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Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3) + CD4 + ] and M2 macrophages (CD68 + arginase 1 + IL-10 + ), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule-associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. All rights reserved.)

Aims: To investigate the therapeutic potential of visual stimulation (VS) and BDNF in murine experimental autoimmune uveoretinitis (EAU)., Main Methods: Mice were immunized by subcutaneous injection of interphotoreceptor retinoid-binding protein in Freund's complete adjuvant and intravenous injection of pertussis toxin, and were then exposed to high-contrast VS 12 h/day (days 1-14 post-immunization). EAU severity was assessed by examining clinical score, visual acuity, inflammatory markers, and immune cells in the retina. The transcriptome of activated retinal cells was determined by RNA-seq using RNA immunoprecipitated in complex with phosphorylated ribosomal protein S6. The retinal levels of protein products of relevant upregulated genes were quantified. The effect of BDNF on EAU was tested in unstimulated mice by its daily topical ocular administration (days 8-14 post-immunization)., Key Findings: VS attenuated EAU development and decreased the expression of pro-inflammatory cytokines/chemokines and numbers of immune cells in the retina (n = 10-20 eyes/group for each analysis). In activated retinal cells of control mice (n = 30 eyes/group), VS upregulated genes encoding immunomodulatory neuropeptides, of which BDNF and vasoactive intestinal peptide (VIP) also showed increased mRNA and protein levels in the retina of VS-treated EAU mice (n = 6-10 eyes/group for each analysis). In unstimulated EAU mice, BDNF treatment mimicked the protective effects of VS by modulating the inflammatory and stem cell properties of Müller cells (n = 5 eyes/group for each analysis)., Significance: VS effectively suppresses EAU, at least through enhancing retinal levels of anti-inflammatory and neuroprotective factors, VIP and BDNF. Our findings also suggest BDNF as a promising therapeutic agent for uveitis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The effect of fine particulate matter (PM2.5) on the development of uveitis remains unclear. Therefore, this study was designed to investigate the role of PM2.5 in experimental autoimmune uveitis (EAU) and its potential mechanism. Our results showed that PM2.5 could exacerbate the activity of EAU, as evidenced by severer clinical and pathological changes, correlated with elevated Th17 cells frequency and IL-17A expression. Proteomic analysis revealed ferroptosis was the most significant pathway. In vivo, the levels of Fe 2+ , ROS, lipid ROS, and malondialdehyde, as well as the expression of TFRC, HMOX1, FTH1, and FTL1 in CD4 + T cells were increased, while GSH/GSSG ratio and the expression of ACSL1 and GPX4 were decreased after PM2.5 exposure. In vitro, the expression of TFRC and HMOX1 were increased, while the expression FTH1, FTL1, ACSL1, and GPX4 were decreased after PM2.5 exposure. Ferrostatin-1 effectively alleviated PM2.5-induced intraocular inflammation and suppressed the frequency of Th17 cells. These results suggest that PM2.5 could aggravate intraocular inflammation and immune response in EAU mice through ferroptosis. Ferroptosis could be a potential marker for the prevention and treatment of uveitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D plays a critical role in immunomodulation, and its deficiency is implicated in the pathogenesis of several autoimmune diseases. Nevertheless, its relationship with non-infectious uveitis (NIU), an inflammatory ocular disorder, remains inconclusive., Methods: A systematic search was conducted in three databases from database inception until May 8, 2023, to investigate the potential relationship between vitamin D deficiency and NIU. We included observational studies reporting the measurement of vitamin D levels in patients with NIU and healthy controls without restriction of language or date of publication. Three pairs of authors independently screened the title and abstracts for potential eligibility and then in full text. A third author resolved disagreements. Three pairs of independent reviewers abstracted the data from the fully reviewed records and evaluated the risk of bias. We followed The MOOSE and PRISMA guidelines. Random effects meta-analyses were used for primary analysis. Studies not included in the meta-analysis were summarized descriptively. This review was registered in PROSPERO: CRD42022308105., Findings: Of 933 records screened, 11 studies were included, and five were meta-analyzed, encompassing 354 cases and 5728 controls (mean participant age ranging from 7.1 to 58.9 years). Patients with vitamin D deficiency exhibited an Odds Ratio of 2.04 (95% CI = 1.55-2.68, P < 0.00001) for developing NIU compared to controls. Overall, potential sources of bias were low across most studies., Interpretation: Our findings suggest that vitamin D may play an essential role in the pathophysiology of NIU. While the included studies demonstrated generally low potential bias, additional rigorous prospective studies are necessary to confirm these findings and further elucidate the underlying mechanisms involved. Vitamin D supplementation could represent a possible therapeutic strategy for preventing or managing NIU if substantiated. Clinicians should consider screening for and addressing vitamin D deficiency in patients with or at risk for NIU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Autoimmune uveitis is a sight-threatening intraocular inflammatory disease. For >30 years, the mouse model of experimental autoimmune uveitis has been employed to investigate disease mechanisms and test immunotherapeutic approaches. However, inflammation in this model is self-limited, and does not replicate the chronic, insidious nature prevalent in the human disease. Herein, a robust and reliable model of chronic autoimmune uveitis was developed and characterized in two strains of wild-type mice by modifying interphotoreceptor retinoid-binding protein dose and peptide fragments from conventional experimental autoimmune uveitis models. In both of these murine strains, immunization with our modified protocols resulted in a slowly progressive uveitis, with retinal scars and atrophy observed in the chronic stage by fundoscopy. Optical coherence tomography demonstrated decreased retinal thickness in chronic autoimmune uveitis mice, and electroretinography showed significantly reduced amplitudes of dark-adapted a- and b-waves and light-adapted b-waves. Histologic examination revealed prominent choroiditis with extensive retinal damage. Flow cytometry analysis showed substantially increased numbers of CD44 hi IL-17 + IFN-γ - memory T-helper 17 (Th17) cells in the retina, cervical lymph nodes, inguinal lymph nodes, and spleen. These data establish new modified protocols for inducing chronic uveitis in wild-type mice, and demonstrate a predominant memory Th17 cell response, suggesting an important role for memory Th17 cells in driving chronic inflammation in autoimmune uveitis., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B 4 (LTB 4 ) and inhibiting complement component 5 (C5) activation. Nomacopan has been shown to provide therapeutic benefit in experimental autoimmune uveitis (EAU). Longer acting forms of nomacopan were more efficacious in mouse EAU models, and the long-acting variant that inhibited only LTB 4 was at least as effective as the long-acting variant that inhibited both C5 and LTB 4 , preventing structural damage to the retina and a significantly reducing effector T helper 17 cells and inflammatory macrophages. Increased levels of LTB 4 and C5a (produced upon C5 activation) were detected during disease progression. Activated retinal lymphocytes were shown to express LTB 4 receptors (R) in vitro and in inflamed draining lymph nodes. Levels of LTB 4 R-expressing active/inflammatory retinal macrophages were also increased. Within the draining lymph node CD4 + T-cell population, 30% expressed LTB 4 R +  following activation in vitro, whereas retinal infiltrating cells expressed LTB 4 R and C5aR. Validation of expression of those receptors in human uveitis and healthy tissues suggests that infiltrating cells could be targeted by inhibitors of the LTB 4 -LTB4 receptor 1 (BLT1) pathway as a novel therapeutic approach. This study provides novel data on intraocular LTB 4 and C5a in EAU, their associated receptor expression by retinal infiltrating cells in mouse and human tissues, and in attenuating EAU via the dual inhibitor nomacopan., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Uveitis is a sight-threatening intraocular inflammatory disease that accounts for almost 10% of blindness worldwide. NF-κB signaling plays pivotal roles in inflammatory diseases. We have reported that IMD-0354, which inhibits NF-κB signaling via selective blockade of IKK-β, suppresses inflammation in several ocular disease models. Here, we examined the therapeutic effect of IMD-0354 in an experimental autoimmune uveoretinitis (EAU) model, a well-established animal model for endogenous uveitis in humans. Systemic administration of IMD-0354 significantly suppressed the clinical and histological severity, inflammatory edema, and the translocation of NF-κB p65 into the nucleus of retinas in EAU mice. Furthermore, IMD-0354 treatment significantly inhibited the levels of several Th1/Th17-mediated pro-inflammatory cytokines in vitro. Our current data demonstrate that inhibition of IKKβ with IMD-0354 ameliorates inflammatory responses in the mouse EAU model, suggesting that IMD-0354 may be a promising therapeutic agent for human endogenous uveitis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

