RARE DISEASE
Sympathetic ophthalmia
Sympathetic ophthalmia
Sympathetic ophthalmia
Synonyms: Sympathetic uveitis
Synonyms: Sympathetic uveitis
Synonyms: Sympathetic uveitis
Drug discovery
1
drug
With orphan designation
Overview
Sympathetic Ophthalmia (SO) is a rare, bilateral granulomatous panuveitis occurring days to years after penetrating ocular trauma or surgery. Triggered by autoimmune responses to exposed ocular antigens, it presents with pain, photophobia, choroiditis, Dalen-Fuchs nodules, and vision loss. Diagnosis is clinical, supported by multimodal imaging. Prompt immunosuppression with corticosteroids and immunomodulatory agents is critical to prevent bilateral blindness [1][4][6].
Therapies
First-line: High-dose corticosteroids (oral prednisone 1–2 mg/kg/day or IV pulse therapy) [3][6][10].
Adjuvants: Cyclosporine, azathioprine, or mycophenolate for steroid-sparing effects [3][6][12].
Refractory cases: TNF-α inhibitors (adalimumab, infliximab) show efficacy in restoring vision [12][16][20].
Categories: rare ophthalmic disorders
Research Papers
302 drug discovery papers about Sympathetic ophthalmia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
302 drug discovery papers about Sympathetic ophthalmia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-14 | Fellow eye’s revenge: Navigating sympathetic ophthalmia following penetrating keratoplasty
Sympathetic ophthalmia (SO) is a rare bilateral granulomatous uveitis that may occur following penetrating ocular injury or surgery. We report a 48-year-old man who developed SO in the left eye 3 weeks after therapeutic penetrating keratoplasty with cataract extraction for fungal keratitis in the right eye. He presented with decreased vision and floaters, and multimodal imaging, including optical coherence tomography, fundus fluorescein angiography, and fundus autofluorescence, demonstrated exudative retinal detachment with characteristic posterior segment findings. Prompt treatment with intravenous methylprednisolone followed by tapering oral corticosteroids and mycophenolate mofetil resulted in complete resolution of inflammation and subretinal fluid, with improvement of best-corrected visual acuity to 0.2 logMAR in both eyes at 6 months and no recurrence. This case highlights the importance of maintaining a high index of suspicion for SO after therapeutic penetrating keratoplasty and emphasizes that early diagnosis and aggressive immunosuppressive therapy can preserve vision.
2026-04-01 | Sympathetic Ophthalmitis Following Ocular Trauma and Vitrectomy in a Young Male
We report a case of sympathetic ophthalmitis (SO) in a 25-year-old male following open globe trauma and vitrectomy. The patient presented with left eye hyphema and scleral laceration following trauma from a burst bicycle tyre. He underwent pars plana vitrectomy (PPV) with corneoscleral repair and silicone oil tamponade. Two months later, the sympathizing eye (right eye) developed anterior chamber cells, initially managed as uveitis. Progression prompted multimodal imaging with fundus fluorescein angiography (FFA) and optical coherence tomography (OCT), which revealed pinpoint leaks and subretinal fluid (SRF), confirming SO. Treatment with intravenous methylprednisolone (1 g/day for 3 days) followed by tapering oral corticosteroids restored visual acuity to 6/6 within 4 weeks. This case underscores the importance of early recognition and prompt corticosteroid therapy to preserve vision in SO.
2025-12-22 | Atypical Posterior Sympathetic Ophthalmia Shortly After PRESERFLO™ MicroShunt Implantation Masquerading as Hypotony Maculopathy: A Case Report.
We report a rare case of presumed posterior sympathetic ophthalmia (SO) occurring shortly after PRESERFLO™ MicroShunt (PMS) (Santen Pharmaceutical Co., Ltd., Osaka, Japan) implantation that initially mimicked hypotony maculopathy. A 42-year-old woman with a history of multiple prior intraocular surgeries underwent PMS implantation in her left eye for glaucoma with uncontrolled intraocular pressure (IOP). At three days post-surgery, visual acuity (VA) decreased to hand motion, and IOP dropped to 6 mmHg. Slit-lamp examination showed no keratic precipitates or anterior chamber inflammation, while fundoscopy imaging revealed choroidal folds and serous retinal detachment. Given a provisional diagnosis of hypotony maculopathy, an anterior chamber air injection was performed at six days post-surgery. Despite a resultant rise in IOP, the posterior findings did not improve. Thus, a diagnosis of SO was made, and high-dose intravenous corticosteroid pulse therapy followed by oral corticosteroids was initiated at 10 days post-surgery, which led to anatomic improvement. Human leukocyte antigen (HLA) typing was positive for HLA-DR4. At two years post-surgery, her left eye had a decimal VA of 0.2 and a stable IOP of 10 mmHg. Oral prednisolone was tapered to 5 mg/day without recurrence. Fundoscopy examination of her right eye was difficult due to long-standing total retinal detachment. This case underscores several atypical features of posterior SO, including very early-onset, posterior-predominant disease without anterior inflammation, and diagnostic challenges in the fellow eye, and highlights the importance of considering SO in atypical postoperative presentations, even after less invasive glaucoma surgery, and the need for early recognition with timely corticosteroid therapy to preserve vision.
2025-09-14 | Long-Term Management of Sympathetic Ophthalmia Developing in the Early Period Following Trauma: A Case Report
This case report presents a rare instance of sympathetic ophthalmia (SO) in a patient who developed globe rupture due to blunt ocular trauma. It provides insights into the clinical course and three-year follow-up of successful treatment achieved through systemic immunosuppressive therapy. A 45-year-old male patient sustained blunt trauma to his left eye. Due to clinical signs indicative of rupture, conjunctival exploration was performed, revealing a scleral rupture that was primarily repaired. On postoperative day 18, the patient developed bilateral panuveitis consistent with trauma-induced SO. Diagnosis was supported by clinical signs, optical coherence tomography (OCT), and fundus fluorescein angiography (FFA). Treatment included systemic corticosteroids and immunosuppressive agents (cyclosporine and azathioprine), with dose adjustments during follow-up. Three years later, following cataract surgery, visual acuity in the injured eye improved to 0.7 (Snellen). OCT and FFA findings normalized, and systemic therapy was well tolerated except for mild gingival hyperplasia attributed to cyclosporine. This case underscores the importance of early diagnosis and aggressive immunosuppressive therapy in managing early-onset SO following globe rupture. Long-term follow-up demonstrated effective inflammation control and stable visual acuity, supporting the efficacy of combined immunosuppressive therapy.
