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      The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus

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          Abstract

          We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients.

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          Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

          M Hochberg (1997)
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            Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

            Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
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              Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.

              Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-beta, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'T(H)-9' cells directly. Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: Formal analysisRole: Methodology
                Role: Formal analysisRole: Methodology
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 September 2017
                2017
                : 12
                : 9
                : e0184449
                Affiliations
                [1 ] Department of Internal Medicine and Medical Specialties, Rheumatology; Sapienza University of Rome, Rome, Italy
                [2 ] Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
                [3 ] Geriatric Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
                Keio University, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2889-8962
                http://orcid.org/0000-0002-7757-8092
                Article
                PONE-D-17-11600
                10.1371/journal.pone.0184449
                5587319
                28877244
                bdf47c9d-5d71-4417-9c13-417bdea8ca1c
                © 2017 Scrivo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 March 2017
                : 24 August 2017
                Page count
                Figures: 5, Tables: 2, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004271, Sapienza Università di Roma;
                Award ID: Grandi Ricerche Universitarie 2015, prot. C26H15RWHN
                Award Recipient :
                This work was supported by Grandi Ricerche Universitarie 2015, prot. C26H15RWHN (Progetti d’Ateneo, Sapienza Università di Roma). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Medicine and Health Sciences
                Rheumatology
                Arthritis
                Rheumatoid Arthritis
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Autoimmune Diseases
                Rheumatoid Arthritis
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Rheumatoid Arthritis
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Rheumatoid Arthritis
                Medicine and Health Sciences
                Clinical Medicine
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                Autoimmune Diseases
                Lupus Erythematosus
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                Immunology
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                Autoimmune Diseases
                Lupus Erythematosus
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                Cell biology
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                Sodium Chloride
                Custom metadata
                All relevant data are available from figshare (DOI: 10.6084/m9.figshare.5091940).

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