A deeper appreciation of the pathogenic mechanisms underlying uveitis, or intraocular inflammation involving the uveal tract (i.e., iris, ciliary body, choroid), has contributed to our abilities to treat these potentially vision-threatening conditions. The spectrum of uveitis ranges from acute, self-limited episodes of anterior uveitis to severe, progressive panuveitis syndromes, which may lead to blindness if not properly managed with immunosuppressive treatment regimens.
This chapter highlights our current knowledge regarding the pathogenic immune mechanisms underlying uveitic conditions. Topics discussed include pathologic features and etiologies of common clinical uveitic conditions, animal models of uveitis, the contribution of immunogenetics to uveitis, the cellular immune response described in patients with uveitic disease, and soluble mediators of inflammation (i.e., cytokines and chemokines). We also discuss the key principle of immune tolerance, which is thought to be compromised in uveitic disease. Specific disease entities are mentioned as related to these central concepts; however, a full discussion of the broad range of uveitic diseases is beyond the scope of this chapter and several excellent reviews regarding specific disease entities are available.
The anatomic classification of uveitis using the Standardization of Uveitis Nomenclature (SUN) Working Group scheme is the preferred method of classifying disease for both patient care and research purposes ( Table 79.1 ). The goals of the SUN classification scheme included improving clinical research across centers, permitting the meta-analyses of data, and improving our understanding of the varied therapeutic responses of patients to different disease processes. Ocular inflammatory disease is termed “anterior uveitis” when inflammation involves the iris and ciliary body ( Figure 79.1 ), “intermediate uveitis” with inflammation primarily found in the vitreous cavity ( Figure 79.2 ), and “posterior uveitis” in conditions involving the retina and choroid. The term “panuveitis” refers to inflammation in all three anatomic locations, including the iris/ciliary body, vitreous cavity, and retina and/or choroid ( Figure 79.3 ). Because the literature differs with respect to uveitis classification prior to implementation of the SUN criteria, some of the literature referenced in this chapter classifies disease by systemic entity (e.g., Behçet’s disease-associated uveitis). In the future, it will be important to understand the pathogenesis of specific disease entities (e.g., sarcoidosis-associated intermediate uveitis) in addition to a more general understanding of disease pathogenesis according to anatomic classification (e.g., acute anterior uveitis).
|Primary site of inflammation *
|Retina or choroid
|Anterior chamber, vitreous, and retina or choroid
Pathologic examination of ocular specimens has provided valuable information about the cellular mediators (discussed below), tissue injury, and healing mechanisms that are observed in patients with uveitis. Immune cells identified in pathologic specimens have included T- and B-cell lymphocytes, macrophages, and epithelioid cells.
For example, in sarcoidosis-associated uveitis, CD4+ T cells predominate, although CD8+ T cells and B cells have also been observed. Granulomas consisting of multinucleated giant cells (macrophage aggregates) and epithelioid cells are also seen; however, granulomas have also been identified in other uveitic processes, including ocular tuberculosis and sympathetic ophthalmia.
Following the infiltration of ocular tissue by inflammatory cells, the release of cytokines (discussed below) and the recruitment of additional leukocytes lead to further tissue injury and resultant scarring and fibrosis. These processes are exemplified by the late phase of Vogt–Koyanagi–Harada’s (VKH) disease, in which subretinal fibrosis and choroidal neovascularization are observed in a significant percentage of patients with chronic VKH disease.
Determining the etiology of a particular uveitic syndrome may be a difficult task because of the wide array of diagnostic considerations. However, correct identification of the predominant anatomic location of a disease entity is helpful in narrowing the differential diagnosis. The SUN Working Group criteria were valuable in describing the four major classes of uveitis: (1) anterior uveitis; (2) intermediate uveitis; (3) posterior uveitis; and (4) panuveitis.