The chapter is a review enclosed in the volume "Glaucoma: A pancitopatia of the retina and beyond." No cure exists for glaucoma. Knowledge on the molecular and cellular alterations underlying glaucoma neurodegeneration (GL-ND) includes innovative and path-breaking research on neuroinflammation and neuroprotection. A series of events involving immune response (IR), oxidative stress and gene expression are occurring during the glaucoma course. Uveitic glaucoma (UG) is a prevalent acute/chronic complication, in the setting of chronic anterior chamber inflammation. Managing the disease requires a team approach to guarantee better results for eyes and vision. Advances in biomedicine/biotechnology are driving a tremendous revolution in ophthalmology and ophthalmic research. New diagnostic and imaging modalities, constantly refined, enable outstanding criteria for delimiting glaucomatous neurodegeneration. Moreover, biotherapies that may modulate or inhibit the IR must be considered among the first-line for glaucoma neuroprotection. This review offers the readers useful and practical information on the latest updates in this regard., (© 2020 Elsevier B.V. All rights reserved.)

Objective: Uveitis is the most common ophthalmological finding in the practice of rheumatology and clinical immunology. The condition is frequently idiopathic but about 60 causes of uveitis have been described. Our aim was to analyze the clinical patterns and etiologies of uveitis in a tertiary referral center., Methods: The records of 912 consecutive patients referred to the department of internal medicine (Lyon University Hospital, Lyon, France) for the diagnostic work-up of uveitis were examined. Demographic, clinical, anatomical, and etiological features of uveitis were analyzed., Results: The mean age at onset was 48.8 years; 59.8% of the patients were women and 78.2% were Caucasians. Anterior uveitis was the most common type of uveitis (40.6%), followed by panuveitis (31.7%), posterior (18.75%) and intermediate uveitis (9%). 46.9% of the patients had idiopathic uveitis. The most common etiologies were systemic diseases (37.3%), such as sarcoidosis (17.1%), HLA-B27-related uveitis and/or spondyloarthritis (12.5%), and tuberculosis (7.5%)., Conclusion: We describe one of the largest cohorts of consecutive uveitis patients referred to a department of internal medicine. The high percentage of uveitis associated with underlying (systemic) diseases highlights the need for a multidisciplinary approach, in order to reduce the diagnostic delay., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Th17-type autoreactive T cells contribute to pathogenicity in autoimmune diseases, including autoimmune uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental autoimmune uveitis (EAU). The resultsdemonstrate that γδ T cells have a regulatory effect on Th17 response. The regulatory effects of γδ T cells depend on their action state. Activated γδ T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated γδ T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 autoimmune responses differently. Its activation of γδ T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity., (Copyright © 2018. Published by Elsevier Inc.)

