Immune response towards the amino-terminus of desmoglein 1 prevails across different activity stages in nonendemic pemphigus foliaceus
Immune response towards the amino-terminus of desmoglein 1 prevails across different activity stages in nonendemic pemphigus foliaceus
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DOI：
10.1111/j.1365-2133.2010.09696.x
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发表时间：
2010-06-01
影响因子：
10.3
通讯作者：
Amagai, M.
中科院分区：
文献类型：
--
作者：
Chan, P. T.;Ohyama, B.;Amagai, M.
背景叶天疱疮是一种由桥粒芯糖蛋白抗体(DSG)1介导的水疱性皮肤病，分为非地方性和地方性两种亚型。先前在地方性PF中的研究表明，抗体表位的变化可以调节疾病的复发和缓解。目的研究非地方性肺泡炎不同细胞外区DSG1的免疫反应频率，以及不同活动期的抗原表位变化情况。我们构建了5个DSG1/Dsg2结构域互换的分子，每个分子代表Dsg2主干上的一个DSG1EC1、EC2、EC3、EC4和EC5结构域。结果DSG1EC1、EC2、EC3、EC4和EC5结构域分别被88%、50%、13%、22%和0%的活性PF血清识别。EC3或EC4的免疫反应常与EC1或EC2的免疫反应同时出现。对21例PF患者进行了平均16个月的纵向随访，发现大多数患者在不同活动期对DSG1氨基末端的免疫反应持续存在，仅有2例患者在缓解期失去EC1反应性，并将其主要受体(S)变为EC2+/-EC3。结论在非地方性PF中，大多数抗DSG1抗体与DSG1氨基末端结合，这是钙粘素细胞间黏附的关键区域，这种倾斜的氨基末端免疫反应在大多数患者甚至在缓解期也普遍存在。这些发现对于理解DSG介导的细胞黏附的生物学以及开发基于表位的监测和治疗策略是有价值的。
Background Pemphigus foliaceus (PF) is a blistering skin disease mediated by antibodies to desmoglein (Dsg) 1. The two major subtypes are nonendemic and endemic PF. A previous study in endemic PF demonstrated that changes in antibody epitope could modulate disease relapse and remission. Objectives To characterize the frequency of immunoreactivity to various Dsg1 extracellular (EC) domains in nonendemic PF and to study if there is any change in epitope profile across various activity stages.Methods Sera from 34 patients with nonendemic PF were selected. To map the conformational epitopes by immunoprecipitation-immunoblotting, we constructed five Dsg1/Dsg2 domain-swapped molecules, with each molecule representing one EC domain of Dsg1 on a backbone of Dsg2.Results Dsg1 EC1, EC2, EC3, EC4 and EC5 domains were recognized by 88%, 50%, 13%, 22% and 0% of active PF sera, respectively. Immunoreactivity to EC3 or EC4 often cosegregated with that to either EC1 or EC2. Longitudinal follow-up of 21 patients with PF for a median of 16 months revealed that, in most cases, immunoreactivity to the amino-terminus of Dsg1 persisted across various activity stages; only two patients lost their EC1 reactivity upon remission and changed their majorepitope(s) to EC2 +/- EC3.Conclusions Most of the anti-Dsg1 antibodies in nonendemic PF bind to the amino-terminus of Dsg1, a region critical for intercellular adhesion of cadherins, and this skewed amino-terminal immunoreactivity prevails across various activity stages in most patients, even upon remission. These findings are valuable for understanding the biology of Dsg-mediated cellular adhesion as well as for the development of epitope-based monitoring and therapeutic strategies.