Etiologies of anterior uveitis include sarcoidosis, human leukocyte antigen (HLA)-B27-associated uveitis, syphilis, tuberculosis, and Lyme disease. Causes of intermediate uveitis also include sarcoidosis, syphilis, Lyme disease, and tuberculosis. However, entities more commonly associated with intermediate uveitis (cf. anterior uveitis) include multiple sclerosis (MS), human T-cell lymphotrophic virus-1 (HTLV-1), and primary intraocular lymphoma, which may masquerade as a chronic vitritis in an elderly patient (i.e., masquerade syndrome). Posterior uveitis may be caused by systemic conditions, including sarcoidosis, syphilis, tuberculosis, and Lyme disease. Some causes of posterior uveitis isolated to the eye include serpiginous choroidopathy, birdshot retinochoroidopathy, and multiple evanescent white-dot syndrome ( Box 79.1 ). Panuveitis, which includes anterior-chamber, vitreous, retina, and choroidal inflammation, may be observed in sarcoidosis, syphilis, tuberculosis, VKH disease, and sympathetic ophthalmia. Endophthalmitis may also manifest as a panuveitis, and infectious etiologies of ocular inflammation (e.g., bacterial, fungal, viral) should also be considered in certain clinical situations. For example, in immunosuppressed patients (e.g., cancer patients on chemotherapy, patients with indwelling catheters and lines), fungal and bacterial endophthalmitis should be considered in cases of panuveitis. In other clinical settings (e.g., African-American patients with hilar adenopathy) other considerations such as sarcoidosis should be higher on the differential diagnosis of panuveitis.
The anatomic classification of uveitis based on the Standardization of Uveitis Nomenclature Working Group criteria is currently the preferred method of describing uveitis for patient care and research purposes
The four major classes of uveitis include anterior, intermediate, posterior uveitis, and panuveitis, which may be useful in narrowing the differential diagnosis of a uveitic syndrome
CD4+ T cells play a key role in mediating ocular inflammation in uveitis; however, CD8+ T cells, B lymphocytes, and macrophages have also been implicated
Systemic autoimmune conditions such as sarcoidosis and Vogt–Koyanagi–Harada’s disease may cause uveitis. Infectious causes include syphilis, tuberculosis, and Lyme disease
Etiologies of posterior uveitis with localized ocular inflammation include birdshot retinochoroidopathy, serpiginous choroidopathy, and multiple evanescent white-dot syndrome
Animal models of uveitis
Experimental models of uveitis have contributed greatly to our understanding of uveitis. Each of these models involves the activation of the immune system against specific retinal or uveal tract antigens ( Box 79.2 ). During induction of experimental autoimmune uveitis or uveoretinitis (EAU), animals are sensitized to known retinal antigens such as retinal S-antigen, RPE65, or interphotoreceptor-binding protein (IRBP), which are emulsified in complete Freund’s adjuvant to augment the immune response. A second agent such as pertussis toxin is also used to activate the immune response further. Using this technique, inflammation of the iris, ciliary body, retina, and choroid is consistently observed. With this reproducible technique, it is possible to study the cellular components, soluble mediators and their receptors, therapies, and drug delivery systems targeted against the inflammatory response.
Animal models of uveitis, particularly experimental autoimmune uveitis, have been important in characterizing the pathogenesis of uveitis, as well as in studying immunosuppressive agents for the treatment of disease
The relationship between immunogenetics and the clinical expression of uveitis remains under investigation; however, the recent identification of the NOD2 gene mutation in patients with ocular and systemic granulomatous inflammation is supportive of the importance of genetics in uveitis
Immune cells implicated in uveitis include CD4+ T-helper cells, cytotoxic CD8+ T cells, B cells, macrophages, and natural killer cells
Subtypes of CD4+ T-helper cells include Th1 and Th17 cells, which are thought to be proinflammatory. Other CD4+ T-helper cell subtypes may play an immunoregulatory role
Interleukin-1, interleukin-6, and tumor necrosis factor-α are key proinflammatory cytokines seen in uveitis
Mechanisms of immunoregulation include peripheral tolerance (active suppression and immune ignorance) and central tolerance (thymic-negative selection). Loss of these control mechanisms may be relevant to the clinical expression of uveitis
Endotoxin-induced uveitis (EIU) has also been a useful animal model of uveitis. In this animal model, lipopolysaccharide (endotoxin) is administered to the animal, leading to an acute inflammatory response in the uveal tract that occurs 6 hours after endotoxin injection and peaks within 24 hours. Iris hyperemia, miosis, increased aqueous humor protein, and infiltration of the anterior chamber and uvea by inflammatory cells are observed following EIU induction.
