Noninfectious immune-mediated uveitis and ocular inflammation.

Noninfectious uveitis encompasses a diverse group of ocular inflammatory disorders that share an underlying immune etiology and may be associated with systemic disease or confined primarily to the eye. Uveitis is commonly classified by anatomical location of inflammation into anterior, intermediate, posterior, and panuveitis. The treatment of noninfectious uveitis consists of corticosteroids, immunosuppressive agents, and surgically placed steroid implants. We review the epidemiology, immunopathology, and clinical features of several noninfectious immune-mediated uveitides, including HLA-B27 acute anterior uveitis, juvenile idiopathic arthritis, intermediate uveitis, sarcoidosis, Behcet's disease, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, and white dot syndromes. We also discuss the stepwise approach to medical treatment of immune-mediated uveitis as well as the characteristics, safety, and efficacy of immunosuppressive agents used to treat ocular inflammatory disease.

[Sympathetic ophthalmia--clinical case]. / Oftalmia simpatica --caz clinic.

This paper presents a case of Sympathetic ophthalmia following a penetrating ocular injury produced 30 days ago, of a patient who postponed the presentation to the ophthalmologist.

2-Methoxyestradiol Alleviates Experimental Autoimmune Uveitis by Inhibiting Lymphocytes Proliferation and T Cell Differentiation.

Purpose. To investigate the effect of 2-Methoxyestradiol (2ME2) on experimental autoimmune uveitis (EAU) and the mechanism. Method. C57BL/6 male mice were used to establish the EAU model. 2ME2 was abdominal administrated in D0-D13, D0-D6, and D7-D13 and control group was given vehicle from D0-D13. At D14, pathological severity was scored. Lymphocyte reaction was measured using MTT assay. T cell differentiation in draining lymph nodes and eye-infiltrating cells was tested by flow cytometry. Proinflammatory cytokines production from lymphocytes was determined by ELISA. Result. The disease scores from 2ME2 D0-D13, 2ME2 D0-D6, 2ME2 D7-D13, and vehicle groups were 0.20 ± 0.12, 1.42 ± 0.24, 2.25 ± 0.32, and 2.42 ± 0.24. Cells from all 2ME2 treated groups responded weaker than control (p < 0.05). The inhibitory effect of 2ME2 on lymphocyte proliferation attenuated from 2ME2 D0-D13 to 2ME2 D0-D6 and to 2ME2 D7-D13 groups (p < 0.05). 2ME2 treated mice developed fewer Th1 and Th17 cells both in draining lymph nodes and in eyes than control (p < 0.05). Lymphocytes from 2ME2 group secreted less IFN-γ and IL-17A than those from control (p < 0.05). Conclusion. 2ME2 ameliorated EAU progression and presented a better effect at priming phase. The possible mechanism could be the inhibitory impact on IRBP specific lymphocyte proliferation and Th1 and Th17 cell differentiation.

[Sympathetic ophthalmia. Clinical and morphological study in 6 cases after penetrating injury and subsequent repeated vitreoretinal operations].

The paper outlines the clinical and morphological picture of 6 sympathizing eyes enucleated in 1996 to 2003 after vitrectomy and other endovitreal interventions into early injured or operated eyes. Resurgery was attempted early after wounds or a primary operation on the average following 20 days. Sympathetic ophthalmia (SO) generally occurred in the posterior uveal tract as panuveitis or posterior uveitis and diagnosed in the late periods. Specific granulomatous inflammation in the uveal tract was observed in all eyes and the morphological feature of sympathizing eyes was the spread of an inflammatory process to the retina with the development of the latter's epithelioid-cell granulomas and adhesive chorioretinitis. The authors also discuss the possibility of additional antigenic stimulation accompanied by a progressive autoimmune process in the eye and by the generalization of a granulomatous inflammation, as well as the role of retinal minor lesions in this process as a source of additional autoantigens during repeated vitreoretinal operations. The latter, as the authors believe, are a risk factor of SO. In this connection, when repeated vutreoretinal interventions should be made in the presence of an uncompleted wound process in the eye and when they should be conducted under the conditions of active immunosuppressive therapy gain in great importance.

Human S-antigen determinant recognition in uveitis.