2025-06-09 | Inflammatory Ocular Syndromes without Systemic Associations
In this chapter, we explore inflammatory ocular syndromes without systemic associations: sympathetic ophthalmia, birdshot chorioretinopathy, pars planitis. We also examine a complication of uveitis that often requires use of systemic immunosuppression: steroid-induced ocular hypertension and glaucoma. The rarity of these syndromes often leads to difficulties in timely diagnosis and necessitates long-term follow-up to monitor for disease progression and treatment response. The management of these syndromes is often multifactorial and requires both local and systemic treatment modalities. Specifically, early initiation of systemic immunosuppressive agents has been shown to improve visual outcomes and prevent corticosteroid-induced complications. These include increased intraocular pressure or cataract formation, which is especially important in pediatric patients, who have a higher risk of developing both with local therapy alone.
cell therapies
2023-06-02 | IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis
IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
2018-10-09 | Tolerance Induction in Relation to the Eye
Inflammatory intraocular eye diseases, grouped under the term uveitis are blinding conditions, believed to be mediated by pathogenic autoimmune processes that overcome the protective mechanisms of the immune privilege status of the eye. An animal model for these diseases, named experimental autoimmune uveitis (EAU), is induced by initiation of immunity against ocular-specific antigens, or it develops spontaneously in mice with T-cells that transgenically express TCR specific to the target eye antigen(s). T-Cells specific to ocular antigens are generated in the thymus and their majority are eliminated by exposure to their target antigen expressed in this organ. T-cells that escape this negative selection acquire pathogenicity by their activation with the target antigen. In spontaneous EAU, the microbiota play crucial roles in the acquisition of pathogenicity by providing both antigenic stimulation, by molecules that mimic the target ocular antigen, and an additional stimulation that allows invasion of tissues that harbor the target antigen. The pathogenic process is physiologically inhibited by the peripheral tolerance, composed of antigen-specific T-regulatory (Treg) lymphocytes,. Deleting the Tregs enhances the ocular inflammation, whereas adoptively transferring them suppresses the pathogenic response. Potential usage of Treg cells for suppression of autoimmune diseases in humans is under intensive investigation.
2018-09-28 | Induction of Contrasuppressor Cells and Loss of Immune Privilege Produced by Corneal Nerve Ablation
Purpose: Severing of corneal nerves in preparation of corneal transplantation abolishes immune privilege of subsequent corneal transplants placed into either eye: a phenomenon termed sympathetic loss of immune privilege (SLIP). SLIP is due to the disabling of T regulatory cells (Tregs) by CD11c+ contrasuppressor (CS) cells. This study characterized the induction, function, and manipulation of CS cell activity and the effect of these cells on Tregs induced by anterior chamber-associated immune deviation (ACAID). Methods: CS cells were induced using a 2.0-mm trephine to score the corneal epithelium. CD11c+ CS cells were evaluated by adoptive transfer and by their capacity to disable CD8+ ACAID Tregs in local adoptive transfer (LAT) of suppression assays. CD11c+ cells were deleted from the ocular surface by subconjunctival injection of clodronate-containing liposomes. Results: CD11c+ CS cell were radiosenstive and long lived. As few as 1000 CS cells blocked the suppressive activity of previously generated CD8+ ACAID Tregs, indicating that CS cells act at the efferent arm of the immune response. Depletion of resident CD11c+ cells at the ocular surface prevented the generation of CS cells. Conclusions: Corneal nerve injury that occurs during keratoplasty converts ocular surface CD11c+ cells into CS cells that block CD8+ Tregs, which are induced by introducing antigens into the anterior chamber (i.e., ACAID Tregs). Depletion of CD11c+ cells at the ocular surface prevents the generation of CS cells and may be a useful strategy for preventing SLIP and enhancing the survival of second corneal transplants.
2018-08-31 | Subretinal Transplantation of Human Amniotic Epithelial Cells in the Treatment of Autoimmune Uveitis in Rats
As a featured ocular inflammatory disease, autoimmune uveitis is the major cause of blindness in the clinic. Although current immunosuppressive regimens can alleviate the progression of autoimmune uveitis, they have serious side effects. Therefore, an alternative therapeutic strategy is urgently required. The present study investigated the therapeutic efficacy of human amniotic epithelial cells (hAECs) on autoimmune uveitis in a rat model. Herein, experimental autoimmune uveitis (EAU) was induced in rats via a subcutaneous injection of interphotoreceptor retinoid-binding protein. EAU rats were treated with hAECs or the vehicle solution via a subretinal injection on day 0 and day 6 after immunization, and rats were sacrificed on day 12 and day 18 for further analysis. The pathological development of EAU was evaluated by slit lamp microscopy. Immune cell infiltration and retinal structure damage were examined by histological examination of hematoxylin and eosin (H&E) and immunofluorescence staining. T-cell subsets were detected by flow cytometry, and the levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). hAEC treatment ameliorated the pathological progression of EAU and preserved the retinal structure organization and thickness, especially in the preventive group that received a subretinal injection on day 0. Moreover, hAECs inhibited the retinal infiltration of macrophages and T-cells. Mechanistically, hAECs modulated the balance of T-cell subsets by downregulating T helper (Th)17 cells and upregulating T regulatory (Treg) cells, as confirmed by decreased interleukin (IL)-17 and increased IL-10 levels in the spleens and lymph nodes of EAU rats. Furthermore, hAECs improved the local cytokine environment in EAU rats by suppressing the monocyte chemoattractant protein (MCP)-1, IL-17 and interferon (IFN)-γ levels and enhancing the IL-10 in the aqueous humor. Therefore, subretinal transplantation of hAECs in EAU rats ameliorated ocular inflammation, preserved the retinal structure and coordinated the immune balance. The current study provides a novel therapeutic strategy for autoimmune uveitis and related ocular inflammatory diseases in the clinic.