In contrast to rats, mouse models are nowadays generally used for the investigation of immune responses and immune-mediated diseases, there are many different strains and mouse-specific tools available, and it is easy to generate transgenic and constitutive or inducible knockout mice for any gene. Many immune markers and mechanisms have been detected in mice and have been introduced as gold standard in immunology, however, some turned out to be not unconditionally transferable to the human immune system. Rats have been used more frequently in former days but are mostly outstripped by mice due to the fact that fewer strains are available, they need more space than mice, are more expensive to maintain and breed, and it is extremely difficult to generate transgenic or ko-rats. Consequently, the choice of rat-specific diagnostic tools like antibodies is quite poor and most researchers have switched to mouse models for the investigation of immune mechanisms, while rats are still widely used for toxicology by the pharmaceutical industry. However, it should be taken into consideration that there are some immunological similarities between rats and humans that are not presented in mice. Some of them like MHC class II and Foxp3 expression by activated effector T cells we have detected during our research on the immune response of rat models of experimental autoimmune uveitis., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn's disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies targeting this pathway. Finally, 2 ongoing phase 2 trials of the anti-IL-23 biologic therapy ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with noninfectious uveitis are introduced., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The cells of the innate immune system, in addition to their capacity to elicit immunity, play a substantial role in immune tolerance induction. Our group has recently shown that a distinct subset of MHC II hi B220 hi CD11b mid suppressive macrophages is increased in the lung by intravenous (IV) administration of mesenchymal stem/stromal cells (MSC) and induces immune tolerance. Herein, we demonstrate that circulating CD11b hi Ly6C hi monocytes are precursors to MHC II hi B220 hi CD11b mid macrophages in the lung and required for MSC-induced tolerance in a mouse model of experimental autoimmune uveitis (EAU). Analysis revealed that IV MSC induced an increase in IL-10-expressing MHC II hi B220 hi CD11b mid macrophages in the lung with a concomitant decrease in CD11b hi Ly6C hi monocytes. Selective depletion of circulating CD11b hi Ly6C hi cells abrogated the effects of MSC in the induction of IL-10 hi MHC II hi B220 hi CD11b mid macrophages and immune tolerance in EAU mice. Similarly, an increase in CD4 + CD25 + Foxp3 + Tregs by MSCs was also reversed by CD11b hi Ly6C hi cell depletion. These results suggest that CD11b hi Ly6C hi monocytes are critical for MSC-induced immune tolerance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nivolumab, a new immune checkpoint inhibitor, binds to programmed cell death-protein 1 receptors on T cell, blockades binding of its ligands, and augments the immunologic reaction against tumor cells. Augmented immune response, however, may lead to immune-related adverse events. Herein we describe a rare case of bilateral anterior uveitis induced by nivolumab treatment for metastatic melanoma. A 54-year-old woman presented with mild conjunctival redness and blurred vision two months after initiating nivolumab treatment. Ophthalmological examination revealed bilateral non-granulomatous anterior uveitis. The flare values in the anterior chamber were monitored as an objective inflammatory index during nivolumab therapy and clinical time course was reported in this paper., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Interleukin-6 (IL-6) is a key cytokine that is strongly up-regulated during infection and inflammation. Featuring pleiotropic activity, IL-6 is responsible for the induction of hepatic acute-phase proteins, trafficking of acute and chronic inflammatory cells, differentiation of adaptive T cell responses, homeostatic regulation, and tissue regeneration. Dysregulated IL-6 production has been associated with the development of a wide variety of systemic immune-mediated, chronic diseases, and even certain types of cancer. From the ocular perspective, significant elevation of IL-6 has been found in ocular fluids derived from diabetic macular edema, retinal vein occlusion, and refractory/chronic uveitis patients. During the last decade, tocilizumab, a neutralizing monoclonal antibody (mAb) that targets the IL-6 receptor (IL-6R), has been approved for the treatment of rheumatoid arthritis in >100 countries worldwide. Furthermore, it has been reported to be effective for the treatment of a number of autoimmune diseases including uveitis and its associated macular edema. Currently numerous candidate molecular strategies targeting the IL-6 signaling pathways are in progress through clinical trials in various disorders. Herein we discuss the basic biology of IL-6 and its pathological role in the development of immune-mediated conditions, particularly focusing on inflammatory eye diseases. It also provides an overview of the on-going clinical trials with the new anti-IL-6 mAbs and their potential use in the clinical practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Antiretinal antibodies (ARAs) have previously been described in noninfectious uveitis. However, the antigen specificity of these ARAs has not been investigated. The purpose of this study was to identify antigen-specific ARAs in noninfectious uveitis., Methods: A total of 18 patients with noninfectious uveitis were enrolled. Surface plasmon resonance was used to measure binding responses of patient and control sera against several uveitogenic proteins: recoverin, S-antigen, interphotoreceptor retinoid binding (IRBP), retinal-pigment-epithelium-specific 65-kDa protein (RPE65), tyrosinase-related protein 1 (TRYP1), and tyrosinase-related protein 2 (TRYP2)., Results: The frequency of ARA positivity against S-antigen, IRBP, RPE65, TYRP1, and TYRP2 in patients with uveitis did not differ significantly from that of normal controls. However, ARA positivity for recoverin was more frequently observed in patients with uveitis (p = 0.002). A total of 10 patients in the uveitis cohort had birdshot chorioretinopathy, and all 10 were positive for anti-recoverin ARAs., Conclusions: Patients with noninfectious uveitis have increased frequency of ARA positivity against recoverin. This ARA deserves further investigations as a potential biomarker and pathogenic agent in noninfectious uveitis, especially in birdshot chorioretinopathy., (Copyright © 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease in children and JIA-associated uveitis its most frequent extra-articular manifestation. The uveitis is potentially sight-threatening and thus carries a considerable risk of morbidity with associated reduction in quality of life. The commonest form of uveitis seen in association with JIA is chronic anterior uveitis, which is almost always asymptomatic in the initial stages. Therefore, screening for JIA-associated uveitis in at-risk patients is essential. The aim of early detection and treatment is to minimise intraocular inflammation and to avoid complications that lead to visual loss, which can result from both disease activity and medications. The sight-threatening complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy, and macular oedema. There is increasing evidence for the early introduction of systemic immunosuppressive therapies to reduce topical and systemic use of glucocorticoids. A recently published randomised controlled trial of adalimumab in JIA-associated uveitis now provides convincing evidence for the use of this biologic in patients who fail to respond adequately to methotrexate. Tocilizumab and abatacept are being investigated as alternatives in children inadequately treated with anti-tumour necrosis factor drugs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Understanding the immunopathogenesis of autoimmune and inflammatory diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a role in one subtype of disease, Sjögren' syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which adequately represents both diseases. However, there is evidence to suggest that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Granulocyte colony-stimulating factor (G-CSF) is a regulator of neutrophil production, function, and survival. Herein, we investigated the role of G-CSF in a murine model of human uveitis-experimental autoimmune uveoretinitis. Experimental autoimmune uveoretinitis was dramatically reduced in G-CSF-deficient mice and in anti-G-CSF monoclonal antibody-treated, wild-type (WT) mice. Flow cytometric analysis of the ocular infiltrate in WT mice with experimental autoimmune uveoretinitis showed a mixed population, comprising neutrophils, macrophages, and T cells. The eyes of G-CSF-deficient and anti-G-CSF monoclonal antibody-treated WT mice had minimal neutrophil infiltrate, but no change in other myeloid-derived inflammatory cells. Antigen-specific T-cell responses were maintained, but the differentiation of pathogenic type 17 helper T cells in experimental autoimmune uveoretinitis was reduced with G-CSF deficiency. We show that G-CSF controls the ocular neutrophil infiltrate by modulating the expression of C-X-C chemokine receptors 2 and 4 on peripheral blood neutrophils, as well as actin polymerization and migration. These data reveal an integral role for G-CSF-driven neutrophil responses in ocular autoimmunity, operating within and outside of the bone marrow, and also identify G-CSF as a potential therapeutic target in the treatment of human uveoretinitis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Elevated tumor necrosis factor (TNF) α levels are associated with chronic autoimmune diseases in which effects of TNFα on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNFα and a significant population of CD4(+)TNFα(+) cells in the periphery and the eye at peak disease (TNFα(hi)). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNFα(lo) model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNFα(hi) disease, whereas glucocorticoid treatment is successful. TNFα has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNFα blockade suppressed severe ocular disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNFα blockade with SIRT1 activation, a synergistic suppression of severe disease compared with TNFα blockade alone occurred. Our data suggest a new role for TNFα in exacerbating the severity of autoimmune disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNFα inhibitors., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab' antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results., (Copyright © 2014. Published by Elsevier B.V.)

Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow-derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4(+) T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Uveitis is the most common ophthalmological finding in the practice of rheumatology and clinical immunology. The condition is frequently idiopathic and defined by the inflammatory status of the uvea, the part of the middle eye that includes the iris, ciliary body and choroid. Anterior uveitis involves the iris and ciliary body, while the posterior form is limited to the retina and choroid. Both forms represent indications for an urgent evaluation by an ophthalmologist as untreated cases may cause blindness. Anterior uveitis is associated with the HLA-B27 allele and is a classification criterion for seronegative arthritis forms such as ankylosing spondylitis, psoriatic arthropathy, arthritis associated with Crohn's disease and ulcerative colitis, and reactive arthritis. Posterior uveitis is associated with Behcet's disease and HLA-B51. The clinical suspicion is raised by self-reported symptoms in the case of anterior involvement and floaters for posterior uveitis while the diagnosis, in the absence of established criteria, is made by an experienced ophthalmologist., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Reactive arthritis is a form of seronegative spondyloarthritis clinically associated with inflammatory back pain, additive or migratory oligoarthritis, and extra-articular symptoms that typically follow a gastrointestinal or urogenital infection by a minimum of 1 to a maximum of 3-6 weeks. Once arthritis is observed, however, microbial tests and blood or synovial fluid cultures are negative, and only serum antibodies are detected. Reactive arthritis commonly affects young adults, most frequently white and carrying the HLA-B27 allele. The genetic susceptibility appears as necessary with only 1-15% of cases of infection developing reactive arthritis. Clinical symptoms are different from septic arthritis which manifests with fever, systemic signs of infection, and monoarthritis. The presence of large joint oligoarthritis, urogenital tract infection, and uveitis characterizes Reiter's syndrome as a clinical subtype. Ocular, skin, and heart involvement are not uncommon and may be largely variable in severity. Diagnostic criteria are based on the ACR guidelines and include rheumatological signs along with a proof of infection., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms., (Copyright © 2014. Published by Elsevier Inc.)

Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: Sarcoidosis is an idiopathic inflammatory disorder involving multiple organs, and ocular manifestation (represented by granulomatous uveitis) is one of the common features. A well-known immunologic feature in sarcoidosis is an increased CD4+ helper T-cell type 1 lymphocyte subset in bronchoalveolar lavage (BAL) fluid. The current study investigated the vitreous lymphocyte subsets of ocular sarcoidosis to elucidate the immunologic features of this disorder in the eye., Design: Case-control study., Participants and Controls: Fifty-one eyes of 38 patients with ocular sarcoidosis, confirmed by international diagnostic criteria, were enrolled in this study. Twenty-seven eyes of 26 patients with other causes of uveitis were enrolled as nonsarcoid controls., Methods: Evaluation of diagnostic tests for cell profiles of ocular sarcoidosis. Lymphocytes in the vitreous samples were analyzed by cytology, polymerase chain reaction, and flow cytometry. Peripheral blood was also obtained from each patient and analyzed in comparison with the vitreous samples., Main Outcome Measures: CD4/CD8 ratios of vitreal and peripheral T lymphocytes., Results: CD4/CD8 ratios of the vitreous T lymphocytes were significantly higher in ocular sarcoidosis than in nonsarcoidosis vitreous samples. In the patients with ocular sarcoidosis, the CD4/CD8 ratios of vitreal T lymphocytes were significantly higher than the CD4/CD8 ratios of peripheral T lymphocytes. No significant differences were found between the CD4/CD8 ratios of vitreal and peripheral T lymphocytes in the patients without sarcoidosis. Moreover, the CD4/CD8 ratios of peripheral T lymphocytes in the patients with ocular sarcoidosis were significantly higher than in patients without sarcoidosis. The sensitivity and specificity of the vitreal CD4/CD8 ratio were 100% and 96.3%, respectively, for the diagnosis of ocular sarcoidosis., Conclusions: Our findings suggest that the CD4/CD8 ratio of vitreous-infiltrating lymphocytes has high diagnostic value in ocular sarcoidosis, comparable to that of the CD4/CD8 ratio in BAL fluid lymphocytosis for pulmonary sarcoidosis. Furthermore, a high CD4/CD8 ratio of peripheral blood T lymphocytes should be one of the laboratory findings for ocular sarcoidosis. Diagnostic vitrectomy using flow cytometric analysis may be a useful adjunct for the diagnosis of ocular sarcoidosis, particularly in complex cases., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The molecular mechanism which enables activated immune cells to cross the blood-retinal barrier in spontaneous autoimmune uveitis is yet to be unraveled. Equine recurrent uveitis is the only spontaneous animal model allowing us to investigate the autoimmune mediated transformation of leukocytes in the course of this sight threatening disease. Hypothesizing that peripheral blood immune cells change their protein expression pattern in spontaneous autoimmune uveitis, we used DIGE to detect proteins with altered abundance comparing peripheral immune cells of healthy and ERU diseased horses. Among others, we found a significant downregulation of talin 1 in peripheral blood granulocytes of ERU specimen, pointing to changes in β integrin activation and indicating a significant role of the innate immune system in spontaneous autoimmune diseases., (Copyright © 2012. Published by Elsevier B.V.)

