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      Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis

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          Abstract

          Background

          The aim was to investigate CD4 +T-cell subsets, immune cells and their cytokine profiles in blood and synovial compartments in rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) to define specific immune signatures.

          Methods

          Peripheral blood, synovial fluid (SF) and synovial membranes (SM) of RA and OA patients were analyzed. CD4 +T-cell subset frequencies were determined by flow cytometry, and cytokine concentrations in serum and SF were measured by ELISA.

          Results

          In peripheral blood, OA patients had altered frequencies of regulatory T-cell subsets, and higher frequencies of Th17 and of Th1/17 cells than RA patients. In the synovial compartment of OA patients, conventional Th17 cells were largely excluded, while Th1/17 cells were enriched and more frequent than in RA patients. Conversely, in the synovial compartment of RA patients, regulatory T cells and Tfh cells were enriched and more frequent then in OA patients. IL-17 and Blys were increased both in serum and SF of RA patients, and correlated with autoantibodies and disease activity. Notably, Blys levels were already significantly elevated in RA patients with low disease activity score in 28 joints (DAS28) and without autoantibody positivity.

          Conclusions

          Although patients with inflammatory OA have immune activation in the synovial compartment, they display different T-cell subset frequencies and cytokine profiles. Soluble mediators such as Blys might help to discriminate mild clinical forms of RA from inflammatory OA particularly at the onset of the disease.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13075-017-1305-1) contains supplementary material, which is available to authorized users.

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          Most cited references13

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          The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis.

          Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression.
            • Record: found
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            • Article: not found

            Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.

            Although osteoarthritis (OA) is considered a non-inflammatory condition, it is widely accepted that synovial inflammation is a feature of OA. However, the role of immune cells and their cytokines in OA is largely unknown. This narrative systematic review summarizes the knowledge of inflammatory properties, immune cells and their cytokines in synovial tissues (STs) of OA patients. Broad literature search in different databases was performed which resulted in 100 articles. Of 100 articles 33 solely investigated inflammation in OA ST with or without comparison with normal samples; the remaining primarily focussed on rheumatoid arthritis (RA) ST. Studies investigating different severity stages or cellular source of cytokines were sparse. OA ST displayed mild/moderate grade inflammation when investigated by means of haematoxylin and eosin (H&E) staining. Most frequently found cells types were macrophages, T cells and mast cells (MCs). Overall the number of cells was lower than in RA, although the number of MCs was as high as or sometimes even higher than in RA ST. Cytokines related to T cell or macrophage function were found in OA ST. Their expression was overall higher than in normal ST, but lower than in RA ST. Their cellular source remains largely unknown in OA ST. Inflammation is common in OA ST and characterized by immune cell infiltration and cytokine secretion. This inflammation seems quantitatively and qualitatively different from inflammation in RA. Further research is needed to clarify the role of inflammation, immune cells and their cytokines in the pathogenesis of OA. Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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              Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases.

              To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune-based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. Sera from 185 patients with various systemic immune-based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1-month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti-double-stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic-range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune-based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.

                Author and article information

                Contributors
                alessandra.penatti@gmail.com
                Federica.facciotti@ieo.it , federica.facciotti@ieo.ie
                roberta.dematteis@unimi.it
                larghi@ingm.org
                paroni@ingm.org
                antonella.murgo@asst-pini-cto.it
                oraziodelucia@alice.it
                pagani@ingm.org
                luca.pierannunzii@gpini.it
                marcelloclaudio.truzzi@gpini.it
                A.Ioan@lumc.nl
                abrignani@ingm.org
                geginat@ingm.org
                pierluigi.meroni@unimi.it
                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                19 May 2017
                19 May 2017
                2017
                : 19
                : 103
                Affiliations
                [1 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, , DISCCO-Department of Clinical Science and Community Health Università degli Studi di Milano, ; 20122 Milan, Italy
                [2 ]ISNI 0000 0004 1802 9805, GRID grid.428717.f, , INGM-National Institute of Molecular Genetics “Romeo ed Enrica Invernizzi”, ; 20122 Milan, Italy
                [3 ]ASST-Gaetano Pini/CTO Orthopedic and Traumatology Specialist Center, Rheumatology and Orthopedic Department, 20122 Milan, Italy
                [4 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Rheumatology, , Leiden University Medical Center, ; 2300 Leiden, The Netherlands
                [5 ]ISNI 0000 0004 1757 9530, GRID grid.418224.9, Laboratory of immuno-rheumatological researches, , IRCCS Istituto Auxologico Italiano, ; 20149 Milan, Italy
                [6 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Pathophysiology and Transplantation, , Università degli Studi di Milano, ; 20122 Milan, Italy
                Author information
                http://orcid.org/0000-0002-2541-9428
                Article
                1305
                10.1186/s13075-017-1305-1
                5437517
                28526072
                46f08a32-6f65-4474-b945-d75c84ea758c
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 December 2016
                : 2 May 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002803, Fondazione Cariplo;
                Funded by: Romeo ed Enrica Invernizzi foundation
                Funded by: Ricerca Corrente 2015-16 IRCCS Istituto Auxologico Italiano
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Orthopedics
                rheumatoid arthritis,inflammatory osteoarthritis,t helper subsets,cytokines,blys
                Orthopedics
                rheumatoid arthritis, inflammatory osteoarthritis, t helper subsets, cytokines, blys

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