inflammation and immunity• 5 chapterOcular

MECHANISMS OF PATHOGENESIS

NONINFECTIOUS POSTERIOR AND PANUVEITIS

The posterior segment of the eye is protected by an efficient blood– retinal barrier produced by tight junctions between RPE cells and retinal vascular endothelial cells. There is no direct lymphoid drainage, although antigens in the posterior segment may reach the anterior chamber and thereby the venous circulation. There are few APCs in the uninflamed posterior segment. Anti-inflammatory molecules abound, including membrane-bound TGF-β, Fas ligand (FasL), B7-CTLA4 interaction, galectin-1, thrombospondin, and complement inhibitors.11 This aggregate control of immune and inflammatory reactions has been termed immune privilege.

Immune privilege has been mainly studied in the anterior chamber but also exists in the vitreous12 and subretinal space.13 Many factors may contribute to the immune privilege of the anterior chamber14: absence of blood vessels in the cornea and specialized endothelium of the iris stroma; direct drainage of the anterior-chamber fluid into the venous circulation rather than lymphatic drainage; soluble and cell surface molecules that reduce inflammation; and tolerance-promoting APCs in the iris stroma and trabecular meshwork. Normal murine anterior-chamber fluid has been shown to suppress CD4+ T-cell proliferation, polymorphonuclear leukocyte activation, macrophage activation, and C1q (a subcomponent of complement 1 and complement C (C3). Aqueous TGF-β probably contributes to partial inhibition of the immune response. Corneal endothelial cells have been shown to express CD46, CD55, and CD59, known to inhibit complement activation, as well as FAS ligand, which has been found to promote T-cell apoptosis. Analogous mechanisms likely exist in the posterior segment.

Antigen-specific autoimmune reactions are controlled by tolerance. Central tolerance to self-antigens consists of clonal deletion of the developing T lymphocytes in the thymus that recognize intraocular proteins. Wild-type B10.RIII mice grafted with an IRBP KO thymus had high EAU scores when immunized with a dose of IRBP that induced minimal or no disease in mice with a wild-type thymus.15 Mice with mutations in a transcription factor known as the “autoimmune regulator” (AIRE) do not express IRBP in the thymus and develop spontaneous uveitis similar to EAU. Double knockouts, which also do not produce IRBP in the retina, do not develop uveitis. Interestingly, humans with mutations in the AIRE transcription factor develop the monogenic recessive disorder autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, but not posterior uveitis. Patients with the syndrome do have corneal disease similar to congenital hereditary endothelial dystrophy (CHED).

Peripheral tolerance is maintained by a number of mechanisms. These include immunologic ignorance, anergy, and T-cell-mediated active suppression. Immunologic ignorance is the inability of small amounts of low-avidity self-antigens to elicit an immune response even if peripheral T cells with the appropriate specificity are present. Anergy is tolerance to self-antigens found in higher concentrations but presented to T cells in the absence of costimulatory signals. The expression of appropriate costimulatory signals is often dependent on the context of antigen presentation. For example, cytokines from nearby neutrophils or natural killer cells that have been activated in an antigenindependent manner, can cause costimulatory molecules to be upregulated on local APCs. Tregs can suppress other lymphocytes via cytokines such as TGF-β or IL-10.16

INFECTIOUS RETINITIS AND CHORoIDITIS

The protozoan obligate intracellular parasite Toxoplasma gondii commonly infects humans and is a leading cause of posterior uveitis. Infection results in IgM and IgG antibodies but these are insufficient to provide immunity because the organism persists intracellularly. As one

would expect, the intracellular parasite elicits a predominantly CD8+ T-cell response. The T cells in turn release cytokines, particularly IFN-γ, that activate macrophages, recruiting them to sites of infection where they function both as effector and APCs. Toxoplasma actively invades both phagocytic and nonphagocytic cells, forming a nonfusogenic compartment, called the parasitophosphorus vacule, within the host cell cytosol.17 By blocking fusion with lysosomes the organism prevents pathogen-derived peptides from being expressed on the host cell’s MHC molecules and evading the host immune system. Hence Toxoplasma may remain dormant within intracytoplasmic vesicles without exciting an immune response. Intracellular Toxoplasma has also been shown to interfere with transcription factors necessary for cytokine expression, including IL-12, IFN-γ, TNF-α, and others.18 Furthermore, induced apoptotic pathways in macrophages infected with Toxoplasma are strongly inhibited, allowing intracellular parasites to survive longer in the host cell.

Herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein–Barr virus can cause fulminant acute retinal infections, termed the acute retinal necrosis (ARN) syndrome. Viral infection manifests as fibrinoid necrosis of the retinal vessels with vascular occlusion and focal necrosis of the RPE and retinal layers with overlying vitritis. Areas of necrosis are well defined with sharp borders separating uninvolved retina and viral intranuclear inclusions in retinal cells at the borders. The choroid is inflamed with vascular occlusion. Virus can migrate from the brain to the retina via retrograde axonal transport through the optic nerve from the suprachiasmatic nucleus of the hypothalamus. At this site, it is possible for virus to gain access to the contralateral optic pathway and fellow eye. HSV-specific T cells have been demonstrated and characterized in clinical samples of intraocular fluid derived from patients with ARN.19 Retinal and choroidal ischemia leads to breakdown of the blood–retina barrier, presumably promoting RPE and fibroblast activation and migration, leading to the development of proliferative vitreoretinopathy. This process, in addition to the development of retinal breaks in areas of retinal necrosis, often leads to retinal detachment. Patients with VZV ARN have inhibited delayed-type hypersensitivity reactions, and intact antibody responses to VZV, a pattern that suggests that the immune privilege of the eye is genetic and involved in pathogenesis.20

AGE-RELATED MACULAR DEGENERATION

The inflammatory contribution to AMD has long been suspected. Contributions of cytomegalic infection or macrophage activation were published by Cousins beginning in 2004,21,22 but real progress was not made until genetic polymorphisms in complement genes were identified as risk factors for AMD.23 In the protected environment of the subretinal space, natural immunity is ideally tightly regulated to limit complement activation and tissue destruction. Complement factor H polymorphisms may account for 60% of the attributable risk for AMD.24 Other polymorphisms, and complicated relationships with environmental damage such as smoking and antioxidants, also exist.25 These discoveries fit well with what was presumed to be a complex genetic predisoposition to AMD, but nonetheless was surprising to many ophthalmologists, who may have presumed that the genes would be related to RPE or matrix. There is undoubtedly a contribution of other aging changes such as progressive choroidal ischemia26 and systemic inflammatory mediators such as C-reactive protein.27 The current hypothesis, however, is that inflammation involving the innate immune system is a primary determinant of AMD.

Perhaps even more intriguing is the concept that adaptive immunity may also play a role. Peroxidation products of lipids present in high concentration in Ruysch’s complex (RPE–Bruch’s–inner choroid) are antigenic. In a mouse model patterned after EAU, immunization with oxidized drusen produces drusen and other changes typical of dry macular degeneration.28 It is conceivable that a model of wet macular degeneration could be created by immunizing a mouse with the equivalent polymorphisms in the complement system as have been identified in humans to predispose to exudative AMD.

DIABETIC RETINOPATHY

Inflammatory mechanisms are suspected to contribute to the pathogenesis of diabetic retinopathy, in part because of aberrant cytokine levels and adhesion molecules in intraocular specimens.29,30 Increased adhesion molecules may indicate disruption of the blood–retinal barrier. Increased vascular endothelial growth factor (VEGF) levels in diabetic eyes have been associated with proliferative diabetic retinopathy and macular edema, yet in other vascular beds, low VEGF levels may contribute to pathology.31 Increased TNF-α is present in both serum and vitreous fluids at higher than normal levels in patients with proliferative diabetic retinopathy. Unlike AMD, strong genetic contributions to diabetic retinopathy have not been identified, and certainly not to genes controlling the inflammatory pathways.32

IMPLICATIONS FOR RETINAL

PHARMACOTHERAPY

In the previous sections we have discussed innate immunity and complement in macular degeneration, humoral immunity, and T-cell- mediated diseases such as EAU, and infectious uveitis such as ARN with significant destructive immune-mediated components. The treatment of a wide spectrum of ocular diseases therefore involves the pharmacologic modulation of the immune system. This section briefly introduces the immunomodulators used in ocular inflammatory disease. These agents, along with therapeutic monoclonal antibodies, will be discussed further in Section 4.

Corticosteroids bind to specific receptors in the cytosol of immunocompetent cells and then are transported to the nucleus, where they influence DNA transcription and suppress transcription of proinflammatory cytokines, prostaglandins, and other proinflammatory factors. Additionally, corticosteroids at high concentrations reduce calcium and sodium cycling across plasma membranes, which is thought to result in anti-inflammatory effects.33 Membrane-bound corticosteroid receptors have also been identified and have been shown to exert antiinflammatory effects. They are only immunosuppressive in high doses.

Antimetabolites reduce DNA synthesis and are immunosuppressive. Methotrexate is a folic acid analog that inhibits folate metabolism via dihydrofolate reductase and suppresses rapidly proliferating cells such as activated lymphocytes. Adenosine release increases T-cell apoptosis due to increased intracellular reactive oxygen species and increased sensitivity to the proapoptic pathways involving CD95, and other mechanisms.34 Since adenosine release occurs intraocularly without systemic processing, methotrexate is predicted to be effective on intravitreal injection.

