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Uveitis is a leading cause of blindness in the world and autoimmune uveitis is an ocular tissue specific autoimmune disease. Utilizing experimental autoimmune uveitis (EAU), we can interrogate different immune responses in the mouse that are relevant to the human disease. cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint molecule that has different roles depending on the target tissue. In this work we investigate the role of CTLA-4 on CD4 T cells in ocular tissue during EAU. We find that CTLA-4 is needed for both the severity of disease but also timely resolution of disease. Regulatory T cells (Tregs) that emerge in the spleen during resolution of EAU require CTLA-4 to suppress disease, but ocular Tregs that emerge in the eye do not require CTLA-4 to suppress disease. This report provides an additional understanding of CTLA-4 on Tregs that is specific for ocular tissue. The implications of this work are that circulating Tregs in uveitis patients may require CTLA-4 to suppress ocular inflammation but once in the eye the function of CTLA-4 is dispensable. 

Corticosteroids are effective therapy for autoimmune diseases but serious adverse effects preclude their prolonged use. However, immune-suppressive biologics that inhibit lymphoid proliferation are now in use as corticosteroid sparing-agents but with variable success; thus, the need to develop alternative immune-suppressive approaches including cell-based therapies. Efficacy of -generated IL-35-producing regulatory B-cells (i35-Bregs) in suppressing/ameliorating encephalomyelitis or uveitis in mouse models of multiple sclerosis or uveitis, respectively, is therefore a promising therapeutic approach for CNS autoimmune diseases. However, i35-Breg therapy in human uveitis would require producing autologous Bregs from each patient to avoid immune-rejection. Because exosomes exhibit minimal toxicity and immunogenicity, we investigated whether i35-Bregs release exosomes that can be exploited therapeutically. Here, we demonstrate that i35-Bregs release exosomes that contain IL-35 (i35-Exosomes). In this proof-of-concept study, we induced experimental autoimmune uveitis (EAU), monitored EAU progression by fundoscopy, histology, optical coherence tomography and electroretinography, and investigated whether i35-Exosomes treatment would suppress uveitis. Mice treated with i35-Exosomes developed mild EAU with low EAU scores and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses. In contrast, significant increase of Th17 cells in vitreous and retina of control mouse eyes was accompanied by severe choroiditis, massive retinal-folds, and photoreceptor cell damage. These hallmark features of severe uveitis were absent in exosome-treated mice and visual impairment detected by ERG was modest compared to control mice. Absence of toxicity or alloreactivity associated with exosomes thus makes i35-Exosomes attractive therapeutic option for delivering IL-35 into CNS tissues.

Autoimmune uveitis is a sight-threatening inflammatory eye disease driven by immune dysregulation. We previously introduced a therapeutic strategy involving the induction of retinal-antigen-specific regulatory T cells (Tregs) via αCD4 antibody injection followed by administration of the retinal self-peptide IRBP1-20, which effectively suppresses inflammation during the onset of experimental autoimmune uveitis (EAU). We evaluated the long-term therapeutic efficacy of this approach in a chronic EAU model. EAU was induced in C57BL/6 mice, and treatment was administered at each onset or relapse episode over a 28-week period. Disease progression was monitored by clinical scoring and funduscopy, with further assessment using histopathology and optical coherence tomography (OCT). Flow cytometry was employed to analyze immune cell infiltration, and RNA sequencing of ocular tissue was performed to assess gene expression changes. Mice receiving aCD4 antibody and IRBP1-20 showed sustained disease control up to 28 weeks, with reduced ocular inflammation, less retinal damage on OCT, and decreased immune cell infiltration compared to untreated controls. Transcriptomic analysis revealed significant downregulation of inflammation-related genes following treatment. These findings support the long-term immunomodulatory effect of combining αCD4 antibody and retinal antigen injection, offering a potential strategy for managing chronic progressive autoimmune uveitis.

Autoimmune uveitis is a major cause of vision loss and glucocorticoids are major traditional medications, which may induce serious complications. Rapamycin has been demonstrated to exhibit immunosuppressive effects and is promising to be used in treating uveitis by intravitreal injection. However, repeated and frequent intravitreal injections increase the risk of severe ocular complications, while the efficacy of subconjunctival injection of rapamycin is low since it is difficult for rapamycin to penetrate eyeball. Recently, small extracellular vesicles (sEVs) have attracted considerable research interest as natural drug delivery systems that can efficiently cross tissues and biological membranes. SEVs derived from mesenchymal stem cells (MSC-sEVs) also can exert immunosuppressive effect and ameliorate experimental autoimmune uveitis (EAU). The aim of this study was to construct a Rapamycin-loaded MSC-sEVs delivery system (Rapa-sEVs) and investigate its therapeutic effect on EAU by subconjunctival injection. Rapa-sEVs were prepared by sonication and characterized by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Clinical and histological scores were obtained to assess the treatment efficacy. Additionally, T cell infiltration was evaluated by flow cytometry. The results indicated that Rapa-sEVs could reach the retinal foci after subconjunctival injection. Compared to sEVs and rapamycin alone, Rapa-sEVs can produce a more marked therapeutic effect and reduce ocular inflammatory cell infiltration. Overall, MSC-sEVs have significant potential for the delivery of rapamycin to treat EAU. Subconjunctival injection of Rapa-sEVs may be contender for efficacious steroid-sparing immunomodulatory therapy.