PURPOSE: Soluble antigen (S-Ag) is a member of the arrestin family of protein with which it shares a high level of homology. It is an immunologically privileged retinal antigen that can elicit experimental autoimmune uveitis (EAU) and is thought to be a target for ocular inflammatory diseases. This study was conducted to identify in humans, the immunogenic determinants of human S-Ag and to establish whether a specific response profile occurs in particular ocular inflammatory conditions. METHODS: Peripheral blood lymphocyte responses were measured against a panel of 40 overlapping synthetic peptides of human S-Ag in patients with chronic uveitis and compared with control subjects. Patients with Behçet disease, sarcoidosis, Vogt-Koyanagi-Harada, and sympathetic ophthalmia were tested. RESULTS: A limited number of immunodominant determinants were identified for Behçet disease and sarcoidosis. These were all located at sites of limited homology with other known arrestins. In addition, several individual patients had prominent proliferative responses to multiple determinants well above that of control subjects. This determinant spread was observed in all disease entities except sympathetic ophthalmia, which did not show any immunoreactivity to S-Ag. Significant response shifts were also noted over time in two patients. CONCLUSIONS: The results indicate that there are specific immunodominant determinants to human S-Ag in patients with certain forms of uveitis. However, in individual patients, response is not limited to these determinants. In the chronic stage of disease, response is spread over many determinants.

The role of the penetrating wound in the development of sympathetic ophthalmia experimental observations.

Clinical observations have established that sympathetic ophthalmia (SO) develops after a penetrating wound but not subsequent to often more severe intraocular disturbances such as extensive photocoagulation. A feature of the penetrating wound that appears important in the pathogenesis of SO is the access it provides for intraocular antigens to reach regional lymph nodes. The intraocular compartment has no lymphatic drainage and appears to function like a number of alymphatic biologic sites. In an experimental model of SO, subconjunctival injection of retinal S antigen in one eye induced a bilateral sympathetic uveitis, whereas intraocular injection in one eye was ineffective in inducing sympathetic disease.

Human sympathetic ophthalmia. Immunologic analysis of the vitreous and uvea.

The inflammatory cell reaction within the vitreous and uvea of a human eye with atypical sympathetic ophthalmia was studied immunohistologically and with the fluorescence-activated cell sorter. The uveal infiltrate consisted predominantly of T cells of the helper/inducer subset, with less than 5% of the cells characterized as B cells, plasma cells, or monocytes. These results suggest that T cells perform an important role in atypical human sympathetic ophthalmia. A similar population of mononuclear cells was observed in the vitreous inflammatory infiltrate, in marked contrast to the peripheral blood, where there was a significant depression of circulating T cells. The similarity between the inflammatory cell populations within the vitreous cavity and uvea, in contrast to the peripheral blood, underlines the importance of studying the intraocular inflammatory reaction in uveitis to gain further insight into the mechanism of this disease.

Early stage of human sympathetic ophthalmia. Histologic and immunopathologic findings.

Sympathetic uveitis developed in a 64-year-old woman 11 weeks after posttraumatic vitrectomy accompanied by vitreous hemorrhage. After removal of the exciting eye three weeks later, the sympathetic inflammation in the second eye subsided. Histologic examination revealed typical signs of an early stage of sympathetic ophthalmia characterized by a focally pronounced infiltration of lymphoid and T cells exclusively in the choroid. These T cells consisted of Leu 2a+ suppressor-cytotoxic T cells and a few Leu 3a+ inducer T cells situated near HLA-DR+ cells of the uvea. The latter contained electron-lucent cytoplasm without pigment granules and may represent the accessory cells for the initiation of the T-cell reaction. The findings suggest that sympathetic ophthalmia represents a T-cell-mediated cytotoxic reaction (similar to allograft rejection and graft-v-host disease) toward antigens on or near the pigment epithelium or the uveal melanocytes.

Recent advances in sympathetic ophthalmia.

Recent advances in understanding the pathogenesis of sympathetic ophthalmia are helping to remove the pigmented cloud which has obstructed the view of researchers on this disease for many years. Clinical features, diagnostic testing, histopathologic variations and principles of treatment are evaluated in the context of our increasing understanding of the pathogenesis of this disease. The relationship of sympathetic ophthalmia to Harada's disease and phacoantigenic uveitis are reviewed.

Histocompatibility antigens in sympathetic ophthalmia.

Twenty patients with histopathologically confirmed sympathetic ophthalmia (Group 1) and eight patients with "presumed sympathetic ophthalmia," based on a clinical history of bilateral uveitis occurring within four months of a perforating ocular injury (Group 2), were typed for HLA-A, HLA-B, and HLA-C antigenic determinants by a micro-lymphocytotoxicity technique. HLA antigenic determinants found in Groups 1 and 2 were compared to a control group of 107 patients with sequelae of perforating ocular injuries from accidents, intraocular surgery, or corneal ulcers (Group 3). HLA-A11 antigen showed an increased frequency of 30% in Group 1 (relative risk = 11.0; P less than .002) and an increased frequency of 32% in Groups 1 + 2 (relative risk = 10.5; P less than .0005) compared to Group 3 (frequency = 4%). This finding was validated against a second control group of 453 healthy subjects without ocular disease or trauma (Group 4). This association suggests that a genetic factor may play an important role in the pathogenesis of sympathetic ophthalmia.

