This chapter provides an overview of some immunologic characteristics of the eye and ocular inflammation, as well as a perspective on current and future research in the expanding field of uveitis. Therapeutic implications and novel approaches to immunomodulation with potential to treat ocular inflammatory conditions include antisense treatment, antiadhesive treatment, peptide blocking, antigen feeding, inhibition of effector cells, and monoclonal anitbodies directed against key antigens of the inflammatory response, as discussed later. Because detailed explanations of the multiple immune processes involved in ocular inflammation are beyond the scope of this text, readers are encouraged to consult standard texts of immunology for background information.

Class I MHC molecules are found in all nucleated cells,¹ and are classically encoded by three loci in humans: A, B, and C. More recent work has revealed multiple additional class I genes, including HLA-E, -F and -G.² Class I MHC molecules function as T-lymphocyte differentiation markers, components of hormone receptors, and determine class I restriction of cytolytic T cells in recognition of endogenous antigens. The term restriction means that an antigen must be presented in association with autologous class I or class II MHC antigens in order for immune recognition by T cells to occur. In the case of class I molecules, endogenous antigens synthesized within the target cell are degraded into peptide fragments, which bind to grooves on the MHC class I molecules. The resulting complex moves to the cell surface, where interaction with T cells may occur.

In contrast, class II MHC molecules, also known as Ia antigens, are produced by the HLA-D/DR locus, also known as immune response (Ir) genes, and serve to restrict the recognition of foreign antigens by helper T cells. Class II molecules are found on B cells, antigen presenting cells (APCs), and macrophages, and they bind endocytosed exogenous antigen peptides. On intraocular cells of the normal eye, class II MHC antigen expression is minimal. During inflammation, however, surface expression of HLA-DR (Ia) antigen on ocular cells such as retinal Müller cells, retinal pigment epithelium (RPE) cells, and ciliary body cells is induced,3 and this has been documented in both uveitis and retinitis pigmentosa.⁴ Such cells are likely participants in the ocular inflammatory response. Lymphokines produced by activated CD4⁺ helper T cells, such as interferon-gamma (IFN-γ), can induce class II expression on uveal and RPE cells.

The class III MHC region comprises more than 20 diverse genes. The gene products of this region include components of the complement cascade (two C4 isotypes, C2, factor B), 2,1-steroid hydroxylase enzyme, tumor necrosis factors (TNF-α and TNF-β), and two components of the human 70-kilodalton heat-shock proteins.

Specific MHC alleles do not directly cause ocular inflammation. Yet it is clear that certain associations exist between specific HLA phenotypes and various forms of both anterior and posterior uveitis, as shown in Table 1. The most striking of these is the association between HLA-B27 and ankylosing spondylitis.⁵ Although the exact reasons for HLA associations with various uveitides remain somewhat obscure,⁶ the mechanisms appear to be multifactorial. A few interesting explanations have emerged. First, the potential role of the interaction between microbial antigens and class I MHC antigens within the eye has been described. There is an increased frequency of Klebsiella in stool samples, or infection with other gram-negative bacteria, among patients in the active phase of ankylosing spondylitis⁷ and anterior uveitis.⁸ Antigenic homology between HLA-B27 and Klebsiella pneumoniae nitrogenase residues has been documented. Furthermore, patients with Reiter's syndrome and ankylosing spondylitis, both associated with HLA-B27, produce cross-reactive autoantibodies against these residues⁹; this finding thus provides a possible explanation for the observed HLA association.

TABLE 1. HLA Associations in Ocular Inflammatory Diseases

More recently, peptide B27PD has been isolated from class I antigens of HLA-B27, HLA-B51, HLA-B18, HLA-B44, and HLA-B45.¹⁰ This peptide shares several amino acid homologies with an uveitogenic peptide (PDSAg) derived from retinal S antigen (S-Ag). S-Ag is a normally sequestered retinal antigen able to cause uveitis and commonly used to induce experimental autoimmune uveitis (EAU). Both animal models and human uveitis patients show a high degree of cross-reactivity between B27PD and PDSAg. B27PD may be naturally processed and presented by class II HLA antigens to HLA-peptide-specific T cells. These T cells are normally eliminated or downregulated in the thymus (see later discussion). Infection, trauma, or stress may, however, lead to increased elaboration of cytokines, causing increased expression and turnover of MHC molecules. This stimulates local presentation of class I peptides by class II molecules, and may permit stimulation of some normally suppressed T-cell clones that recognize autologous MHC molecules. These are likely heteroclitic for recognition of S-Ag peptide presented by ocular cells such as RPE cells. Activated T cells recognizing S-Ag peptide may ultimately result in autoimmune intraocular inflammation.

