CORRELATION OF PEPTIDE SPECIFICITY AND IGG SUBCLASS WITH PATHOGENIC AND NONPATHOGENIC AUTOANTIBODIES IN PEMPHIGUS-VULGARIS - A MODEL FOR AUTOIMMUNITY
CORRELATION OF PEPTIDE SPECIFICITY AND IGG SUBCLASS WITH PATHOGENIC AND NONPATHOGENIC AUTOANTIBODIES IN PEMPHIGUS-VULGARIS - A MODEL FOR AUTOIMMUNITY
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DOI：
10.1073/pnas.92.11.5239
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发表时间：
1995-05-23
影响因子：
11.1
通讯作者：
AHMED, AR
中科院分区：
文献类型：
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作者：
BHOL, K;NATARAJAN, K;AHMED, AR
寻常型天疱疮(PV)是一种罕见的、可能致命的自身免疫性疾病，影响皮肤和粘膜。PV抗原(PVA)被鉴定为桥粒芯糖蛋白3。PV患者携带携带人类白细胞抗原-DR4或人类白细胞抗原-DR6的扩展单倍型。我们最近证实，活动性疾病患者具有高滴度的IgG1和IgG4亚类PV自身抗体。缓解期患者、健康的未受影响的亲属和一些MHC匹配的正常人的PV自身抗体水平较低，仅为IgG1。此外，活动性疾病患者的免疫球蛋白注射会引起小鼠的临床疾病，而缓解期患者、健康亲属或MHC匹配的正常人的免疫球蛋白则不会。我们制备了12个多肽，每个30个氨基酸(多肽Bos1-12)，跨越PVA的胞外区。活动期疾病患者识别自身抗体滴度较高的Bos 1和Bos 6多肽。缓解期患者仅有抗多肽Bos1的IgG1自身抗体，滴度显著低于对照组(P<；0.01)。他们不再有抗多肽Bos 6的IgG4亚类自身抗体。健康亲属和正常无血缘关系的人只有很低水平的仅识别Bos 1的IgG1自身抗体。体外研究表明，Bos 6特异性的IgG和较小程度的Bos 1特异性的IgG可以引起棘层松解。我们的数据表明，Bos6特异性的IgG4可能是主要的棘层溶解自身抗体，而Bos1特异性的IgG4可能是这一过程的促进剂或增强剂。在这项研究中，我们举例说明了在自身免疫过程中MHC、自身抗体亚类和自身抗体的多肽特异性之间的相互作用的一些范例。因此，PV为研究自身免疫的发病机制提供了一个重要的模型。
Pemphigus vulgaris (PV) is a rare, potentially fatal, autoimmune disease that affects the skin and mucous membranes. The PV antigen (PVA) has been characterized as desmoglein 3. PV patients carry HLA-DR4- or HLA-DR6-bearing extended haplotypes. We recently demonstrated that patients with active disease have high titers of PV autoantibodies of the IgG1 and IgG4 subclasses. Patients in remission, healthy unaffected relatives, and some MHC-matched normal individuals have low levels of PV autoantibodies, which are IgG1 only. Furthermore, intraperitoneal injection of IgG from patients with active disease caused clinical disease in mice, but IgG from patients in remission, healthy relatives, or MHC-matched normal individuals did not. We prepared 12 peptides of 30 amino acids each (peptides Bos 1-12) spanning the extracellular domain of PVA. Patients with active disease recognize peptides Bos 1 and Bos 6 with high titers of IgG1 and IgG4 autoantibodies. Patients in remission have IgG1 autoantibodies to peptide Bos 1 only, in statistically significantly lower titers (P < 0.01). They no longer have IgG4 subclass autoantibodies to peptide Bos 6. Healthy relatives and normal unrelated individuals have low levels of only IgG1 autoantibodies that recognize only Bos 1. In vitro studies indicate that Bos 6-specific IgG and, to a lesser extent, Bos 1-specific IgG can cause acantholysis. Our data suggest that Bos 6-specific IgG4 is probably the main acantholytic autoantibody, while Bos 1-specific IgG4 may act as a facilitator or enhancer of the process. In this study we illustrate some of the paradigms that demonstrate the interactions between the MHC, subclass of autoantibodies, and peptide specificities of the autoantibodies in the autoimmune process. Thus, PV provides an important model to study the pathogenesis of autoimmunity.