Pathogenesis Of Autoimmune Uveitis Research Articles

Steroidal nanoformulations for the treatment of uveitis: potential, promises and future perspectives.

Intraocular inflammation, commonly referred to as uveitis, is a prevalent ocular disease. The categorization of uveitis may be based on the prevailing anatomical site, which includes anterior, intermediate, and posterior uveitis. There exists a significant body of evidence indicating that T cells play a pivotal role in the pathogenesis of autoimmune uveitis. In addition to the presence of T cells, an elevation in levels of inflammatory cytokines and a reduction in regulatory cytokines were also noted. The primary pharmacological interventions for uveitis comprise of corticosteroids, methotrexate, anti-vascular endothelial growth factor (VEGF) agents, anti-tumor necrosis factor-alpha (TNF-α) antibodies, and sirolimus. These medications offer prompt alleviation for inflammation. Nevertheless, prolonged administration of corticosteroids invariably leads to unfavorable adverse reactions. The traditional topical corticosteroids exhibit certain limitations, including inadequate transcorneal permeation and low corneal retention, leading to reduced ocular bioavailability. Consequently, there is a growing inclination towards the creation of innovative steroid drug delivery systems with the aim of reducing the potential for adverse effects, while simultaneously enhancing the drug's corneal permeation and retention. This review is an attempt to compile all the research work done so far in this field and provides a brief overview of the global efforts to develop innovative nanocarrier-based systems for corticosteroids.

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Complement has long been recognized as a critical component of the innate immune system. It comprises proteins that play a central role in host defense against infection and in the modulation of antigen-specific immune and inflammatory responses. The complement system can be activated by three proteolytic cascades namely, the classical, the alternative, and the lectin pathways. The activation of complement components by all three pathways leads to the formation of a membrane attack complex (MAC). There are studies about complement system involvement in different ocular pathologies, like macular degeneration, glaucoma, diabetic retinopathy, and autoimmune uveitis. Dysregulation of the complement cascade has emerged as a key contributor to the pathophysiology of age-related macular degeneration and there has been a revolution in the treatment of the geographic type. The drug pegcetagoplan, which was approved by the FDA on February 17, 2023, is a C3 inhibitor that binds to C3 or C3b, disrupting further activation of the complement system. There are studies about the relationship between diabetic retinopathy and dysregulation of the complement system. Some authors found activation of C5a in the vitreous body, other authors found an increase of C9 and factor D in the vitreous body. Several studies have investigated the role of the complement system in the pathogenesis of glaucoma, especially the role of C3, C1, and complement regulatory proteins. There are studies about experimental autoimmune uveitis and the role of the complement system in the pathogenesis of ocular autoimmune disease. The studies provided the novel finding that complement activation plays a central role in the pathogenesis of ocular autoimmunity and may serve as a potential target for therapeutic intervention. Thus, summing up the results of studies conducted by various authors, we conclude that the complement system has its role in the pathogenesis of various eye pathologies. Identification of the complement system activation as a new direction of local ocular immunity in the pathogenesis of autoimmune uveitis will provide an opportunity for the development of targeted treatment regimens.

The pro-inflammatory effect of triglyceride on human CD4+ T cells and experimental autoimmune uveitis

Aberrant lipid metabolism plays a role in inflammation and progression of autoimmune diseases but the definite mechanism remains unclear. In this study we investigate lipidomic profiles in Behçet's disease (BD) and the role of triglyceride (TAG) in the pathogenesis of autoimmune uveitis. Lipidomics revealed a distinct lipid metabolite profile including increased TAG metabolites in plasma of active BD patients. TAG could stimulate the proliferation, IL-17 and IFN-γ expression by CD4+ T cells and Th1, Th17 cell differentiation in vitro, but did not influence neutrophils. A922500 inhibited the TAG generation, ameliorated the EAU severity, decreased Th17 frequency and IL-17 expression by CD4+ T cells in vivo. The proteomocis analysis showed an up-regulation of apoptosis-related protein, Pik3r2, in CD4+ T cells from A922500-treated mice. In conclusion, TAG can stimulate human CD4+ T cells and the inhibition of its generation could significantly ameliorate EAU activity in association with down-regulated Th17 cell response.

