads to a prodromal 'flu­ such as in birdshot retinochoroidopathy (HLA like illness involving mild fever and lymphadeno­ A29)11,12 and Beh<;et's disease (HLA B51)Y pathy. This leads to an acquired immune response On this basis, several factors can be suggested which after initial resolution of the illness leaves a which are likely to affect the site of primary pool of antigen-specific memory T cells circulating inflammation within the eye. These include the through the lymphoid tissues. If the original antigen nature and localisation of the antigen; the degree of is not completely removed but finds its way to a systemic immune cell activation; access of activated sequestered site in the tissues, it may induce immune cells to the antigenic site; the potential for recurrent attacks of inflammation even when the local antigen presentation; and the influence of the memory T cells are non-specifically activated, e.g. on local microenvironment in which the inflammation exposure to cytokines such as interferon-gamma takes place. (IFN)') and tumour necrosis factor alpha (TNFa) released during the course of an intercurrent infec­ tion from an unrelated virus. Ophthalmologists have NATURE AND LOCALISATION OF THE long recognised the association between minor ANTIGEN febrile illness and the reactivation of uveitis. The nature and localisation of the antigen are In a similar way apparently unrelated infections paramount in determining the site of inflammation. may cause reactivation of autoimmune disease For instance, the Toxoplasma parasite has a pre­ through postulated mechanisms such as molecular dilection for neural tissue, especially the eye and the mimicry. According to this notion, homology brain (for review see Pavesio et aI.14). However, in between autoantigens and foreign antigens ensures the retina it can persist in the encysted state without that during activation of T cells occurring in response causing significant inflammation. Experimentally, to an infection, T cells specific for the autoantigen as this has also been found to hold true and it appears well as for the foreign antigen are primed due to 164 J. V. FORRESTER ET AL. presentation of autoantigen 'look-a-like' peptides adhesion and activation molecules, such as MHC derived from the micro-organism. Such primed T class II and intracellular cell adhesion molecule I cells, if they find their target antigen in the tissue, can (ICAM-I)?O Such changes are probably induced then be activated locally by appropriate antigen through systemic cytokine activation, especially presenting cells? Thus, autoimmune disease induced IFNI', interleukin-I (IL-I) and TNFa derived from by this mechanism is initiated in the periphery as part primed T cells and monocytes?1-23 This synergistic of a systemic inflammatory response. It can also be interaction between the T cell and the target tissue is seen how the degree of T cell priming will determine central to the development of the inflammation. in part whether an attack of 101 will occur. It can be predicted, therefore, that the site of inflammation will in part be determined by changes in the vessels peculiar to that tissue. There is now ACCESS OF PRIMED IMMUNE CELLS TO considerable evidence that the microvasculature of ANTIGENIC SITES each tissue has specific properties, a little like a postal Access to tissues by circulating lymphoid cells is code, for targeting cells to that tissue, and thus restricted by tissue barriers. In the central nervous conditions such as pars planitis and idiopathic retinal system (CNS) the blood-CNS barrier is highly vasculitis occur because the vessels in those tissues developed and under normal circumstances is an are expressing the appropriate markers while the effective barrier to cells and molecules. In the eye, vessels in other tissue have remained quiescent. How the blood-retinal barrier is equally efficient even this mechanism is achieved is not clear. However, though it is distributed at two sites, i.e. the retinal there is potential for manipulating this in therapeutic vasculature and the RPE. In the uveal tract there is terms since blocking the expression of adhesion effectively no barrier to proteins, with ready molecules with specific antibodies and/or analogous exchange of molecules between the tissue space peptides is an effective mechanism for downregulat­ and the vessels. There may be some degree of ing and/or preventing inflammation. restriction to the movement of cells which depends on the expression of adhesion molecules for trans­ LOCAL ANTIGEN PRESENTATION AT THE endothelial migration. However, several adhesion TARGET SITE molecules and integrin receptors (see below) are expressed constitutively in the choroid/s suggesting With most of the players in place at the target site, that extravasation of cells in the choroid may readily i.e. the antigen, the primed T cells and potential occur. effector monocytes/macrophages, and the activated, The blood-ocular barrier at the is also leaky blood-tissue barrier, there is an essential reasonably effective, being formed in this case by the requirement for cells which can present the antigen double layer of epithelial cells, and inhibiting transfer to the T cells and thus allow activation of the effector of cells and molecules from the fenestrated ciliary cells. In the eye, it was previously assumed that part body vessels. However, the barrier at the iris is less of the condition of immunological privilege was due effective: posterior movement of cells and molecules to a lack of 'professional' antigen presenting cells