Pathogenesis Of Uveitis Research Articles

The Role ofM. lepraeHsp65 Protein and Peptides in the Pathogenesis of Uveitis

Experimental autoimmune uveitis (EAU) is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae K409A mutant protein and the synthetic peptides Leader pep and K409A pep (covering amino acids residues 352–371 of WT and K409A proteins of M. leprae Hsp65, resp.) on the pathogenesis of EAU. Mice received the 161–180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K409A protein or the Leader pep or K409A pep. The Leader pep aggravated the disease, but mice receiving the K409A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.

Psoriatic Eye Manifestations

The relationship between the eye and psoriasis has been recognized for decades, but the precise eye manifestations in patients with psoriasis and psoriatic arthritis are only recently coming to light. Psoriatic eye findings may include conjunctivitis, dry eye, episcleritis, and uveitis, all of which may precede articular changes. Uveitis, seen in 7% to 25% of psoriatic arthritis patients, may be recognized by the presence of conjunctival injection, photophobia, pain, lid swelling, or otherwise unexplained visual changes. Early recognition is paramount because its natural course may lead to vision loss. Immunopathogenesis has shown evidence for T-helper cell (Th) type 1 (Th1) and Th17 involvement in the pathogenesis of uveitis according to the murine experimental autoimmune uveitis model. Corticosteroids are the primary treatment modality; however, increasing emphasis has been placed on immunomodulators and biologics for more intractable cases. Referral to an ophthalmologist is essential for definitive diagnosis and treatment.

Cytokines in Autoimmune Uveitis

Autoimmune uveitis is a complex group of sight-threatening diseases that arise without a known infectious trigger. The disorder is often associated with immunological responses to retinal proteins. Experimental models of autoimmune uveitis targeting retinal proteins have led to a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and have provided a template for the development of novel therapies. The disease in humans is believed to be T cell-dependent, as clinical uveitis is ameliorated by T cell-targeting therapies. The roles of T helper 1 (Th1) and Th17 cells have been major topics of interest in the past decade. Studies in uveitis patients and experiments in animal models have revealed that Th1 and Th17 cells can both be pathogenic effectors, although, paradoxically, some cytokines produced by these subsets can also be protective, depending on when and where they are produced. The major proinflammatory as well as regulatory cytokines in uveitis, the therapeutic approaches, and benefits of targeting these cytokines will be discussed in this review.

Killer Immunoglobulin-like Receptor Genes in Uveitis

Purpose: to review the function and genetics of killer immunoglobulin-like receptors (KIRs) and studies of KIR genetic associations with uveitis.Methods: Review of published studies.Results: KIRs are receptors on NK and some T cells. They may inhibit or activate cellular function, such as cytotoxicity and cytokine production. Studies have been published examining KIR gene associations with birdshot chorioretinopathy (BCR), Vogt-Koyanagi-Harada (VKH) disease, and HLA-B27-associated acute anterior uveitis (AAU) and axial spondyloarthropathy. Evidence for increased activating and/or less inhibitory KIR and HLA gene combinations was found for BCR and VKH disease. In HLA-B27-associated disease, a trend toward decreased activation and stronger inhibition was found, except for the weakly inhibitory 3DL1 and Bw4T80 combination. This latter combination was also found to confer risk in BCR.Conclusions: KIR genetics are complex, as are the functions of KIR-bearing cells. Nonetheless, evidence for KIRs in the pathogenesis of uveitis has been found.

Problems and resolutions in the basic research of uveitis

Great achievements have been obtained in the studies on the pathogenesis of uveitis during recent years. However, the cellular and molecular mechanisms involved in the anterior chamber associated immune deviation, the development of autoimmune response and uveitis following infections are still not completely understood. The reason as to why there is a big difference concerning the clinical process between human uveitis and its counterpart, uveitis induced in animal, is expected to be investigated. Gene susceptibility to uveitis is not well understood. Behcet disease and Vogt-Kayanagi-Harada syndrome are the two most common uveitis entities in China. Therefore, studies should be focused on both diseases to clarify the aforementioned issues, which will greatly contribute to the development of strategy in the treatment and prevention of uveitis.