2009-02-05 | Generating tolerogenic dendritic cells with neuropeptides
Induction of antigen-specific tolerance is critical to prevent autoimmunity, to maintain immune homeostasis, and to achieve transplant tolerance. In addition to their classic role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune and inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. Some neuropeptides that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance. Here, we examine the latest research findings indicating that the role of these neuropeptides in immune tolerance is partially mediated through differential effects on DC functions, which depend on the differentiation and activation states. Importantly, neuropeptides such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and melanocyte-stimulating hormone have demonstrated an ability to induce tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells. The possibility of generating or expanding ex vivo tolerogenic DCs with neuropeptides indicates the therapeutic potential for autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.
antibodies
2026-07-07 | Sympathetic ophthalmia induced by vitrectomy for endogenous fungal endophthalmitis: a case report and literature review
Introduction Sympathetic ophthalmia (SO) is a rare but serious inflammatory ocular disorder. We report a case of endogenous fungal endophthalmitis caused by Aspergillus flavus infection, which resulted in SO in the contralateral eye after two vitrectomy procedures. Case report A 22-year-old man presented to our hospital with a 2-week history of redness and blurred vision in his right eye. Three months earlier, he had undergone two vitrectomy procedures for fungal endophthalmitis in his left eye, with culture results positive for Aspergillus flavus . Upon admission, antifungal therapy was administered; however, his health condition did not improve and progressively deteriorated. Metagenomic sequencing and microbial culture of intraocular fluid from the right eye revealed no fungi. Multimodal imaging, including optical coherence tomography (OCT), ocular B-scan ultrasonography, fundus examination, and indocyanine green angiography (ICGA), supported a definitive diagnosis of sympathetic ophthalmia. Treatment with prednisone and adalimumab stabilized the patient’s condition. During the 13-month follow-up period, the patient’s best-corrected visual acuity (BCVA) was 1.0 in the right eye and 0.04 in the left eye, with no observed recurrences. Conclusion Sympathetic ophthalmia is a complex ocular disorder characterized by diverse clinical and imaging features, making early diagnosis and treatment challenging. This case underscores the importance of timely intervention and aggressive therapeutic strategies for managing this condition.
2026-05-28 | Efficacy of Adalimumab Therapy for Non-Infectious Uveitis in Japanese Patients: Methotrexate Concomitance Across Different Uveitis Etiologies and the Effect of Dose Spacing.
To evaluate the long-term efficacy of adalimumab (ADA) in Japanese patients with non-infectious uveitis (NIU), with particular attention to etiologic differences in methotrexate (MTX) requirements and the feasibility of ADA dose spacing. This retrospective study included patients with chronic NIU or sclerouveitis treated with ADA for more than 6 months. Data included ocular inflammation control, systemic corticosteroid dose, and MTX use. The prespecified primary time point was 12 months. The primary endpoints were patient-level inactive uveitis and change in oral corticosteroid dose. Eye-level outcomes were analyzed using mixed-effects models and generalized estimating equations. Survival analysis compared MTX requirements among etiologies, and dose spacing outcomes and adverse events were also assessed. Eighty-three patients (160 eyes) were included in this study. ADA reduced systemic corticosteroid dosage (mean 13.7 mg/day at baseline to 0.9 mg/day at 12 months; Wilcoxon signed-rank test p < 0.0001 for baseline-to-12-month change) and improved best-corrected visual acuity (mixed-effects model: p = 0.035 at 12 months) and inflammation markers. Inactive uveitis was observed in 61.5% (48/78) at 12 months. Patients with late- or chronic-stage Vogt-Koyanagi-Harada disease/sympathetic ophthalmia showed a trend toward a higher requirement for MTX concomitance than Behçet's disease patient. Over half of the 24 patients attempting dose spacing relapsed (14/24), but disease control was regained by shortening intervals. The median relapse-free survival was 20.8 months (95% CI 14.5-25.2). ADA effectively controlled NIU and provided significant steroid-sparing benefits. Possible etiology-dependent differences in MTX requirements and relapse risk during dose spacing, support the optimization of individualized, closely monitored treatment.
2026-04-21 | Adalimumab Therapy as a Rescue Treatment Option in Refractory Acute Sympathetic Ophthalmia: Case Series and Review of Literature.
To report the efficacy of adalimumab (ADA) in controlling inflammation and salvaging vision in a series of patients with sympathetic ophthalmia (SO) refractory to conventional maximal medical therapy with systemic steroids and immunomodulatory treatment (IMT) or with contraindications to steroid therapy, with a focus on its novel application in acute refractory cases of SO. Retrospective chart review of three patients with acute SO and exudative retinal detachment (ExRD), refractory to corticosteroids and IMT or with contraindication to steroids, termed refractory SO. All patients received ADA 40 mg subcutaneously every 2 weeks under rheumatologist supervision. Clinical response was closely monitored using multimodal imaging. All three patients had acute active SO with ExRD. Two patients had persistent inflammation despite intravenous methylprednisolone (IVMP) or high dose oral steroids; the third could not be given systemic steroids due to uncontrolled diabetes. Following ADA initiation, all showed rapid resolution of inflammation and subretinal fluid (SRF) with reduction in the subfoveal choroidal thickness (SFCT) and improvement in best corrected visual acuity (BCVA). This allowed successful tapering of systemic steroids while maintaining inflammatory control at final follow-up. We report a case series of three patients with SO refractory to pulse steroids and IMT, which showed rapid anatomical and functional improvement with ADA. ADA is highly efficacious in acute refractory SO, resulting in prompt resolution of active inflammation and maintenance of remission. This case series adds to the limited existing evidence on the role of TNF-α inhibitors in managing this rare but sight-threatening condition.
2025-12-31 | Neural modulation of ocular immunity: Exploring a sympathetic-macrophage neuroimmune link in the human ciliary body.
The ciliary body (CB) represents an immunoregulatory compartment for the ocular system and we questioned whether local immune regulation in the CB in humans could be under neural control. In this study, we explored whether the human CB contains a sympathetic-macrophage neuroimmune link. Seven right eyes from donated cadavers (five male, two female) were enucleated. After removal of the cornea, lens, and vitreous body, each eye was divided into quadrants. One quadrant per eye was processed for light microscopy to assess overall morphology, general and sympathetic nerve presence, varicosities, macrophages, and the proximity of sympathetic nerves to macrophages. Additional quadrants (whole-mount samples) were examined with three-dimensional (3D) confocal microscopy to visualize the spatial relationship between sympathetic nerves and macrophages and to determine whether these macrophages expressed β₂-adrenergic receptors. Our study shows that the human CB contains sympathetic nerves of which a significant amount was spatially associated to β2-adrenergic receptor expressing macrophages. The current study provides morphological evidence for a possible sympathetic-macrophage ocular neuroimmune link in humans which may constitute a novel field for the study of degenerative and inflammatory eye disease. Further understanding of the CB sympathetic nerves and their immunomodulatory capacity is needed for the development of future therapeutics.
