Laboratory I3 Immunology, Immunopathology, Immunotherapy, Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, Paris, France.
J Allergy Clin Immunol. 2011 Sep;128(3):655-64. doi: 10.1016/j.jaci.2011.05.029. Epub 2011 Jul 2.
Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology.
To determine the nature of T cells driving inflammatory lesions in BD.
T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = 20]) and 20 healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis.
We found a marked increase in T(H)17 cells and a decrease in the frequency of CD4(+) forkhead box P3(+) regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4(+) T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21- and IL-17A-producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4(+) T cells with IL-21 increased T(H)17 and T(H)1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the T(H)17 and Treg homeostasis in patients with BD.
We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting T(H)17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD.
贝赫切特病（BD）是一种病因不明的慢性全身性炎症性疾病。
确定导致 BD 炎症病变的 T 细胞性质。
使用 Luminex、流式细胞术、免疫组织化学和免疫荧光分析，分析了 45 名成年 BD 患者（活动期和未经治疗的 BD [n=25]和缓解期患者[n=20]）和 20 名健康供体的外周血和脑炎症病变中的 T 细胞稳态和细胞因子产生情况。
我们发现，外周血中 T(H)17 细胞明显增加，CD4(+)叉头框 P3(+)调节性 T 细胞（Tregs）频率降低，这是由 IL-21 产生诱导的，与 BD 活动相关。在健康供体的分选 CD4(+) T 细胞培养物中加入来自活动期 BD 患者的血清，可诱导 IL-17A 的显著且剂量依赖性产生，并降低叉头框 P3 的表达。我们在活动期 BD 患者的脑脊液、脑实质炎症浸润物和颅内血管以及伴有中枢神经系统受累的患者中发现了 IL-21 和 IL-17A 产生的 T 细胞。用 IL-21 刺激 CD4(+) T 细胞可增加 T(H)17 和 T(H)1 分化，并降低 Treg 细胞的频率。相反，用 IL-21R-Fc 阻断 IL-21 恢复了 BD 患者的 T(H)17 和 Treg 稳态。
我们在这里首次提供了证据，证明 IL-21 通过促进 T(H)17 效应器和抑制 Treg 细胞在 BD 中驱动炎症病变中起关键作用。IL-21 代表 BD 新型治疗的有希望的靶点。