Specific factors identified in permissive genetic backgrounds include (1) hormonal regulation, (2) lymphokine regulation, (3) vascular mechanisms, and (4) T-cell repertoire, which may be influenced by minor lymphocyte-stimulating (Mls) antigen genes.¹¹ Mls molecules are superantigens that control thymic deletion of lymphocytes bearing T-cell receptors (TCRs) with affinity for Mls. This produces gaps in the T-cell repertoire, thereby increasing permissiveness to autoimmune inflammation. The role of genetic influences on the TCR repertoire in autoimmunity is discussed further in a later section. Gene expression in active uveitis has also been studied. In a model of lens-induced EAU, increased expression of proto-oncogenes (c-fos, c-jun, and Ha-ras), interleukin-2 (IL-2), and heat-shock protein HSP-27, as well as reduced expression of transforming growth factor beta (TGF-β), have been reported.¹²

OCULAR IMMUNOLOGIC PRIVILEGE

Ocular immunologic privilege is conferred by multiple contributory factors, including the following: (1) the blood-ocular barrier; (2) the absence of intraocular lymphatic drainage; (3) intraocular APCs; (4) immunosuppressive ocular fluids¹³; and (5) Fas ligand (Fas l)-mediated apoptosis. Ocular immune privilege likely represents an evolutionary adaptation to downregulate immunogenic ocular inflammation, with its potential threat to vulnerable intraocular tissues, in order to thereby preserve vision. This exists, however, in delicate counterbalance with the threat of unchecked infection due to inadequate immune responses.

The blood-ocular barrier comprises the zonulae occludentes of the nonpigmented ciliary epithelium and RPE cells, as well as the nonfenestrated vascular endothelium of retinal and iris blood vessels. Disruption of vascular tight junctions may increase vascular permeability, promoting chronicity and recurrence of inflammation as well as other consequences, such as cystoid macular edema. The presence of uveitis or systemic immune responses to ocular antigens generally indicates a breach of the blood-ocular barrier. The choroid, by virtue of its high rate of blood flow and its anatomy, is particularly susceptible to blood-borne diseases. It may function as a repository for immune cells, including antibody-producing lymphocytes with immunologic memory.¹⁴ The local humoral response to an intraocular antigen is not entirely directed against this antigen, but also activates other antibody-producing cells that have migrated to the choroid. For example, in recurrent allergic uveitis due to degranulation of choroidal mastocytes, the triggering antigen may vary with each recurrence. The vitreous may serve as a long-term depot for foreign antigens.

Because of the absence of intraocular lymphatic drainage, intraocular antigens are presented to the immune system via the bloodstream, and not via lymphatics.^15,16 This produces an atypical immune response in which the spleen, rather than the local lymphatics, functions as the primary lymphoid organ. In contrast, the response to antigens presented to external ocular tissues or soluble antigens placed in areas with lymphatic drainage elicit typical complete immune responses with both antibody and cell-mediated components.

Another unusual factor in ocular immune privilege is the presence of marrow-derived MHC class II+ APCs within the uveal tract, which have been implicated in the induction of deviant immune responses, such as ACAID (see later discussion).¹³ Antigens must be presented in association with MHC class II (HLA-DR) molecules in order for recognition by T cells to occur. In the normal uninflamed eye, MHC class II expression is conspicuously deficient in certain structures, such as corneal endothelium, trabecular meshwork, anterior iris layer, vascular endothelium, RPE, and retinal cells. Thus, the normal eye is generally a poor site in which to elicit an immune response. However, both blood-borne (ED1+ ) and resident ocular (ED2+ ) macrophages, as well as MHC class II+ dendritic cells, have been identified in the eye. Iris macrophages may contribute to the development of ACAID. Furthermore, dendritic cells, which are found throughout the uveal tract and in close apposition to the RPE, have been shown to be effective presenters of retinal antigens to naive T cells, and are able to induce proliferative responses to both S-Ag and interphotoreceptor retinoid binding protein.³

The local ocular factors found in aqueous humor also inhibit intraocular immune responses. Human aqueous humor is able to suppress tumor cell growth and mitogen-stimulated T-cell proliferation.¹⁷ Normal iris and ciliary body epithelial cells produce TGF-β₂,^18,19 an immunosuppressive cytokine with multiple functions, including negative regulation of cell growth in the immune system.²⁰ Other immunoinhibitory ocular fluid components include alpha-melanocyte-stimulating hormone, vasoactive intestinal peptide, calcitonin gene-related peptide and anticomplement activity (not yet defined). In addition, low levels of cortisol-binding globulin permit higher effective cortisol concentrations.¹³ The end result is a reduction in antigen-driven T-cell activation. There is little influence on systemic immune responses or local response to extraocular antigen. Soluble and membrane-bound inhibitors of complement activation and fixation have also been described.^21,22

An important mechanism involved in ocular immune privilege is Fas l-mediated apoptosis. Fas l expression within the eye has been localized to the corneal epithelium and endothelium, iris, ciliary body, and retina. By means of a Fas-Fas l interaction, eyes expressing Fas l are able to delete Fas+ T cells by apoptosis.^23,24 Fas- eyes are unable to delete Fas- or Fas+ cells. Thus ocular Fas l expression permits direct destruction of invading activated cells with the potential to destroy vision.