THE ROLE OF INTERLEUKINS AND THEIR INHIBITORS IN THE DEVELOPMENT OF AUTOIMMUNE UVEITIS

Introduction: Autoimmune uveitis (AU) is an inflammation of the uvea due to an autoimmune reaction to self-antigens. There are no standardized treatment protocols for AU. A new class of drugs called biologics, that target the various mediators of the inflammation cascade, may potentially provide more effective and less toxic corticosteroids treatment of AU. The aim: The aim of this review was to make the evaluatation of the interleukins influence on intraocular inflammation in available literature and summarize the expediency of using anti-interleukins agent in case of AU. Material and methods: This article is a review and summary of the up-to-date results of pivotal experimental and clinical trials targeting the Interleukins (IL), including IL-6, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor alpha (TNF-α). Also reviews focus on the potential use of anti-interleukin therapy for the treatment of autoimmune diseases (AD). Conclusions: AU is an inflammation of the uvea due to an autoimmune reaction to self-antigens. The most important IL in the pathogenesis of AU are IL-6, IL-10, IL-17, IL-22, IL-23 and TNF-α. Anti-interleukin therapy is partially described. Future randomized controlled trials are urgently needed to be conduct.

Complement Component C4 Regulates the Development of Experimental Autoimmune Uveitis through a T Cell-Intrinsic Mechanism.

In addition to its conventional roles in the innate immune system, complement has been found to directly regulate T cells in the adaptive immune system. Complement components, including C3, C5, and factor D, are important in regulating T cell responses. However, whether complement component C4 is involved in regulating T cell responses remains unclear. In this study, we used a T cell-dependent model of autoimmunity, experimental autoimmune uveitis (EAU) to address this issue. We compared disease severity in wild-type (WT) and C4 knockout (KO) mice using indirect ophthalmoscopy, scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, and histopathological analysis. We also explored the underlying mechanism by examining T cell responses in ex vivo antigen-specific recall assays and in in vitro T cell priming assays using bone marrow-derived dendritic cells, splenic dendritic cells, and T cells from WT or C4 KO mice. We found that C4 KO mice develop less severe retinal inflammation than WT mice in EAU and show reduced autoreactive T cell responses and decreased retinal T cell infiltration. We also found that T cells, but not dendritic cells, from C4 KO mice have impaired function. These results demonstrate a previously unknown role of C4 in regulating T cell responses, which affects the development of T cell-mediated autoimmunity, as exemplified by EAU. Our data could shed light on the pathogenesis of autoimmune uveitis in humans.

Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis.

BackgroundMüller glial cells are important regulators of physiological function of retina. In a model disease of retinal inflammation and spontaneous recurrent uveitis in horses (ERU), we could show that retinal Müller glial cells significantly change potassium and water channel protein expression during autoimmune pathogenesis. The most significantly changed channel protein in neuroinflammatory ERU was aquaporin 11 (AQP11). Aquaporins (AQP, 13 members) are important regulators of water and small solute transport through membranes. AQP11 is an unorthodox member of this family and was assigned to a third group of AQPs because of its difference in amino acid sequence (conserved sequence is only 11 %) and especially its largely unknown function.MethodsIn order to gain insight into the distribution, localization, and function of AQP11 in the retina, we first developed a novel monoclonal antibody for AQP11 enabling quantification, localization, and functional studies.ResultsIn the horse retina, AQP11 was exclusively expressed at Müller glial cell membranes. In uveitic condition, AQP11 disappeared from gliotic Müller cells concomitant with glutamine synthase. Since function of AQP11 is still under debate, we assessed the impact of AQP11 channel on cell volume regulation of primary Müller glial cells under different osmotic conditions. We conclude a concomitant role for AQP11 with AQP4 in water efflux from these glial cells, which is disturbed in ERU. This could probably contribute to swelling and subsequent severe complication of retinal edema through impaired intracellular fluid regulation.ConclusionsTherefore, AQP11 is important for physiological Müller glia function and the expression pattern and function of this water channel seems to have distinct functions in central nervous system. The significant reduction in neuroinflammation points to a crucial role in pathogenesis of autoimmune uveitis.

Increased CD1c+ mDC1 with mature phenotype regulated by TNFα–p38 MAPK in autoimmune ocular inflammatory disease

In this study we investigated the role of blood CD1c+ myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c+ mDC1 in uveitis patients. The increased CD1c+ mDC1 exhibited high HLADR expression and less antigen uptake. CD1c+ mDC1 were divided into two subpopulations. CD1chi mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1clo mDC1 subpopulation. Importantly, the CD1chi mDC1 subpopulation was increased in uveitis patients. In vitro, mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD4+CD62L- T helper cell proliferation. The mature phenotype and function of CD1c+ mDC1 were regulated by TNFα via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c+ mDC1.

