Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Kamini Shah, Won Woo Lee, Seung Hyun Lee, Sang Hyun Kim, Seong Wook Kang, Joe Craft, Insoo Kang

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224 Scopus citations

Abstract

Introduction: Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4+ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4+ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.Methods: Twenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4+ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses.Results: Patients with SLE had an increased frequency of CD4+IL-17+ T cells compared with healthy subjects. However, the frequency of CD4+IFN-γ+ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4+CCR4+CCR6+ T cells that are known to produce IL-17. The frequency of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups.Conclusions: We demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4+ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.

Original languageEnglish
Article numberR53
JournalArthritis Research and Therapy
Volume12
Issue number2
DOIs
StatePublished - 24 Mar 2010

Bibliographical note

Funding Information:
We thank Ms. Amy Shelton and Yale Center for Clinical Investigation (UL1 RR024139 from the NCRR) as well as Drs. Una Makris, Vivian Vlamakis, Richard Bryan, Minna Kohler, and Robert Schoen for assisting in the recruitment of human subjects. This work was supported in part by grants from the National Institutes of Health (AG028069, AG030834, AR049444, U19 AI082713 all to IK; AI075157 to JC; T32AR00107 to KS). Insoo Kang is a participant in the World Class University Program of Republic of Korea. Seung-Hyun Lee is a recipient of Kunkuk University Research Scholarship.

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