UNIQUE ORGAN-SPECIFIC ANTIGENS SEQUESTERED WITHIN THE EYE

Several sequestered antigens able to induce uveitis reside within the eye, which lends support to the concept of an autoimmune basis for uveitis, as proposed by Elschnig²⁵ in 1910. Most of these antigens are of retinal origin, and the retina is more effective in producing uveitis than uveal tissue²⁶; such antigens include S-Ag, interphotoreceptor retinoid binding protein, and rhodopsin. Systemic sensitization to retinal antigens causes inflammation of the uvea and the aqueous and vitreous humors, as well as retinal destruction.²⁷ Injection of S-Ag at a remote site causes bilateral immune-mediated uveitis.^28–31 This observation has been manipulated to produce the experimental model of EAU, which is associated with the production of autoreactive T cells and antibodies, and resembles sympathetic ophthalmia in humans. Lens antigens are also sequestered during embryologic development of immune self-tolerance. Later release of crystallin proteins leads to recognition of antigens as foreign rather than self, and elicits lens-induced uveitis.^32,33 Many patients with uveitis or cataracts demonstrate sensitization to lens antigens, whereas many patients with choroiditis or retinitis are sensitized to retinal antigens.³⁴

ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION

Inoculation of antigens or alloantigens into the anterior chamber, vitreous, or subretinal space elicits a deviant systemic immune response. A selective, transient depression of cell-mediated immunity (CMI), particularly delayed-type hypersensitivity (DTH), is observed, while the humoral response mediated by B cells that produce complement fixing antibodies is preserved.³⁵ This phenomenon is known as anterior chamber-associated immune deviation (ACAID). Antigens reported to induce ACAID include lymph node cell suspensions,36,37 neoplastic cells,^38,39 hapten-derived splenocytes,⁴⁰ and soluble antigens.⁴¹

An intact oculosplenic axis enabling splenic stimulation while completely bypassing local lymphatic antigen processing is essential for the development of ACAID. A splenectomy performed before or within 6 days of intracameral antigen stimulation will prevent ACAID.⁴² The route of antigen administration is significant, because the absence of intraocular lymphatics permits the requisite bypass of lymphatics to produce ACAID with intraocular antigen stimulation. In contrast, subconjunctivally administered antigen is drained via lymphatics to regional lymph nodes for conventional processing and elicits conventional immune responses.⁴³

Bone marrow-derived cells within the iris and ciliary body stroma serve a critical function in the induction of ACAID. These cells are unable to present antigen to T cells and also inhibit antigen-driven T-cell activation.⁴⁴ Introduction of donor Ia+ APCs into the anterior chamber can subvert ocular immune privilege and elicit instead a normal systemic alloimmune response.⁴⁵ Similarly, under chronic pathologic conditions or when HLA-DR+ APCs develop within the eye, local DTH can occur.

The mechanisms of ACAID have been the focus of much study and are summarized in Figure 1. Intraocular APCs, such as iris and ciliary body dendritic cells/macrophages (F4/80+ cells), are influenced by local immunoregulatory factors, particularly TGF-β, to acquire ACAID-inducing potential. APCs capture antigens entering the eye and direct these to the spleen, where deviant processing occurs.¹³ A good humoral response ensues, along with specific cytotoxic cells directed against the inciting antigen.⁴⁶ Priming of DTH effectors does not occur.⁴⁷ ACAID is dominant to conventional immunity. If the same antigen is injected subconjunctivally and into the anterior chamber (theoretically permitting conventional or deviant antigen processing and, therefore, conventional immune responses or ACAID to develop), ACAID develops rather than conventional immune responses because ACAID is dominant.

Although DTH is an effective means of eliminating pathogens, it is also potentially very destructive to surrounding tissues because of the intense lymphokine-induced secondary inflammation. Suppression of intraocular DTH by ACAID may have evolved as a means of preserving vision while permitting some degree of local immunity,³⁵ producing what Streilein⁴⁸ termed a “dangerous compromise” between the eye and the immune system.

  Type I: Anaphylactoid responses
  Type II: Antibody-mediated responses
  Type III: Immune complex-mediated responses
  Type IV: CMI
  Type V: Stimulatory antibody responses

Of these, type IV hypersensitivity or CMI, including DTH, is the most important mechanism in the pathogenesis of most uveitides (see later discussion).

Anaphylactoid responses rarely cause uveitis. In addition, neither antibody-dependent cytotoxicity, mediated by activated complement or antibodydependent killer lymphocytes, nor stimulatory antibodies are generally directly causative in ocular inflammation. Indirect damage may occur, however, if immune complexes form with antigens. Although low levels of circulating immune complexes are found in most normal persons and are normally removed by the reticuloendothelial system, they may occasionally lead to a hypersensitivity reaction. IgG and IgM antibodies are able to bind complement, and immune complexes can activate complement by binding to tissue receptors. Complement activation releases chemotactic factors, which attract and activate neutrophils to release enzymes. The resulting tissue damage and necrosis release more tissue antigens, which may then form additional immune complexes.

Various mechanisms of immune complex-mediated inflammation have been described. Persistent active ocular infection produces local immune complex formation, which may induce a secondary reactive anterior uveitis or retinal vasculitis. Alternatively, autoimmune disease with prolonged production of autoimmune complexes overwhelms the mononuclear phagocytic system responsible for their removal. This mechanism is associated with lens-induced uveitis and the retinal vasculitis of systemic lupus erythematosus. Finally, cross-reactive autoantibodies (usually IgG) may react with ocular tissues to form immune complexes, as seen in thyroid-related orbitopathy.

