Intraocular Inflammatory Disease Research Articles

SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy

Uveitis is an intraocular inflammatory disease mediated by Th1 lymphocytes. Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. Long-term humanized anti-interleukin-2 (IL-2) receptor α (Daclizumab) therapy has few side effects and is as effective as standard immunosuppression for treating severe uveitis. However, it is necessary to carefully monitor levels of activated T cells in the eye to allow prompt re-institution of standard immunosuppressive therapy to non-responders to Daclizumab therapy. Suppressors of cytokine signaling (SOCS) are feedback regulators of Th1/Th2 cytokines. SOCS5 and SOCS3 are preferentially expressed in Th1 and Th2 cells, respectively, and are thought to be lineage markers for T-helper cells. In this study, we have investigated whether SOCS3 or SOCS5 expression can serve as surrogate markers of T-cell levels in the eye. Compared to healthy volunteers, SOCS5 mRNA is significantly elevated in PBMC of uveitis patients while SOCS3 is decreased. However, after Daclizumab therapy SOCS5 mRNA level is significantly decreased, suggesting that SOCS5 mRNA can be used as diagnostic tool to monitor therapeutic response of uveitis patients. Our data also suggest that SOCS5 may serve as a new therapeutic target for uveitis and other autoimmune diseases.

Iron chelation abrogates excessive formation of hydroxyl radicals and lipid peroxidation products in monocytes of patients with Eales' disease: Direct evidence using electron spin resonance spectroscopy

Purpose. Eales' disease (ED) is an idiopathic retinal vasculitis condition, which affects the retina of young adult males. Retinal changes include perivasculitis, non-perfusion and neovascularization. Disruption of blood-retinal barrier (BRB) is the common feature in intra-ocular inflammatory diseases. Disruption of BRB results in vascular hyper permeability and infiltration of circulating leukocytes into the retinal parenchyma. Monocyte (MC) activation results in oxidant thrust and subsequent tissue damage. This has been reported in various intra-ocular inflammatory diseases such as uveitis and Behcet's disease. However, there are no such reports available in ED. Hence in the present study we have investigated the role of MC activation and hydroxyl radicals (•OH) production and its possible involvement in promoting the development of retinal vasculitis in patients with ED. Methods. Twelve patients with ED and twelve healthy volunteers were recruited for the study. MC was separated from their peripheral blood. MC from patients with ED and control subjects was stimulated with phorbol-12-myristate - acetate (PMA) and •OH generated was analyzed using an electron spin resonance spectrometer (ESR). Superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), and iron content was determined in MC to assess the oxidant thrust and antioxidant defense. Results.•OH generation was elevated in MC from patients with ED, which coincided with diminished SOD activity and elevated levels of iron and TBARS, when compared with healthy control subjects. •OH generation was abrogated when MC from ED were co-incubated with PMA and iron chelators such as diethylenetriaminepentacetic acid (DTPA) and desferrioxamine. Iron chelation also inhibited TBARS accumulation restored SOD activity in MC of patients with ED. Conclusions. For the first time we have demonstrated the production of •OH generation in MC of patients with ED using ESR. Further we have shown the beneficial effect of iron chelation in mitigating free radical mediated changes in cellular metabolism. Based on our findings, we provide further evidence for the role of oxidant thrust in promoting retinal tissue damage in patients with ED.

Bartonella vinsoniisubspeciesberkhoffias a possible cause of anterior uveitis and choroiditis in a dog