The Effects of Th17 Cytokines on the Inflammatory Mediator Production and Barrier Function of ARPE-19 Cells

Th17 cells have emerged as a key factor in the pathogenesis of uveitis as well as other autoimmune disorders. They secrete a number of cytokines including IL-17A, IL-17F and IL-22 and until now the effects of these cytokines on resident cells of the eye were not yet clear. The purpose of this study was to investigate the effects of Interleukin (IL)-17A, IL-17F and IL-22 on the production of inflammatory mediators and barrier function of retinal pigment epithelium cells. We showed that ARPE-19 cells, a spontaneously arisen cell line of retinal pigment epithelium (RPE), constitutively expressed IL-17RC and IL-22R, but not IL-17RA. IL-17A significantly enhanced the production of CXCL8, CCL2, CCL20 and IL-6 by these cells. IL-17F had a similar effect on the production of CXCL8, CCL2 and IL-6 by ARPE-19 cells, but did not influence the expression of CCL20. Both IL-17A and IL-17F significantly decreased the transepithelial electrical resistance (TER) of the ARPE-19 monolayer and increased the diffusion rate of fluorescein isothiocyanate (FITC)-dextran. They also disrupted the distribution of the junction proteins zonula occludens (ZO)-1 and occludin at the interface of adjacent cells. IL-22 did not have a detectable effect on the production of the tested inflammatory mediators by ARPE-19 cells, TER of the ARPE-19 monolayer, the diffusion rate of FITC-dextran or the distribution of ZO-1 and occludin. This study demonstrates that IL-17A and IL-17F, but not IL-22, significantly promoted ARPE-19 cells to secrete inflammatory mediators and compromised the ARPE-19 monolayer barrier function in association with a disrupted distribution of ZO-1 and occludin. These results suggest that both IL-17A and IL-17F may play a role in posterior segment inflammation of the eye.

Recent advances in uveitis studies in China

Uveitis has become an intensive study area and great achievements have been obtained during recent years. Uveitis study team in China has become one of the most productive uveitis study groups in the world. Ophthalmologists in China have addressed the clinical patterns and characteristics of uveitis in China. Studies by Chinese ophthalmologists, for the first time, revealed that IL-23/IL-17 played an important role in the pathogenesis of uveitis. Decreased frequency and function of CD4+CD25high T cells were shown to be actively involved in the development of Vogt-Koyanagi-Harada syndrome. A number of immune-related genes were found to be associated with the susceptibility to or resistance against Behcet's disease or Vogt-Koyanagi-Harada syndrome. Various molecules, such as Tim-3 and IDO protein, and Treg cells including CD4+CD25+T, CD4+PD-1+T, CD8+Foxp3+T and CD8+CD94+T were found to be involved in the development of anterior chamber associated immune deviation, an important mechanism against intraocular inflammation. These studies have greatly contributed to the understanding as well as the treatment of this disease.

A look at autoimmunity and inflammation in the eye

Autoimmune and inflammatory uveitis are a group of potentially blinding intraocular inflammatory diseases that arise without a known infectious trigger and are often associated with immunological responses to unique retinal proteins. In the United States, about 10% of the cases of severe visual handicap are attributed to this group of disorders. As I discuss here, experimental models of ocular autoimmunity targeting retinal proteins have brought about a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and are serving as templates for the development of novel therapies.

Expression and Function of Inducible Costimulator on Peripheral Blood CD4+T Cells in Behçet's Patients with Uveitis: A New Activity Marker?

Inducible costimulator (ICOS) is an important costimulatory molecule involved in T-cell activation. In this study, the role of ICOS in the pathogenesis of uveitis in Behçet's disease (BD) was investigated. Peripheral blood mononuclear cells (PBMCs) were obtained from BD patients with uveitis in the active or remission phase and in healthy subjects. Total RNA was isolated from PMBCs, and mRNA expression was analyzed on an oligonucleotide microarray. ICOS expression on CD4(+) T cells was determined by flow cytometry, and the functional costimulatory effect of ICOS/B7RP-1 interaction was assessed on stimulation with concanavalin A (conA) or IRBP in the presence or absence of anti-ICOS mAb. As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared with healthy control subjects. ICOS expression on CD4(+) T cells in BD patients with uveitis was significantly higher than that in healthy individuals, both before and after conA stimulation. Among the BD patients, ICOS expression on CD4(+) T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 (B7RP-1) interaction by anti-ICOS mAb significantly decreased IFN-γ, IL-17, and TNF-α production by PBMCs when stimulated with conA or IRBP in BD with active uveitis. High ICOS expression in BD patients with uveitis contributed to the upregulation of IFN-γ, IL-17, and TNF-α production, suggesting that abnormal ICOS costimulation may play an immunopathologic role in the pathogenesis of uveitis in BD.