Subretinal transfection of chitosan-loaded TLR3-siRNA for the treatment of experimental autoimmune uveitis

The local interaction between retinal pigment epithelium (RPE) and immigrated effector T cells is crucial for the pathogenesis of autoimmune uveitis. After being activated by the pattern recognition receptors (PRRs) signaling pathway, RPE can present the antigen reactivated invading autoreactive T cells, resulting in uveitis. In the present study, we showed that the transfection of chitosan-loaded TLR3-siRNA toward RPE could effectively remit experimental autoimmune uveitis (EAU) in B10RIII mice. Initially, we verified the constitutive expression of Tlr3 in RPE at high levels, which was not altered in response to TNFα, IFNγ and IL-17A treatments. Compared with other TLRs, the activation of TLR3 signaling following polyIC treatment resulted in increased IL-6 and IFNγ secretion from and MHCII expression on RPE. It is polyIC-, but not other TLR ligands, treated RPE showed significant synergetic effect with IL-17 on stimulating RPE secreting CXCL8 and CCl2, which might be resulted from elevated Il17ra expression in RPE following polyIC treatment. Furthermore, polyIC-treated RPE caused a robust stimulation of differentiation of CD4 cell toward Th1 or Th17 cells, in addition to the secretion of the cytokines IFNγ and IL-17. The in vitro knockdown of TLR3 expression in RPE by chitosan/TLR3-siRNA transfection could effectively block polyIC-induced MHCII expression, pro-inflammatory cytokine secretion and autoreactive CD4 cell activation. Studies conducted in firefly luciferase gene transgenic mice demonstrated that the subretinal CS/Luci-siRNA transfection specifically reduced the luciferase activity in RPE but not in the liver and spleen. Finally, the CS/TLR3-siRNA was locally administered in the EAU induced B10RIII mice. The results revealed that chitosan-mediated TLR3-siRNA transfection had a significant therapeutic effect on either delaying the outbreak or remitting the severity of uveitis.

Biologic Therapy For Ocular Inflammatory Diseases: An Update

Uveitis comprehends a wide and heterogeneous group of intraocular inflammatory conditions potentially sight-threatening and vari - able therapeutic strategies have been proposed. Classical treatment with steroids and conventional immunosuppressive agents is often used as first-step. However, a number of patients may not respond properly or tolerate these medications with well-known side ef - fects. Over the last two decades, advances in the understanding of the pathogenesis of autoimmune uveitis, as well as improved bio- technology, have enabled the development of a new class of drugs called biologics, which provide selective targeting of the immune mediators of the inflammation cascade. Biologic therapies were introduced as a new option for patients with autoimmune rheumatic conditions refractory to conventional therapy and due to their success have posteriorly been used in ophthalmology to treat ocular inflammatory disorders. These new agents may potentially provide more effective and less toxic treatment than conventional therapy. Biologic therapies include a wide variety of drugs with different mechanisms of action, including monoclonal antibodies against cell surface markers, cytokines and their receptors, or recombinant forms of natural inhibitory molecules. Although some results are based on investigations with insufficient clinical trials, the majority of biologics indicate preferable outcomes on refractory uveitis, with remarkable promise to increase the possibility of long-term remission. The development of these new drugs is one of the most revo- lutionary advances in recent years, and the promise of shifting paradigms makes it an exciting time for uveitis specialists worldwide.

AB0083 Blocade of cd28 costimulatory signal reduces autoimmune uveitis in mice model

BackgroundA number of biologic agents have been shown to be effective for the treatment of rheumatoid arthritis (RA). Despite the improvements in the treatment for RA, less progress has been...

Characterization of retinal expression of vascular cell adhesion molecule (VCAM1) during experimental autoimmune uveitis

Abstract Purpose Leukocyte adhesion to the blood retinal barrier is a critical step in the pathogenesis of autoimmune uveitis and is mediated through adhesion molecule expression. Here, we have investigated the retinal expression of VCAM1 in an adoptive transfer model of experimental autoimmune uveitis (EAU). Methods C57Bl6 mice were immunized with interphotoreceptor retinoid‐binding protein (IRBP) peptide 1–20. Activated IRBP‐specific T cells were prepared from their draining lymph nodes and spleens, cultured with IRBP peptide 1‐20 and adoptively transferred in C57BL/6 mice. The animals were sacrified after 3 weeks and the eyes processed for immunohistology. The severity of the disease was determined by histological grading. The expression of VCAM1 was analysed by immunofluorescence. Co‐labelling with GFAP (glial cells markers) and endoglin (endothelial cell marker) were also performed in order to determine which cell type expressed VCAM1. Results In eyes with low grade uveitis, VCAM1 was only expressed at certain location of the internal limiting membranes and epithelial cells of the ciliary body. In correlation with disease severity, the staining extend to all the limiting membranes, vasculitis lesions, Muller cells extension, the outer limiting membranes and RPE cells. VCAM1 expression on the inner limiting membrane and Müller cells extension co stained with GFAP. On vasculitis lesions, VCAM1 expression co localized with either GFAP or endogline. Conclusion VCAM1 is expressed on blood retinal cells during EAU. Moreover, the intensity and extension of its expression correlates with disease severity. Those data suggest that VCAM1 plays an important role in EAU development.