Dendritic cells: potential triggers of autoimmunity and targets for therapy
Dendritic cells: potential triggers of autoimmunity and targets for therapy
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DOI：
10.1136/ard.2005.044560
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发表时间：
2005-11-01
影响因子：
27.4
通讯作者：
Hardin, JA
中科院分区：
文献类型：
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作者：
Hardin, JA
树突状细胞（DC）通常被称为身体的哨兵，不断抵御病原体。1-3在这种作用中，它们是抗原呈递细胞，在体内引发初始T细胞。4 DC还通过多种机制帮助维持对“自身”物质的耐受性，包括T细胞缺失和无反应性以及调节性T细胞的产生。5-7这种调节免疫应答和免疫耐受的双重作用表明，DC可能在自身免疫性疾病如狼疮中起作用。这些可能性包括“自身”抗原作为免疫原的呈递，未能删除自身反应性T细胞，炎症细胞因子的过度产生以及调节性T细胞的诱导不足。如下文所述，对狼疮的这些发病机制的认识开始出现。还清楚的是，DC的这些活性中的至少一些可以通过药理学试剂来操纵。长期以来，人们一直认为调节性T细胞与狼疮的发病机制有关。10 11现在，这一考虑的最前沿是DC在平衡自身反应性T细胞阵列与相应的调节性T细胞组中发挥关键作用的可能性。[12]很明显，未成熟DC诱导外周中自身反应性T细胞的缺失耐受。13 - 15然而，未成熟DC负责耐受性和成熟DC诱导免疫应答的原始概念已经让位于更复杂的情况，其中不同成熟状态的DC能够诱导CD4 + CD25+调节性T细胞。在这篇论文中，我的目的是考虑这样一种可能性，即DCs的成熟可能以这样一种方式被操纵，即增强调节性T细胞的产生或减少狼疮患者中自身反应性效应T细胞的引发。DC亚群如图1所示和参考文献20所述，DCs来源于两种来源，骨髓中的干细胞和循环中发现的前体细胞。很可能在这里显示的四个主要DC组中的每一个中存在多个亚型-在分子特征和功能特性上不同。目前还不清楚这些亚种在多大程度上是通过谱系差异或对环境刺激（如细胞因子）的反应而产生的。20 - 23朗格汉斯细胞的特征在于存在Birbeck颗粒以及表达langerin。由于这些细胞位于表皮内，它们准备与入侵的病原体进行第一次相互作用。24 25朗格汉斯细胞有几种特殊的特性。首先，朗格兰及其相关的Birbeck颗粒被认为代表了这些细胞特有的抗原摄取系统。26其次，它们被认为是独特设计的，可以将抗原从真皮运输到区域淋巴结27，并且由于它们缺乏白细胞介素（IL）-10分泌，它们可能更专注于产生专门的T辅助细胞（Th）1应答。最后，这些细胞有助于但不是接触性超敏反应所必需的。29、有可能
Dendritic cells (DCs) are often referred to as the body’s sentinels, constantly guarding against pathogens. 1–3 In this role they are the antigen presenting cell that primes naive T cells in vivo. 4 DCs also help maintain tolerance to ‘‘self’’substances through multiple mechanisms that include T cell deletion and anergy as well as the generation of regulatory T cells. 5–7 This dual role in regulating both immune responses and immune tolerance suggests that DCs are likely to have a role in autoimmune diseases such as lupus. The possibilities include presentation of ‘‘self’’antigens as immunogens, a failure to delete autoreactive T cells, overproduction of inflammatory cytokines, and inadequate induction of regulatory T cells. As noted below, insights into these pathogenetic mechanisms in lupus are beginning to emerge. It is also clear that at least some of these activities of DCs can be manipulated through pharmacological agents. 8 9 It has been thought for a long time that regulatory T cells are related to the pathogenesis of lupus. 10 11 Now, at the forefront of this consideration is the possibility that DCs play a critical role in balancing the array of autoreactive T cells with a corresponding set of regulatory T cells. 12 It is clear that immature DCs induce deletional tolerance of autoreactive T cells in the periphery. 13–15 However, the original concept that immature DCs are responsible for tolerance and mature DCs induce immune responses has given way to a more complex scenario in which DCs in different states of maturation are able to induce CD4+ CD25+ regulatory T cells. 16 17 In this paper, my aim is to consider the possibility that the maturation of DCs might be manipulated in such a way as to either enhance regulatory T cell generation or diminish priming of autoreactive effector T cells in patients with lupus.DC SUBSETS As illustrated in fig 1 and reviewed in reference 20, DCs derive from two sources, stem cells in the bone marrow and precursor cells found in the circulation. It is likely that there are multiple subtypes—differing in molecular characteristics and functional properties—within each of the four major groups of DCs shown here. It remains unclear to what extent these subspecies arise through differences in lineage or in response to environmental stimuli such as cytokines. 20–23 Langerhans’ cells are characterised by the presence of Birbeck’s granules as well as expression of langerin. Since these cells reside within the epidermis they are poised to have the first interaction with an invading pathogen. 24 25 Langerhans’ cells have several specialised properties. Firstly, langerin and its associated Birbeck’s granules are thought to represent an antigen uptake system unique to these cells. 26 Secondly, they are thought to be uniquely designed to transport antigens from the dermis to regional lymph nodes27 and they may be more focused on generating exclusively T helper (Th) 1 responses because of their lack of interleukin (IL)-10 secretion. 28 Finally, these cells contribute to, but are not essential for, contact hypersensitivity. 29 It is possible these