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      Sodium Chloride Aggravates Arthritis via Th17 Polarization

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          Abstract

          Purpose

          Sodium chloride (NaCl) has been proposed as a driving factor in autoimmune diseases through the induction of pathogenic CD4 + T helper cells that produce interleukin-17 (Th17 cells). This study investigated the effects of NaCl on inflammatory arthritis in mice and humans.

          Materials and Methods

          Collagen-induced arthritis (CIA) mice were fed a normal or high-salt diet ad libitum, and clinical and histologic features of arthritis were evaluated. The proportion of Th17 cells in the spleens of CIA mice fed a normal or high-salt diet was evaluated by flow cytometry, and the expression of IL-17 in joints and intestines was determined by immunohistochemical staining. We also analyzed the effect of NaCl on Th17 differentiation from peripheral blood monocytes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and evaluated the contents of sodium and IL-17 in the synovial fluid of RA and OA patients.

          Results

          NaCl increased murine and human Th17 cell differentiation in a dose-dependent manner. Clinical and histological arthritis was more severe in the high-salt-fed CIA mice, compared to control CIA mice. The proportion of Th17 cells among splenocytes was higher in CIA mice fed a high-salt diet. Expression of synovial and intestinal IL-17 was also higher in high-salt-fed CIA mice. Comparison of synovial fluid between RA patients and OA patients revealed that Na + and IL-17 were more abundant in RA synovial fluid.

          Conclusion

          This study suggests that NaCl can aggravate arthritis by affecting Th17 differentiation. Accordingly, limiting salt intake may be helpful for treating inflammatory arthritis, such as RA.

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          Most cited references27

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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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            Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.

            Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease. Copyright 2010 Elsevier Inc. All rights reserved.
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              Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.

              Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.
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                Author and article information

                Journal
                Yonsei Med J
                Yonsei Med. J
                YMJ
                Yonsei Medical Journal
                Yonsei University College of Medicine
                0513-5796
                1976-2437
                01 January 2019
                13 December 2018
                : 60
                : 1
                : 88-97
                Affiliations
                [1 ]Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
                [2 ]Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
                Author notes
                Corresponding author: Ji Hyeon Ju, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Tel: 82-2-2258-6893, Fax: 82-2-3476-2274, juji@ 123456catholic.ac.kr

                *Seung Min Jung and Youngkyun Kim contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-3465-2181
                https://orcid.org/0000-0003-3078-6852
                https://orcid.org/0000-0001-9571-1734
                https://orcid.org/0000-0002-1231-8660
                https://orcid.org/0000-0002-6786-4327
                https://orcid.org/0000-0001-9541-3075
                https://orcid.org/0000-0002-4859-1351
                https://orcid.org/0000-0002-6142-8364
                https://orcid.org/0000-0003-1711-2060
                https://orcid.org/0000-0002-1381-5466
                Article
                10.3349/ymj.2019.60.1.88
                6298894
                30554495
                63b5d39c-bc5d-4523-a3f6-b4733a6e0d94
                © Copyright: Yonsei University College of Medicine 2019

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 June 2018
                : 31 October 2018
                : 07 November 2018
                Funding
                Funded by: Ministry of Health and Welfare, CrossRef https://doi.org/10.13039/501100003625;
                Award ID: A092258
                Funded by: National Research Foundation of Korea, CrossRef https://doi.org/10.13039/501100003725;
                Award ID: 2013R1A1A1076125
                Funded by: National Institute of Food and Drug Safety Evaluation, CrossRef https://doi.org/10.13039/501100003655;
                Award ID: 14172 CENST 974
                Categories
                Original Article
                Rheumatology

                Medicine
                rheumatoid arthritis,salt,sodium chloride,th17 cells,collagen-induced arthritis
                Medicine
                rheumatoid arthritis, salt, sodium chloride, th17 cells, collagen-induced arthritis

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