ANTIGEN-SPECIFIC IMMUNOADSORPTION OF PATHOGENIC AUTOANTIBODIES IN PEMPHIGUS FOLIACEUS
ANTIGEN-SPECIFIC IMMUNOADSORPTION OF PATHOGENIC AUTOANTIBODIES IN PEMPHIGUS FOLIACEUS
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DOI：
10.1111/1523-1747.ep12606168
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发表时间：
1995-06-01
影响因子：
6.5
通讯作者：
NISHIKAWA, T
中科院分区：
文献类型：
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作者：
AMAGAI, M;HASHIMOTO, T;NISHIKAWA, T
患有自身免疫性起泡疾病落叶型天疱疮（PF）的患者具有针对桥粒钙粘蛋白桥粒芯糖蛋白1（Dsg 1）的循环自身抗体。基于来自PF患者的纯化IgG组分在器官培养物和新生小鼠模型中诱导细胞粘附丧失的事实，已经提出这些抗Dsg1抗体在水疱形成中起致病作用。为了直接解决PF血清中特异性针对Dsg1胞外结构域的抗体是否确实在疾病中具有致病性，通过杆状病毒表达产生PFIg，其为含有人Dsg1的整个胞外结构域和人IgG1的恒定区的嵌合蛋白。用PFIg杆状蛋白孵育PF患者的血清，去除了所有20个PF和8个巴西PF患者血清中针对角质形成细胞表面的自身抗体的免疫反应性。这种吸附是构象依赖性的，因为PFIg蛋白被低pH或心脏变性不再能够吸附PF血清的免疫反应性。此外，在天疱疮的新生小鼠模型中，与PFIg杆状蛋白一起孵育消除了PF患者血清的致病活性并防止了总水疱形成。从PFIg蛋白柱洗脱的抗Dsg1抗体是致病性的，因为它们导致新生小鼠出现严重水泡，具有典型的PF组织学结果。这些观察结果表明，杆状病毒表达的Dsg1的细胞外结构域能够特异性地免疫吸附PF患者血清中的致病性自身抗体，并提供直接证据表明PF血清中的抗Dsg1自身抗体确实是致病性的。这种Dsg1重组蛋白的可用性可能有助于发展抗原特异性血浆置换作为一种新的治疗策略天疱疮。
Patients with the autoimmune blistering disease pemphigus foliaceus (PF) have circulating autoantibodies directed against the desmosomal cadherin desmoglein 1 (Dsg1). Based on the fact that purified IgG fractions from PF patients induce loss of cell adhesion in organ culture and in a neonatal mouse model, it has been proposed that these anti-Dsg1 antibodies play a pathogenic role in blister formation. To directly address whether antibodies in PF sera specific for the Dsg1 extracellular domain are indeed pathogenic in the disease, PFIg, a chimeric protein containing the entire extracellular domain of human Dsg1 and the constant region of human IgG1, was produced by baculovirus expression. Incubation of PF patients' sera with the PFIg baculoprotein removed the immunoreactivity of autoantibodies against keratinocyte cell surfaces in all 20 PF and eight Brazilian PF patients' sera tested. This adsorption was conformation dependent, because PFIg protein denatured by low pH or heart was no longer able to adsorb the immunoreactivity of PF sera. Furthermore, the incubation with the PFIg baculoprotein eliminated the pathogenic activity of PF patients' sera and prevented gross blister formation in a neonatal mouse model of pemphigus. Anti-Dsg1 antibodies eluted from the PFIg protein column were pathogenic as they resulted in the appearance of gross blisters in neonatal mice with typical histologic findings of PF. These observations indicate that the extracellular domain of Dsg1 expressed by baculovirus is capable of specifically immunoadsorbing pathogenic autoantibodies from PF patients' sera and provide direct evidence that the anti-Dsg1 auto-antibodies in PF sera are indeed pathogenic. The availability of this Dsg1 recombinant protein may facilitate the development of antigen-specific plasmapheresis as a novel therapeutic strategy in pemphigus.