2025-03-14 | Sympathetic ophthalmia with bilateral vision loss: A case report
Sympathetic Ophthalmia [SO] is a rare condition with potentially devastating outcomes, characterized by bilateral uveitis following ocular trauma or surgery. We present a case of a male in his 60s with no notable medical history who experienced bilateral vision loss following a traumatic injury. In 2006, the patient sustained trauma to his right eye after being elbowed by a patient, leading to a detached retina. Despite treatment with corticosteroids, immunomodulators, and multiple surgical interventions—including three buckle surgeries and two nitrous oxide gas treatments—the retina remained detached, resulting in complete vision loss and eventual enucleation of the right eye in 2012. Approximately one year later, the patient developed floaters and flashing lights in the left eye, diagnosed as a partial retinal tear, which was treated with laser therapy. Over the next decade, the left eye underwent six additional surgeries, immunotherapy, and participation in a clinical trial involving monthly intraocular injections to reduce swelling. Despite these efforts, intraocular pressure fluctuated significantly, reaching as high as 58 mmHg, and the patient ultimately lost all vision in the left eye by November 2023, requiring enucleation. Histopathology confirmed the diagnosis, and all tests for autoimmune conditions were negative. This case highlights the challenges of managing recurrent retinal detachment and refractory intraocular inflammation despite aggressive medical and surgical interventions. • Sympathetic ophthalmia (SO) is a rare, bilateral granulomatous uveitis triggered by ocular trauma or surgery. • It presents with progressive vision loss, panuveitis, and retinal complications , requiring prompt immunosuppressive therapy. • This case is significant due to its rarity and highlights the need for early diagnosis and aggressive management to prevent irreversible blindness.
proteins
2025-12-16 | The Latest Research Progress on Sympathetic Ophthalmia—A Brief Literature Overview
Sympathetic ophthalmia (SO) is a rare bilateral granulomatous panuveitis, usually secondary to penetrating ocular trauma or intraocular surgery. Symptoms typically occur 5 days to 56 years after trauma or surgery, but most commonly manifest 2 weeks to 2 months postoperatively. The main clinical features include acute or chronic granulomatous uveitis, accompanied by Dalen-Fuchs nodules and choroiditis. Systemic glucocorticoids and steroid-sparing immunosuppressants remain the first-line treatments. This article systematically summarizes the latest research advances in the epidemiology, pathogenesis, and clinical management of SO, aiming to provide references for clinical practice and scientific research.
2025-06-09 | General Overview of the Eye in Health and in Autoimmune Disease
During the dawn of modern immunology, when the term horror autotoxicus was used to deride endorsement of autoimmune disease, an Austrian ophthalmologist gathered preliminary evidence that the disorder known as sympathetic ophthalmia was autoimmune in nature. The hypothesis was overlooked or discounted by most scientists. The eyes are a blend of neural and somatic tissues that develop and remain throughout life mostly sequestered from the immune system. The eye as tool of discovery finally gained the attention of immunologists after World War II, when allogenic skin grafts placed in the anterior segment appeared to defy immunologic rejection. By the latter decades of the century, the accumulation of immunologic contradictions associated with the eye so fascinated scientists that they could no longer ignore it. The eye displayed properties of immune privilege yet bore a considerable burden of autoimmune disease, particularly the corneal-scleral tunic and the uveal tract. This chapter traces the evolution in understanding of ocular immunology over the last century and reviews the recent understanding of the molecular pathogenesis of uveitis.
2022-02-24 | Sympathetic Nerve-Mediated Fellow Eye Pain During Sequential Cataract Surgery by Regulating Granulocyte Colony Stimulating Factor CSF3
Patients were found to experience more pain during their second eye cataract surgery compared with their first eye surgery. This study aimed to explore the inflammatory alterations along time in the fellow eye after the first eye surgery and to reveal the underlying mechanism. Eighty patients with bilateral cataracts were recruited and were divided into four groups based on the time of having the second eye surgery. The second eye aqueous humor samples were collected just before surgery and analyzed by mass spectrometry and PCR array. Cytokine activity was enriched in the aqueous humor of the contralateral eye with granulocyte colony-stimulating factor CSF3 significantly upregulated at both gene and protein levels. Rabbits with or without superior cervical ganglionectomy (SCGx) were subjected to lensectomy to mimic human situations. In both human and rabbit models, the fellow eye CSF3 peaked at 1 week post the first eye surgery. Consistently, more neutrophils were recruited to the contralateral eye aqueous humor. Corneal sensitivity and trigeminal electrophysiology were recorded to imply the pain severity in rats receiving capsulorrhexis with or without SCGx. A more intense pulse was detected in the contralateral trigeminal ganglion after the rat received one eye surgery. SCGx could effectively reduce the fellow corneal sensitivity and trigeminal nerve pain. These alterations were under direct regulation of the sympathetic nerves on the surgical eye side. Our results suggest that CSF3 and sympathetic activity could serve as potential analgesic targets during ocular surgeries.
2021-01-25 | Regulated Tristetraprolin Overexpression Dampens the Development and Pathogenesis of Experimental Autoimmune Uveitis
Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3’-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651–670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.
2018-05-06 | A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis
Abstract We describe an immunosuppressive peptide corresponding to the kinase inhibitory region (KIR) of the intracellular checkpoint protein suppressor of cytokine signaling 1 (SOCS-1) that binds to the phospho-tyrosine containing regions of the tyrosine kinases JAK2 and TYK2 and the adaptor protein MAL, and thereby inhibits signaling downstream from these signaling mediators. The peptide, SOCS1-KIR, is thus capable of downregulating overactive JAK/STAT or NF-kB signaling in somatic cells, including those in many compartments of the eye. Attachment of poly-arginine to this peptide (R9-SOCS1-KIR) allows it to penetrate the plasma membrane in aqueous media. R9-SOCS1-KIR was tested in ARPE-19 cells and was found to attenuate mediators of inflammation by blocking the inflammatory effects of IFNγ, TNFα, or IL-17A. R9-SOCS1-KIR also protected against TNFα or IL-17A mediated damage to the barrier properties of ARPE-19 cells, as evidenced by immunostaining with the tight junction protein, zona occludin 1 (ZO-1), and measurement of transepithelial electrical resistance (TEER). Experimental autoimmune uveitis (EAU) was generated in B10.RIII mice using a peptide of interphotoreceptor retinal binding protein (IRBP 161-180 ) as immunogen. Topical administration of R9-SOCS1-KIR protected ocular structure and function as seen by fundoscopy, optical coherence tomography (OCT), and electroretinography (ERG). The ability R9-SOCS1-KIR to suppress ocular inflammation and preserve barrier properties of retinal pigment epithelium makes it a potential candidate for aqueous treatment of autoimmune uveitis. Highlights peptide corresponding to the kinase inhibitory region of SOCS-1 linked to poly-arginine (R9-SOCS1-KIR) and its inactive control peptide were chemically synthesized. R9-SOCS1-KIR attenuated pro-inflammatory effects of IFNγ, TNFα, and IL-17 in ARPE-19 cells, thus showing a simultaneous inhibition Th1 and Th17 cell functions. Damage to barrier properties of ARPE-19 cells caused by TNFα or IL-17 was prevented in the presence of R9-SOCS1-KIR. Topical administration of R9-SOCS1-KIR prevented ocular damage in a mouse model of experimental autoimmune uveitis.