A 2-year old, neutered, female spaniel mixed breed was referred to the North Carolina State University Veterinary Teaching Hospital for evaluation of bilateral anterior uveitis. The dog was febrile and, in addition to anterior uveitis, multifocal hyporeflective lesions were present in the tapetal fundus of both eyes. The antibody titer for Bartonella vinsonii subspecies berkhoffi was positive (1 : 512). Aqueous paracentesis was performed for PCR in an attempt to detect B. vinsonii in the eye but was unsuccessful. The ocular manifestations of Bartonella infection in humans are currently expanding as more sensitive serologic and PCR techniques are being developed to identify Bartonella spp. In addition to optic neuritis and neuroretinitis, retinochoroidal lesions are one of the most common manifestations of B. henselae infection, and are frequently accompanied by vitreous or anterior segment inflammation. Diagnosis of a Bartonella infection in humans can be made on serology alone, in conjunction with ocular examination findings. The ultimate proof of B. vinsonii (berkhoffi) as a direct cause of ocular disease would be detection of the infectious agent in the eye. However, it is unknown at this time whether Bartonella causes ocular disease primarily, secondarily via an autoimmune reaction, or both. Due to the difficulties associated with culture of Bartonella spp. and the limitations of PCR, serology is currently the most useful tool for screening dogs for possible Bartonella spp. infection. In the case presented here, even though the PCR was negative, the clinical signs of anterior uveitis and choroiditis might reasonably be associated with B. vinsonii (berkhoffi) seroreactivity, which was repeatable on three separate occasions. Clinical improvement was also accompanied by a post-treatment decrease in B. vinsonii (berkhoffi) seroreactivity, potentially supporting resolution of Bartonella infection in this dog. This is the first reported case of a possible association between uveitis, choroiditis and Bartonella infection in the dog, without clinical manifestations of other organ or tissue involvement. Future studies based on PCR analysis of intraocular fluids may clarify the involvement of B. vinsonii (berkhoffi) in dogs with intraocular inflammatory disease. Furthermore, performing fluorescein angiography in dogs with elevated Bartonella titers may also prove useful in the identification and characterization of lesions.

Cytokines and immunopathogenesis of intraocular posterior segment inflammation

Summary Intraocular inflammatory eye disease remains a significant cause of visual handicap in the working age population within developed countries. The development of inflammation is unquestionably multifactorial, including genetic susceptibility, nutritional status, innate stimuli such as injury and concomitant ocular and systemic infection, and presence of autoreactive T cells. When no overt infectious agent is identified in uveitic patients, we presume that autoimmunity is the underlying pathogenesis. Although retinal antigen-specific Th1 CD4 + T cells mediate experimental models of posterior uveitis, confirmation of such in man has yet to be fully established. Antigen is the initiator of all acquired immune responses, whereupon the primary function of the immune system is to recognise exogenous antigens and eliminate pathogens. Additionally, the maintenance of immune regulation is brought about by tolerance to self-antigens acquired during development (central tolerance) or actively during adult life (peripheral tolerance) and in the case of exogenous antigens (viral and bacterial) immune responses are, in part, kept in check by inhibitory cytokines and soluble cytokine receptors. The dynamic and continual regulation of immune responses is orchestrated by cytokines, controlling leukocyte behaviour and activation including antigen-presenting cells (dendritic cells; DC), antigen-specific T cells, and non-specific leukocytes such as macrophage and granulocytes. Moreover, tissues such as the eye are endowed with powerful immunomodulatory mechanisms, in which cytokines play a pivotal role to control immune responses, limit tissue damage, and restore homoeostasis.

Changing patterns of intraocular inflammatory disease in Japan

Purpose: We investigated the frequencies and clinical characteristics of Japanese patients with uveitis. Methods: Records of 189 patients referred from April 1999 to March 2001 were retrospectively reviewed. Results: Fifty-six patients (29.6%) had anterior uveitis, 13 (6.9%) intermediate uveitis, 59 (31.2%) posterior uveitis, 58 (30.7%) panuveitis, and three (1.6%) papillitis. The most common diagnoses were Vogt-Koyanagi-Harada (VKH) disease (10.1%), biopsy-proven or presumed sarcoidosis (9.5%), acute anterior uveitis (7.9%), tuberculosis (6.9%), and Behçet’s disease (5.8%). Seventy-three patients (38.6%) were treated with local therapy alone, and 95 patients (50.3%) required systemic therapy. Ocular complications developed in 19.6% of patients, and systemic complications in 2.1%. Conclusions: These results confirm a continued high frequency of VKH disease and sarcoidosis, but suggest a decreased frequency of Behçet’s disease and an increased frequency of tuberculosis. Roughly one-half of the patients required systemic treatment in addition to local therapy, and ocular and/or systemic complications developed in one-fifth of the patients.

