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, 2019, 8421479
eCollection

Imbalance of Circulatory T Follicular Helper and T Follicular Regulatory Cells in Patients With ANCA-Associated Vasculitis

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Imbalance of Circulatory T Follicular Helper and T Follicular Regulatory Cells in Patients With ANCA-Associated Vasculitis

Ying Xu et al. Mediators Inflamm.

Abstract

Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is characterized by small-vessel inflammation in association with autoantibodies. Balance between T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells is critical for humoral immune responses. Accumulating evidence supports that Tfh and Tfr are involved in autoimmune diseases; however, their roles in AAV are unclear. In this study, we tested the changes of circulatory Tfh and Tfr in patients with AAV. Twenty patients with AAV and twenty healthy controls were enrolled. Sixteen AAV patients had kidney involvement. We found that the AAV patients had increased circulating Tfh cells (CD4+CXCR5+CD25-CD127interm-hi), decreased Tfr cells (CD4+CXCR5+CD25+CD127lo-interm), and elevated Tfh/Tfr ratios compared with healthy controls (P < 0.01). The Tfh percentage and Tfh/Tfr ratio, but not Tfr percentage, were positively correlated to proteinuria levels and BVAS scores in patients with AAV (P < 0.01). In addition, AAV patients had decreased circulating Tfh1 (CCR6-CXCR3+), but increased Tfh2 cells (CCR6-CXCR3-), compared with healthy controls (P < 0.01), indicating a Tfh1-to-Tfh2 shift. Furthermore, remission achieved by immunosuppressive treatment markedly attenuated the increase of total Tfh (P < 0.01) and Tfh2 cells (P < 0.05), promoted the Tfh1 response (P < 0.05), and recovered the balance between Tfh/Tfr cells (P < 0.05) and between Tfh1/Tfh2 cells (P < 0.05) in patients with AAV. Plasma levels of IL-21, a cytokine secreted by Tfh cells, were elevated in AAV patients compared with healthy controls (P < 0.01), which was attenuated by immunosuppressive treatment (P < 0.05). Taken together, our findings indicate that circulatory Tfh/Tfr ratios, Tfh2/Tfh1 shift, and plasma IL-21 levels are associated with AAV and disease activity.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Circulatory Tfh and Tfr cells in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV). (a) The gate strategy for circulatory Tfh and Tfr cells. The percentage and count of circulatory Tfh (b, c) and Tfr (d, e) cells and Tfh/Tfr ratios (f) in patients with AAV and healthy controls. (g) Mean fluorescence intensity (MFI) of FOXP3 in Tfh and Tfr cells. ∗∗P < 0.01. Tfh: T follicular helper cells; Tfr: T follicular regulatory cells.
Figure 2
Figure 2
Correlation between circulatory Tfh/Tfr cells and renal injury. Correlation of the percentages of circulatory Tfh cells (a–d), Tfr cells (e–h), and Tfh/Tfr ratios (i–l) with serum creatinine, blood urea nitrogen, 24 h urinary protein levels, and BVAS scores in patients with AAV.
Figure 3
Figure 3
Circulatory Tfh1 and Tfh2 cells in patients with AAV. (a) The gate strategy for circulatory Tfh1 and Tfh2 cells. The percentage and count of circulatory Tfh1 (b, c) and Tfh2 (d, e) cells and Tfh2/Tfh1 ratios (f) in patients with AAV and healthy controls. P < 0.05; ∗∗P < 0.01. Tfh: T follicular helper cells.
Figure 4
Figure 4
Effects of immunosuppressive treatment on circulatory Tfh/Tfr and Tfh2/Tfh1 ratios. The percentage and count of circulatory Tfh (a, b) and Tfr (c, d) cells and Tfh/Tfr ratios (e) in patients with AAV at baseline and after remission were achieved by immunosuppressive treatment. The percentage of circulatory Tfh1 (f, g) and Tfh2 (h, i) cells and Tfh2/Tfh1 ratios (j) in patients with AAV at baseline and after remission was achieved by immunosuppressive treatment. P < 0.05; ∗∗P < 0.01.
Figure 5
Figure 5
Plasma levels of cytokine IL-21. Plasma IL-21 levels were detected in healthy controls and patients with AAV at baseline and after remission achieved by immunosuppressive treatment. P < 0.05; ∗∗P < 0.01.

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