Immunopathology of progressive subretinal fibrosis: a variant of sympathetic ophthalmia.

PURPOSE: We report the immunopathology of progressive subretinal fibrosis, a variant of sympathetic ophthalmia. DESIGN: Brief case report. METHOD: Review of medical record and immunopathology of a chorioretinal biopsy of a 40-year-old man who presented with left total retinal detachment (RD) following multiple vitrectomies in the right eye for RD. Small peripherally retinal holes, snow banks, and inflammatory nodules along the ora serrata were observed during left vitrectomy. Both eyes deteriorated rapidly to blindness with progressive subretinal fibrosis and inflammation over 3 months, and the patient was unresponsive to systemic prednisolone and azathioprine. RESULT: Immunopathology of the chorioretinal biopsy of the right eye revealed aggregates of CD20+ B cells, surrounded by CD3+ T cells. CD68+ macrophages were scattered throughout. CONCLUSION: The rapid clinical course described in this case may be related to the unique immunopathology of rapidly forming peudogerminal centers in the choroids and retina.

Immunological investigations in post-traumatic granulomatous and non-granulomatous uveitis.

Histopathological and immunological investigations have been performed in 16 cases of post-traumatic granulomatous (10) and non-granulomatous uveitis (6). Most cases of sympathetic ophthalmitis showed evidence of cell mediated immunity to uveoretinal antigens, though it was not possible to make a definitive diagnosis on immunological grounds alone. Three patients with post-traumatic non-granulomatous uveitis showed a positive immunological response to ocular antigens, and 2 of these later developed clinical evidence of sympathetic ophthalmitis, which suggests that post-traumatic non-granulomatous uveitis in such cases may represent a presympathetic (i.e., incipient) or modified stage of the disease.

Humoral and cellular immune reactions against retinal antigens in clinical disease.

Autoimmune reactions against retinal antigens have been suggested to play an important role in clinical uveitis in man. As yet the evidence for this assertion is very weak. Sympathetic Ophthalmia is a disease entity which comes closest to acceptance as an autoimmune disease although the autoantigen involved has not been identified. Both cellular and humoral autoreactivity against retinal antigens have been found both in uveitis patients as well as in healthy controls. Very high levels of retinal antibodies were found in onchocerciasis patients but no relation was observed with the occurrence of chorioretinitis. Differences were observed when testing patient sera against human or bovine retinal antigens (S-antigen or IRBP) emphasizing the need for using human tissue when investigating autoimmune responses. Circumstantial evidence in favor of an autoimmune etiology of uveitis include the morphology of the inflammatory infiltrate, effect of immuno-suppressive therapy and especially the establishment of experimental animal models. The experimental models of S-antigen or IRBP induced uveitis are primarily T cell mediated and also show pineal gland involvement. As yet no "established" human autoimmune disease has been described with a dominant role for T cells. Furthermore there is no evidence for pineal gland involvement in clinical uveitis. Analysis of the specificity of the T cell infiltrate or deposited immunoglobulins obtained from the diseased tissues may provide conclusive evidence for a possible autoimmune character of certain clinical uveitis entities.

Sympathetic ophthalmia, a genuine autoimmune disease.

Intraocular inflammation of exogenous origin, which may lead to the loss of visual function in both eyes, i.e. SO confronts ophthalmologists much less rarely than might be expected. Epidemiological studies comprising ergophthalmological aspects underscore this. Questions with regard to therapy should consider the fact that the T cell-mediated cytotoxic disease which causes the transition from the initially unilateral subthreshold exogenous uveitis into the bilateral progressive phase is by no means a rare disorder, especially in secondary surgical operations on predamaged eyes with fresh intraocular hemorrhages, vascular neoplasia and secondary glaucoma. This should be recalled again by practicing ophthalmologists, thus enabling the prevention of SO. If SO is a "forme fruste" of retinitis pigmentosa, as is very likely to be the case, further clarification requires clinicopathologic studies in close collaboration with immunologists.

Sympathetic orchidopathia.