small molecules
2026-07-14 | Fellow eye’s revenge: Navigating sympathetic ophthalmia following penetrating keratoplasty
Sympathetic ophthalmia (SO) is a rare bilateral granulomatous uveitis that may occur following penetrating ocular injury or surgery. We report a 48-year-old man who developed SO in the left eye 3 weeks after therapeutic penetrating keratoplasty with cataract extraction for fungal keratitis in the right eye. He presented with decreased vision and floaters, and multimodal imaging, including optical coherence tomography, fundus fluorescein angiography, and fundus autofluorescence, demonstrated exudative retinal detachment with characteristic posterior segment findings. Prompt treatment with intravenous methylprednisolone followed by tapering oral corticosteroids and mycophenolate mofetil resulted in complete resolution of inflammation and subretinal fluid, with improvement of best-corrected visual acuity to 0.2 logMAR in both eyes at 6 months and no recurrence. This case highlights the importance of maintaining a high index of suspicion for SO after therapeutic penetrating keratoplasty and emphasizes that early diagnosis and aggressive immunosuppressive therapy can preserve vision.
2026-04-01 | Sympathetic Ophthalmitis Following Ocular Trauma and Vitrectomy in a Young Male
We report a case of sympathetic ophthalmitis (SO) in a 25-year-old male following open globe trauma and vitrectomy. The patient presented with left eye hyphema and scleral laceration following trauma from a burst bicycle tyre. He underwent pars plana vitrectomy (PPV) with corneoscleral repair and silicone oil tamponade. Two months later, the sympathizing eye (right eye) developed anterior chamber cells, initially managed as uveitis. Progression prompted multimodal imaging with fundus fluorescein angiography (FFA) and optical coherence tomography (OCT), which revealed pinpoint leaks and subretinal fluid (SRF), confirming SO. Treatment with intravenous methylprednisolone (1 g/day for 3 days) followed by tapering oral corticosteroids restored visual acuity to 6/6 within 4 weeks. This case underscores the importance of early recognition and prompt corticosteroid therapy to preserve vision in SO.
2025-12-22 | Atypical Posterior Sympathetic Ophthalmia Shortly After PRESERFLO™ MicroShunt Implantation Masquerading as Hypotony Maculopathy: A Case Report.
We report a rare case of presumed posterior sympathetic ophthalmia (SO) occurring shortly after PRESERFLO™ MicroShunt (PMS) (Santen Pharmaceutical Co., Ltd., Osaka, Japan) implantation that initially mimicked hypotony maculopathy. A 42-year-old woman with a history of multiple prior intraocular surgeries underwent PMS implantation in her left eye for glaucoma with uncontrolled intraocular pressure (IOP). At three days post-surgery, visual acuity (VA) decreased to hand motion, and IOP dropped to 6 mmHg. Slit-lamp examination showed no keratic precipitates or anterior chamber inflammation, while fundoscopy imaging revealed choroidal folds and serous retinal detachment. Given a provisional diagnosis of hypotony maculopathy, an anterior chamber air injection was performed at six days post-surgery. Despite a resultant rise in IOP, the posterior findings did not improve. Thus, a diagnosis of SO was made, and high-dose intravenous corticosteroid pulse therapy followed by oral corticosteroids was initiated at 10 days post-surgery, which led to anatomic improvement. Human leukocyte antigen (HLA) typing was positive for HLA-DR4. At two years post-surgery, her left eye had a decimal VA of 0.2 and a stable IOP of 10 mmHg. Oral prednisolone was tapered to 5 mg/day without recurrence. Fundoscopy examination of her right eye was difficult due to long-standing total retinal detachment. This case underscores several atypical features of posterior SO, including very early-onset, posterior-predominant disease without anterior inflammation, and diagnostic challenges in the fellow eye, and highlights the importance of considering SO in atypical postoperative presentations, even after less invasive glaucoma surgery, and the need for early recognition with timely corticosteroid therapy to preserve vision.
2025-09-14 | Long-Term Management of Sympathetic Ophthalmia Developing in the Early Period Following Trauma: A Case Report
This case report presents a rare instance of sympathetic ophthalmia (SO) in a patient who developed globe rupture due to blunt ocular trauma. It provides insights into the clinical course and three-year follow-up of successful treatment achieved through systemic immunosuppressive therapy. A 45-year-old male patient sustained blunt trauma to his left eye. Due to clinical signs indicative of rupture, conjunctival exploration was performed, revealing a scleral rupture that was primarily repaired. On postoperative day 18, the patient developed bilateral panuveitis consistent with trauma-induced SO. Diagnosis was supported by clinical signs, optical coherence tomography (OCT), and fundus fluorescein angiography (FFA). Treatment included systemic corticosteroids and immunosuppressive agents (cyclosporine and azathioprine), with dose adjustments during follow-up. Three years later, following cataract surgery, visual acuity in the injured eye improved to 0.7 (Snellen). OCT and FFA findings normalized, and systemic therapy was well tolerated except for mild gingival hyperplasia attributed to cyclosporine. This case underscores the importance of early diagnosis and aggressive immunosuppressive therapy in managing early-onset SO following globe rupture. Long-term follow-up demonstrated effective inflammation control and stable visual acuity, supporting the efficacy of combined immunosuppressive therapy.