A model of experimental autoimmune anterior uveitis (EAAU) has also been described previously. EAAU is induced in animal models via injection of a number of peptides, including myelin basic protein, melanin-bound antigens of the retinal pigment epithelium, or melanin-associated antigen. Experimental models have also been described for specific uveitic syndromes, including VKH disease in dogs and rats, ocular histoplasmosis, and ocular toxoplasmosis. Because much of our knowledge stems from studies in animal models, some of these studies are referenced in the discussion of clinical uveitis throughout this chapter. Table 79.2 highlights various details of the animal models used in the study of uveitis.
|Anatomic/histologic localization of uveitis
|Experimental autoimmune uveitis
|Retinal S-antigen, IRBP, recoverin (antigens emulsified with complete Freund’s adjuvant) *
|Mouse, rat, rabbit, guinea pig, nonhuman primates
|Anterior chamber, iris, ciliary body, vitreous infiltrates, retina, subretinal space
|Anterior chamber, iris, ciliary body, vitreous
|Experimental autoimmune encephalomyelitis
|Myelin basic protein
|Anterior uveitis, retinal vasculitis
|Tyrosinase related protein 1 (TRP1)
|Anterior-chamber infiltrates, vitreous infiltrates, choroidal and retinal inflammation, exudative retinal detachments
Immunogenetics and uveitis
The relationship between immunogenetics and the clinical manifestation of ocular inflammatory disease has been the subject of several recent reviews. Genes may influence individual susceptibility to an inflammatory disease; however, the mechanisms leading from a specific genetic profile to the disease phenotype may also involve environ mental triggers, loss of regulatory elements preventing ocular autoimmunity, and other yet undefined mechanisms.
The HLA genes, which are located on chromosome 6, are responsible for expression of major histocompatibility complex (MHC) class I and II antigens. MHC class I antigens are found on almost all cells in the human body, whereas MHC class II antigens are located primarily on cells involved in antigen presentation, such as lymphocytes and dendritic cells (tissue macrophages). Both HLA class I MHC and class II MHC associations with uveitis have been reported in a number of uveitic syndromes. Specifically, the association of HLA-B27 with acute anterior uveitis and a variety of associated systemic diseases, including the seronegative spondyloarthropathies, has been observed. A class I MHC association with uveitis has been observed in the posterior uveitic syndrome birdshot retinochoroidopathy; greater than 90% of individuals diagnosed with this syndrome carry a copy of the HLA-A29 allele. Behçet’s disease, which may present with panuveitis, retinal vasculitis, or acute anterior uveitis, has been associated previously with HLA-B51. Class II MHC associations have been identified in patients with VKH disease (HLA-DR1 and -DR4) and in pars planitis (HLA-DR2). Table 79.3 summarizes the known HLA-associations of various uveitic syndromes.
|Acute anterior uveitis
|Ocular cicatricial pemphigoid
|Presumed ocular histoplasmosis
Single-nucleotide polymorphisms (SNPs) that may predispose individuals to a certain disease phenotype have also been studied recently. El-Shabrawi et al reported an association of specific SNPs within the tumor necrosis factor-α (TNF-α) promoter that may increase the susceptibility of HLA-B27-positive individuals towards the development of intraocular inflammation. A correlation of clinical phenotype in patients with anterior uveitis and SNPs within the cytokine genes interleukin (IL)-1R, IL-6, IL-10, and TNF has also been reported.