IgG4-RSD should be suspected in any patient presenting with lacrimal or salivary gland enlargement, particularly if male and manifesting mild glandular dysfunction. A serum IgG4 level, if increased, may be helpful, although a gland biopsy staining for IgG4-positive plasma cells is the definitive test. Primary low-grade B cell lymphomas of the glandular tissue, specifically MALT lymphoma and other glandular malignancy, should be considered, particularly in patients with asymmetric glandular enlargement. Patients with idiopathic uveitis should have a thorough evaluation to exclude malignancy, in particular PIOL and melanoma in adults, and diffuse retinoblastoma and ALL in children. RF remains a diagnostic challenge and atypical features such as outward displacement of the retroperitoneal structures should raise the suspicion for a malignant infiltrative process. CRPS rarely may be the first presentation of an occult malignancy and requires a thorough review of age-appropriate cancer screening. Carpal tunnel syndrome, if bilateral or associated with other systemic features, should prompt a search for amyloidosis., (Published by Elsevier Inc.)

Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B cells and widely used in the treatment of non-Hodgkin's lymphoma and rheumatoid arthritis. There is a growing amount of literature which suggests that rituximab may be useful for inflammatory ocular diseases and intraocular lymphoma. Few cases have been reported on treatment of refractory scleritis, peripherative ulcerative keratitis, uveitis and ocular surface inflammatory disorders. Rituximab may be effective in the treatment of ocular inflammatory diseases in particular the most aggressive, recalcitrant and sight-threatening forms of inflammation such as uveitis associated to juvenile idiopathic arthritis. We review the literature covering the use of Rituximab in these conditions and report our results on the efficacy of Rituximab in the treatment of 8 children with very severe and long-standing uveitis who failed to respond to one or more TNF blockers. Our patients showed improvement in activity of uveitis, reduction of concomitant corticosteroids and immunosuppressants after a mean follow-up time of 14.87 months on rituximab. No serious adverse events were encountered in our treated patients. Although further studies are needed for assessing the efficacy of rituximab and the exact dosing regimen, rituximab may be considered as a treatment alternative in patients with the most aggressive forms of inflammatory ocular diseases who fail to respond to conventional and anti-TNF immunosuppressive agents., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aqueous humor (AH) samples from patients with Behçet's disease (BD) (n=29), Vogt-Koyanagi-Harada (VKH) disease (n=21), and HLA-B27-associated uveitis (n=8), and 42 control patients were assayed for the neutrophil chemoattractants CXCL1/GRO-α and CXCL8/IL-8 and the lymphocyte chemoattractants CXCL9/MIG, CXCL10/IP-10 and CXCL12/SDF-1 with the use of a multiplex chemokine assay. Chemokine levels except SDF-1 were significantly higher in the 3 disease groups than in normal controls. Considering all patients, mean GRO-α levels were 15-fold higher than IL-8 levels and mean IP-10 levels were 22-fold higher than MIG levels. In patients with the same disease activity, AH levels of GRO-α and IP-10 were significantly higher in patients with BD than in patients with VKH disease and HLA-B27-associated uveitis (p=0.0474; p<0.001, respectively). These data suggest that GRO-α and IP-10 are the predominant CXC chemokines involved in neutrophil and activated T lymphocyte chemoattraction in endogenous uveitis, particularly in BD., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Uveitis is an intraocular inflammatory disease causing a significant visual impairment. The disease can be idiopathic, associated with infectious and systemic disorders or arisen from an unknown cause. Over the last 20years the model of EAU in mice has contributed significantly for the establishment of parameters for diagnostic evaluations and therapies for posterior uveitis in human. Many studies using recently discovered molecules which present proinflammatory and anti-inflammatory effects have been described. Moreover, new approaches of research provided by the increasing body of knowledge on components of immune responses such as cytokines, T-cell subpopulations and their associated functions have contributed for the further understanding of uveitis and possible treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Uveitis is a major and common cause of visual disability. Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next, results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40.

