Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

Xuebing Feng,Xia Li,Betty P Tsao,Dandan Wang,Lingyun Sun,Lin Lu,Jingjing Chen,Bingzhu Hua,Gernot Zissel

doi:10.1371/journal.pone.0051982

Xuebing Feng, Xia Li + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0051982

Copy DOI

Abstract

ObjectiveTo observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients.MethodsPeripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5+PD1+/CD4+ T cells (Tfh), CD4+CCR6+ T cells (Th17-like) and CD19+CD138+ plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours.ResultsCompared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013).ConclusionsWe demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

Highlights

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by the production of multiple autoantibodies, antinuclear antibodies (ANA)
It has been demonstrated that co-expressions of CXCR5 with ICOS and/or programmed death 1 (PD-1) are a useful phenotypic profile to distinguish this T helper cell subset, and circulating T follicular helper (Tfh) cells are in proportion to their germinal center (GC) counterparts [3,4,5]
CD4+ T cells from 42 Chinese systemic lupus erythematosus (SLE) patients and 22 normal controls were analyzed by flow cytometry

Summary

Introduction

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by the production of multiple autoantibodies, antinuclear antibodies (ANA). Both the B-cell and T-cell compartments exhibit functional abnormalities that could lead to the autoantibody production in SLE. Much attention has focused on the role of the T follicular helper (Tfh) cell in supporting antibody production. This CD4+ T subset helps the generation of germinal center (GC) responses where somatic hyper-mutation and affinity maturation take place leading to the generation of memory B cells and plasma cells [1]. In SLE patients, expression of Tfh cell phenotypes by circulating peripheral blood cells has been shown to correlate with diversity and titers of autoantibodies and with disease severity [5]

Methods

Results

Conclusion