Efficiency of mycophenolate mofetil in the treatment of intermediate and posterior uveitis

The severity of disease and the side-effects of long-term corticosteroid treatment support the rationale for other immunosuppressive drugs in the management of uveitis. Mycophenolate mofetil (MMF) is a selective inhibitor of ionosine monophosphate dehydrogenase and exerts its major effects by modulation of the function of T and B lymphocytes. This study was undertaken to evaluate the clinical effect of MMF in the control of intermediate and posterior uveitis. A retrospective study of 18 consecutive patients with intermediate or posterior uveitis treated with MMF was performed. Activity of intraocular inflammation was graded according to the guidelines of the international uveitis study group before and during treatment with MMF. Furthermore, the ability of MMF treatment to reduce the steroid dosage and/or substitute other immunosuppressive agents with unacceptable side-effects (cyclosporin A, tacrolimus, azathioprine) was evaluated. The indication for treatment with MMF in all 18 patients (age range: 11-73 years) was either poor control of ocular inflammation by the previous immunosuppressive therapy or unacceptable side-effects of this therapy. The daily MMF dose was 2 g and therapy was combined with cyclosporin A and/or prednisolone. One patient received MMF monotherapy. Corticosteroids were discontinued in 4 patients and the steroid dose could be reduced in 14 patients following MMF therapy. Marked resolution of ocular inflammatory activity occurred in 13 patients. The most frequently observed side-effects of MMF were myalgia, fatigue, headache and gastrointestinal problems. MMF was effective in disease control in the majority of patients with intermediate and posterior uveitis and proved to be a useful second line immunosuppressant for refractory intraocular inflammatory disease with an acceptable profile of side-effects.

BENCH TO BEDSIDE: NEW APPROACHES TO THE IMMUNOTHERAPY OF UVEITIC DISEASE

Intraocular inflammatory disease, or uveitis, appears to be due in large part to noninfectious, cell-mediated mechanisms. Experimental autoimmune uveitis (EAU) has been a valuable tool to better understand underlying mechanisms of this disorder, and it provides the possibility to evaluate new approaches to immunotherapy as well. Two approaches described here are oral tolerance and anti-IL2 receptor therapy. Both therapies were evaluated in the animal model and showed positive therapeutic effects. Based on these observations, both approaches were used in the treatment of patients with uveitis. Oral tolerance showed initial promising results. Anti-IL2 receptor therapy has been used for over 4 years in uveitis patients with an additional study evaluating this therapy in Behçet's disease. Future plans are to expand this approach to a larger number of patients. The use of animal models has been very useful in better understanding mechanisms of ocular disease and bringing new therapeutic approaches to the clinic.

Human Retinal S-Antigen: T Cell Epitope Mapping in Posterior Uveitis Patients

Uveitis, an intraocular inflammatory disease which affects the uveal tract and the retina of the eye in humans, is one of the major causes of visual impairment. Posterior uveitis is often associated with inflammation of the retina and vitreous. Unfortunately, etiological diagnosis of the disease is not possible in the majority of patients. It is generally felt that an autoimmune mechanism may be involved in so-called idiopathic cases. The role of retinal S-antigen, its 20 linear peptides spanning the entire sequence, and 2 additional peptides, known to be uveitopathogenic in experimental animals, was studied in 26 patients with uveitis. Lymphocyte proliferative response was tested in vitro to identify the epitopes of S-antigen involved and to establish their role in the pathogenesis of uveitis. Of 26 uveitis patients tested, 11 showed a significant T cell proliferative response in vitro to at least 1 antigen used. None among the controls showed any response to the peptides or native S-antigen used in this study. We have found that uveitis patients respond most frequently to peptide 4 (61–80), peptide 5 (81–100), peptide 8 (141–160), peptide 9 (161–180), peptide 12 (221–240), and peptide 13 (241–260) of the human S-antigen. These results further confirm that autoimmunity to retinal S-antigen may play a role in the etiopathogenesis of a subset of patients with idiopathic uveitis.

