The involvement of ADAM10 in acantholysis in mucocutaneous pemphigus vulgaris depends on the autoantibody profile of each patient
The involvement of ADAM10 in acantholysis in mucocutaneous pemphigus vulgaris depends on the autoantibody profile of each patient
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DOI：
10.1111/bjd.18382
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发表时间：
2019-10-15
影响因子：
10.3
通讯作者：
Lopez-Zabalza, M. J.
中科院分区：
文献类型：
--
作者：
Ivars, M.;Espana, A.;Lopez-Zabalza, M. J.
背景寻常型天疱疮（PV）的溶血作用可能由桥粒芯糖蛋白（Dsg）和非Dsg自身抗体触发。每个患者的自身抗体谱导致不同的细胞内信号传导模式。目的基于我们先前的研究结果，我们的目的是阐明小鼠模型中PV棘层松解是否可能通过激活解整合素和金属蛋白酶10（ADAM 10）介导。方法我们使用来自不同患者的三种PV-IgG组分，其含有高或低水平的抗Dsg 1和抗Dsg 3抗体，以及存在或不存在抗桥粒胶原（Dsc）抗体，使用被动转移PV小鼠模型。结果尽管所有PV IgG组分均能引起基底上棘层松解，但只有那些含有抗Dsg 1/3抗体的组分能以Src依赖的方式诱导ADAM 10活化，表皮生长因子（EGF）受体配体EGF和β细胞素（BTC）含量增加，而含有抗Dsc 2/3抗体的组分则不能。相比之下，抗Dsc 2/3抗体的存在下，除了抗Dsg 1/3，触发早期和ADAM 10独立的表皮脱离，没有增加EGF和BTC，这是与早期和更强烈的棘层松解。结论所有PV-IgG组分均产生基底上棘层松解，但我们的结果表明，根据抗Dsg抗体水平或非Dsg抗体（如抗Dsc）的存在，更严重的细胞-细胞表皮脱离将在不同时间发生，并以ADAM 10依赖的方式或不依赖。在这些不同的PV患者组中，血管溶解可能是与Dsg或非Dsg蛋白结合的自身抗体下游特异性细胞内机制激活的结果，因此应在PV中使用更特异性的治疗方法。关于这个话题我们已经知道了什么？寻常型天疱疮（PV）的基底上棘层松解可由桥粒芯糖蛋白（Dsg）和非Dsg自身抗体触发。每个患者的自身抗体谱与不同的细胞内信号传导模式相关。这项研究增加了什么？在具有抗Dsg 3和抗Dsg 1抗体但不具有抗桥粒胶原（Dsc）3抗体的PV患者中，以Src依赖性方式诱导ADAM 10活化，同时表皮生长因子受体（EGFR）配体EGF和β细胞素增加。抗Dsc 3抗体的存在触发了早期和ADAM 10非依赖性棘层松解，而不增加EGFR配体，并与更严重的表皮脱离相关。较低水平的抗Dsc 3抗体与较不严重的棘层松解相关。翻译的信息是什么？在一些PV患者中，细胞间脱离的严重程度和时间似乎取决于抗Dsg 1/3抗体的水平，尽管其他尚未表征的抗体也可能参与其中。这些PV患者可通过Src、ADAM 10、EGF和EGFR抑制剂来抑制棘层松解。在其他患者中，存在非Dsg抗体，如抗Dsc 2/3，将产生更早和更严重的ADAM 10非依赖性基底上棘层松解。
Background Acantholysis in pemphigus vulgaris (PV) may be triggered by desmoglein (Dsg) and non-Dsg autoantibodies. The autoantibody profile of each patient results in distinct intracellular signalling patterns. Objectives Based on our previous findings, we aimed to elucidate whether PV acantholysis in a mouse model may be mediated by activation of a disintegrin and metalloproteinase 10 (ADAM10). Methods We used three PV-IgG fractions from different patients containing high or low levels of anti-Dsg1 and anti-Dsg3 antibodies, and the presence or not of anti-desmocollin (Dsc) antibodies, using a passive transfer mouse model of PV. Results Although all of the PV-IgG fractions produced suprabasal acantholysis, only those containing anti-Dsg1/3, but not anti-Dsc2/3 antibodies, induced ADAM10 activation in a Src-dependent way, and an increase in the epidermal growth factor (EGF) receptor ligands EGF and betacellulin (BTC). In contrast, the presence of anti-Dsc2/3 antibodies, in addition to anti-Dsg1/3, triggered earlier and ADAM10-independent epidermal detachment, with no increase in EGF and BTC, which was associated with an earlier and more intense acantholysis. Conclusions All PV-IgG fractions produced suprabasal acantholysis, but our results reveal that depending on the levels of anti-Dsg antibodies or the presence of non-Dsg antibodies, such as anti-Dsc, more severe cell-cell epidermal detachment will occur at different times, and in an ADAM10-dependent manner or not. Acantholysis in these different groups of patients with PV may be a consequence of the activation of specific intracellular mechanisms downstream of Autoantibodies binding to Dsg or non-Dsg proteins, and therefore more specific therapeutic approaches in PV should be used. What's already known about this topic?Suprabasal acantholysis in pemphigus vulgaris (PV) may be triggered by both desmoglein (Dsg) and non-Dsg autoantibodies. The autoantibody profile of each patient is associated with a distinct intracellular signalling pattern. What does this study add?In patients with PV with anti-Dsg3 and anti-Dsg1, but not anti-desmocollin (Dsc)3 antibodies, ADAM10 activation is induced in an Src-dependent way, together with an increase in the epidermal growth factor receptor (EGFR) ligands EGF and betacellulin. The presence of anti-Dsc3 antibodies triggers an earlier and ADAM10-independent acantholysis, without increasing EGFR ligands, and is associated with more severe epidermal detachment. Lower levels of anti-Dsc3 antibodies are associated with less severe acantholysis. What is the translational message?In some patients with PV, the severity and the timing for cell-cell detachment seem to depend on the level of anti-Dsg1/3 antibodies, although other as yet uncharacterized antibodies may also participate. These patients with PV would exhibit inhibition of acantholysis by Src, ADAM10, EGF and EGFR inhibitors. In other patients, the presence of non-Dsg antibodies, such as anti-Dsc2/3, would produce an earlier and more severe ADAM10-independent suprabasal acantholysis.