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      The change of Th17/Treg cells and IL-10/IL-17 in Chinese children with Henoch–Schonlein purpura : A PRISMA-compliant meta-analysis

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          Abstract

          Background:

          To date, the relationship of Th17 and Treg cells to Henoch–Schonlein purpura (HSP) in children remains controversial. Therefore, a systematic review and meta-analysis was conducted to reveal the potential role of the Th17 and Treg cells in children in acute stage of HSP.

          Methods:

          PubMed, Embase, Web of Science and China National Knowledge Internet (CNKI) were systematically searched for eligible studies up to November 03, 2017. Quality assessment was carried out according to the modification of the Newcastle-Ottawa Scale (NOS). The data were analyzed by Stata SE12.0 (StataCorp, College Station, TX). Standard mean difference (SMD) with 95% confidence intervals (CI) was calculated continuous data.

          Results:

          A total of 25 eligible studies were identified after a thorough literature search. The pooled results of the meta-analysis showed that values of Th17 frequency (SMD = 2.60; 95% CI: 1.98 to 3.23; P < .0001; I 2 = 90.3%, P < .0001) and IL-17 level (SMD = 3.53; 95% CI: 2.71 to 4.35; P < .0001; I 2 = 95.6%, P < .001) were significantly higher in children with HSP as compared to healthy children. In contrast, our analysis showed significant lower values of Treg frequency (SMD = -2.86; 95% CI: -3.53 to -2.19; P < .001; I 2 = 92.4%, P < .001). However, no significance of IL-10 level was observed between children with HSP and healthy children (SMD = -1.22; 95% CI: -2.78 to 0.33; P < .01; I 2 = 95.9%, P < .001).

          Conclusion:

          In conclusion, our meta-analysis indicated that increased frequency of Th17 cells and level of IL-17, but lower frequency of Treg cells are associated with HSP in childhood. Considering the limitations of this meta-analysis, large-scaled studies need to be conducted to validate the current results.

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          Most cited references41

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          The biological functions of T helper 17 cell effector cytokines in inflammation.

          T helper 17 (Th17) cells belong to a recently identified T helper subset, in addition to the traditional Th1 and Th2 subsets. These cells are characterized as preferential producers of interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22. Th17 cells and their effector cytokines mediate host defensive mechanisms to various infections, especially extracellular bacteria infections, and are involved in the pathogenesis of many autoimmune diseases. The receptors for IL-17 and IL-22 are broadly expressed on various epithelial tissues. The effector cytokines of Th17 cells, therefore, mediate the crucial crosstalk between immune system and tissues, and play indispensable roles in tissue immunity.
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            IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.

            On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.
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              Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.

              Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                January 2019
                18 January 2019
                : 98
                : 3
                : e13991
                Affiliations
                [a ]Department of Pediatrics
                [b ]Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.
                Author notes
                []Correspondence: Yuning Li, Department of Pediatrics, The First Hospital of Lanzhou University, Lanzhou, China (e-mail: drliyn@ 123456sina.com ).
                Article
                MD-D-18-00346 13991
                10.1097/MD.0000000000013991
                6370168
                30653104
                0e4da0bc-7ddb-444f-84cb-f2fa3109362e
                Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 12 January 2018
                : 29 October 2018
                : 13 December 2018
                Categories
                3600
                Research Article
                Systematic Review and Meta-Analysis
                Custom metadata
                TRUE

                henoch–schonlein purpura (hsp),meta-analysis,th17,treg

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