Kininogen in Autoimmune Uveitis: Decrease in Peripheral Blood Stream versus Increase in Target Tissue

Equine recurrent uveitis (ERU) is an incurable disease affecting the inner eye that leads to blindness, through activated T cells that pass the blood-retinal barrier and destroy the retina. Serum markers are a desirable choice for monitoring development of disease, as serum is easy accessible and the markers could serve to predict the beginning of disease or an imminent relapse. In this study, serum proteomes (depleted of high-abundance serum proteins) of horses with ERU and healthy controls were compared with the 2-D DIGE (two-dimensional gel electrophoresis) technique to identify differentially expressed proteins. The expression pattern of a candidate protein in retina and vitreous was validated by Western blots and immunohistochemistry. Ten differentially expressed proteins could be identified by mass spectrometry (MALDI-TOF/TOF). Five proteins--IgM, IgG4 hc, serotransferrin, alpha-2HS-glycoprotein, and complement factor B--were upregulated in the uveitic state, whereas the five proteins albumin, apolipoprotein A-IV and H, IgG5 hc, and high-molecular-weight kininogen (HK) showed a significantly lower expression in sera of uveitis cases. Of interest, kininogen was significantly upregulated in the target tissues vitreous and retina. HK is a plasma protein with multiple physiological functions, with an important role in inflammation and promoting neovascularization. Most interesting is the as of yet unaddressed association of HK with uveitis. Immunohistochemistry showed coexpression of kininogen and VEGF in inflamed eyes. Since neovascularization plays a major role in the pathogenesis of uveitis, the identification of a proangiogenic factor in the retina presents an important finding and may contribute to elucidating the pathogenesis of uveitis.

CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis

Uveitis is an inflammatory ocular disease characterized by the infiltration of T lymphocytes and other leukocytes into the eye. The recruitment of these inflammatory cells from systemic vasculature to ocular tissue is a well-coordinated multistep process including rolling, firm adhesion and transmigration. CXCL12 (SDF-1α) is an endothelial cell-derived cytokine interacting with CXCR4 and CXCR7, two chemokine receptors mainly expressed in T cells, neutrophils and monocytes. Recent studies have shown that CXCR4, CXCR7 and their ligand, CXCL12, are important for the regulation of leukocyte mobilization and trafficking. However, it is unclear whether these two chemokine receptors are implicated in the pathogenesis of uveitis. In this study, we used DO11.10 mice, whose CD4+ T cells are genetically engineered to react with ovalbumin (OVA), to investigate the role of CXCR4 and CXCR7 in an animal model of uveitis. Intravital microscopy revealed that intravitreal OVA challenge of DO11.10 mice caused the infiltration of both T cells and neutrophils. The invasion of these inflammatory cells coincided with the detection of transcriptional up-regulation of CXCR4 and CXCR7 in the eye. In addition, both real-time-PCR and immunohistochemistry revealed an enhanced expression of endothelial CXCL12. Furthermore, intraperitoneal injection of AMD3100 (a specific CXCR4 antagonist) significantly attenuated OVA-induced uveitis and CXCL12-mediated transwell migration. In contrast, intraperitoneal administration of CXCR7 neutralizing antibody did not significantly alter ocular infiltration of inflammatory cells caused by OVA challenge. Our data suggest that CXCR4 but not CXCR7 plays a critical role in antigen-induced ocular inflammation by facilitating leukocyte infiltration. This study not only enhances our knowledge of the immunopathological mechanism of uveitis but also provides a novel rationale to target CXCR4 as an anti-inflammatory strategy to treat uveitis.

Recent developments in the treatment of uveitis: an update

The management of complex uveitis is often based around the use of oral corticosteroids. To spare the side effects of corticosteroids, second-line oral immunosuppressant drugs are used. Newer systemic immunosuppressive drugs, including biologics, and locally delivered treatments are being evaluated. This article reviews current conventional treatments, discusses their limitations and evaluates newer treatment strategies. Current theories about the pathogenesis of uveitis and potential targets for treatment are discussed in this context. We are still in search of a low-risk, where possible, locally delivered and targeted treatment for uveitis.

Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice

T cell-mediated uveitis is strongly associated with many systemic inflammatory disorders. Th17 cells are a novel T cell subset characterized by production of interleukin (IL)-17. In this study, we used DO11.10 mice to investigate the role of IL-17 in the pathogenesis of uveitis. CD4 + T cells in DO11.10 mice are genetically engineered to react with ovalbumin (OVA). IL-17 expression was determined by real-time PCR and ELISPOT. Uveitis was induced by intravitreal injection of OVA, and ocular inflammation was evaluated by intravital microscopy. OVA challenge significantly induced IL-17 production by DO11.10 splenocytes in vitro. Next, we examined whether OVA challenge could elicit local inflammation and induce IL-17 in vivo. OVA elicited marked neutrophil-predominant inflammatory cell infiltration in the eyes. This leukocyte influx was mediated by CD4 + lymphocytes as evidenced by significant inhibition of the ocular inflammation by CD4+ depleting antibody. Compared to control mice, OVA treatment induced IL-17 expression. Moreover, anti-IL-17 antibody markedly reduced OVA-mediated ocular inflammation. Finally, the neutralization of IL-17 attenuated ocular expression of CXCL2 and CXCL5, two cytokines which are chemotactic for neutrophils. Our study suggests that IL-17 is implicated in the pathogenesis of this T cell-mediated model of uveitis in part through neutrophil chemotaxis as a downstream effect of IL-17.

NOD1 Expression in the Eye and Functional Contribution to IL-1β–Dependent Ocular Inflammation in Mice

NOD1 plays an important role in host defense and recognizes the minimal component of bacterial cell walls, meso-diaminopimelic acid (iE-DAP). Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn's disease and sarcoidosis. NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored. The induction of uveitis by iE-DAP in mice and the potential contribution of interleukin (IL)-1beta were investigated. BALB/c mice or mice deficient in caspase-1 or IL-1R1 and their congenic controls were injected intravitreally with iE-DAP or saline. The time course, dose response, and contribution of IL-1beta to ocular inflammation were quantified by intravital video microscopy, histology, and immunohistochemistry. NOD1 and IL-1beta were measured in eye tissue by immunoblotting and ELISA. NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose- and time-dependent fashion. The authors previously defined the role of IL-1beta in NOD2 uveitis and tested whether NOD1 and NOD2 used similar mechanisms. Treatment with iE-DAP significantly increased IL-1beta, which was caspase-1 dependent. However, in contrast to NOD2, caspase-1 and IL-1R1 were essential mediators of iE-DAP-induced uveitis, suggesting that NOD1 and NOD2 induce ocular inflammation by distinct mechanisms involving IL-1beta. These findings demonstrate that NOD1 is expressed within the eye and that its activation results in uveitis in an IL-1beta-dependent mechanism. Characterizing the differences between NOD1 and NOD2 responses may provide insight into the pathogenesis of uveitis.

Serum Prolactin Levels in Hla-B27-Associated Uveitis

To evaluate basal serum prolactin levels in patients with HLA-B27-associated uveitis. Prospective, nonrandomized comparative trial. Thirty-three patients with HLAB27- associated uveitis and 30 age- and sex-matched healthy control subjects were included. Age, systemic disease, treatment, and uveitis activity were recorded for comparative analysis between groups. Fourteen out of 23 patients with arthritic disease had ankylosing spondylitis. Basal serum prolactin levels were determined by electrochemiluminescence immunoassay on a Modular Analytics E170 analyzer. Prolactinemia was significantly higher (mean=15.84 ng/mL) in patients vs controls (mean=11.50 ng/mL) (p=0.026). Subgroup analysis revealed prolactinemia in arthritic disease patients (mean=17.21 ng/mL) significantly higher than controls (mean=11.50 ng/mL) (p=0.009) and in ankylosing spondylitis (mean=17.65 ng/mL) vs controls (mean=11.50 ng/mL) (p=0.006). No correlation was found between prolactinemia and systemic treatment. Prolactinemia did not correlate with disease activity. Autoimmunity features also correlated with higher prolactinemia (mean=17.26 ng/mL) vs controls (mean=11.50 ng/mL) (p=0.015). These results suggest the role of serum prolactin levels in HLA-B27-associated uveitis pathogenesis and its subgroups. There was no correlation with disease activity.

