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Dot plots of immune mediators, IL-1β, IL-6, IFN-γ and TNF-α. IL-1β, IL-6, IFN-γ and TNF-α in serum of noninflammatory controls patients (cataract age-related) (CTL) (N = 36) as compared with immune mediators in the serum of patients with idiopathic uveitis (n = 51) but differences in both groups are not significant. Note that few isolated patients with idiopathic uveitis had cytokines increased in serum samples. � = P<0.05 ; �� = P<0.01; ��� = P<0.001. https://doi.org/10.1371/journal.pone.0254972.g002
Source publication
To investigate which cytokines, chemokines and growth factors are involved in the immunopathogenesis of idiopathic uveitis, and whether cytokine profiles are associated with. Serum and aqueous humor (AH) samples of 75 patients with idiopathic uveitis were analyzed by multiplex immunoassay. Infectious controls consisted of 16 patients with ocular to...
Context in source publication
Context 1
... patients with idiopathic uveitis had increased levels of chemokines, cytokines and growth factors as compared with the cut-off defined in control patients (mean + 3 standard deviation): IL-23 in 6 patients, IL-7 in 7 patients, IL-1β and PDGF-BB in 5 patients; IL-6 in 4 patients ; IL-1Rα in 3 patients; IL-2, IL-4, IL-10, IL-12, GM-CSF, VEGF in 2 patients and IL-15, G-CSF, IFN-γ, MIP-1α, MIP-1β, RANTES, TNF-α in one patient ; nonetheless, differences between median levels found in the samples from patients with idiopathic uveitis as compared with the controls' were not significant for those mediators (Fig 2). ...
Citations
... It is widely assumed by ophthalmology researchers that the AH cytokine levels are influenced by the retina. The AH cytokine levels have been reported to be correlated with retinal conditions, such as age-related macular degeneration, diabetic macular edema, chronic central serous chorioretinopathy, and glaucoma [19,[75][76][77][78][79][80][81]. ...
Background:
Although the current role of cytokines and neuroinflammation in glaucoma remains obscure, it represents an expanding field in research. The purpose of this study was to analyze cytokines in the aqueous humor (AH) of glaucoma patients and in retinas from an ex vivo glaucoma animal model, to aid in determining the role of neuroinflammation in glaucoma.
Methods:
AH samples were collected from 20 patients during cataract surgeries (controls: n = 10, age = 70.3 ± 9.742; glaucoma: n = 10, age: 66.5 ± 8.073) in Shanghai East Hospital, an affiliate of Tongji University, between September 2018 and March 2019 and analyzed in duplicate by Luminex cytokine polystyrene color bead-based multiplex assay. Retinas from female Sprague-Dawley rats (n = 6) were harvested ex vivo and cultured with or without 60 mmHg of hydrostatic pressure for 24 hours. Retinal ganglion cells (RGCs) were quantified using Brn3a staining. Cytokines in the retina and culture medium were analyzed by rat cytokine array (Abcam).
Results:
At baseline, patients with primary angle closure glaucoma (PACG) have significantly lower levels of IL-6 and IP-10 and a higher level of PDGF-BB in their AH, compared to the controls. Postoperatively, patients with PACG have significantly higher levels of IL-1ra, IL-13, and MIP-1α and a lower level of IL-6. Elevated hydrostatic pressure led to significant RGC loss in the retina, ex vivo, as well as the upregulation of ciliary neurotrophic factor (CNTF), IL-6, IL-10, IL-4, and TIMP-1 alongside the downregulation of PDGF-AA, MMP-8, TNF-α, and IFN-γ. Furthermore, eight cytokines were detected as being downregulated in the culture medium, including PDGF-AA, MMP-8, and IL-4.
Conclusions:
Proinflammatory cytokines showed changes in both AH and ex vivo. Further studies are needed on the role of these cytokines and their corresponding signaling pathways in both neurodegeneration and glaucoma.