2025-06-09 | Inflammatory Ocular Syndromes without Systemic Associations
In this chapter, we explore inflammatory ocular syndromes without systemic associations: sympathetic ophthalmia, birdshot chorioretinopathy, pars planitis. We also examine a complication of uveitis that often requires use of systemic immunosuppression: steroid-induced ocular hypertension and glaucoma. The rarity of these syndromes often leads to difficulties in timely diagnosis and necessitates long-term follow-up to monitor for disease progression and treatment response. The management of these syndromes is often multifactorial and requires both local and systemic treatment modalities. Specifically, early initiation of systemic immunosuppressive agents has been shown to improve visual outcomes and prevent corticosteroid-induced complications. These include increased intraocular pressure or cataract formation, which is especially important in pediatric patients, who have a higher risk of developing both with local therapy alone.
cell therapies
2023-06-02 | IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis
IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
2018-10-09 | Tolerance Induction in Relation to the Eye
Inflammatory intraocular eye diseases, grouped under the term uveitis are blinding conditions, believed to be mediated by pathogenic autoimmune processes that overcome the protective mechanisms of the immune privilege status of the eye. An animal model for these diseases, named experimental autoimmune uveitis (EAU), is induced by initiation of immunity against ocular-specific antigens, or it develops spontaneously in mice with T-cells that transgenically express TCR specific to the target eye antigen(s). T-Cells specific to ocular antigens are generated in the thymus and their majority are eliminated by exposure to their target antigen expressed in this organ. T-cells that escape this negative selection acquire pathogenicity by their activation with the target antigen. In spontaneous EAU, the microbiota play crucial roles in the acquisition of pathogenicity by providing both antigenic stimulation, by molecules that mimic the target ocular antigen, and an additional stimulation that allows invasion of tissues that harbor the target antigen. The pathogenic process is physiologically inhibited by the peripheral tolerance, composed of antigen-specific T-regulatory (Treg) lymphocytes,. Deleting the Tregs enhances the ocular inflammation, whereas adoptively transferring them suppresses the pathogenic response. Potential usage of Treg cells for suppression of autoimmune diseases in humans is under intensive investigation.
2018-09-28 | Induction of Contrasuppressor Cells and Loss of Immune Privilege Produced by Corneal Nerve Ablation
Purpose: Severing of corneal nerves in preparation of corneal transplantation abolishes immune privilege of subsequent corneal transplants placed into either eye: a phenomenon termed sympathetic loss of immune privilege (SLIP). SLIP is due to the disabling of T regulatory cells (Tregs) by CD11c+ contrasuppressor (CS) cells. This study characterized the induction, function, and manipulation of CS cell activity and the effect of these cells on Tregs induced by anterior chamber-associated immune deviation (ACAID). Methods: CS cells were induced using a 2.0-mm trephine to score the corneal epithelium. CD11c+ CS cells were evaluated by adoptive transfer and by their capacity to disable CD8+ ACAID Tregs in local adoptive transfer (LAT) of suppression assays. CD11c+ cells were deleted from the ocular surface by subconjunctival injection of clodronate-containing liposomes. Results: CD11c+ CS cell were radiosenstive and long lived. As few as 1000 CS cells blocked the suppressive activity of previously generated CD8+ ACAID Tregs, indicating that CS cells act at the efferent arm of the immune response. Depletion of resident CD11c+ cells at the ocular surface prevented the generation of CS cells. Conclusions: Corneal nerve injury that occurs during keratoplasty converts ocular surface CD11c+ cells into CS cells that block CD8+ Tregs, which are induced by introducing antigens into the anterior chamber (i.e., ACAID Tregs). Depletion of CD11c+ cells at the ocular surface prevents the generation of CS cells and may be a useful strategy for preventing SLIP and enhancing the survival of second corneal transplants.
2018-08-31 | Subretinal Transplantation of Human Amniotic Epithelial Cells in the Treatment of Autoimmune Uveitis in Rats
As a featured ocular inflammatory disease, autoimmune uveitis is the major cause of blindness in the clinic. Although current immunosuppressive regimens can alleviate the progression of autoimmune uveitis, they have serious side effects. Therefore, an alternative therapeutic strategy is urgently required. The present study investigated the therapeutic efficacy of human amniotic epithelial cells (hAECs) on autoimmune uveitis in a rat model. Herein, experimental autoimmune uveitis (EAU) was induced in rats via a subcutaneous injection of interphotoreceptor retinoid-binding protein. EAU rats were treated with hAECs or the vehicle solution via a subretinal injection on day 0 and day 6 after immunization, and rats were sacrificed on day 12 and day 18 for further analysis. The pathological development of EAU was evaluated by slit lamp microscopy. Immune cell infiltration and retinal structure damage were examined by histological examination of hematoxylin and eosin (H&E) and immunofluorescence staining. T-cell subsets were detected by flow cytometry, and the levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). hAEC treatment ameliorated the pathological progression of EAU and preserved the retinal structure organization and thickness, especially in the preventive group that received a subretinal injection on day 0. Moreover, hAECs inhibited the retinal infiltration of macrophages and T-cells. Mechanistically, hAECs modulated the balance of T-cell subsets by downregulating T helper (Th)17 cells and upregulating T regulatory (Treg) cells, as confirmed by decreased interleukin (IL)-17 and increased IL-10 levels in the spleens and lymph nodes of EAU rats. Furthermore, hAECs improved the local cytokine environment in EAU rats by suppressing the monocyte chemoattractant protein (MCP)-1, IL-17 and interferon (IFN)-γ levels and enhancing the IL-10 in the aqueous humor. Therefore, subretinal transplantation of hAECs in EAU rats ameliorated ocular inflammation, preserved the retinal structure and coordinated the immune balance. The current study provides a novel therapeutic strategy for autoimmune uveitis and related ocular inflammatory diseases in the clinic.
2009-02-05 | Generating tolerogenic dendritic cells with neuropeptides
Induction of antigen-specific tolerance is critical to prevent autoimmunity, to maintain immune homeostasis, and to achieve transplant tolerance. In addition to their classic role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune and inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. Some neuropeptides that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance. Here, we examine the latest research findings indicating that the role of these neuropeptides in immune tolerance is partially mediated through differential effects on DC functions, which depend on the differentiation and activation states. Importantly, neuropeptides such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and melanocyte-stimulating hormone have demonstrated an ability to induce tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells. The possibility of generating or expanding ex vivo tolerogenic DCs with neuropeptides indicates the therapeutic potential for autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.
antibodies
2026-07-07 | Sympathetic ophthalmia induced by vitrectomy for endogenous fungal endophthalmitis: a case report and literature review
Introduction Sympathetic ophthalmia (SO) is a rare but serious inflammatory ocular disorder. We report a case of endogenous fungal endophthalmitis caused by Aspergillus flavus infection, which resulted in SO in the contralateral eye after two vitrectomy procedures. Case report A 22-year-old man presented to our hospital with a 2-week history of redness and blurred vision in his right eye. Three months earlier, he had undergone two vitrectomy procedures for fungal endophthalmitis in his left eye, with culture results positive for Aspergillus flavus . Upon admission, antifungal therapy was administered; however, his health condition did not improve and progressively deteriorated. Metagenomic sequencing and microbial culture of intraocular fluid from the right eye revealed no fungi. Multimodal imaging, including optical coherence tomography (OCT), ocular B-scan ultrasonography, fundus examination, and indocyanine green angiography (ICGA), supported a definitive diagnosis of sympathetic ophthalmia. Treatment with prednisone and adalimumab stabilized the patient’s condition. During the 13-month follow-up period, the patient’s best-corrected visual acuity (BCVA) was 1.0 in the right eye and 0.04 in the left eye, with no observed recurrences. Conclusion Sympathetic ophthalmia is a complex ocular disorder characterized by diverse clinical and imaging features, making early diagnosis and treatment challenging. This case underscores the importance of timely intervention and aggressive therapeutic strategies for managing this condition.
