当前位置: X-MOL 学术Clin. Exp. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
B(effector)reaking bad in systemic sclerosis: role of a novel B cell subset.
Clinical & Experimental Immunology ( IF 4.6 ) Pub Date : 2020-08-12 , DOI: 10.1111/cei.13501
S O'Reilly 1 , J van Laar 2
Affiliation  

Systemic sclerosis (SSc) is an autoimmune idiopathic connective tissue disease characterized by fibrosis of skin and internal organs such as lung, heart and gut. The disease results from an interplay between vascular damage, autoimmunity, inflammation [1], cytokine dysregulation and resulting differentiation of fibroblasts to myofibroblasts that deposit copious amounts of extracellular matrix molecules, including collagen and fibronectin [2].

Although the disease is complex and has an unpredictable clinical course, recent discoveries have uncovered a role for the immune system in the disease – especially that of the adaptive immune system [3, 4]. In this issue, Higashioka et al . describe the generation of granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐producing B cell effector cells which are enriched in SSc patients, particularly those with the diffuse cutaneous subtype (dcSSc) [5]. Furthermore, they demonstrated that these cells generated under T helper type 2 (Th2)‐polarized conditions could enable the differentiation of CD14+ monocytes to a dendritic cell that promoted proliferation of naive T cells.

Within a complex and incompletely understood pathogenesis, B cells have been found to be aberrant in SSc [6], and specific autoantibodies reacting to various intracellular components, including RNA polymerase, are indeed diagnostic in the disease. In fact, it has been shown that B regulatory cells, that are anti‐inflammatory and potentially regulatory in autoimmune disease, are reduced both numerically and functionally in SSc [6]. The authors of this study examined the GM‐CSF‐producing B effector cells and their generation in vitro . They found that interleukin (IL)‐4 significantly promoted the generation of these GM‐CSF‐producing B effector cells. This is of interest, as IL‐4 is a Th2‐polarizing cytokine and SSc is characterized by a Th2 domination [3, 7], and elevated serum levels of IL‐4 and IL‐13. IL‐4 and IL‐13 are virtually identical cytokines. Interestingly, the master profibrotic cytokine, transforming growth factor (TGF)‐β1, involved in many fibrotic conditions, further potentiated the induction of GM‐CSF‐producing B effector cells by the Th2‐polarizsing cytokines IL‐4 and IL‐13, which suggests that a TGF‐β1 niche promotes the development of this specific cell type. Furthermore, tofacitinib reduced IL‐4‐mediated, but not TGF‐β‐mediated, induction of GM‐CSF in these effector B cells. Tofacitinb is a small‐molecule Janus kinase (JAK) inhibitor with a good safety profile, which is licensed for treatment of rheumatoid arthritis (RA) and has shown clinical efficacy in psoriatic arthritis [8]. Tofacitinib works by blocking JAKs, being a pan‐inhibitor with potent inhibition of JAK1 and JAK3, and subsequent downstream phosphorylation of signal transducers and activators of transcription (STATs). STAT signalling has also been found to be critical in SSc fibrosis [9], and highly targeted JAK2 inhibition in vitro has shown some anti‐fibrotic effects [10]. We have found the use of tofacitinib in vitro to be extremely effective in reducing fibrosis using cultured dermal fibroblasts from SSc patients (unpublished observations).

Furthermore, Higashioka et al . demonstrated that GM‐CSF‐producing B effector cells cultured in Th2‐polarizing conditions facilitated the differentiation of CD14+ monocytes to DC‐SIGN+CD1a+CD14CD86+ cells, presumably by IL‐4 and GM‐CSF. These DCs subsequently promoted naive T cell proliferation; however, the reproducibility of this is not clear.

Rituximab is a chimeric monoclonal antibody that specifically targets the transmembrane CD20 receptor on B cells, leading to a significant depletion of autoreactive B cells. In light of that, in a study in 20 patients with dcSSc treatment with rituximab led to significant improvements in skin fibrosis scores and preservation of lung function [11]. A recent study in a Japanese cohort also showed significant benefit in both skin fibrosis and lung preservation in comparison to cyclophosphamide in anti‐topo1 antibody‐positive patients [12]. Although both studies are small, they offer a positive indication towards B cell depletion therapy and suggest that a specific subset of patients may respond well to treatment with rituximab. Indeed, in the study in this issue of Clinical and Experimental Immunology , the authors found overall higher numbers of GM‐CSF‐producing B effector cells, but this was particularly high in the dcSSc with concomitant interstitial lung disease. The implication is that this particular subset of B effector cells could be used as a possible predictor to select patients for B cell‐depleting biological therapy in diffuse SSc with concomitant lung disease. Heterogeneity in clinical trials of interventions in SSc is a critical issue, so a predictor of who will respond to a specific therapy would be useful.

The observation that tofacitinib, a JAK inhibitor, blocked production of GM‐CSF‐producing B effector cells suggests that targeting JAKs could be therapeutic in SSc. Indeed, a clinical trial is under way for examining the safety and tolerability of tofacitinib in diffuse SSc (NCT03274076). Although the authors show evidence of this specific B effector cell in the blood of SSc patients, demonstration of these cells in lesional skin would substantiate the pathogenic role of this cell type. Direct action of this particular B effector cell on myofibroblast transition was not demonstrated in this study; indeed, SSc fibroblasts have been shown to have higher expression of the GM‐CSF receptor [13], and therefore could be particularly sensitive to this cytokine.