Besides examining single-nucleotide changes in DNA, other investigators have examined the role of differential gene expression in producing various ocular inflammatory phenotypes. In a recent study by Li et al, gene expression profiling using cDNA microarray analysis of peripheral blood samples in patients with noninfectious uveitis revealed increased expression of several cytokine, chemokine, and chemokine receptor genes when compared to normal controls. The examination of local gene expression in EAU demonstrated a local upregulation of inflammatory cytokines and chemokines with a bias towards a T-helper cell type 1 (Th1)-immune response (see below); specifically, upregulation of interferon-γ (IFN-γ), RANTES/CCL5, and MIG/CXCL9 with low levels of the T-helper cell type 2 (Th2) cytokines IL-4 and IL-5 was observed. Further analysis of differential gene expression may help to identify inflammatory mediators responsible for specific disease phenotypes in the future.
In 2001, a single gene mutation in the nucleotide oligomerization domain (NOD2) gene was identified as a cause of the familial form of uveitis known as familial juvenile systemic granulomatosis (Blau syndrome or Jabs disease). Blau syndrome consists of a triad of uveitis, arthritis, and skin inflammation. The uveitis has been previously characterized in 16 patients from eight families. In this series, 15 of 16 patients presented with multifocal choroiditis and panuveitis whereas only one patient presented with anterior uveitis. The NOD2 gene mutation causes structural changes in an intracellular protein named CARD15, which is thought to be involved in the recognition of intracellular bacteria via recognition peptide motifs in microbial cell walls. The precise pathways that result in uveitis clinically are under investigation.
Cellular mediators of uveitis
Immune cellular mediators of uveitis have been studied extensively in animal models of uveitis, as well as from the peripheral blood, aqueous, and vitreous samples from patients with uveitis.
Macrophages play a significant role in the ocular immune response, serving at least three major functions. These include the direct killing of foreign pathogens and clearing of diseased tissue, the activation of the immune system via antigen presentation, and the secretion of potent inflammatory cytokines IFN-γ, TNF-α, and IL-1 that augment the immune response.
The T-cell response is thought to be the arm of the immune system primarily responsible for the majority of uveitic syndromes, with CD4+ T-helper (Th) cells being the subset of immune cells most commonly implicated. The successful use of a humanized monoclonal blocking antibody against T-cell growth factor IL-2 receptor (CD25) in treating uveitis further supported the critical role of T cells in the pathogenesis of human uveitis. T-cell receptors recognize specific antigen epitopes presented in the context of MHC by antigen-presenting cells (e.g., macrophages, dendritic cells). CD8+ T cells recognize antigen presented in the context of class I MHC molecules, whereas CD4+ T cells recognize antigen presented by class II MHC molecules. A second signal, or costimulatory signal, via the interaction of CD28 (T-cell surface antigen) and B7 antigen (antigen-presenting cell), is required for T-cell activation. Ophthalmic inflammatory diseases thought to be CD4+ T-helper cell-mediated include sarcoidosis, VKH disease, and intermediate uveitis. Pathologic evidence from patients with sarcoidosis has demonstrated a predominantly CD4+ T-cell population. However, other disease entities such as Behçet’s disease have been associated with a cytotoxic CD8+ T-cell population.
The Th cell response is divided into Th1, Th2, and recently described Th17 subtypes, all of which are associated with specific cytokine profiles and cellular responses. The Th1 cellular response is thought to be proinflammatory and is most commonly associated with proinflammatory cytokines, including IFN-γ, IL-12, IL-1, IL-6, and TNF-α. The Th2 cellular response is more commonly associated with atopic disease, and often an anti-inflammatory response. Its associated cytokines include IL-4, IL-5, and IL-10. Recently, Th17 cells, associated with IL-17 and the IL-23 family of cytokines, have been implicated in the pathogenesis of uveitis and scleritis. One report described an elevation of IL-23p19 mRNA, IL-23 levels, and increased IL-17 by stimulated peripheral blood mononuclear cells and CD4+ T cells in patients with VKH disease. Recent evidence has also suggested that the presence of Th17 cells in inflamed tissue may contribute to chronicity of ocular inflammation; further studies are underway to characterize this pathway better.
