Antibodies to the Desmoglein 1 Precursor Proprotein but Not to the Mature Cell Surface Protein Cloned from Individuals without Pemphigus
Antibodies to the Desmoglein 1 Precursor Proprotein but Not to the Mature Cell Surface Protein Cloned from Individuals without Pemphigus
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DOI：
10.4049/jimmunol.0901691
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发表时间：
2009-11-01
影响因子：
4.4
通讯作者：
Stanley, John R.
中科院分区：
文献类型：
--
作者：
Yamagami, Jun;Kacir, Stephen;Stanley, John R.
在落叶型天疱疮（PF）中，抗桥粒芯糖蛋白1（Dsg 1）的自身抗体引起水疱。利用噬菌体抗体展示技术，我们从一个PF患者中克隆了单克隆抗体。这些单克隆抗体，像那些从以前的病人，针对成熟的Dsg 1（matDsg 1）的角质形成细胞的细胞表面和细胞质中的前体Dsg 1（preDsg 1）。为了确定没有天疱疮的个体是否对Dsg 1有B细胞耐受性，我们从两名血栓性血小板减少性紫癜患者和一名健康人中克隆了mAb。我们发现了针对preDsg 1的mAb，但没有发现针对matDsg 1的mAb。来自PF患者和无PF患者的23种抗preDsg 1 mAb中，除1种外，所有mAb均使用VH 3 -09（或密切相关的VH 3 -20）H链基因，而无PF抗matDsg 1使用这些基因。V-H cDNA编码抗preDsg 1有显着较少的体细胞突变比抗matDsg 1 cDNA，与慢性Ag驱动的超突变，后者相比，前者。这些数据表明，没有PF的个体不具有对preDsg 1的B细胞耐受性，并且对matDsg 1的耐受性丧失不是由于抗preDsg 1 B细胞的表位移位（由于不同的V-H基因使用）。然而，preDsg 1特异性B细胞呈现Dsg 1的肽可能是PF发生自身免疫的一个步骤。《免疫学杂志》，2009，183：5615-5621。
In pemphigus foliaceus (PF), autoantibodies against desmoglein 1 (Dsg1) cause blisters. Using Ab phage display, we have cloned mAbs from a PF patient. These mAbs, like those from a previous patient, were directed against mature Dsg1 (matDsg1) on the cell surface of keratinocytes and precursor Dsg1 (preDsg1) in the cytoplasm. To determine whether individuals without pemphigus have B cell tolerance to Dsg1, we cloned mAbs from two patients with thrombotic thrombocytopenic purpura and a healthy person. We found mAbs against preDsg1, but not matDsg1. All but 1 of the 23 anti-preDsg1 mAbs from PF patients and those without PF used the VH3-09 (or closely related VH3-20) H chain gene, whereas no PF anti-matDsg1 used these genes. V-H cDNA encoding anti-preDsg1 had significantly fewer somatic mutations than did anti-matDsg1 cDNA, consistent with chronic Ag-driven hypermutation of the latter compared with the former. These data indicate that individuals without PF do not have B cell tolerance to preDsg1 and that loss of tolerance to matDsg1 is not due to epitope shifting of anti-preDsg1 B cells (because of different V-H gene usage). However, presentation of peptides from Dsg1 by preDsg1-specific B cells may be one step in developing autoimmunity in PF. The Journal of Immunology, 2009, 183: 5615-5621.