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Innate immunity in systemic sclerosis.
Clinical & Experimental Immunology ( IF 4.6 ) Pub Date : 2020-05-27 , DOI: 10.1111/cei.13452
S O'Reilly 1
Affiliation  

Summary

Systemic sclerosis (SSc) is an autoimmune idiopathic connective tissue disease that results in skin and lung fibrosis. In line with all autoimmune diseases, women are disproportionally affected. The end target cell that results in the tissue fibrosis is the fibroblast that differentiates into a myofibroblast, which produces copious amounts of extracellular matrix and alpha‐smooth muscle actin that endows the cell with a contractile phenotype. However, in recent times it has become clear that, along with the adaptive immune system, the innate immune system is critically involved [1, 2]. A renaissance in innate immunity research has recently taken place, and this has led to new understanding of disease processes. This collection is a series of reviews on the role of innate immunity in SSc.

Toll‐like receptors (TLRs) are a family of germline‐encoded innate pattern recognition receptors that are both membrane‐bound and intracellular. Activation of these TLRs results in downstream signalling through a variety of transcription factors that drive inflammation [1]. In recent years, identification of dysregulated TLRs in SSc has led to a resurgence of research in this area and the identification of endogenous ligands that mediate activation. Recent endogenous ligands that elicit a TLR response in SSc include DNA and single‐stranded RNA [3]. These may be released from damaged cells in the endothelium instigating the activation of the TLRs. In this special collection, Frasca and Lande examine the role of TLRs in SSc with a focus on endogenous damage‐associated molecular patterns (DAMPs) [4] that can mediate the activation of both immune cells and stromal cells [5].

Carvalheiro et al . review the roles of dendritic cells in the pathogenesis of SSc [6]. Dendritic cells are the sentinels of the immune system, sensing their environment for antigen, and are the most potent antigen‐presenting cells promoting T cell activation, thus directing adaptive immunity. Therefore, their role in SSc can be profound. Dendritic cells in the form of Langerhans cells are found within the skin, and plasmacytoid dendritic cells are also found in the blood. It has recently emerged that plasmacytoid dendritic cells are particularly prominent in systemic sclerosis pathogenesis, with alterations in epigenetic marks associated with enhanced maturation of these cells. Carvalheiro et al . examine, in particular, the role of plasmacytoid dendritic cells in disease pathogenesis and how their development can be regulated epigenetically. Plasmacytoid dendritic cells are particularly efficient at producing and releasing larger amounts of type I interferons, as well as cytokines such as B cell‐activating factor (BAFF) that can direct antibody production; thus, they can be important for many facets of the disease.

Servaas et al . describe the role of the innate immune system in the context of autologous haematopoietic stem cell transplantation [7]. It has been demonstrated that autologous stem cell transplant can reverse fibrosis in carefully selected diffuse systemic sclerosis patients, although the treatment is not without risk [8]. The mechanism of immune system ‘resetting’ is unclear; however, Servaas et al . suggest that alterations in the innate immune system could underpin the therapeutic effect of this transplant. They examine this in more detail expanding on possible mechanisms that lead to ‘tolerance’.

Recent advances in understanding the role of the innate immune system and the intricate network of cytokines in SSc pathogenesis may yield opportunities for therapeutic intervention, particularly in the earliest stages of disease, where inflammation is predominant [9]. Advances in genetic sequencing and the omics revolution have allowed us to gain insights into the pathogenesis of the disease at unprecedented resolution, and I am convinced that this will allow us to tailor our treatments.



中文翻译:

系统性硬化症的先天免疫力。

概要

系统性硬化症(SSc)是一种自身免疫性特发性结缔组织疾病,可导致皮肤和肺纤维化。与所有自身免疫性疾病一样,妇女受到的影响也很大。导致组织纤维化的最终靶细胞是分化为成肌纤维细胞的成纤维细胞,后者产生大量的细胞外基质和α-平滑肌肌动蛋白,赋予细胞收缩型。然而,近来已经清楚地发现,与适应性免疫系统一起,先天免疫系统也至关重要[ 1、2 ]。近来先天免疫研究的复兴,这使人们对疾病过程有了新的认识。该系列是关于先天免疫在SSc中的作用的一系列综述。

Toll样受体(TLR)是种系编码的先天模式识别受体的一个家族,既是膜结合型的,也是细胞内的。这些TLR的激活通过各种驱动炎症的转录因子导致下​​游信号传导[ 1 ]。近年来,鉴定SSc中TLRs失调已导致该领域的研究重新流行,并鉴定了介导激活的内源性配体。最近引起SSc中TLR反应的内源性配体包括DNA和单链RNA [ 3]。这些可能会从内皮中受损的细胞中释放出来,从而促使TLR激活。在这个特别的文献中,Frasca和Lande考察了TLR在SSc中的作用,重点研究了内源性损伤相关分子模式(DAMPs)[ 4 ],它可以介导免疫细胞和基质细胞的激活[ 5 ]。

Carvalheiro。综述了树突状细胞在SSc发病机理中的作用[ 6 ]。树突状细胞是免疫系统的前哨,感知其抗原环境,并且是促进T细胞活化从而指导适应性免疫的最有力的抗原呈递细胞。因此,它们在SSc中的作用可能很深远。在皮肤中发现了朗格汉斯细胞形式的树突状细胞,并且在血液中也发现了浆细胞样树突状细胞。最近发现,浆细胞样树突状细胞在系统性硬化病发病机理中特别显着,其表观遗传标记的改变与这些细胞的成熟增强有关。Carvalheiro。特别研究浆细胞样树突状细胞在疾病发病机理中的作用,以及如何在表观遗传学上调节它们的发育。浆细胞样树突状细胞在产生和释放大量I型干扰素以及可指导抗体产生的细胞因子(例如B细胞激活因子(BAFF))方面特别有效;因此,它们对于疾病的许多方面都可能很重要。

Servaas。描述了先天免疫系统在自体造血干细胞移植中的作用[ 7 ]。已经证明,自体干细胞移植可以在精心选择的弥漫性系统性硬化症患者中逆转纤维化,尽管这种治疗并非没有风险[ 8 ]。免疫系统“重置”的机制尚不清楚;然而,Servaas。提示先天免疫系统的改变可能巩固这种移植物的治疗效果。他们更详细地研究了导致“宽容”的可能机制。

在了解先天免疫系统和复杂的细胞因子网络在SSc发病机制中的作用方面的最新进展可能会提供治疗干预的机会,特别是在炎症占主导地位的疾病的早期阶段[ 9 ]。基因测序的进步和组学革命使我们能够以前所未有的分辨率深入了解疾病的发病机理,我坚信这将使我们能够定制治疗方案。

更新日期:2020-05-27
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