The role of a population of regulatory T cells has been characterized in EAU but regulatory T cells have been difficult to isolate and characterize in patients with uveitis. In EAU mice immunized with IRBP, adoptively transferred CD4+CD25+ regulatory T cells (obtained from naïve mice) resulted in decreased clinical severity and histopathologic scores. In addition, EAU mice that received CD4+CD25+ cells demonstrated reduced proliferation of uveitogenic T cells isolated from their cervical lymph nodes and spleens. In another study by Silver et al, vaccination of naked DNA encoding IRBP protected mice from the development of EAU following immunization with IRBP at least 10 weeks after vaccination. In addition, IRBP-specific CD4+CD25(high) T cells derived from vaccinated mice conferred protection to EAU-challenged recipients and were found in vitro to be FoxP3-positive and antigen-specific.
While T cells are thought to be the immune cell most intimately associated with the pathogenesis of the majority of uveitic syndromes, B cells may also play a limited role in some forms of uveitis. For example, in the subretinal fibrosis and uveitis syndrome, histopathologic investigation has revealed a markedly inflamed choroid with a predominance of plasma cells and B cells. The deposition of complement and IgG within Bruch’s membrane was reported in this syndrome; another report of this syndrome implicated the involvement of T cells, as similar proportions of T and B cells were found in areas of choroid with infiltrating immune cells. Several other ocular inflammatory diseases in which B cells have been identified in limited numbers in pathologic specimens include VKH, ocular sarcoidosis, and sympathetic ophthalmia ; however, these conditions are thought to be primarily T-cell-mediated conditions.
Recent interest in the precise role of natural killer (NK) cells in patients with autoimmune disease has arisen from several studies suggesting that a distinct population of immunoregulatory NK cells arises during the treatment of active uveitis or MS with humanized monoclonal antibody (mAb) against IL-2 receptor (daclizumab, Zenapax). In both MS and in active uveitis, the administration of daclizumab was associated with an increase in a population of CD56 bright NK cells. In MS patients, daclizumab therapy was associated with a decrease in T-cell populations and an increase in CD56 bright NK cells, which correlated with clinical treatment response. Furthermore, in vitro studies demonstrated that NK cells inhibited T-cell survival via a contact-dependent mechanism. In patients with active uveitis, a smaller population of CD56 bright cells was observed when compared to patients with inactive uveitis following treatment with daclizumab. Additionally, CD56 bright cells were able to secrete IL-10 in large amounts, whereas CD56 dim cells were unable to do so, suggesting a possible mechanism by which CD56 bright cells could potentially serve an immunoregulatory function.
Soluble mediators of uveitis and cell adhesion molecules
The most well-characterized group of soluble mediators of inflammation in uveitis are cytokines, chemical mediators involved in the recruitment of ocular immune cells, augmentation of the immune response, and tissue damage in some cases. A number of soluble inflammatory mediators of uveitis have been characterized in both peripheral blood serum samples and ocular fluids (i.e., aqueous and vitreous), as well as in experimental models of uveitis.
In EAU, the Th1-mediated cellular immune response and its associated cytokines predominate. Foxman et al observed an elevation of Th1-associated cytokines and chemokines, including IL-1α, IL-1ß, IL-1R antagonist, IL-6, TNF-α, and IFN-γ in the EAU model. IL-1 and TNF-α receptor-deficient mice show decreased inflammation in an immune complex model of uveitis, suggesting a role for these cytokines in this animal model of uveitis ( Figure 79.4 ). Antagonists of cytokines and chemokines associated with Th1-mediated ocular inflammation have demonstrated some efficacy in the treatment of uveitis (see below), and further exploration of therapeutic agents targeting these soluble mediators of inflammation is warranted.