Purpose: To describe the 5-year outcomes of patients with cytomegalovirus (CMV) retinitis and AIDS in the era of highly active antiretroviral therapy (HAART)., Design: Prospective, multicenter, observational study., Participants: A total of 503 patients with AIDS and CMV retinitis., Methods: Follow-up every 3 months with medical history, ophthalmologic examination, laboratory testing, and retinal photographs. Participants were classified as having previously diagnosed CMV retinitis and immune recovery (CD4+ T cells ≥ 100 cells/μl), previously diagnosed retinitis and immune compromise, and newly diagnosed CMV retinitis (diagnosis <45 days before enrollment)., Main Outcome Measures: Mortality, retinitis progression (movement of the border of a CMV lesion ≥ ½ disc diameter or occurrence of a new lesion), retinal detachment, immune recovery uveitis (IRU), and visual loss (< 20/40 and ≥ 20/200)., Results: Overall mortality was 9.8 deaths/100 person-years (PY). Rates varied by group at enrollment from 3.0/100 PY for those with previously diagnosed retinitis and immune recovery to 26.1/100 PY for those with newly diagnosed retinitis. The rate of retinitis progression was 7.0/100 PY and varied from 1.4/100 PY for those with previously diagnosed retinitis and immune recovery to 28.0/100 PY for those with newly diagnosed retinitis. The rate of retinal detachment was 2.3/100 eye-years (EY) and varied from 1.2/100 EY for those with previously diagnosed retinitis and immune recovery to 4.9/100 EY for those with newly diagnosed retinitis. The rate of IRU was 1.7/100 PY and varied from 1.3/100 PY for those with previously diagnosed retinitis and immune recovery at enrollment to 3.6/100 PY for those with newly diagnosed retinitis who subsequently experienced immune recovery. The rates of visual loss to < 20/40 and to ≤ 20/200 were 7.9/100 EY and 3.4/100 EY, respectively; they varied from 6.1/100 EY and 2.7/100 EY for those with previously diagnosed retinitis and immune recovery to 11.8/100 EY and 5.1/100 EY for those with newly diagnosed retinitis. Although the event rates tended to decline with time, in general, at no time did they reach zero., Conclusions: Despite the availability of HAART, patients with AIDS and CMV retinitis remain at increased risk for mortality, retinitis progression, complications of the retinitis, and visual loss over a 5-year period., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Uveitis is a sight threatening inflammatory disorder that affects all ages and remains a significant cause of visual loss. Animal models of autoimmune and inflammatory disease in the eye allow the scientist and clinician to study the basic mechanism of the disease, and serve as templates for the development of therapeutic approaches. The accumulating knowledge of the various steps that are involved in the pathogenesis make it possible to devise specific strategies that disrupt discrete stages in the process. Some of the strategies are in the process of being translated to the clinic. New technologies emerge, promising more specific and more easily applied therapies. In this review, we will concentrate specifically on mechanisms and recent advances in the therapy of uveitis., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Ocular brucellosis is usually diagnosed by clinical criteria and serological tests. Little is known with regard to the ocular immunology of brucellosis and the use of intraocular diagnostic tests. We report retrospectively the laboratory findings of patients with ocular involvement associated with brucellosis., Materials and Methods: Patients with uveitis with no evident etiologic diagnosis were evaluated at the Instituto de Medicina Tropical "Alexander von Humboldt" of the Universidad Peruana Cayetano Heredia and the Hospital Nacional Cayetano Heredia. Patients were tested for brucellosis, tuberculosis, syphilis, toxoplasmosis, toxocariasis, and human T-cell lymphotropic virus-1. Blood and intraocular fluid samples were examined. Patients with a diagnosis of brucellar uveitis were selected as cases and patients with a diagnosis of uveitis of other etiology were included as controls. The Goldmann-Witmer coefficient was determined., Results: Twelve patients with clinical and laboratory findings suggestive of brucellar uveitis were considered as cases. Seven patients with uveitis of other etiology were selected as controls. Four (33.3%) patients with ocular brucellosis had negative ocular agglutinations and eight (66.7%) had positive agglutinations. No control cases had positive agglutinations for Brucella melitensis. The sensitivity of the test was 66.7% and the specificity 100%. Only one patient had a positive culture for B. melitensis in subretinal fluid. The Goldmann-Witmer coefficient was calculated in six cases of brucellosis uveitis and five uveitis controls. It was highly positive in three patients with ocular brucellosis. Tissue samples showed lymphoplasmacytic infiltrates., Conclusions: Intraocular serological tests could be used to support the diagnosis of ocular brucellosis.

Uveitis is a common ophthalmic disorder that can be induced in hamsters by a single intravitreal injection of bacterial lipopolysaccharide (LPS). To examine the therapeutic effects of melatonin on uveitis, a pellet of melatonin was implanted subcutaneously 2 hours before the intravitreal injection of either vehicle or LPS. Both 24 hours and 8 days after the injection, inflammatory responses were evaluated in terms of i) the integrity of the blood-ocular barrier, ii) clinical signs, iii) histopathological studies, and iv) retinal function. Melatonin reduced the leakage of proteins and cells in the anterior segment of LPS-injected eyes, decreased clinical signs such as dilation of the iris and conjunctival vessels, and flare in the anterior chamber, and protected the ultrastructure of the blood-ocular barrier. A remarkable disorganization of rod outer segment membranous disks was observed in animals injected with LPS, whereas no morphological changes in photoreceptor outer segments were observed in animals treated with melatonin. Furthermore, melatonin prevented a decrease in LPS-induced electroretinographic activity. In addition, melatonin significantly abrogated the LPS-induced increase in retinal nitric-oxide synthase activity, tumor necrosis factor-alpha, and nuclear factor kappaB p50 and p65 subunit levels. These results indicate that melatonin prevents the clinical, biochemical, histological, ultrastructural, and functional consequences of experimental uveitis, likely through a nuclear factor kappaB-dependent mechanism, and support the use of melatonin as a new therapeutic strategy for the treatment of uveitis.