Azathioprine, another antimetabolite, inhibits purine synthesis and both DNA and RNA production. Azathioprine undergoes extensive systemic metabolism before incorporation as a thioguanine nucleotide that causes DNA–protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchanges and is unlikely to be useful as an intraocular drug. Thiopurine methyltransferase (TPMT) metabolizes azathioprine; specific polymorphisms in the TPMT gene lead to deficient clearance and increased toxicity. Measurement of TPMT activity can proactively identify patients at higher risk of bone marrow toxicity.35

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase (IMPDH).36 This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. T and B lymphocytes are more dependent on this pathway than other cell types; consequently MMF is more lymphocyte-specific than azathioprine or methotrexate. MMF exerts additional antiinflammatory effects, such as induced apoptosis of activated T lymphocytes, decreased expression and glycosylation of adhesion molecules involved in lymphocyte recruitment, and inhibited inducible nitric oxide synthetase activity.

Cyclosporine is a fungal protein peptide that binds a cytosolic protein named cyclophilin.37 The resulting complex then inhibits calcineurin phosphatase, a protein which controls the transcription of IL-2, IL-2

receptor, IL-4, CD40L, and IFN-γ genes. Although cyclosporine has a substantial side-effect profile, it is a T-cell-specific therapy and therefore appropriate for use in a T-cell-mediated process such as noninfectious uveitis.

Tacrolimus is macrolide lactone which also acts by inhibiting calcineurin, but binds to immunophilins. The mechanism of action is similar to cyclosporine, but tacrolimus additionally inhibits cytokine production by activated monocytes and macrophages, thereby increasing its immunosuppressive effect relative to cyclosporine.38 Sirolimus is also a macrolide lactone39 that binds to immunophilins, but the resultant complex inhibits the mammalian target of rapamycin (mTOR) protein kinase pathway, rather than calcineurin. Sirolimus acts to block intracellular events associated with CD-28 cross-linking and sustained T-cell activation. Sirolimus blocks cell proliferation even after initial activation in both T cells and B cells. It possesses VEGF-mediated antiangiogenic effects as well and has been shown to inhibit choroidal neovascularization in an animal model, leading to interesting possibilities as both an antiproliferative and immunosuppressive drug for posterior uveitis complicated by neovascularization.40

Biologic therapeutic agents mimic the molecular mechanisms of the immune system to regulate disease. Polymorphisms in the TNF-α gene are associated with greater susceptibility to Behçet disease and TNF-α levels are generally increased in Behçet disease.41 Interferons both activate and control the inflammatory response.42 Type I interferons consist of at least 13 different IFN-α isotypes and IFN-β, and type II interferons consisting of a single member, IFN-γ. Type I interferons share a common receptor, the IFN-α/IFN-β receptor, whereas type II interferons bind to the IFN-γ receptor. Type I interferons are used therapeutically to exert antiproliferative and proapoptotic affects on lymphocytes, especially in Behçet disease.43 They initiate transcription of anti-inflammatory mediators such as TGF-β, IL-1 receptor antagonist and soluble TNF receptors as well as many inflammatory cytokines such as TNF-α.

DIAGNOSIS AND ANCILLARY

LABORATORY METHODS

Polymerase chain reaction (PCR) has allowed for improved diagnosis of intraocular infections44 by detection of DNA from vitreous45 or ante- rior-chamber fluid. “Universal” panbacterial or panfungal primers can be used first, then narrowed with specific primers.46,47 Numerous case reports outline the utility of anterior-chamber tap PCR for the identification of cytomegalovirus (CMV),48,49 HSV, VZV,50 toxoplasmosis,51 and tuberculosis52 from anterior-chamber fluid. Quantifiable PCR technologies such as real-time PCR help avoid false-positives by estimating the initial copies of pathogen DNA.53 Multiplex PCR technologies allow for the simultaneous assay for multiple primers from one ocular sample.54 PCR has identified previously unrecognized syndromes, such as CMV anterior uveitis, which may represent a subset of cases of glaucomatocyclitic crisis and Fuchs heterochromic iridocylitis.55–59 Fomivirsen, a cDNA molecule that interferes with CMV replication, was briefly available as intravitreal injection approved by the Food and Drug Administration for the treatment of CMV retinitis.47 Identification of other viral targets may lead to other such molecular drugs.60

Treatment of AMD already relies heavily on molecular targeting of VEGF. There is a wide range of new therapeutic interventions that can be devised, such as specific complement inhibitors, and other strategies to reduce inflammation.61 In diabetic retinopathy, links between inflammation and diabetic complications support the use of antiinflammatory medications such as nonsteroidal anti-inflammatories, corticosteroids, and specific agents directed again TNF-α and VEGF.62

SUMMARY AND KEY POINTS

1.  Multiple immunologic mechanisms are involved in ocular and vitreoretinal diseases.

2.Experimental studies support the concept of the eye as an immune-privileged site.

Retina in Sciences Basic • 1 section

inflammation and immunity• 5 chapterOcular

3.  Anti-inflammatory and immunosuppressive treatments used for ocular inflammatory disease have multiple mechanisms of actions.

4.  Molecular diagnostics of ocular fluids is helpful to diagnose intraocular infections with targets amenable to treatment with molecularly specific drugs.

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