2026-05-28 | Efficacy of Adalimumab Therapy for Non-Infectious Uveitis in Japanese Patients: Methotrexate Concomitance Across Different Uveitis Etiologies and the Effect of Dose Spacing.
To evaluate the long-term efficacy of adalimumab (ADA) in Japanese patients with non-infectious uveitis (NIU), with particular attention to etiologic differences in methotrexate (MTX) requirements and the feasibility of ADA dose spacing. This retrospective study included patients with chronic NIU or sclerouveitis treated with ADA for more than 6 months. Data included ocular inflammation control, systemic corticosteroid dose, and MTX use. The prespecified primary time point was 12 months. The primary endpoints were patient-level inactive uveitis and change in oral corticosteroid dose. Eye-level outcomes were analyzed using mixed-effects models and generalized estimating equations. Survival analysis compared MTX requirements among etiologies, and dose spacing outcomes and adverse events were also assessed. Eighty-three patients (160 eyes) were included in this study. ADA reduced systemic corticosteroid dosage (mean 13.7 mg/day at baseline to 0.9 mg/day at 12 months; Wilcoxon signed-rank test p < 0.0001 for baseline-to-12-month change) and improved best-corrected visual acuity (mixed-effects model: p = 0.035 at 12 months) and inflammation markers. Inactive uveitis was observed in 61.5% (48/78) at 12 months. Patients with late- or chronic-stage Vogt-Koyanagi-Harada disease/sympathetic ophthalmia showed a trend toward a higher requirement for MTX concomitance than Behçet's disease patient. Over half of the 24 patients attempting dose spacing relapsed (14/24), but disease control was regained by shortening intervals. The median relapse-free survival was 20.8 months (95% CI 14.5-25.2). ADA effectively controlled NIU and provided significant steroid-sparing benefits. Possible etiology-dependent differences in MTX requirements and relapse risk during dose spacing, support the optimization of individualized, closely monitored treatment.
2026-04-21 | Adalimumab Therapy as a Rescue Treatment Option in Refractory Acute Sympathetic Ophthalmia: Case Series and Review of Literature.
To report the efficacy of adalimumab (ADA) in controlling inflammation and salvaging vision in a series of patients with sympathetic ophthalmia (SO) refractory to conventional maximal medical therapy with systemic steroids and immunomodulatory treatment (IMT) or with contraindications to steroid therapy, with a focus on its novel application in acute refractory cases of SO. Retrospective chart review of three patients with acute SO and exudative retinal detachment (ExRD), refractory to corticosteroids and IMT or with contraindication to steroids, termed refractory SO. All patients received ADA 40 mg subcutaneously every 2 weeks under rheumatologist supervision. Clinical response was closely monitored using multimodal imaging. All three patients had acute active SO with ExRD. Two patients had persistent inflammation despite intravenous methylprednisolone (IVMP) or high dose oral steroids; the third could not be given systemic steroids due to uncontrolled diabetes. Following ADA initiation, all showed rapid resolution of inflammation and subretinal fluid (SRF) with reduction in the subfoveal choroidal thickness (SFCT) and improvement in best corrected visual acuity (BCVA). This allowed successful tapering of systemic steroids while maintaining inflammatory control at final follow-up. We report a case series of three patients with SO refractory to pulse steroids and IMT, which showed rapid anatomical and functional improvement with ADA. ADA is highly efficacious in acute refractory SO, resulting in prompt resolution of active inflammation and maintenance of remission. This case series adds to the limited existing evidence on the role of TNF-α inhibitors in managing this rare but sight-threatening condition.
2025-12-31 | Neural modulation of ocular immunity: Exploring a sympathetic-macrophage neuroimmune link in the human ciliary body.
The ciliary body (CB) represents an immunoregulatory compartment for the ocular system and we questioned whether local immune regulation in the CB in humans could be under neural control. In this study, we explored whether the human CB contains a sympathetic-macrophage neuroimmune link. Seven right eyes from donated cadavers (five male, two female) were enucleated. After removal of the cornea, lens, and vitreous body, each eye was divided into quadrants. One quadrant per eye was processed for light microscopy to assess overall morphology, general and sympathetic nerve presence, varicosities, macrophages, and the proximity of sympathetic nerves to macrophages. Additional quadrants (whole-mount samples) were examined with three-dimensional (3D) confocal microscopy to visualize the spatial relationship between sympathetic nerves and macrophages and to determine whether these macrophages expressed β₂-adrenergic receptors. Our study shows that the human CB contains sympathetic nerves of which a significant amount was spatially associated to β2-adrenergic receptor expressing macrophages. The current study provides morphological evidence for a possible sympathetic-macrophage ocular neuroimmune link in humans which may constitute a novel field for the study of degenerative and inflammatory eye disease. Further understanding of the CB sympathetic nerves and their immunomodulatory capacity is needed for the development of future therapeutics.
2025-03-14 | Sympathetic ophthalmia with bilateral vision loss: A case report
Sympathetic Ophthalmia [SO] is a rare condition with potentially devastating outcomes, characterized by bilateral uveitis following ocular trauma or surgery. We present a case of a male in his 60s with no notable medical history who experienced bilateral vision loss following a traumatic injury. In 2006, the patient sustained trauma to his right eye after being elbowed by a patient, leading to a detached retina. Despite treatment with corticosteroids, immunomodulators, and multiple surgical interventions—including three buckle surgeries and two nitrous oxide gas treatments—the retina remained detached, resulting in complete vision loss and eventual enucleation of the right eye in 2012. Approximately one year later, the patient developed floaters and flashing lights in the left eye, diagnosed as a partial retinal tear, which was treated with laser therapy. Over the next decade, the left eye underwent six additional surgeries, immunotherapy, and participation in a clinical trial involving monthly intraocular injections to reduce swelling. Despite these efforts, intraocular pressure fluctuated significantly, reaching as high as 58 mmHg, and the patient ultimately lost all vision in the left eye by November 2023, requiring enucleation. Histopathology confirmed the diagnosis, and all tests for autoimmune conditions were negative. This case highlights the challenges of managing recurrent retinal detachment and refractory intraocular inflammation despite aggressive medical and surgical interventions. • Sympathetic ophthalmia (SO) is a rare, bilateral granulomatous uveitis triggered by ocular trauma or surgery. • It presents with progressive vision loss, panuveitis, and retinal complications , requiring prompt immunosuppressive therapy. • This case is significant due to its rarity and highlights the need for early diagnosis and aggressive management to prevent irreversible blindness.