Photoreceptor function in eyes with macular edema

Purpose The irreversible loss of visual acuity in macular edema is usually attributed to permanent loss of photoreceptor cells, although there is hardly any information on changes in photoreceptor function in macular edema. The purpose of this study was to assess photoreceptor function in various stages of macular edema and to relate the findings to visual acuity and angiographic changes. Methods Directional sensitivity (optical Stiles-Crawford effect) and visual pigment density of foveal cones was measured with a custom-built scanning laser ophthalmoscope (SLO) in 19 eyes of 19 patients. Twelve eyes exhibited macular edema: five of inflammatory origin, and seven of diabetic origin. Seven eyes with an intraocular inflammatory disease without clinical or angiographic evidence of edema were also included (four of which had previous macular edema and one of which had shown development of macular edema at the 1-year follow-up). Results of SLO measurements were related to findings using fluorescein angiography and Snellen visual acuity, both assessed at the time of SLO measurement and 6 months thereafter. Results Eyes with macular edema exhibited diminished directional sensitivity of photoreceptor cells in the fovea compared with eyes without (P = 0.02). Visual pigment density of eyes with macular edema was decreased and associated with both initial and follow-up visual function and with the angiographic macular edema grade at follow-up. Abnormal directional sensitivity and pigment density were already present in eyes with slight edematous changes and normal visual acuity. Conclusions Eyes with inflammatory or diabetic macular edema showed decreased directional sensitivity and visual pigment density in the macular area. These findings may support a role for SLO measurements in detecting retinal damage due to macular edema.

Management of intraocular inflammatory disease

The uvea of the eye is divided into the anterior uvea (iris and ciliary body) and posterior uvea (choroid). Clinical signs of anterior uveitis include conjunctival hyperemia, corneal edema, aqueous flare, miosis, and a decrease in intraocular pressure. Inflammation of the posterior uvea often involves the retina as well resulting in a chorioretinitis. Clinical signs of chorioretinitis may include multifocal lesions in tapetal or nontapetal fundus, retinal detachment, and a decrease in vision. The etiology of uveitis is complex and includes numerous infectious, neoplastic, immune-mediated, and other diseases. Treatment is directed at the underlying systemic disease, if present, as well as symptomatic treatment for the eye. The diagnostic and therapeutic approach to a patient with uveitis is discussed.

Ocular manifestations of systemic infections.

Ocular involvement, mainly uveitis or retinochoroiditis, is common in various systemic diseases, such as endogenous endophthalmitis, Lyme disease, human T-cell lymphotropic virus type I infection, toxoplasmosis, and toxocariasis. Recent progress, especially in laboratory microbiologic testing, has enabled us to reliably diagnose many formerly idiopathic intraocular inflammatory diseases. A group of systemic infectious diseases, including those discussed here, are implicated as a body of emerging or re-emerging diseases that have appeared in the past two decades and are thought to have a close relation with global socioenvironmental changes. This paper discusses recent clinical and experimental studies of the most important systemic infectious diseases that affect the eye.

Presumed ocular bartonellosis

BACKGROUNDThe spectrum of diseases caused by Bartonella henselae continues to expand and ocular involvement during this infection is being diagnosed with increasing frequency.METHODSThe clinical features and visual prognosis for 13...

IFN-γ Increases the Severity and Accelerates the Onset of Experimental Autoimmune Uveitis in Transgenic Rats

AbstractExperimental autoimmune uveitis (EAU) is a predominantly Th1-mediated intraocular inflammatory disease that serves as a model for studying the immunopathogenic mechanisms of uveitis and organ-specific autoimmune diseases. Despite the well-documented role of IFN-γ in the activation of inflammatory cells that mediate autoimmune pathology, recent studies in IFN-γ-deficient mice paradoxically show that IFN-γ confers protection from EAU. Because of the implications of these findings for therapeutic use of IFN-γ, we sought to reexamine these results in the rat, another species that shares essential immunopathologic features with human uveitis and is the commonly used animal model of uveitis. We generated transgenic rats (TR) with targeted expression of IFN-γ in the eye and examined whether constitutive ocular expression of IFN-γ would influence the course of EAU. We show here that the onset of rat EAU is markedly accelerated and is severely exacerbated by IFN-γ. In both wild-type and TR rats, we found that the disease onset is preceded by induction of ICAM-1 gene expression and is characterized by selective recruitment of T cells expressing a restricted TCR repertoire in the retina. In addition, these events occur 2 days earlier in TR rats. Thus, in contrast to the protective effects of IFN-γ in mouse EAU, our data clearly show that intraocular secretion of IFN-γ does not confer protection against EAU in the rat and suggest that IFN-γ may activate distinct immunomodulatory pathways in mice and rats during uveitis.