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.

Glucocorticoids (GCs) are widely used immunosuppressive drugs for autoimmune diseases, although considerable gaps exist between current knowledge of the mechanisms of GCs and their conclusive immune-regulatory effects. Here we generated a single-cell transcriptional immune cell atlas based on prednisone-treated or untreated experimental autoimmune uveitis (EAU) mice. Immune cells were globally activated in EAU, and prednisone partially reversed this effect in terms of cell composition, gene expression, transcription factor regulation, and cell-cell communication. Prednisone exerted considerable rescue effects on T and B cells and increased the proportion of neutrophils. Besides commonly regulated transcriptional factors (Fosb, Jun, Jund), several genes were only regulated in certain cell types (e.g. Cxcr4 and Bhlhe40 in T cells), suggesting cell-type-dependent immunosuppressive properties of GC. These findings provide new insights into the mechanisms behind the properties and cell-specific effects of GCs and can potentially benefit immunoregulatory therapy development.

Background Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear. Methods To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing. Results We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4 ) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD. Conclusions Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.

Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials conducted in the last 12 years for the treatment of AU are summarized and critically discussed.

Background Bruton’s tyrosine kinase (BTK), a key regulator of immune responses, has been extensively studied in B cells and innate immunocytes. Small-molecule BTK inhibitors (BTKi) have shown remarkable efficacy in multiple preclinical and clinical studies for autoimmune diseases via mediating the activation of B cells and innate immunocytes. Recent studies have demonstrated functional BTK expression in T cells, contributing to T cell activation and the pathogenesis of aplastic anemia. Whether BTK is involved in uveitis, the CD4+ T cell-mediated autoimmune disease, and whether it could be a therapeutic target remain unclear. Methods We assessed BTK expression and phosphorylation levels in CD4+ T cells from Autoimmune uveitis (AU) patients and experimental autoimmune uveitis (EAU) mice. By administering BTKi to EAU mice, we evaluated its effects on ocular and systemic inflammation levels through fundus photography, histopathology, qPCR, and flow cytometry. In vitro, we assessed its impact on the Th1/Th17/Treg differentiation, and the pathogenicity of CD4+ T cells. Transcriptomic sequencing and flow cytometry were employed to explore the potential mechanism by which BTK regulates CD4+ T cells. Results BTK expression and activation were upregulated in CD4+ T cells from AU patients and EAU mice. BTK inhibition suppressed the polarization of Th17 and Th1 cells, but not Treg differentiation. BTK inhibition upregulated the PPAR-γ signaling, alleviating oxidative stress and inflammatory responses in CD4+ T cells, thereby reducing ocular and systemic inflammation in EAU mice. Additionally, BTKi exhibited significant anti-inflammatory effects in CD4+ T cells from AU patients. Conclusion This study demonstrates the critical role of BTK in CD4+ T cell-driven AU. BTK inhibition ameliorates oxidative stress and inflammatory responses via PPAR-γ involved signaling in CD4+ T cells and suppresses their differentiation to Th1/Th17 to restore immune homeostasis, thereby mitigating AU. These findings identify BTK as a potential therapeutic target and provide a theoretical foundation for the clinical application of BTKi in AU.

Experimental autoimmune uveoretinitis (EAU) is an animal model of non-infectious uveitis and is developed by immunization with retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2) is responsible for regulating antioxidant and inflammatory responses. In this study, we investigated the role of Nrf2 on the development of EAU. Clinical and pathological examination demonstrated that retinal inflammation was exacerbated in Nrf2 knockout (Nrf2 KO) mice compared to wild type (WT) mice, and the expression of inflammatory cytokines (IFN-γ, IL-6, and IL-17) in the retina was significantly elevated in Nrf2 KO mice. GFAP positive cells (astrocytes) and Iba-1 positive cells (microglia cells) in the retina were more numerous in Nrf2 KO mice compared to WT mice. Furthermore, we examined the suppressive effect of the Nrf2 activator CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline) on the development of EAU. The treatment with CDDO-Im significantly reduced the clinical and pathological score of EAU compared to those of vehicle-treated mice. These findings suggest that Nrf2 plays a regulatory role in the pathogenesis of autoimmune uveoretinitis and the activation of the Nrf2 system may have therapeutic potential for protecting vision from autoimmune neuroinflammation.