... We endeavored to expand the generalizability of the findings in our small cohort by comparing with aqueous/blood ratios derived from a published data set which included a larger cohort of healthy patient samples. 7 Although CCL2, CXCL10, CXCL8, and IL-6 were similarly enriched in the aqueous in both cohorts, several aqueous-enriched molecules in our cohort were not enriched in the aqueous in the Errera cohort. Most notably, IL-17, TNFa, IL-1B, and IFNg were enriched in the aqueous in our cohort, but present at higher levels in the blood in the Errera cohort. ...
Purpose
Uveitis is a heterogenous group of inflammatory eye disease for which current cytokine-targeted immune therapies are effective for only a subset of patients. We hypothesized that despite pathophysiologic nuances that differentiate individual disease states, all forms of eye inflammation might share common mechanisms for immune cell recruitment. Identifying these mechanisms is critical for developing novel, broadly acting therapeutic strategies.
Design
Experimental study.
Subjects
Biospecimens from patients with active or inactive uveitis and healthy controls.
Methods
Protein concentration and single cell gene expression were assessed in aqueous fluid biopsies and plasma samples from deidentified patients with uveitis or healthy controls.
Main Outcome Measures
The concentration of 31 inflammatory proteins was measured in all aqueous samples, as well as plasma samples from patients with active uveitis. Chemokine and cytokine ligand and receptor expression were assessed in individual cell types from aqueous biopsies obtained from patients with active uveitis.
Results
We identified 6 chemokines that were both elevated in active uveitis compared with controls and enriched in aqueous compared with plasma during active uveitis (C-C motif chemokine ligand [CCL]2, C-X-C motif chemokine ligand [CXCL]10, CXCL9, CXCL8, CCL3, and CCL14), forming potential gradients for migration of immune cells from the blood to the eye. Of these, CCL2 and CXCL10 were consistently enriched in the aqueous of all patients in our cohort, as well as in a larger cohort of patients from a previously published study. These data suggest that CCL2 and CXCL10 are key mediators in immune cell migration to the eye during uveitis. Next, single cell RNA sequencing suggested that macrophages contribute to aqueous enrichment of CCL2 and CXCL10 during human uveitis. Finally, using chemokine ligand and receptor expression mapping, we identified a broad signaling network for macrophage-derived CCL2 and CXCL10 in human uveitis.
Conclusions
These data suggest that ocular macrophages may play a central role, via CCL2 and CXCL10 production, in recruiting inflammatory cells to the eye in patients with uveitis.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
... AH, which fills the anterior chamber of the eye and maintains IOP, serves as an informative biofluid that reflects the physiological and pathological conditions of ocular tissues, including miRNA expression [35,36]. AH contains a diverse array of cells and molecules, including cytokines, growth factors, prostaglandins, and miRNAs, all of which contribute to ocular homeostasis and immunity [37][38][39][40]. The collection of AH samples offers stability and resistance to degradation by nucleases and environmental factors [41]. ...
Glaucoma, a neurodegenerative disorder that leads to irreversible blindness, remains a challenge because of its complex nature. MicroRNAs (miRNAs) are crucial regulators of gene expression and are associated with glaucoma and other diseases. We aimed to review and discuss the advantages and disadvantages of miRNA-focused molecular studies in glaucoma through discussing their potential as biomarkers for early detection and diagnosis; offering insights into molecular pathways and mechanisms; and discussing their potential utility with respect to personalized medicine, their therapeutic potential, and non-invasive monitoring. Limitations, such as variability, small sample sizes, sample specificity, and limited accessibility to ocular tissues, are also addressed, underscoring the need for robust protocols and collaboration. Reproducibility and validation are crucial to establish the credibility of miRNA research findings, and the integration of bioinformatics tools for miRNA database creation is a valuable component of a comprehensive approach to investigate miRNA aberrations in patients with glaucoma. Overall, miRNA research in glaucoma has provided significant insights into the molecular mechanisms of the disease, offering potential biomarkers, diagnostic tools, and therapeutic targets. However, addressing challenges such as variability and limited tissue accessibility is essential, and further investigations and validation will contribute to a deeper understanding of the functional significance of miRNAs in glaucoma.