Experimental autoimmune anterior uveitis (EAAU) serves as an animal model for human idiopathic AU, the most common form of intraocular inflammation of significant morbidity whose recurrence can lead to permanent vision loss. This study was undertaken to inhibit EAAU by inducing tolerance to melanin-associated antigen (MAA) and to investigate the underlying mechanisms responsible for tolerance induction. Intravenous administration of MAA both induced tolerance and inhibited EAAU in Lewis rats. Flow cytometric analysis revealed that the proliferation of lymph node cells in response to antigenic stimulation was drastically reduced in the state of tolerance both in vivo and in vitro. Our results from co-culture experiments demonstrated that intravenous administration of MAA led to the generation of T-regulatory cells that suppress T-cell proliferative responses and induce tolerance. Expression levels of both interleukin-10 and transforming growth factor-beta2 were elevated whereas reduced levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin-2 were detected in tolerance-induced animals. Tolerance was reversed by replenishing these animals with recombinant interleukin-2. Tolerance could be adoptively transferred by removing lymph node cells from tolerance-induced donors and giving them to recipient rats. Interestingly, adoptive transfer of tolerance failed when lymph nodes cells were depleted of CD4(+)CD25(+) T cells. In conclusion, T-cell nonresponsiveness because of active suppression mediated by T-regulatory cells facilitates the development of tolerance to MAA in EAAU.

Background: It has been reported that abnormalities in the balance of T-helper cells type 1/2 (Th1/Th2) may account for the pathophysiology of human autoimmune diseases. The purpose of this study was to define the role of the Th1/Th2 balance in the pathogenesis of uveitis in Behçet's disease (BD)., Methods: From February 2003 to August 2005, we studied 31 patients with active BD. Of these patients, 21 (12 female, 9 male; mean age 35.5 [SD 10] years) presented with acute uveitis, and 10 (7 female, 3 male; mean age 34 [SD 11] years) presented with inflammatory arthritis but no prior uveitis attack. The control group consisted of 10 (7 female, 3 male; mean age 34.7 [SD 8] years) age-matched, healthy individuals. CD4+ CD26+ and CD4+ CD30+ cell surface expression of the peripheral blood CD4+ T lymphocytes was evaluated by analytic flow cytometry in order to determine percentages of Th1 and Th2 lymphocyte subsets., Results: The mean percentage of CD4+ CD26+ and CD4+ CD30+ cells was 26.27 (SD 6.18) % and 2.56 (SD 0.82) %, 17.42 (SD 5.90) % and 2.86 (SD 0.72) %, and 14.99 (SD 3.96) % and 3.11 (SD 1.25) % in BD with active uveitis, BD with inflammatory arthritis but no prior uveitis attack, and control groups, respectively. T-helper 1 (Th1) cell percentage was significantly higher in the BD with active uveitis group than the BD with arthritis and no prior uveitis attack group (p = 0.001). With respect to the percentage of CD30+ Th2 cells, there was no statistical difference between the 2 BD groups (p = 0.529) or among the 3 groups (p = 0.375)., Interpretation: Th1 lymphocyte dominance in peripheral circulating blood may play a role in the pathogenesis of BD uveitis.

Nitric oxide (NO) plays a critical role in the pathogenesis of endotoxin-induced uveitis (EIU). Since NO is a labile free radical, it is difficult to examine the dynamics of NO directly in vivo. In this study, we established a system for direct monitoring of the dynamics of NO and partial pressure of oxygen (pO(2)) in EIU in rabbits. The currents (calculated concentrations) of NO and pO(2) in the vitreous were monitored after the intravitreal injection of lipopolysaccharide (LPS). In addition, the protein concentrations and nitrite levels in the aqueous humor were analyzed. The eyes were enucleated, and a histologic study was performed on their posterior segments. The tissue slices were also immunostained with anti-nitrotyrosine as a marker of peroxinitrite and/or nitrogen-related oxidants. The NO level decreased temporarily after LPS injection and then increased from 1 to 7 h. pO(2) increased temporarily for about 30 min after LPS injection. The change in NO current was inversely proportional to pO(2) after LPS injection and vice versa. The protein concentration and nitrite level after LPS injection increased significantly. These changes were suppressed by pretreatment with N(G)-nitro-l-arginine-methyl-ester. Immunohistochemical study showed enhanced immunoreactivity of nitrotyrosine in the inflamed retina. Since nitrotyrosine was detected, it appears that NO readily reacts with oxygen to produce cytotoxic species, peroxynitrite, and/or nitrogen-related oxidants. This process may be related to the retinal injury in EIU. This monitoring system can provide useful information on dynamic changes in intravitreal NO and pO(2) for understanding EIU.

Purpose: To evaluate the use of intravitreal triamcinolone (IVTA) for the treatment of macular edema secondary to immune recovery uveitis (IRU) in patients with AIDS., Design: Prospective, consecutive, interventional case series., Participants: Eight eyes of 7 patients receiving 13 injections., Methods: Prospective, consecutive, interventional case series of 13 injections involving 8 eyes in 7 patients who underwent an intravitreal injection of 20 mg decanted triamcinolone acetate for fluorescein angiographically proven IRU-related macular edema., Main Outcome Measures: The primary outcome measure was vision (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included fluorescein angiography and optical coherence tomography., Results: Visual acuity improved at all time points and was statistically significant at the 1-month and 3-month follow-up examinations. The average visual improvement was 3 lines at 3 months. Retinal volume and thickness improvement were statistically significant at all time points. All patients had a minimum follow-up of 9 months, and there were no cases of cytomegalovirus reactivation., Conclusions: Previous studies showed that treatment with sub-Tenon repository steroids for the treatment of macular edema of IRU was only marginally effective. However, the current study shows that IVTA can be an effective short-term treatment for macular edema secondary to IRU in patients with AIDS. Longer follow-up is needed to assess the durability of the effect and to monitor for longer-term complications and outcomes.

Purpose: To describe the clinical features in a series of patients with poststreptococcal uveitis and to review literature on the pathophysiology and management., Design: Retrospective and descriptive case series., Participants: Ten consecutive cases of poststreptococcal syndrome uveitis diagnosed between 1996 and 2003., Methods: Review of patient case notes., Main Outcome Measures: Age, laterality, clinical features, and anti-streptococcal lysin O titers., Results: Ten consecutive cases of poststreptococcal syndrome uveitis were identified. All our cases had bilateral nongranulomatous inflammation and raised anti-streptococcal lysin O titers. Collating data from previous reports and this series showed that 96% of the patients were below 40 years of age, and 87.5% had evidence of previous streptococcal infection. One third of the patients had posterior segment involvement. In our patients, this was in the form of vitritis, focal retinitis, optic disc swelling, and multifocal choroiditis., Conclusions: Poststreptococcal syndrome uveitis should be considered in the etiology of acute bilateral nongranulomatous uveitis in children and young patients.