Strategies for the treatment of intraocular inflammatory disease

Strategies for the treatment of intraocular inflammatory disease

Bartonella serology for patients with intraocular inflammatory disease.

To determine the role of Bartonella henselae in intraocular inflammatory disease and identify its clinical features. We retrospectively determined the serum immunoglobulin (Ig)G and IgM antibodies against B. henselae and Bartonella quintana by enzyme immunoassays in stored sera of 138 consecutive newly referred patients with uveitis who, during the acute stage of their ocular disease, underwent a standardized screening protocol to determine the cause of uveitis. For the entire series, the frequency of high positive levels of IgG (above 1:900) or IgM (above 1:300) antibody against B. henselae was 6% (8/138) and 3% (4/138), respectively. Except for cross-reactions between B. henselae and B. quintana, we did not find additional evidence for cross-reactions among the various bacteria tested (Coxiella burnetii and Chlamydia pneumoniae). All patients with proven infectious uveitis (n = 21) and those with established uveitic entities (n = 37) had negative B. henselae serology. High positive IgG levels were observed in 9% of patients (5/54) with unknown cause of uveitis, in two subjects with human leukocyte antigen (HLA)-B27 positive uveitis, and in one with sarcoidosis. Five patients with uveitis of unknown origin and highly elevated IgG levels against B. henselae exhibited clinical features characterized by papillitis with surrounding retinal focal lesions or edema. The serologic and clinical data indicate that uveitis in seropositive cases may be caused by B. henselae. We do not recommend including testing for B. henselae in initial screening of patients with uveitis, but consider it worthwhile for those with papillitis and screening results within normal limits.

Cytokine Regulation of RANTES Production by Human Retinal Pigment Epithelial Cells

The mechanism whereby inflammatory cells gain access to the retina in posterior intraocular inflammatory disease remains unclear. The chemokine RANTES has the potential to influence the migration of memory T cells and monocytes across the blood–retinal barrier during inflammatory eye disease. We have therefore examined the production of RANTES by cultured human retinal pigment epithelial cells (RPE), which form a part of the blood–retinal barrier, in response to cytokines likely to be present in the microenvironment. IL-1β and TNFα stimulated RANTES production by these cells. IFN-γ acted synergistically with TNFα to increase RANTES production. In contrast, IL-4 down-regulated RANTES production stimulated by TNFα. RT–PCR studies showed that RANTES mRNA from RPE followed the same pattern of expression in response to cytokines as did RANTES production indicating that RANTES production was controlled at, or prior to, transcription. RANTES is producedin vitroby RPE in response to the proinflammatory cytokines IL-1β, TNFα, and IFN-γ and is therefore likely to play a role in the development of the inflammatory eye disease endogenous posterior uveitis.

Experimental autoimmune uveitis: molecular mimicry and oral tolerance.

Intraocular inflammatory disease or uveitis, which affects the uveal tract and the retina of the eyes in human, is the major cause of visual impairment. Experimental autoimmune uveitis (EAU) is a T-cell-mediated autoimmune disease directed against retinal proteins and has been studied in several mammalian species including subhuman primates as a model for human posterior uveitis. Autoimmune responses provoked by molecular mimicry occur when the nonself and host determinants are similar enough to cross-react yet different enough to break immunological tolerance, and is one of the proposed mechanisms for induction of autoimmune diseases. Therapeutic immunomodulatory strategies have been used to induce antigen-specific peripheral immune tolerance in animal models of T-cell-mediated autoimmune diseases by oral administration of autoantigens. Oral tolerance leads to unique mechanisms of tissue and disease-specific immunosuppression, which would circumvent the immunotherapeutic problem of multiple target tissue autoreactivity. Several groups have investigated the effects of delivering autoantigens across gastric mucosal surfaces. This review briefly discusses molecular mimicry and the mechanism of induction of oral tolerance with respect to immunopathogenesis of T-cell-mediated autoimmune disease in general and EAU in particular.

