Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation
Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation
复制标题
DOI：
10.1038/cmi.2014.117
复制
发表时间：
2015-09-01
影响因子：
24.1
通讯作者：
Bayry, Jagadeesh
中科院分区：
文献类型：
--
作者：
Maddur, Mohan S.;Trinath, Jamma;Bayry, Jagadeesh
CD 41 FoxP 31调节性T细胞（Treg）是免疫抑制细胞，对于免疫耐受至关重要。几项研究已经证明，静脉注射免疫球蛋白（IVIg）的抗炎作用机制之一涉及Tcl 3的扩增。最近，我们证明了IVIg介导的Treg扩增涉及环氧化酶-2（考克斯-2）依赖性诱导人树突状细胞（DC）中的前列腺素E2（PGE 2）。然而，这些发现在自身免疫性患者中的有效性是缺乏的。在这份报告中，我们证明了IVIg介导的自身免疫性患者的Tcl 4扩增与循环PGE 2水平升高有关。由于其对各种免疫细胞的免疫调节作用，PGE 2的这种增加代表了IVIg发挥抗炎作用的途径之一。IVIg是从许多健康供体的合并血浆中获得的正常循环IgG的治疗制剂。目前，高剂量IVIg疗法（1- 2g/kg体重）用于治疗多种自身免疫和炎性病症，例如格林-巴利综合征（GBS）、川崎、特发性血小板减少性紫癜和炎性肌炎。1 IVIG的有益作用是由许多相互非排他性的细胞和分子机制介导的。这些机制间接表明循环IgG在维持免疫稳态中的功能。IVIg的提出的机制包括以下：抑制先天免疫细胞如DC、巨噬细胞、单核细胞和中性粒细胞的活化;抑制致病性Th 1和Th 17亚群并使CD 41 FoxP 31 T细胞亚群扩增;抑制炎性细胞因子并增强抗炎分子;阻断补体活化;调节B细胞功能;中和致病性自身抗体。2，3几项研究表明，IVIg在人体和实验模型中均能扩增TcR。4，5这些发现也在IVIg治疗的自身免疫患者中得到证实。6，7最近，我们证明了IVIg介导的Treg扩增需要在人DC中诱导考克斯-2依赖性PGE 2。8在实验性自身免疫性脑脊髓炎模型中，DC中考克斯-2活性的抑制导致体外和体内IVIg介导的Treg扩增的消除。然而，IVIg治疗对自身免疫性患者PGE 2水平的影响尚未研究。IVIg被推荐作为GBS患者的一线治疗。因此，我们的目的是探讨静脉注射免疫球蛋白介导的5例GBS患者的TGFAP扩增是否与循环中PGE 2水平升高有关。在IVIg治疗前和治疗后1周，从5名GBS患者（3名男性和2名女性，年龄范围为57至82岁）中获得肝素化血液样本。这些患者均未接受过IVIg治疗，并且在过去三个月内未接受过任何免疫抑制或免疫调节治疗。相关伦理委员会批准
CD41FoxP31 regulatory T cells (Tregs) are immunosuppressive cells that are critical for immune tolerance. Several studies have demonstrated that one of the anti-inflammatory mechanisms of action of intravenous immunoglobulin (IVIg) involves the expansion of Tregs. Recently, we demonstrated that IVIgmediated Treg expansion involves the cyclooxygenase-2 (COX-2)-dependent induction of prostaglandin E2 (PGE2) in human dendritic cells (DCs). However, the validity of these findings in autoimmune patients is lacking. In this report, we demonstrate that the IVIg-mediated expansion of Tregs in autoimmune patients is associated with increased levels of circulatory PGE2. Due to its immunomodulatory effects on various immune cells, this increase in PGE2 represents one of the pathways by which IVIg exerts anti-inflammatory effects. IVIg is a therapeutic preparation of normal circulating IgG obtained from the pooled plasma of many healthy donors. Currently, high-dose IVIg therapy (1–2 g/kg body weight) is used in the treatment of diverse autoimmune and inflammatory conditions, such as Guillain–Barré syndrome (GBS), Kawasaki disease, idiopathic thrombocytopenic purpura and inflammatory myositis. 1 The beneficial effects of IVIg are mediated by numerous mutually non-exclusive cellular and molecular mechanisms. These mechanisms indirectly suggest the functions of circulating IgG in the maintenance of immune homeostasis. The proposed mechanisms of IVIg include the following: inhibiting the activation of innate immune cells, such as DCs, macrophages, monocytes and neutrophils; suppressing pathogenic Th1 and Th17 subsets and reciprocally expanding CD41FoxP31 Tregs; inhibiting inflammatory cytokines and enhancing anti-inflammatory molecules; blocking complement activation; modulating B-cell functions; and neutralizing pathogenic autoantibodies. 2, 3 Several studies have demonstrated that IVIg expands Tregs in both humans and experimental models. 4, 5 These findings have also been confirmed in IVIg-treated autoimmune patients. 6, 7 Recently, we demonstrated that IVIg-mediated Treg expansion requires the induction COX-2-dependent PGE2 in human DCs. 8 The inhibition of COX-2 activity in DCs led to the abrogation of IVIg-mediated Treg expansion both in vitro and in vivo in an experimental autoimmune encephalomyelitis model. However, the effect of IVIg therapy on PGE2 levels in autoimmune patients has not yet been investigated. IVIg is recommended as a first-line therapy for patients with GBS. Therefore, we aimed to explore whether the IVIgmediated expansion of Tregs in five patients with GBS was associated with increased levels of circulatory PGE2. Heparinized blood samples were obtained from five GBS patients (three men and two women, with ages ranging from 57 to 82 years) before and 1 week following IVIg therapy. The patients were naive to IVIg therapy and had not been under any immunosuppressive or immunomodulatory treatments in the previous three months. Relevant ethical committee approval