Notwithstanding, the role of immune complexes in uveitis remains unclear. Much evidence negates any significant role of immune complex mediation in uveitis, because both aqueous and iris specimens from uveitic eyes primarily demonstrate T cells, rather than plasma cells.^49,50 Immune complexes have been documented, however, in the aqueous and blood of uveitis patients.⁵¹ Although the mere persistence of complexes in blood is not harmful per se, deposition in ocular tissues may cause active disease. Although Behçet's disease is cited as a prototypical immune complex-mediated disease,⁵² newer evidence implicates T-cell-mediated mechanisms as well, because only about one third of patients have elevated circulating immune complex levels, which, in turn, are associated with disease quiescence rather than activity.⁵³ Furthermore, patients who have circulating immune complexes tend to have better visual outcomes than those who do not.⁵⁴

Some studies suggest that at least two different fractions of circulating immune complexes in autoimmune uveitis exist, each with differing functions.⁵⁵ One fraction may be immunoregulatory in that it maintains tolerance to retinal autoantigens (i.e., is protective against autoimmune inflammation). The other fraction may be proinflammatory in that it is involved in the pathogenesis of uveitis. One's propensity to develop autoimmune disease may be influenced by the ability of the corresponding idiotypic network to resist disruption and by the ability of protective circulating idiotype-anti-idiotype complexes to maintain and restore tolerance to self antigens via downregulation of autoantibody production.

TABLE 2. Major Cytokines in Uveitis

Studies of lymphokine production profiles in EAU have shown an elevation of IL-2, IFN-γ, and to a lesser extent IL-4, in early phases of EAU.⁵⁹ Interleukins may contribute to blood-ocular barrier breakdown.⁵⁹ IL-2 is an important T-cell proliferative agent and favors differentiation of helper T cells into helper T1 cells (see later discussion), which are essential for mounting a CMI response. These functions are complemented by those of IFN-γ, which promotes MHC class II expression, thereby enhancing antigen presentation, and also promotes adhesion molecules on vascular endothelium, which furthers the propagation of inflammation. In late phases of EAU, IL-4 persists while IFN-γ and IL-2 levels decrease. IL-4 promotes B-cell activation and IgG₁ and IgE production, as well as differentiation of helper T cells into helper T2 cells. All of these are associated with humoral immunity. IL-4 may also increase the effector cell function of macrophages in uveitis.

TGF-β comprises a family of five isoforms that stimulate connective tissue growth and collagen formation while inhibiting almost all immune and hematopoietic functions. In ocular inflammation, TGF-β₂ appears to be the most significant of the isoforms, and functions to confer ACAID-inducing potential upon intraocular APCs.

Prostaglandins (PGs) also appear to be involved in the ocular inflammatory response⁶⁰ as well as the vascular response to injury. Certain PGs elicit an ocular response resembling anterior uveitis. Uveitic aqueous contains significant levels of PGE₁ (because of leukocyte immigration) and PGE₂ (synthesized in the anterior uvea). There is a correlation between intensity of inflammation and PG levels. Iris fluorescein angiography reveals iris vasodilation and increased vascular permeability with administration of PGE₁, PGE₂, and PGF₂α or induction of EAU.^61–63 However, although PGF₂α is known to be proinflammatory, PGE is actually anti-inflammatory in its action.

Tumor necrosis factor (TNF) is another proinflammatory cytokine important in the pathogenesis of uveitis. Inhibition of TNF activity in EAU provides significant protection against autoimmune destruction of specifically targeted tissue despite the influx of a quantitatively normal magnitude of activated CD4⁺ T cells into the target tissue.⁶⁴ In addition, the onset of EAU is delayed. Thus, TNF inhibition prevents target tissue destruction without reducing leukocyte extravasation into the tissue.

TABLE 3. Major Adhesion Molecules in Uveitis

ICAM-1 is one of the most extensively studied of the adhesion molecules. Its expression is induced by IFN-γ, IFN-1β, and TNF-α. ICAM-1 serves as a ligand for LFA-1 and complement receptor 2. The ICAM-1/LFA-1 and LFA-3/CD2 ligand interactions mediate leukocyte adhesion in immune and inflammatory mechanisms such as antigen presentation to T cells. ICAM-1 is also involved in the mediation of granulocyte extravasation and lymphocyte-mediated cytotoxicity.⁶⁶ In addition, expression of ICAM-1 has been demonstrated on corneal endothelium corresponding in timing with active anterior chamber inflammation and the presence of keratic precipitates.⁶⁷ This suggests a modulatory role of the corneal endothelium in anterior uveitis, in which ICAM-1 may contribute to inflammatory cell-endothelial adhesion. The significance of keratic precipitates as markers of inflammation is also supported.

Another inducible adhesion molecule, ELAM-1, functions in the attachment of neutrophils to endothelium and neutrophil recruitment in local endotoxin responses.⁶⁸ Within the context of uveitis it may be significant particularly in early phases of inflammation.