is prevented by the posterior iris epithelium, which is (APCs)?4-26 (a second component being a lack of continuous with the ciliary body epithelium, but tissue lymphatics). However, it is now clear that anteriorly there is no effective barrier between the there are rich networks of dendritic cells and resident iris stroma and the anterior chamber. However, macrophages27 within the uveal tract although there under normal circumstances there is little transport are no APCs in the retina propers (it has also been of cells and molecules at the iris vessels unless there shown recently that there are lymphatic communica­ is significant engorgement as in inflammation. tions between the intraocular and the upper cervical In fact, it has recently become clear that the iris lymph nodes?9 Dendritic cells in the choroid lie in vessels are the first to be breached by cells in models of close apposition to the RPE, i.e. at the site of the EAU.19 This is followed within hours by cellular efflux blood-retinal barrier, and are likely to be inducers of from the ciliary body vessels and vessels in the choroid. the microgranulomas found in many uveitis condi­ Retinal vessels and the RPE layer are the last to be tions such as sympathetic ophthalmia, multifocal breached in EAU despite the fact that the photo­ choroiditis and the numerous white dot syndromesP receptor is the target cell?O In fact their distribution may explain the clinical In real terms, of course, breakdown of the presentation of these disorders.17 blood-retinal barrier occurs during the early stages Similarly, dendritic cells in the iris probably of inflammation at all sites including the blood­ underlie the pathology of iris granulomas and their retinal barrier. Indeed, prior to the extravasation of numbers in the ciliary body may account for the cells from the retinal vessels there are morphological frequency of cyclitis in many 101 syndromes. and immunological changes which present as 'high­ Remarkably, the turnover of dendritic cells in the endothelial venule' -like changes and expression of eye is only a few days, compared with the longer THE SITE OF INFLAMMATION IN UVEITIS AND CHORIORETINITIS 165 turnover time of their counterpart in the skin, the regulated by the cytokines to which the T cells are Langerhans cells.3o exposed. Under normal conditions, the RPE cell In vitro studies have shown that ocular dendritic produces inhibitory mediators such as prostaglandin cells have the capacity to present retinal antigens to E2 (PGE2) and nitric oxide (NO) and in general naive and sensitised T cells and are much more deactivates dendritic cell function. However, if potent in their antigen presenting ability than exposed to pro-inflammatory cytokines such as IL­ macrophages?l Resident macrophages, however, do l, the RPE cell can be induced to secrete cytokines play an accessory, supportive role in this process and chemokines which attract T cells and macro­ (Forrester, in preparation). phages and generate an immune response. In In the retina itself, dendritic cells do not occur. contrast, if exposed to TGF[3 these cells can instead Instead the resident tissue macrophage is the release anti-inflammatory cytokines such as IL-6 microglial cell, and it has previously been suggested which shunt the immune response towards antibody that this cell may act as the local APC within the production and away from tissue damage. These retina. However, recent studies have shown that mechanisms have been reviewed elsewhere.34 microglial cells are in fact poor presenters of antigen and may even have immunosuppressive properties CONCLUSION themselves. In conclusion, therefore, it can be seen that there are Since most inflammatory responses in CNS neural several factors which determine the site at which 101 tissue commence around blood vessels as a perivas­ will be initiated if not restricted. cular cuff, perivascular macrophages have been For foreign antigens, these include the natural implicated in local antigen presentation. These rare predilection of micro-organisms for certain cells and cells also occur in the retina and currently represent tissues, the systemic activation of memory T cells in the likeliest candidate as the professional APe. recurrent infections, the release and/or expression of antigen locally within the tissues and the ease with REGULATION OF INTRAOCULAR which local antigen presentation can overwhelm the INFLAMMATION BY THE LOCAL tissue inhibitory effects. MICROENVIRONMENf For self antigens, the same general factors also hold true. In addition, there must be mechanisms From the foregoing discussion it might appear that acting to break self-tolerance within the tissue which 101 should occur with much greater frequency than it depend somewhat on the tissue specificity of the does. That it does not is due to mechanisms which antigen. For instance, S-antigen-like molecules can exist in the eye to limit the inflammation and the be found in other tissues but IRBP is restricted to the resulting damage. This has been recognised for very photoreceptor matrix. many years and has been the subject of numerous immunological investigations. This work was supported by the Guide Dogs for the Blind, In the anterior chamber ocular immune privilege the Leverhulme Trust and the Wellcome Trust. has been linked to a phenomenon known as ACAID REFERENCES (anterior-chamber-associated immune deviation) in which it has been shown that antigens introduced 1. Forrester JV, Liversidge JM, Dua HS, Towler HM, McMenamin PG. 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