Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus - PubMed (original) (raw)

Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Kamini Shah et al. Arthritis Res Ther. 2010.

Erratum in

Arthritis Res Ther. 2010;12(3):402

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)-gamma 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-gamma 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-gamma(+) 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-1beta, IL-21, IL-23, and transforming growth factor (TGF)-beta 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.

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Figures

Figure 1

Patients with SLE have an increased frequency of Th17 cells but not Th1 cells. PBMCs from patients with SLE (n = 25) and healthy control subjects (HC, n = 26) were stimulated for 4 hours ex vivo with PMA and ionomycin or PBS (control) in the presence of Golgiplug. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. (a) Representative dot plots showing CD4+ T cells producing IL-17 and/or IFN-γ. (b) The frequency (% of CD4+IL-17+ T cells, CD4+IL-17+IFN-γ+ T cells and CD4+IFN-γ+ T cells in patients with SLE and in healthy control subject (HC). Numbers in dot plots indicate the frequency of cells for each quadrant. Bars show the means.

Figure 2

Correlation of Th17 and Th1 response is dysregulated in patients with SLE. (a) The frequency (% of CD4+IL-17+ T cells correlates with the frequency of CD4+IFN-γ+ T cells in healthy control subjects (HC, n = 26) but not in patients with SLE (n = 25). (b) Patients with SLE have a higher Th17/Th1 ratio (frequency of CD4+IL-17+ T cells/frequency of CD4+IL-IFN-γ+ T cells) compared with healthy control subjects. Bars and numbers in (b) indicate the means.

Figure 3

The frequency of IL-17+ CD4+ T cells correlates with disease activity. (a-c) Relation between SLEDAI score and the frequency (%) of (a) CD4+IL-17+ T cells, (b) CD4+IL-17+IFN-γ+ T cells and (d) CD4+IFN-γ+ T cells in patients with SLE (n = 25). (d) Dot plots showing the frequency of CD4+ T cells producing IL-17 and/or IFN-γ in a patients with SLE at the times of high and low disease activities (SLEDAI score, 16 and 6, respectively). Representative data from two patients with SLE. (e) The frequency of CD4+IL-17+ T cells in patients with (+, n = 11) and without (-, n = 14) lupus nephritis. Numbers in dot plots indicate the frequency of cells for each quadrant. Bars show the means.

Figure 4

Patients with SLE have an increased frequency of CD4+CCR4+ CCR6+ T cells. The frequency of CCR4+ CCR6+ CD4+ T cells in peripheral blood was analyzed in patients with SLE and healthy control subjects by using flow cytometry. (a) Representative dot plots showing CD4+ T cells expressing CCR4 and CCR6. (b) The frequency (%) of CD4+CCR4+CCR6+ T cells in patients with SLE (n = 14) and healthy control subject (HC, n = 25). (c) Correlation between the frequencies of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells in patients with SLE (n = 11). (d) Correlation between the frequency of CD4+CCR4+CCR6+ T cells and SLEDAI score in patients with SLE (n = 14). (e) Representative dot plots showing the frequency of CD4+ T cells expressing CCR4 and/or CCR6 in a patients with SLE at the times of high and low disease activities (SLEDAI score, 16 and 6, respectively). Representative data from three patients with SLE. Numbers in dot plots indicate the frequency of cells for each quadrant. Bars show the means.

Figure 5

Plasma levels of Th17-driving cytokines and IL-10 in patients with SLE and healthy controls. Plasma levels of Th17-polarizing cytokinesg(IL-1β, IL-6, IL-21, TGF-β, and IL-23) and IL-10 were measured in patients with SLE and healthy control subjects (HCs) by using ELISA or multiplex cytokine assay. Bars show the means. Samples from 21 patients with SLE and 24 healthy controls for cytokines except TGF-β (n = 20 and n = 19 for lupus patients and healthy controls, respectively).

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Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus - PubMed (original) (raw)