... IL-6, TNFα, and CXCL10 were found to be significantly elevated in the aqueous humor (AH) of patients with BD uveitis, sarcoidosis, and toxoplasmosis uveitis as compared to non-inflammatory controls [28]. Another study aimed at investigating the potential markers for BD uveitis and uveitis associated with Vogt Koyanagi Harada (VKH) disease compared to healthy controls (HCs), showed that IL-6, CXCL10, G-CSF, and IFNγ were in higher concentrations in AH samples from both BD and VKH patients whereas IL-2, IL-8, IL-13, TNFα, eotaxin, and IL-1ra showed statistically significant higher concentrations only in AH samples from BD patients. ...
... Anti-endothelial cell antibodies (AECAs) have been described in BD [25][26][27] and could trigger inflammation through complement or antibody-dependent cell toxicity, causing vasculitis. IL-6, TNFα, and CXCL10 were found to be significantly elevated in the aqueous humor (AH) of patients with BD uveitis, sarcoidosis, and toxoplasmosis uveitis as compared to non-inflammatory controls [28]. Another study aimed at investigating the potential markers for BD uveitis and uveitis associated with Vogt Koyanagi Harada (VKH) disease compared to healthy controls (HCs), showed that IL-6, CXCL10, G-CSF, and IFNγ were in higher concentrations in AH samples from both BD and VKH patients whereas IL-2, IL-8, IL-13, TNFα, eotaxin, and IL-1ra showed statistically significant higher concentrations only in AH samples from BD patients. ...
Uveitis in Behçet’s disease (BD) is frequent (40% of cases) and is a major cause of morbidity. The age of onset of uveitis is between 20 and 30 years. Ocular involvement includes anterior, posterior, or panuveitis. Uveitis may be the first sign of the disease in 20% of cases or it may appear 2 or 3 years after the first symptoms. Panuveitis is the most common presentation and is more commonly found in men. Bilateralization usually occurs on average 2 years after the first symptoms. The estimated risk of blindness at 5 years is 10–15%. BD uveitis has several ophthalmological features that distinguish it from other uveitis. The main goals in the management of patients are the rapid resolution of intraocular inflammation, the prevention of recurrent attacks, the achievement of complete remission, and the preservation of vision. Biologic therapies have changed the management of intraocular inflammation. The aim of this review is to provide an update to a previous article by our team on pathogenesis, diagnostic approaches, and the therapeutic strategy of BD uveitis.
... Uveitis can also present as a standalone condition configuring idiopathic uveitis [57]. Although the etiology of NIU is not fully elucidated, a potential role for the IL-17 pathway is emerging [58][59][60][61]. Several studies reported significant elevation in IL-17A expression in the serum of patients with active uveitis and demonstrated in animal models of uveitis that IL17-A inhibition can suppress disease activity [59][60][61][62]. ...
... Although the etiology of NIU is not fully elucidated, a potential role for the IL-17 pathway is emerging [58][59][60][61]. Several studies reported significant elevation in IL-17A expression in the serum of patients with active uveitis and demonstrated in animal models of uveitis that IL17-A inhibition can suppress disease activity [59][60][61][62]. Moreover, IL-17A levels have been found to be higher in the peripheral blood of patients with BS-associated uveitis compared with healthy controls or affected patients with quiescent uveitis [63]. ...
Introduction:
Interleukin-17 (IL-17) is a family of cytokines that plays a key role in several rheumatic diseases in both adults and children. In the last few years, several drugs targeting IL-17 have been developed.