A state of immune tolerance to self antigens is normally maintained by various processes to prevent the body's immune attack of its own tissues.⁶⁹ Thus the initial genetic repertoire, the genetically encoded pattern of TCR usage, is reshaped by T-cell deletion and foreign antigens to produce a final expressed repertoire of TCRs.⁷⁰ These “editing mechanisms” include the selective intrathymic deletion of differentiating T cells that express specific TCRs with a high affinity for autoantigens represented within the thymus. Low-affinity self-reactive T cells, as well as T cells with TCRs specific for antigens that are absent in the thymus, are permitted to mature and enter the peripheral T-cell population. For potentially autoreactive T cells that may escape the thymus, additional protective mechanisms exist to prevent autoimmunity. Self antigens may be overlooked if the antigens are sequestered, or go unrecognized because of a lack of coexpression of MHC molecules on the antigen-bearing cells. Peripheral deletion or anergy of self-reactive T cells has also been reported.⁶⁹

Autoimmunity develops when the normal framework of immunologic self-tolerance is disrupted. Potential mechanisms include defective intrathymic T-cell selection processes, cross-reactive inducer cells, or alteration of suppressor cell modulation permitting bypass of natural tolerance. Other contributory factors may include the presence of an immunogenic stimulus (not necessarily an autoantigen), activation of autoreactive clones, and progression from an acute to a chronic autoimmune response. In uveitis, another possibility is the aberrant expression of MHC class II antigens by nonimmune cells of the vascular endothelium, provoking recognition by circulating autoreactive T cells.⁷¹

Regardless of the specific mechanism of autoimmunity, the involvement of activated helper T cells is absolutely necessary. Specific TCR elements are directly involved in the pathogenesis of autoimmunity.⁷⁰ This is subject to both genetic and environmental influences. Genetic susceptibility is implicitly encoded by (1) genomic differences in TCR gene sequences, which ultimately influence the final expressed repertoire; and (2) other genomically encoded products, such as MHC molecules, which influence the selective deletion of T cells. Environmental influences include the role of superantigens, which may induce proliferation of specific T-cell populations, altering the TCR repertoire sufficiently to collapse immune self-tolerance. Specific T cell populations may expand in response to certain antigenic stimuli. As discussed above, foreign antigens contribute to shaping final expressed TCR repertoire, which in turn influences immune selftolerance. Cross-reactive T cells recognizing both foreign and self antigens also may exist.

At least three subsets of CD4⁺ helper T cells (helper T1 cells, helper T2 cells, and helper T0 cells) with differing functions and unique cytokine production profiles have been identified. Precursor T cells may differentiate into helper T1 or helper T2 cells depending on the following three factors: (1) the type of APC involved; (2) the strength of interaction between TCR and peptide; and (3) the specific cytokines present.⁵⁶ Helper T1 cells produce IL-2, lymphotoxin, and IFN-γ. Helper T2 cells produce IL-4, -5, -6, -10, and -13. Helper T0 cells may represent an autonomous, transitory, or precursor cell type, and produce IL-4 and IFN-γ. Helper T1 cells are mainly associated with CMI. These cells help CD8+ T cells via IL-2 production, help B cells to produce immunoglobulins, and collaborate with macrophages via IFN-γ release, which increases macrophage bactericidal efficacy. Helper T2 cells, in contrast, are mainly associated with humoral immunity, and help B cells to produce immunoglobulins and to attract and activate eosinophils. Helper T1 and helper T2 cells are able to downregulate each other by producing IFN-γ and IL-10, respectively.

T-cell responses are elicited by direct contact of T cells with antigens presented by APCs in conjunction with autologous MHC molecules, whereas tissue effects are mediated by release of lymphokines. T-cell-mediated inflammation can be subdivided into three phases:

1. The initiating phase involves migration of a few antigen-specific T cells to the target tissue with in situ activation via antigen presentation by APCs.
   
2. This first phase elicits an amplification cascade phase of cytokine release, leading to recruitment and activation of increasing numbers of additional lymphocytes, which, in turn, release more cytokines.
   
3. The process may then terminate or advance to a final effector phase of overt inflammation mediated by nonspecific inflammatory effector cells.⁷⁷
   

Increased numbers of activated lymphocytes expressing IL-2 receptors are found in uveitic intraocular fluids.⁷⁸ There is a positive correlation between the degree of lymphocyte activation and clinical uveitis activity. CD4⁺ T cells predominate within the retina in early EAU. This is followed in late phases by an increase in CD8+ T cells, B cells, and CD45R⁺ CD4⁺ T cells, which may represent memory cells.^59,79 A mixed profile of lymphokine production suggests the involvement of either helper T0 cells or a mixed population of helper T1 and helper T2 cells, with a relative shift toward helper T2 differentiation in late EAU. The majority of T cells present in EAU are not actually specific for the target antigen.⁵⁷ Corticosteroids may exert some anti-inflammatory effect in uveitis by shifting the immune response from helper T1 predominant to helper T2 predominant by decreasing IL-2 and increasing IL-4 production.

Immunointervention may be initiated at various stages in the evolution of immune-mediated inflammatory disease.⁷⁴ Antigen presentation may be targeted in an attempt to prevent specific T-cell activation early in the inflammatory sequence. Using this concept, monoclonal antibodies directed against S-Ag have been shown to inhibit EAU induction. Peptide blocking is another strategy in which limited digestion of S-Ag (using Staphylococcus aureus protease) yields nonfunctional peptides unable to induce EAU. Antibodies directed against MHC class II antigen or against CD4 antigen are also reported to inhibit EAU.