Regional immunity of the eye: T lymphocytes and ocular pigment epitherial cells

AbstractIntraocular inflammation is mediated by activated CD4+ T lymphocytes. This notion was classically demonstrated by experimental autoimmune uveoretinitis induced by retinal antigens. In human, activated CD4+ T lymphocytes also play the essential role in the pathogenesis of uveitis. Such examples are Vogt‐Koyanagi‐Harada (VKH) disease and human T‐cell leukemia virus type 1 (HTLV‐1) uveitis. VKH disease is a classical autoimmune disease specific to melanocytes and activated CD4+ T lymphocytes sensitized to melanocyte‐associated antigen, tyrosinase, are infiltrated in the eye, resulting in ocular inflammation. HTLV‐1 uveitis is an intraocular inflammation caused by inflammatory cytokines produced by HTLV‐1‐infected CD4+ T lymphocytes infiltrating in the eye. Not only these diseases but also many other inflammatory disorders in the eye are mediated by activated CD4+ T lymphocytes. However, the eye has a unique regional immune defense system that protects the eye from sight‐threatening inflammation mediated by activated CD4+ T lymphocytes. Recent studies of our group together with many others indicate that the aqueous humor, the corneal endotherial cells, the ocular pigment epitherial cells of the iris, ciliary body and retina, the vitreous have unique capacity to suppress activated CD4+ T lymphocytes infiltrating in the eye and down‐regulate intraocular inflammation. The immune suppression against infiltrating CD4+ T lymphocytes is caused by both these ocular resident cells and regulatory T cells induced by ocular resident cells through various unique molecules, such as B7‐2, CTLA4, TBF‐β, thrombospondin 1, or CTLA‐2α. One of the most amazing features of this regional defense system in the eye is that molecular mechanisms of each cells and tissues are adapted to its anatomical characteristics and allowing the defense system to exhibit its capacity most efficiently at their site in the eye. For instance, the iris pigment epitherial cells surrounded by aqueous humor down‐regulate activated T lymphocytes via cell‐to‐cell contact mechanisms, but not soluble factors. On the other hand, the retinal pigment epitherial cells surrounded by cells in the retina and choroid exhibit their immunoregulatory function by soluble factors. In this lecture, the molecular mechanisms of the local defense system in the eye, with particular attention to ocular pigment epitherial cells, will be discussed based on our recent studies.

A clinical grading system for retinal inflammation in the chronic model of experimental autoimmune uveoretinitis using digital fundus images

Experimental autoimmune uveoretinitis (EAU), a widely used animal model of human posterior/pan-uveitis, is extremely valuable in allowing understanding of the pathogenesis of uveitis as well as in developing new treatments. Depending on the animal strain and immunization protocol used, the clinical course of EAU can be acute, severe and involving the anterior and posterior part of the eye, or chronic, mild and involving only the posterior part of the eye. Clinical signs of EAU can be examined by bio-microscopy. Using appropriate criteria EAU can be quantitatively evaluated clinically in living animals. However, correlation of research within different laboratories is difficult since clinical grading systems are subjective and susceptible to considerable variability. In this study, we have developed a recordable, image-based clinical grading system for the chronic models of EAU. Fundus images were taken from EAU mice using an endoscopic imaging system. Fundus changes were classified as (1) inflammatory changes (including optic disc inflammation, vasculitis and retinal tissue inflammation) and (2) retinal structural damage. Each element was scored separately based on the severity of the lesions, and the average score of the three inflammatory elements was used as the overall EAU clinical inflammation grade of the eye. The validity and reproducibility of the grading system was tested using a set of images scored independently in a masked manner by 5 individuals. The grading system proved robust, easy to use and reliable. We offer this image-based EAU clinical grading system as a useful quantitative evaluation method for clinical grading of the severity of inflammation in the chronic EAU model, in which the inflammation can be mild and mainly involves posterior part of the eye.

Associations of Seroreactivity against Crystallin Proteins with Disease Activity and Cataract in Patients with Uveitis

