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      Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema

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          Abstract

          Purpose

          To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME).

          Methods

          Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) > 300 μm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1β, IL-6, IL-8, IL-17, MCP-1, TNF-α, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3 +CD4 +FoxP3 + in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels.

          Results

          Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67, 95% CI (0.45–1.00), P = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, 95% CI: 1.12–2.56, P = 0.049).

          Conclusions

          Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.

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          Most cited references41

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          Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First International Workshop

          To begin a process of standardizing the methods for reporting clinical data in the field of uveitis. Consensus workshop. Members of an international working group were surveyed about diagnostic terminology, inflammation grading schema, and outcome measures, and the results used to develop a series of proposals to better standardize the use of these entities. Small groups employed nominal group techniques to achieve consensus on several of these issues. The group affirmed that an anatomic classification of uveitis should be used as a framework for subsequent work on diagnostic criteria for specific uveitic syndromes, and that the classification of uveitis entities should be on the basis of the location of the inflammation and not on the presence of structural complications. Issues regarding the use of the terms "intermediate uveitis," "pars planitis," "panuveitis," and descriptors of the onset and course of the uveitis were addressed. The following were adopted: standardized grading schema for anterior chamber cells, anterior chamber flare, and for vitreous haze; standardized methods of recording structural complications of uveitis; standardized definitions of outcomes, including "inactive" inflammation, "improvement'; and "worsening" of the inflammation, and "corticosteroid sparing," and standardized guidelines for reporting visual acuity outcomes. A process of standardizing the approach to reporting clinical data in uveitis research has begun, and several terms have been standardized.
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            Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses.

            Foxp3(+) T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. Here we identified Foxp3(+) T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT(+) Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
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              The possible impact of uveitis in blindness: a literature survey.

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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 September 2020
                2020
                : 11
                : 579005
                Affiliations
                [1] 1Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona , Barcelona, Spain
                [2] 2Department of Ophthalmology, BioCruces Health Research Institute, Hospital Cruces, University of the Basque Country , Baracaldo, Spain
                [3] 3Ophthalmology Department and Health Research Institute (IdISSC), Hospital Clinic of San Carlos , Madrid, Spain
                [4] 4Valle Hebron Research Institute, Autonomous University of Barcelona , Barcelona, Spain
                Author notes

                Edited by: Peizeng Yang, First Affiliated Hospital of Chongqing Medical University, China

                Reviewed by: Yohei Tomita, Boston Children’s Hospital and Harvard Medical School, United States; Kuender D. Yang, Mackay Memorial Hospital, Taiwan

                *Correspondence: Blanca Molins, bmolins@ 123456clinic.cat

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.579005
                7545109
                33101305
                c9a81603-bcb1-431b-9652-433d8db5e31f
                Copyright © 2020 Matas, Llorenç, Fonollosa, Díaz-Valle, Esquinas, de la Maza, Figueras-Roca, Artaraz, Berasategui, Mesquida, Adán and Molins

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 July 2020
                : 14 September 2020
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 41, Pages: 9, Words: 5111
                Funding
                Funded by: Instituto de Salud Carlos III 10.13039/501100004587
                Award ID: PI13/00217
                Funded by: Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya 10.13039/501100002943
                Categories
                Immunology
                Original Research

                Immunology
                macular edema,uveitis,cytokines,regulatory t cells,biomarkers
                Immunology
                macular edema, uveitis, cytokines, regulatory t cells, biomarkers

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