We tested the hypothesis that interaction between autoantigens and chemoattractant receptors may be an important step in the development of autoimmunity. The retinal autoantigens S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) can induce autoimmune uveitis in rodent models. We evaluated the chemotactic activity of S-Ag and IRBP and found that both induced migration of human and mouse immature dendritic cells (iDCs) and lymphocytes, but not neutrophils, monocytes, or mature DCs. Cross-desensitization studies and single-receptor transfected cells revealed that subfamily of alpha chemokine receptors CXCR5 and CXCR3 mediated the chemotactic effect of IRBP, while only CXCR3 was required for the chemotactic response to S-Ag. Examination of the relationships between chemoattraction and the ability to elicit pathology at the protein or peptide levels in the mouse uveitis model revealed dissociation of the capacity to induce uveitis, lymphocyte proliferation, and chemoattraction. These studies suggest that IRBP and S-Ag can initiate innate and, in sensitive individuals, adaptive immune response by attracting iDCs and T and B cells expressing CXCR3 and CXCR5.

Autoimmunity directed against antigens of immune privileged sites, which are hidden from the immune system by blood-organ-barriers, is difficult to explain: it would require already activated cells to enter the tissue where the respective autoantigens are sequestered. Autoimmune uveitis, a sight-threatening inflammatory disease of the eye, is such an example. To induce disease autoreactive T cells must have been activated outside the eye to pass the blood-retina-barrier and then crossreact with retinal autoantigen. We have described two environmental peptides mimicking a highly pathogenic epitope from retinal S-antigen. One mimicry antigen is from rotavirus, a common pathogen causing gastroenteritis, the other from bovine milk alpha s2casein, a frequent nutritional protein ought to induce oral tolerance. Lewis rats develop uveitis after immunization with both mimicry peptides and casein protein. However, these mimicry antigens failed to induce oral tolerance for protection from uveitis, suspecting that they rather induce immunity than tolerance. Humoral and cellular immune responses to these antigens are enhanced and more frequent in patients with uveitis compared to healthy individuals. Our findings suggest that multiple environmental antigens mimic autoantigens and might cause autoimmune diseases by eliciting defensive immune responses, however, they are not necessarily useful for therapeutic tolerance induction.

Uveitis is an inflammation of the uveal tract and is one of the major causes of visual impairment. Several lines of evidence suggest an important role for activated T lymphocytes in the perpetuation of posterior uveitis. In sequel to our preliminary observations with human S-antigen, we have further investigated the proliferative response of peripheral blood lymphocytes of posterior uveitis patients against 20 linear and 9 overlapping peptides of retinal S-antigen. The expression of surface markers CD4, CD8, CD29, CD45RA in peripheral blood was detected by flow cytometry. We have also assessed the pattern of cytokines present in peripheral blood mononuclear cells (PBMCs) using ribonuclease protection assay (RPA). Nineteen out of 32 patients' lymphocytes showed proliferative response to S-antigen, one or more of its 20 linear and nine overlapping synthetic peptides. Six patients showed significant lymphoproliferative response against various peptides. The maximum response was found to peptides from the 231-270 amino acid region of human S-antigen sequence. The percentage of CD29(+) (memory cells) and CD45RA(+) (naive cells) T-lymphocytes was higher in patients compared to healthy volunteers. There was a demonstrable difference in the percentage of CD4(+) and CD8(+) lymphocytes in the patients (P <== 0.05) as compared to controls. Higher message for interleukin (IL)-5, IL-10, IL-15, IL-9, IL-2, IL-13, and interferon (IFN)-gamma was observed in uveitis patients than in healthy individuals. In brief, our study suggests that a particular region of S-antigen plays an important role in idiopathic uveitis.

Autoimmune uveitis is a sight threatening disease, which is conventionally treated with immunosuppressive medication. New treatment strategies include immunological approaches and aim at antigen specificity like oral tolerance. A peptide from the sequence of certain HLA-class I molecules plays a central role in the pathogenesis. When T cells recognize the HLA-peptide and are activated they are enabled to pass the blood-retina barrier. In the eye they recognize a cross-reactive organ-specific peptide and cause inflammation, which presents as uveitis. Here, we used the HLA-peptide as oral tolerogen to treat uveitis patients in an open study. All patients showed a positive therapeutic response and could reduce their long-lasting conventional immunosuppressive treatment. We did not observe any side effects. Moreover, side effects from conventional therapy could be reduced significantly.

Experimental autoimmune uveitis (EAU) is a Th1-cell-mediated autoimmune disease. In this study, the correlation between IRBP-specific Th1 cells in PBLs and the histological grading in the eyes was evaluated kinetically during EAU induction. EAU was induced in B10.A mice with IRBP immunization and the eyes were enucleated for histological examination on days 0, 3, 7, 15, and 21 after immunization. To determine the Th1-cell-mediated immune response, Th1 cytokines (IL-12p40 and IFN-gamma) were measured by RT-PCR in inflamed eyes. At mean time, CD4(+) and IFN-gamma(+) double positive T cells (Th1 cells) from PBLs were analyzed by flow cytometry. The level of the IRBP-specific Th1 cells was significantly increased and kinetically changed during EAU induction, but the cells reached peak time early before the disease was onset. Those IRBP-specific Th1 cells in the PBLs were evidence for EAU disease, but its peak time was different from EAU disease in the eyes. Our data suggested that it is very important to collect blood from patients at a suitable time point and the Th1 cells measured by flow cytometry are good marker for disease diagnosis.