Causes and frequency of blindness in patients with intraocular inflammatory disease.

Uveitis, an intraocular inflammatory disease, is a significant cause of visual impairment. It is not known how many patients with uveitis will retain visual acuity and how many develop visual impairment or even blindness. The aim of this study was to assess the frequency of blindness in patients with uveitis and, more specifically, to identify the clinical profile of patients at risk for visual loss. A cross sectional and retrospective study of 582 patients with uveitis who visited the ophthalmology departments of two university hospitals in the Netherlands was performed. Within the group of 582 patients, 203 (35%) exhibited blindness or visual impairment; bilateral legal blindness developed in 22 (4%) patients, 26 (4.5%) had one blind eye with visual impairment of the other, and nine (1.5%) had bilateral visual impairment. Unilateral blindness developed in 82 (14%) patients, whereas 64 (11%) exhibited unilateral visual impairment. The most important cause of both blindness and visual impairment was cystoid macular oedema (29% and 41%, respectively). Complications of uveitis were encountered in more than half of the patients and 23% underwent one or more surgical procedures. When the patients were subdivided according to anatomical site, those with panuveitis had the worst visual prognosis. The systemic diseases associated with a poor visual prognosis were juvenile chronic arthritis and sarcoidosis. Ocular toxoplasmosis was the most frequent cause of unilateral visual loss. Cystoid macular oedema is the most frequent complication of uveitis and its occurrence plays a decisive role in the visual outcome of this disease.

Intraocular inflammatory disease (uveitis) and the use of oral tolerance: a status report.

Intraocular inflammatory disease, or uveitis, is a disorder that mostly affects children and young adults. It is the cause of about 10% of the severe visual handicap in the United States. Many of the severe, sight-threatening uveitic conditions are thought to be driven by putative autoimmune mechanisms, often with high-dose oral prednisone use as treatment, along with cytotoxic agents, antimetabolites, and cyclosporine adjunctively. The feeding of the uveitogenic retinal S-Ag to rats immunized with the same antigen resulted in clinical protection. A pilot study in which two patients, one with pars planitis and the other with Behcet's disease, were fed with the retinal S-Ag resulted in these patients' immunosuppressive medication being decreased and/or stopped. The trial also provided us with information concerning dosage and expected immune responses. A randomized, masked study looking at the effect of feeding retinal antigens to uveitis patients is ongoing.

Antineutrophil Cytoplasmic Antibodies in Chronic Idiopathic Intraocular Inflammatory Disease

Antineutrophil cytoplasmic antibodies (ANCA) are found in the sera of patients with Wegener's granulomatosis and other systemic necrotising vasculitides. Antibody levels correlate closely with disease activity so that follow-up of ANCA titres might be helpful in guiding therapy. The authors assessed in a cohort of patients with chronic ocular inflammatory disease ANCA titres prospectively over a two-year period, by an indirect immunofluorescent technique. They found that sera from 10/64 patients (15.6%) stained positive for c-ANCA antibodies, and none stained for p-ANCA. Six c-ANCA positive patients had one or more clinical relapses (range one to three) during this study period. Each relapse correlated with a rise in ANCA titre. The remaining four patients who were found to have persistently low titres of c-ANCA had no clinical relapses. The authors conclude that although c-ANCA is only present in a small proportion of patients with idiopathic chronic intraocular inflammatory disease, the ANCA titre may be used to monitor disease activity in this group of patients. Further study to assess the potential of c-ANCA titres in predicting disease relapse is indicated, which in the future may minimise the side effects of currently used immunosuppressive therapies.