Subfertility has recently been shown to follow unilateral torsion of the spermatic cord in more than half the patients studied. Since the anatomical anomaly that predisposes to torsion (a high investment of the tunica vaginalis) is commonly bilateral, there could be an associated congenital defect in spermatogenesis on each side. Alternatively, autoantigens escaping from the ischaemic or 'exciting' testis could trigger an immunological response which damages the contralateral or 'sympathising' testis. Demonstration of an autoallergic (sympathetic) orchidopathia, analogous to sympathetic ophthalmia, would fundamentally alter the management of testicular torsion.

[Sympathetic ophthalmia in an elderly man].

A 78-years-old man suffered from sympathetic ophthalmia. He had been treated with 5-fluorouracil (5-FU) for metastasis of colon cancer in the liver. He received a perforating eye injury in the left eye thereafter the eye became phthisic. Two months after the injury, he noticed visual disturbance in the right eye. He was treated with large doses of systemic corticosteroid after a diagnosis of uveitis of the right eye, but the visual acuity of the right eye became worse. The eye showed non-specific diffuse uveitis. A diagnosis of sympathetic ophthalmia was made from previous history and ocular findings. We enucleated the injured eye and continued the systemic corticosteroid. Then the right eye improved. Histopathological examination of the enucleated eye revealed the choroid was infiltrated with a granulomatous lesion of lymphocytes and epithelioid cells. HLA typing showed DR4, DR8, DR52, DR53, and DQ1, and we made a final diagnosis of sympathetic ophthalmia. It is probable that the clinical findings were modified by the 5-FU treatment and the patient's advanced age.

[Immuno-correcting therapy of sympathetic ophthalmia]. / Immunokorrigiruiushchaia terapiia simpaticheskoi oftal'mii.

Exchange plasmapheresis was used in correction of the immune homeostasis in 5 patients with sympathetic ophthalmia. The inflammatory process ceased in all the cases. Exchange plasmapheresis resulted in improvement of the blood supply to ocular vessels, of intraocular vessel function, and of metabolic processes in the external layers of the retina. Cellular and humoral immunity parameters normalized. The hemo- and hydrodynamic parameters of the eye improved; all these results evidence that exchange plasmapheresis is an effective method in the treatment of sympathetic ophthalmia.

[Sympathetic ophthalmia as an autoimmune disease]. / Simpaticheskaia oftal'miia kak autoimunnoe zabolevaniie.

Discusses published reports and one's own findings indicating that sympathetic ophthalmia can be regarded as an autoimmune disease.

[Cataract extraction in a patient with sympathetic uveitis after immunity correcting therapy]. / Ekstraktsiia katarakty u bol'nogo s simpaticheskim uveitom posle provedeniia immunokorregiruiushchei terapii.

A complicated cataract on the only eye was effectively extracted in a patient with uveitis running a sluggish course with manifest disorders of T-cell immunity. Immune correction in combination with routine therapy of uveitis helped prepare the patient to surgery for cataract and attain good results.

Immunopathologic processes in sympathetic ophthalmia as signified by microRNA profiling.

PURPOSE: Recent discovery of microRNAs and their negative gene regulation have provided new understanding in the pathogenesis of inflammatory diseases. This study demonstrated microRNA expression profiling and their likely role in sympathetic ophthalmia, using formalin-fixed, paraffin embedded samples. METHODS: Two groups of four enucleated globes (total eight globes) from patients with clinical and histopathological diagnosis of SO (experimental samples) and one group of four age-matched, noninflamed enucleated globes (control samples) were used. Human genome-wide microRNA PCR array was performed and results were subjected to bioinformatics calculation and P values stringency tests. The targets were searched using the recently published and periodically updated miRWalk software. Quantitative real-time PCR and immunohistochemical staining were performed to confirm the validated targets in the mRNA and in the protein levels, respectively. RESULTS: No microRNA was significantly upregulated in SO, but 27 microRNAs were significantly downregulated. Among these, four microRNAs (hsa-miR-1, hsa-let-7e, hsa-miR-9, and hsa-miR-182) were known to be associated with the inflammatory signaling pathway. Only hsa-miR-9 has the validated targets, tumor necrosis factor-α, and nuclear factor kappa B1, which have been previously shown to be associated with mitochondrial oxidative stress-mediated photoreceptor apoptosis in eyes with SO. CONCLUSIONS: Identification of altered levels of microRNAs by microRNA expression profiling may yield new insights into the pathogenesis of SO by disclosing specific microRNA signatures. In the future these may be targeted by synthetic microRNA mimic-based therapeutic strategies.