Areas covered:
We present a review on the current state of the art regarding the use of anti-IL17 in childhood chronic rheumatic diseases. To date, the available evidence is limited and mainly focuses on juvenile idiopathic arthritis (JIA) and a specific autoinflammatory disease called deficiency of IL-36 receptor antagonist (DITRA). Recently, a randomized controlled trial resulted in the approval of secukinumab (an anti-IL17 monoclonal antibody) for JIA, due to its demonstrated efficacy and safety. Promising and potential uses of anti-IL17 in Behçet's syndrome, and synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome have also been described.
Expert opinion:
Increasing knowledge about the pathogenetic mechanisms underlying rheumatic diseases is leading to an improvement in the care of several chronic autoimmune diseases. In this scenario, anti-IL17 therapies (such as secukinumab and ixekizumab) might be an optimal choice. Recent data on the use of secukinumab in juvenile spondyloarthropathies can be a starting point for future treatment strategies in other pediatric rheumatic diseases, such as Behçet's syndrome and the chronic non-bacterial osteomyelitis disease spectrum, particularly SAPHO syndrome.
... A better understanding of ocular inflammation pathways has led to the emergence of biological therapies for the treatment of NIU [3,23] that aim to overcome the 30% failure rate obtained under classical immunosuppressive treatment [24]. Different cytokines such as TNFα, IL-6, IL-17, or IL-23 play a key role in NIU inflammatory process [25], therefore becoming very attractive as potential therapeutic targets. Bearing this in mind, randomized prospective studies have been developed in the last years to evaluate the treatment efficacy of biological drugs in NIU [6,7,26]. ...
... The presence of inflammation can alter the biodistribution coefficients at the tissue level. In fact, patients with uveitis experience an increase in vascular permeability due to the release of inflammatory mediators, such as TNFα, IL-6, IL-8, IL-17, or IL-23 [25,111,112]. This increase in vascular permeability has an impact on the integrity of the ocular barriers, which may play an important role in the penetration of high molecular weight drugs such as mAb in tissues with limited access like the eye [113]. ...
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians’ treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.
Одне з найпоширеніших структурних ускладнень увеїтів — це макулярний набряк, який є найчастішою причиною як оборотного, так і стійкого зниження гостроти зору. Втрата зору відбувається і через вторинну дистрофію макули внаслідок переднього увеїту. Крім того, прогресивно наростає частота вторинної глаукоми як ускладнення переднього увеїту. Характеристики гемодинаміки ока при ускладненому перебігу ідіопатичного рецидивуючого переднього увеїту в період загострення та ремісії мають відмінності залежно від характеру ускладнень. Визначення особливостей гемодинаміки ока при ускладненнях переднього увеїту має значення для призначення необхідної терапії і запобігання рецидивам. Значний рівень медико-соціальних та економічних втрат для суспільства в регіонах світу пов’язаний саме з ускладненнями хронічного запалення судинного тракту ока (переднього ідіопатичного увеїту).
Uveitis is a significant cause of ocular morbidity and accounts for approximately 5 – 10% of visual impairments worldwide, particularly among the working-age population. Infections are the cause of ~ 50% cases of uveitis, but it has been suggested that infection might also be implicated in the pathogenesis of immune-mediated “non-infectious” uveitis. There is growing evidence that cytokines (i.e., interleukins, interferons, etc.) are key mediators of immune-mediated “non-infectious” uveitis. For example, activation of the interleukin-23/interleukin-17 signalling pathway is involved in immune-mediated “non-infectious” uveitis. Studies in animal models have been important in investigating the role of cytokines in uveitis. Recent studies of clinical samples from patients with uveitis have allowed the measurement of a considerable array of cytokines even from very small sample volumes (e.g., aqueous and vitreous humour). The identification of complex patterns of cytokines may contribute to a better understanding of their potential pathogenetic role in uveitis as well as to an improved diagnostic and therapeutic approach to treat these potentially blinding pathologies. This review provides further insights into the putative pathobiological role of cytokines in immune-mediated “non-infectious” uveitis.