proteins
2025-12-16 | The Latest Research Progress on Sympathetic Ophthalmia—A Brief Literature Overview
Sympathetic ophthalmia (SO) is a rare bilateral granulomatous panuveitis, usually secondary to penetrating ocular trauma or intraocular surgery. Symptoms typically occur 5 days to 56 years after trauma or surgery, but most commonly manifest 2 weeks to 2 months postoperatively. The main clinical features include acute or chronic granulomatous uveitis, accompanied by Dalen-Fuchs nodules and choroiditis. Systemic glucocorticoids and steroid-sparing immunosuppressants remain the first-line treatments. This article systematically summarizes the latest research advances in the epidemiology, pathogenesis, and clinical management of SO, aiming to provide references for clinical practice and scientific research.
2025-06-09 | General Overview of the Eye in Health and in Autoimmune Disease
During the dawn of modern immunology, when the term horror autotoxicus was used to deride endorsement of autoimmune disease, an Austrian ophthalmologist gathered preliminary evidence that the disorder known as sympathetic ophthalmia was autoimmune in nature. The hypothesis was overlooked or discounted by most scientists. The eyes are a blend of neural and somatic tissues that develop and remain throughout life mostly sequestered from the immune system. The eye as tool of discovery finally gained the attention of immunologists after World War II, when allogenic skin grafts placed in the anterior segment appeared to defy immunologic rejection. By the latter decades of the century, the accumulation of immunologic contradictions associated with the eye so fascinated scientists that they could no longer ignore it. The eye displayed properties of immune privilege yet bore a considerable burden of autoimmune disease, particularly the corneal-scleral tunic and the uveal tract. This chapter traces the evolution in understanding of ocular immunology over the last century and reviews the recent understanding of the molecular pathogenesis of uveitis.
2022-02-24 | Sympathetic Nerve-Mediated Fellow Eye Pain During Sequential Cataract Surgery by Regulating Granulocyte Colony Stimulating Factor CSF3
Patients were found to experience more pain during their second eye cataract surgery compared with their first eye surgery. This study aimed to explore the inflammatory alterations along time in the fellow eye after the first eye surgery and to reveal the underlying mechanism. Eighty patients with bilateral cataracts were recruited and were divided into four groups based on the time of having the second eye surgery. The second eye aqueous humor samples were collected just before surgery and analyzed by mass spectrometry and PCR array. Cytokine activity was enriched in the aqueous humor of the contralateral eye with granulocyte colony-stimulating factor CSF3 significantly upregulated at both gene and protein levels. Rabbits with or without superior cervical ganglionectomy (SCGx) were subjected to lensectomy to mimic human situations. In both human and rabbit models, the fellow eye CSF3 peaked at 1 week post the first eye surgery. Consistently, more neutrophils were recruited to the contralateral eye aqueous humor. Corneal sensitivity and trigeminal electrophysiology were recorded to imply the pain severity in rats receiving capsulorrhexis with or without SCGx. A more intense pulse was detected in the contralateral trigeminal ganglion after the rat received one eye surgery. SCGx could effectively reduce the fellow corneal sensitivity and trigeminal nerve pain. These alterations were under direct regulation of the sympathetic nerves on the surgical eye side. Our results suggest that CSF3 and sympathetic activity could serve as potential analgesic targets during ocular surgeries.
2021-01-25 | Regulated Tristetraprolin Overexpression Dampens the Development and Pathogenesis of Experimental Autoimmune Uveitis
Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3’-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651–670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.
2018-05-06 | A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis
Abstract We describe an immunosuppressive peptide corresponding to the kinase inhibitory region (KIR) of the intracellular checkpoint protein suppressor of cytokine signaling 1 (SOCS-1) that binds to the phospho-tyrosine containing regions of the tyrosine kinases JAK2 and TYK2 and the adaptor protein MAL, and thereby inhibits signaling downstream from these signaling mediators. The peptide, SOCS1-KIR, is thus capable of downregulating overactive JAK/STAT or NF-kB signaling in somatic cells, including those in many compartments of the eye. Attachment of poly-arginine to this peptide (R9-SOCS1-KIR) allows it to penetrate the plasma membrane in aqueous media. R9-SOCS1-KIR was tested in ARPE-19 cells and was found to attenuate mediators of inflammation by blocking the inflammatory effects of IFNγ, TNFα, or IL-17A. R9-SOCS1-KIR also protected against TNFα or IL-17A mediated damage to the barrier properties of ARPE-19 cells, as evidenced by immunostaining with the tight junction protein, zona occludin 1 (ZO-1), and measurement of transepithelial electrical resistance (TEER). Experimental autoimmune uveitis (EAU) was generated in B10.RIII mice using a peptide of interphotoreceptor retinal binding protein (IRBP 161-180 ) as immunogen. Topical administration of R9-SOCS1-KIR protected ocular structure and function as seen by fundoscopy, optical coherence tomography (OCT), and electroretinography (ERG). The ability R9-SOCS1-KIR to suppress ocular inflammation and preserve barrier properties of retinal pigment epithelium makes it a potential candidate for aqueous treatment of autoimmune uveitis. Highlights peptide corresponding to the kinase inhibitory region of SOCS-1 linked to poly-arginine (R9-SOCS1-KIR) and its inactive control peptide were chemically synthesized. R9-SOCS1-KIR attenuated pro-inflammatory effects of IFNγ, TNFα, and IL-17 in ARPE-19 cells, thus showing a simultaneous inhibition Th1 and Th17 cell functions. Damage to barrier properties of ARPE-19 cells caused by TNFα or IL-17 was prevented in the presence of R9-SOCS1-KIR. Topical administration of R9-SOCS1-KIR prevented ocular damage in a mouse model of experimental autoimmune uveitis.
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Drug Discovery Landscape
1 orphan drug designation for Sympathetic ophthalmia.
1 orphan drug designation for Sympathetic ophthalmia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
HLA-B27 derived peptide (amino acid 125-138) | peptides | EMA | 2004-09-02 | — | Dr Gerhild Wildner |
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