Once activated, autoreactive T cells are subject to homing mechanisms, including transvascular endothelial migration. Adhesive interaction between inflammatory cells and cells of the blood-ocular barrier are crucial at this stage. Thus various “antiadhesive” therapies aimed at inhibiting adhesive interactions have been effective in some inflammatory models. FK506 for example, can disrupt adhesion between CD4⁺ lymphocytes and RPE cells, preventing further evolution of inflammation. Future approaches may also include the use of antisense therapy. The principle of antisense therapy involves the introduction of specifically tailored nonfunctional mRNA in order to disrupt the function of the host's own mRNA, thus blocking its usual product. Antisense therapy using nonfunctional mRNA encoding adhesion molecules has potential as an alternative form of antiadhesive therapy.

A more direct strategy in immunointervention involves inhibition of various effector cells. Targeting effector cell products such as cytokines or their receptors has also been effective. Cyclosporin A, FK506, and rapamycin are each able to prevent development of EAU by acting on antigen-primed T cells to inhibit IL-2 production. Antibodies or immunotoxins directed against the IL-2 receptor are similarly able to suppress EAU. Antibodies specific for CD4 antigen may also function by depleting CD4⁺ T cells sufficiently to prevent their effector cell function.

Finally, another effective approach is the induction of oral tolerance by antigen feeding. In those uveitides where circulating lymphocytes demonstrate responsiveness to S-Ag, S-Ag feeding by mouth before or after induction of EAU can eliminate or reduce uveitis in both animal models and humans.⁸⁰ An intact gut-spleen-ocular axis is required in order for oral tolerance to develop in these patients.

Several promising avenues for future research currently exist. These include new or further studies of (1) the role of exogenous antigens in uveitis; (2) the effects of chronic lymphocyte activation; (3) the immune response to specific intraocular antigens; (4) identification and characterization of the major pathogenic ocular autoantigens using autoreactive sera from patients with uveitis; (5) the correlation of specific autoreactive cells and antibodies with specific ocular diseases; and (6) the application of antisense treatment in uveitis therapy. Improved understanding of the ocular inflammatory response has already begun to yield new therapeutic approaches in uveitis. There remains great promise that continued advances in the field will, in turn, continue to generate progressively better novel strategies, ultimately resulting in significant improvements in the care and outcome of patients with this potentially blinding and debilitating disease.

1. Roitt I: Essential Immunology, 7th ed. Oxford, Blackwell Scientific, 1991

2. Roitt I, Brostoff J, Male D: Immunology, 4th ed. London, Mosby, 1996

3. Forrester JV, McMenamin PG, Liversidge J, Lumsden L: Dendritic cells and “dendritic” macrophages in the uveal tract. Adv Exp Med Biol 329:599, 1993

4. Detrick B, Newsome DA, Pecopo CM et al: Class II antigen expression and gamma interferon modulation of monocytes and retinal pigment epithelial cells from patients with retinitis pigmentosa. Clin Immunol Immunopathol 36:201, 1985

5. Brewerton DA, Hart FD, Nicholls A et al: Ankylosing spondylitis and HLA-B27. Lancet 1:904, 1973

6. Linssen A: B27+ disease versus B27_disease. Scand J Rheumatol 87:111, 1990

7. Ebringer RW, Cawdell DR, Cowling P: Sequential studies in ankylosing spondylitis. Ann Rheum Dis 37:146, 1978

8. Saari KM: Acute anterior uveitis. In Saari KM (ed): Uveitis Update, pp 79–90. Amsterdam, Excerpta Medica, 1984

9. Schwimmbeck PL, Yu DTY, Oldstone MBA: Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter's syndrome. J Exp Med 166:173, 1987

10. Wildner G, Thurau SR: Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease. Eur J Immunol 24:2579, 1994

11. Caspi RR, Chan C-C, Fuhino Y et al: Genetic factors in susceptibility and resistance to experimental autoimmune uveoretinitis. Curr Eye Res 11(suppl):81, 1992

12. Rocha G, Duclos A, Chalifour L et al: Analysis of gene expression during experimental uveitis in the rabbit. Can J Ophthalmol 31:228, 1996

13. Streilein JW: Immunological non-responsiveness and acquisition of tolerance in relation to immune privilege in the eye. Eye 9:236, 1995

14. Hall JM, O'Connor GR: Correlation between ocular inflammation and antibody production: II. Hemolytic plaque formation by cells of the uveal tract. J Immunol 104:440, 1970

15. Franklin RM, Prendergast RA: Primary injection of skin allografts in the anterior chamber of the rabbit eye. J Immunol 104:463, 1970

16. Wilbanks GA, Streilein JW: The differing patterns of antigen release and local retention following anterior chamber and intravenous inoculation of soluble antigen: evidence that the eye acts as an antigen depot. Reg Immunol 2:390, 1989

17. Martow J, Deschenes J, Baines MG et al: Cellular modulation by aqueous humor. McGill Ophthalmol 3:5, 1991

18. Helbig H, Kittredge KL, Coca-Prados M et al: Mammalian ciliary-body epithelial cells in culture produce transforming growth factor-beta. Graefes Arch Clin Exp Ophthalmol 229:84, 1991