betaB1-crystallin is a putative target of an autoantibody observed in a subset of patients with uveitis. The purpose of this study was to determine whether seroreactivity against betaB1 or other specific purified crystallin proteins is observed in patients with uveitis and whether this reactivity is associated with either cataract or active intraocular inflammation. Sera from patients with uveitis were tested for IgG antibodies with reactivity against alphaA-, alphaB-, betaB1-, or betaB2-crystallin proteins using a modified slot-blot protocol. Ophthalmic evaluations included analysis of the degree of intraocular inflammation and assessment of lens opacity by the Lens Opacities Classification System (LOCS) III. Positive anti-crystallin reactivity was defined as greater than the mean + 2 SD of the reactivity of a commercially available control serum panel. Statistical analysis was performed with the Fisher exact test, Kruskal-Wallis test, and Student's t-test. IgG antibodies against alphaA-, alphaB-, or betaB1-crystallin were identified in 70% of 39 subjects; in contrast, only 30% of the control sera exhibited reactivity against one or more of these crystallin proteins (P <or= 0.01). Seroreactivity against alphaA-, alphaB-, or betaB1-, but not betaB2-crystallin was related to active anterior segment inflammation. Seroreactivity against alphaB and betaB1 was significantly related to cortical cataract (P <or= 0.05). Serum antibodies against specific crystallin proteins are present in most patients with uveitis. The relationship between the presence of specific anti-crystallin antibodies and active inflammation may indicate a role for these autoantibodies in uveitis pathogenesis.

Diminished Frequency and Function of CD4+CD25highRegulatory T Cells Associated with Active Uveitis in Vogt-Koyanagi-Harada Syndrome

CD4(+)CD25(high) regulatory T (Treg) cells have been shown to be involved in the pathogenesis of autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is an organ-specific autoimmune disease. This study was designed to phenotypically and functionally characterize peripheral blood CD4(+)CD25(high) Treg cells in VKH patients with active uveitis. Blood samples were taken from 30 patients with active VKH, 19 patients with inactive VKH, and 26 healthy controls. Peripheral blood mononuclear cells were subjected to flow cytometry for analysis of phenotypes of the CD4(+)CD25(high) Treg cells. For functional analysis, CD4(+)CD25(high) Treg cells and CD4(+)CD25(-) T cells were separated by means of magnetic-assisted cell sorting and subsequently cocultured for 6 days. The proliferation of CD4(+)CD25(-) T cells was measured by [(3)H] thymidine incorporation assay. The levels of IFN-gamma, IL-17, and IL-13 in the supernatants were determined by enzyme-linked immunosorbent assay. Significantly decreased frequencies of CD4(+)CD25(high) Treg cells and percentages of FOXP3(+) cells in these Treg cells were shown in patients with active VKH. Treg cells from patients with active VKH showed a significant deficiency in suppressing the proliferation of CD4(+)CD25(-) T cells and inhibiting the production of IFN-gamma and IL-13 by CD4(+)CD25(-) T cells. CD4(+)CD25(high) Treg cells from VKH patients or healthy controls did not markedly inhibit or promote IL-17 production. A significantly decreased frequency and diminished function of CD4(+)CD25(high) Treg cells is associated with active uveitis in patients with VKH syndrome. These results suggest that these dysfunctional CD4(+)CD25(high) Treg cells may play a role in the pathogenesis of uveitis in VKH syndrome.

NOD2, the Gene Responsible for Familial Granulomatous Uveitis, in a Mouse Model of Uveitis

NOD2 plays an important role in the recognition of intracellular bacteria through its ability to sense the components of bacterial peptidoglycan (PGN), namely muramyl dipeptide (MDP) and muramyl tripeptide (MTP). Specific mutations in the human NOD2 gene cause Blau syndrome, an autosomal dominant form of uveitis, arthritis, and dermatitis. As a first step toward understanding the role of NOD2 in the pathogenesis of uveitis, the authors developed a mouse model of MDP-dependent uveitis. BALB/c mice and mice deficient in L-selectin or NOD2 received intravitreal injection of MDP, MTP, or PGN. The intravascular response within the iris and cellular infiltration was quantified by intravital microscopy and histologic assessment. MDP induced an acute, ocular inflammatory response, wherein rolling and adhering leukocytes within the vasculature were significantly increased within 6 hours after MDP treatment. A minor increase in cellular infiltration occurred at 12 hours after MDP treatment. The adhesion molecule L-selectin participated in MDP-induced vascular inflammation because L-selectin knockout mice showed a significant decrease in the number of rolling cells. Importantly, NOD2 plays an essential role in ocular inflammation induced by MDP, as indicated by the fact that uveitis did not develop in Nod2 knockout mice in response to MDP. Nod2 knockout mice also showed abolished ocular inflammation in response to MTP but not to PGN treatment. These findings demonstrate a novel mouse model of uveitis, wherein NOD2 plays an essential role in inflammation induced by the minimal components of PGN. Thus, innate immune responses mediated by NOD2 may participate in the development of uveitis in response to bacterial products.