Institute of Medical Genetics, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
J Dermatol. 2020 Nov;47(11):1236-1248. doi: 10.1111/1346-8138.15583. Epub 2020 Sep 15.
Toxic epidermal necrolysis (TEN) represents a rare drug-induced autoimmune reaction with delayed-type hypersensitivity that initiates the process of developing massive keratinocyte apoptosis, dominantly in the dermoepidermal junction. Although the etiopathophysiology has not yet been fully elucidated, the binding of Fas ligand (FasL, CD95L) to the Fas receptor (CD95) was shown to play a key role in the induction of apoptosis in this syndrome. The knowledge of the role of immunoglobulin G (IgG) in inhibition of Fas-mediated apoptosis contributed to the introduction of i.v. Ig (IVIg) in the therapy of TEN patients. Despite great enthusiasm for this therapy at the end of the 1990s, subsequent studies in various populations and meta-analyses could not unequivocally confirm the efficacy of the IVIg-based treatment concept. Today, therefore, we are faced with the dilemmas of how to adjust therapy of TEN patients most effectively, which patients could benefit from IVIg therapy and what dose of the preparation should be administrated. The ground-breaking question is: do the host genetic profiles influence the responsiveness and side-effects of IVIg therapy in TEN patients? Based on recent pharmacological, immunological and genetic findings, we suggest that the variability of IVIg therapy outcomes in TEN patients may be related to functional variants in Fas, FasL and Fc-γ receptor genes. This novel concept could lead to improved quality of care for patients with TEN, facilitating personalized therapy to reduce mortality.
中毒性表皮坏死松解症(TEN)是一种罕见的药物诱导的自身免疫反应,具有迟发型超敏反应,启动了大量角质形成细胞凋亡的过程,主要发生在真皮表皮交界处。尽管其发病机制尚未完全阐明,但 Fas 配体(FasL,CD95L)与 Fas 受体(CD95)的结合被认为在该综合征中诱导细胞凋亡中起关键作用。免疫球蛋白 G(IgG)在抑制 Fas 介导的细胞凋亡中的作用的知识促使人们将静脉注射免疫球蛋白(IVIg)引入 TEN 患者的治疗中。尽管在 20 世纪 90 年代末对此疗法的热情很高,但随后在不同人群中的研究和荟萃分析不能明确证实基于 IVIg 的治疗概念的疗效。因此,今天我们面临着如何最有效地调整 TEN 患者的治疗、哪些患者可以从 IVIg 治疗中获益以及应给予该制剂的何种剂量的困境。一个开创性的问题是:宿主遗传特征是否会影响 TEN 患者 IVIg 治疗的反应性和副作用?基于最近的药理学、免疫学和遗传学发现,我们认为 TEN 患者 IVIg 治疗结果的可变性可能与 Fas、FasL 和 Fc-γ 受体基因的功能变体有关。这一新概念可能会提高 TEN 患者的护理质量,促进个性化治疗以降低死亡率。