19. Knisely TL, Bleicher PA, Vibbard CA et al: Production of latent transforming growth factor-beta and other inhibitory factors by cultured murine iris and ciliary body cells. Curr Eye Res 10:761, 1991

20. Ellingsworth LR, Nakayama D, Segarini P et al: Transforming growth factor-betas are equipotent growth inhibitors of interleukin-1-induced thymocyte proliferation. Cell Immunol 114:41, 1988

21. Shimata K: The complement components and their inactivators in the intraocular fluids of the guinea pig. Invest Ophthalmol Vis Sci 9:304, 1970

22. Bora NS, Gobleman CL, Atkinson JP et al: Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci 34:3579, 1993

23. Griffith TS, Brunner T, Fletcher SM et al: Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189, 1995

24. Streilein JW: Unraveling immune privilege. Science 270: 1158, 1995

25. Elschnig A: Studien sur sympathischen opthalmis: die antigene wirkung des augenpigmentes. Graefes Arch Ophthalmol 67:509, 1910

26. Wacker WB, Lipton MM: Experimental allergic uveitis: homologous retina as uveitogenic antigen. Nature 206:253, 1965

27. Wacker WB, Lipton MM: Experimental allergic uveitis: I. Production in the guinea pig and rabbit by immunization with retina in adjuvant. J Immunol 101:151, 1968

28. De Kozak Y, Sakai J, Thillaya B et al: S-antigen-induced experimental autoimmune uveo-retinitis in rats. Curr Eye Res 1:327, 1981

29. Dorey C, Cozette J, Faure JP: A simple and rapid method for isolation of retinal S antigen. Ophthalmic Res 14:249, 1982

30. Faure JP: Autoimmunity and the retina. Curr Top Eye Res 2:215, 1980

31. Fujino Y, Kawashima H, Okumura A et al: Purification and uveogenicity of retinal antigens. Acta Soc Ophthalmol Jpn 91:498, 1987

32. Deschenes J, Baines MG, Antecka E: Investigation of antilens antibodies in uveitis and cataract. Invest Ophthalmol Vis Sci 30:257, 1989

33. Deschenes J, Baines MG, Antecka E et al: Antibodies to human lens proteins in uveitis and cataract. Can J Ophthalmol 25:107, 1990

34. Block-Michel E, Belehradek J, Youn YK et al: Evaluation of the reactivity of human lymphocytes to retinal antigen using different in vitro methods in patients with posterior or total uveitis. Ber Dtsch Ophthalmol Ges 78:169, 1981

35. Streilein JW: Anterior chamber associated immune deviation: the privilege of immunity in the eye. Surv Ophthalmol 35:67, 1990

36. Kaplan H, Streilein JW: Immune response to immunization via the anterior chamber of the eye: I. F1 lymphocyte-induced immune deviation. J Immunol 118:809, 1977

37. Kaplan H, Streilein JW: Immune response to immunization via the anterior chamber of the eye: II. An analysis of F1 lymphocyte-induced immune deviation. J Immunol 120: 689, 1978

38. Niederkorn JY, Streilein JW, Kripke ML: Promotion of syngeneic intraocular tumor growth in mice by anterior chamber-associated immune deviation. J Natl Cancer Inst 71:193, 1983

39. Streilein JW, Niederkorn JY, Shadduck JA: Systemic immune unresponsiveness induced in adult mice by anterior chamber presentation of minor histocompatibility antigens. J Exp Med 152:1121, 1980

40. Waldrep JC, Kaplan HJ: Anterior chamber associated immune deviation induced by TNP-splenocytes (TNP-ACAID): I. Systemic tolerance mediated by suppressor cells. Invest Ophthalmol Vis Sci 24:1086, 1983

41. Mizuno K, Clark AF, Streilein JS: Anterior chamber-associated immune deviation induced by soluble antigens. Invest Ophthalmol Vis Sci 30:1112, 1989

42. Streilein JW, Niederkorn JY: Induction of anterior chamber-associated immune deviation requires an intact, functional spleen. J Exp Med 153:1058, 1981

43. Rao NA, Hartmann D, Sweeney JA et al: The role of the penetrating wound in the development of sympathetic ophthalmia: experimental observations. Arch Ophthalmol 101: 102, 1983

44. Streilein JW, Cousins SW: Aqueous humor factors and their effect on the immune response in the anterior chamber. Curr Eye Res 9:175, 1990

45. Benson JL, Niederkorn JY: The presence of donor-derived class II-positive cells abolishes immune privilege in the anterior chamber of the eye. Transplantation 51:834, 1991

46. Whittum JA, Niederkorn JY, McCulley JP, Streilein JW: Intracameral inoculation of herpes simplex virus type I induces anterior chamber associated immune deviation. Curr Eye Res 2:691, 1983

47. Niederkorn JY, Streilein JW: Alloantigens placed into the anterior chamber of the eye induce specific suppression of delayed type hypersensitivity but normal cytotoxic T lymphocyte responses. J Immunol 131:2670, 1983

48. Streilein JW: Immune regulation and the eye: a dangerous compromise. FASEB J 1:199, 1987

49. Deschenes J, Freeman WR, Char DH et al: Lymphocyte subpopulations in uveitis. Arch Ophthalmol 104:233, 1986

50. Stevens G Jr, Chan CC, Wetzig RP et al: Iris lymphocyte infiltration in patient with clinically quiescent uveitis. Am J Ophthalmol 104:508, 1987