中文翻译:

B(效应子)在系统性硬化症中表现不佳:新型 B 细胞亚群的作用。

系统性硬化症 (SSc) 是一种自身免疫性特发性结缔组织疾病,其特征在于皮肤和内脏器官(如肺、心脏和肠道)的纤维化。该疾病是由血管损伤、自身免疫、炎症 [ 1 ]、细胞因子失调和由此导致的成纤维细胞分化为肌成纤维细胞之间的相互作用引起的,肌成纤维细胞沉积了大量的细胞外基质分子,包括胶原蛋白和纤连蛋白 [ 2 ]。

尽管该疾病复杂且临床病程不可预测,但最近的发现揭示了免疫系统在该疾病中的作用,尤其是适应性免疫系统 [ 3, 4 ]。在这个问题上,Higashioka等人。描述了产生粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 的 B 细胞效应细胞,这些细胞在 SSc 患者中富集,尤其是那些具有弥漫性皮肤亚型 (dcSSc) 的患者 [ 5 ]。此外,他们证明了这些在 T 辅助细胞类型 2 (Th2) 极化条件下产生的细胞可以使 CD14 +单核细胞分化为促进幼稚 T 细胞增殖的树突状细胞。

在复杂且尚未完全了解的发病机制中,已发现 B 细胞在 SSc 中异常 [ 6 ],并且与各种细胞内成分(包括 RNA 聚合酶)反应的特异性自身抗体确实可诊断该疾病。事实上,已经表明在 SSc 中具有抗炎和潜在调节作用的 B 调节细胞在 SSc 中在数量和功能上都减少了 [ 6 ]。这项研究的作者检查了产生 GM-CSF 的 B 效应细胞及其体外生成。他们发现白细胞介素 (IL)-4 显着促进了这些产生 GM-CSF 的 B 效应细胞的产生。这很有趣,因为 IL-4 是一种 Th2 极化细胞因子,而 SSc 的特点是 Th2 占主导地位。3, 7 ],以及升高的血清 IL-4 和 IL-13 水平。IL-4 和 IL-13 实际上是相同的细胞因子。有趣的是,主要促纤维化细胞因子转化生长因子 (TGF)-β1 参与许多纤维化条件,进一步增强了 Th2 极化细胞因子 IL-4 和 IL-13 对产生 GM-CSF 的 B 效应细胞的诱导表明 TGF-β1 生态位促进了这种特定细胞类型的发育。此外,托法替尼减少了这些效应 B 细胞中 IL-4 介导的,但不是 TGF-β 介导的 GM-CSF 诱导。Tofacitinb 是一种小分子 Janus 激酶 (JAK) 抑制剂,具有良好的安全性,已获准用于治疗类风湿性关节炎 (RA),并已在银屑病关节炎中显示出临床疗效 [ 8]]。托法替尼通过阻断 JAK 起作用,JAK 是一种泛抑制剂,可有效抑制 JAK1 和 JAK3,随后信号转导和转录激活因子 (STAT) 的下游磷酸化。还发现 STAT 信号传导在 SSc 纤维化中至关重要 [ 9 ],并且在体外高度靶向 JAK2 抑制已显示出一些抗纤维化作用 [ 10 ]。我们发现使用来自 SSc 患者的培养的真皮成纤维细胞,在体外使用托法替尼减少纤维化方面极为有效(未发表的观察结果)。

此外,Higashioka等人。证明在 Th2 极化条件下培养的产生 GM-CSF 的 B 效应细胞促进了 CD14 +单核细胞向 DC-SIGN + CD1a + CD14 - CD86 +细胞的分化,推测是通过 IL-4 和 GM-CSF。这些DC随后促进了幼稚T细胞增殖;然而,这一点的可重复性尚不清楚。

利妥昔单抗是一种嵌合单克隆抗体,专门针对 B 细胞上的跨膜 CD20 受体,导致自身反应性 B 细胞的显着消耗。有鉴于此,在一项对 20 名接受 dcSSc 患者进行利妥昔单抗治疗的研究中,皮肤纤维化评分和肺功能得到显着改善 [ 11 ]。最近在日本队列中进行的一项研究也表明,与抗 topo1 抗体阳性患者中的环磷酰胺相比,在皮肤纤维化和肺保存方面具有显着益处 [ 12 ]。尽管这两项研究都很小,但它们为 B 细胞耗竭疗法提供了积极的指示,并表明特定的患者亚群可能对利妥昔单抗治疗反应良好。事实上,在本期研究中临床和实验免疫学,作者发现总体上产生 GM-CSF 的 B 效应细胞数量较多,但在伴有间质性肺病的 dcSSc 中这一比例特别高。这意味着,这种特殊的 B 效应细胞亚群可作为一种可能的预测因子,为弥漫性 SSc 合并肺病患者选择进行 B 细胞耗竭生物治疗。SSc 干预临床试验的异质性是一个关键问题,因此预测谁将对特定治疗产生反应将是有用的。

观察到 JAK 抑制剂托法替尼阻断了产生 GM-CSF 的 B 效应细胞的产生,这表明靶向 JAK 可能对 SSc 有治疗作用。事实上,一项临床试验正在进行中,以检查托法替尼在弥漫性 SSc 中的安全性和耐受性 (NCT03274076)。尽管作者在 SSc 患者的血液中显示了这种特定 B 效应细胞的证据,但这些细胞在病变皮肤中的证明将证实这种细胞类型的致病作用。在这项研究中没有证明这种特殊的 B 效应细胞对肌成纤维细胞转化的直接作用。事实上,SSc 成纤维细胞已被证明具有更高的 GM-CSF 受体表达 [ 13 ],因此可能对这种细胞因子特别敏感。

更新日期:2020-08-12
down
wechat
bug