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      Effects of β-d-mannuronic acid, as a novel non-steroidal anti-inflammatory medication within immunosuppressive properties, on IL17, RORγt, IL4 and GATA3 gene expressions in rheumatoid arthritis patients

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          Abstract

          Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis characterized by pain, swelling and destruction of joints, with a resultant disability. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can interfere with the disease process. In this study, the effect of β- d-mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive and anti-inflammatory effects together with antioxidant effects was evaluated on IL17, RORγt, IL4 and GATA3 gene expression in 12 RA patients. Previously, M2000 driven from sodium alginate (natural product; patented, DEU: 102016113018.4) has shown a notable efficacy in experimental models of multiple sclerosis, RA and nephrotic syndrome. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. M2000 was administered orally at a dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the expression levels of IL4, GATA3, IL17 and RORγt. The gene expression results showed that M2000 has a potent efficacy, so that it could not only significantly decrease IL17 and RORγt levels but also increase IL4 and GATA3 levels after 12 weeks of treatment. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments. In conclusion, M2000 as a natural novel agent has therapeutic and immunosuppressive properties on RA patients (identifier: IRCT2014011213739N2).

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          Most cited references 28

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            Simultaneous Disruption of Interleukin (IL)-4 and IL-13 Defines Individual Roles in T Helper Cell Type 2–mediated Responses

            Using a single vector targeting strategy, we have generated mice with a combined deficiency of interleukin (IL)-4 and IL-13 to clarify their roles in T helper type 2 (Th2) cell responses. Using immunological challenges normally characterized by a Th2-like response, we have compared the responses of the double-deficient mice with those generated by wild-type, IL-4–deficient, and IL-13–deficient mice. Using a pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that although eosinophil infiltration, immunoglobulin E, and IL-5 production are reduced in the IL-4–deficient mice and IL-13–deficient mice, they are abolished only in the combined absence of both cytokines. Furthermore, IL-4/13–deficient animals are severely impaired in their ability to expel the gastrointestinal nematode Nippostrongylus brasiliensis. Unexpectedly, N. brasiliensis–infected IL-4/13–deficient mice developed elevated IL-5 and eosinophilia, indicating that compensatory mechanisms exist for the expression of IL-5, although serum IgE remained undetectable. IL-4/13–deficient mice default to a Th1-like phenotype characterized by the expression of interferon γ and the production of IgG2a and IgG2b. We conclude that IL-4 and IL-13 cooperate to initiate rapid Th2 cell–driven responses, and that although their functions overlap, they perform additive roles.
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              The central role of T cells in rheumatoid arthritis.

              Rheumatoid arthritis (RA) is one of the most common chronic inflammatory syndromes. As such, RA is often considered the prototype disease for defining both the molecular and pathological basis of immune-mediated chronic inflammatory disease, and for validating targeted therapies. The immunogenetics of RA suggest a key role for aberrant pathways of T-cell activation in the initiation and/or perpetuation of disease. In the T-cell activation process, CD4+ T-cells are engaged by antigenic peptide fragments in a complex with HLA class II molecules, in addition to co-stimulatory molecules, such as CD80/CD86, expressed on the surface of professional antigen presenting cells. The strongest evidence supporting a role for CD4+ T cells in disease pathogenesis is the association between RA and HLA-DRB1; however, the functional role of this association has yet to be defined. Susceptibility to RA may also be linked with several RA-associated allelic variants of genes, especially PTPN22, but also CTLA4, IL2RA, IL-2RB, STAT4, PTPN2 and PADI4, many of which encode molecules directly implicated in pathways of T-cell activation.The presence of inflammatory infiltrates, such as follicular structures, in the synovial membrane provides compelling evidence of ongoing immune reactions in moderate to severe RA. These structures likely play a key role in T cell - B cell cooperation and the local generation of specific autoantibodies; as such, chronically activated synovial T cells represent key cellular targets for therapy. Evidence also supports a role for T-helper (Th) cells, Th17 cells, and impaired CD4+CD25(hi) regulatory T cell (Treg) function in the pathogenesis of RA. In addition to discussing a range of issues regarding T-cell activation in RA, this review describes how therapeutic modulation of T-cell function, as opposed to profound immunosuppression or immunodepletion, has been associated with better disease outcomes in clinical trials. Ultimately, elucidation of the distinct effects of co-stimulation modulation with abatacept on T cells should provide key insights into understanding how to restore immune homeostasis in patients with RA.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                30 March 2017
                : 11
                : 1027-1033
                Affiliations
                [1 ]Department of Immunology, School of Public Health
                [2 ]Iranian Institute for Health Sciences Research, Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
                Author notes
                Correspondence: Abbas Mirshafiey, Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box 14155-6446, Tehran, Iran, Tel +98 21 8895 4913, Fax +98 21 8895 4913, Email mirshafiey@ 123456tums.ac.ir
                [*]

                These authors contributed equally to this work

                Article
                dddt-11-1027
                10.2147/DDDT.S129419
                5384716
                © 2017 Barati et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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