51. Char DH, Stein P, Masi R et al: Immune complexes in uveitis. Am J Ophthalmol 87:678, 1979

52. Lewinsky RJ, Lehner T: Circulating soluble immune complexes in recurrent oral ulceration and Behçet's syndrome. Clin Exp Immunol 32:193, 1978

53. Kasp E, Graham EM, Stanford MR et al: Retinal autoimmunity and circulating immune complexes in ocular Behçet's disease, pp 67–72. London, Royal Society of Medicine Services, 1986

54. Kasp-Grochowska E, Graham E, Sanders MD et al: Autoimmunity and circulating immune complexes in retinal vasculitis. Trans Ophthalmol Soc UK 101:342, 1981

55. Kasp E, Stanford MR, Brown E et al: Circulating immune complexes may play a regulatory and pathogenic role in experimental autoimmune uveoretinitis. Clin Exp Immunol 88:307, 1992

56. Druet P, Sheela R, Pelletier L: Th1 and Th2 cells in autoimmunity. Clin Exp Immunol 101(suppl 1):9, 1995

57. Charteris DG, Lightman SL: Comparison of the expression of interferon-gamma, IL2, IL4, and lymphotoxin mRNA in experimental autoimmune uveoretinitis. Br J Ophthalmol 78:786, 1994

58. Charteris DG, Lightman SL: In vivo lymphokine production in experimental autoimmune uveoretinitis. Immunology 78:387, 1993

59. Barton K, Lightman S: T lymphocyte effector mechanisms in the retina in posterior uveitis. Eye 8:60, 1994

60. Bhattacherjee P: The role of arachidonate metabolites in ocular inflammation. In: The Ocular Effects of Prostaglandins and Other Eicosanoids, pp 211–227. New York, Alan R Liss, 1989

61. Perkins ES: Prostaglandins and the eye. Adv Ophthalmol 29:2, 1975

62. Yamauchi H, Iso T, Iwao J et al: The role of prostaglandins in experimental ocular inflammation. Agents Actions 9: 280, 1979

63. Whitelocke RAF, Eakins KE, Bennett A: Prostaglandins and the eye. Proc R Soc Med 66:429, 1973

64. Dick A, McMenamin P, Korner H et al: Inhibition of tumor necrosis factor activity minimizes target organ damage in experimental autoimmune uveitis despite quantitatively normal activated T cell traffic to the retina. Eur J Immunol 26:1018, 1996

65. Duguid IGM, Boyd AW, Mandel TE: Adhesion molecules are expressed in the human retina and choroid. Curr Eye Res 11(suppl):153, 1992

66. Arocker-Mettinger E, Steurer-Georgiew L, Steurer M et al: Circulating ICAM-1 levels in serum of uveitis patients. Curr Eye Res 11(suppl):161, 1992

67. Sakamoto T, Takahira K-I, Sanui H et al: Intercellular adhesion molecule-1 on rat corneal endothelium in experimental uveitis. Exp Eye Res 56:241, 1993

68. Whitcup SM, Wakefield D, Li Q et al: Endothelial leukocyte adhesion molecule-1 in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 33:2626, 1992

69. Brodsky FM, Guagliardi C: The cell biology of antigen prefacing and presentation. Annu Rev Immunol 9:707, 1994

70. Rosenberg WMC, Moss PAH, Bell JI: Molecular aspects of autoimmunity: a review. Curr Eye Res 11(suppl):17, 1992

71. Lightman S: Immune mechanisms in autoimmune ocular disease. Eye 2:260, 1988

72. Fujino Y, Mochizuki M, Chan CC et al: FK506 treatment of S-antigen induced uveitis in primates. Curr Eye Res 10:679, 1991

73. Kawashima H, Fujino Y, Mochizuki M: Antigen-specific suppressor cells induced by FK506 in experimental autoimmune uveoretinitis in the rat. Invest Ophthalmol Vis Sci 31: 2500, 1990

74. Forrester JV, Liversidge J, Dua HS et al: Experimental uveoretinitis: a model system for immunointervention: a review. Curr Eye Res 11(suppl):33, 1992

75. Deschenes J, Char DH, Freeman WR et al: Uveitis: lymphocyte subpopulation studies. Trans Ophthalmol Soc UK 105:246, 1986

76. Wang X-C, Norose K, Yano A et al: Two-color flow cytometric analysis of activated T lymphocytes in aqueous humor of patients with endogenous versus exogenous uveitis. Curr Eye Res 14:425, 1995

77. Cousins SW: T cell activation within different intraocular compartments during experimental uveitis. Dev Ophthalmol 23:150, 1992

78. Deschenes J, Char DH, Kaleta S: Activated T lymphocytes in uveitis. Br J Ophthalmol 72:83, 1988

79. Barton K, Lightman S: Isolation of retinal lymphocytes in experimental autoimmune uveoretinitis: phenotypic and functional characterization. Immunology 78:393, 1993

80. Nussenblatt RB, Whitcup SM, de Smet MD et al: Intraocular inflammatory disease (uveitis) and the use of oral tolerance: a status report. Ann NY Acad Sci 778:325, 1996