Lucchese Alberta, Mittelman Abraham, Tessitore Luciana, Serpico Rosario, Sinha Animesh A, Kanduc Darja
Dept of Odontostomatology, University of Bari, Italy.
J Transl Med. 2006 Aug 22;4:37. doi: 10.1186/1479-5876-4-37.
A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens.
Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences.
Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK-RE sequence as a common motif with 75% residue identity.
This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.
多种自身免疫性疾病已在临床和病理方面得到表征。相比之下，仅在少数病例中确定了靶抗原，而且在这少数病例中，仍缺乏对确切表位抗原序列的了解。因此，自身免疫领域当前工作的主要目标是鉴定与自身免疫反应相关的表位序列。我们实验室提出，能够引发体液（自身）免疫反应的自身抗原肽表位由与宿主蛋白质组的序列相似性来定义。潜在的科学原理是抗原肽在其蛋白质组相似性水平的背景下获得免疫反应性。蛋白质独特拥有的序列具有引发免疫反应的高潜力，而具有高蛋白质组冗余性的基序应通过耐受现象在免疫原性上沉默。序列冗余与肽免疫反应性之间的关系已在许多实验模型中得到成功验证。在此，该假设已应用于天疱疮疾病及相应的桥粒芯糖蛋白自身抗原。
对桥粒芯糖蛋白3与人类蛋白质组进行序列相似性分析，随后进行斑点印迹/核磁共振免疫测定，以鉴定和验证可能的表位序列。
计算分析导致鉴定出一个线性免疫显性桥粒芯糖蛋白3表位，它与寻常型天疱疮和落叶型天疱疮患者的血清具有高度反应性。该表位肽对应于氨基酸REWVKFAKPCRE序列，位于极端N端区域（第49至60位残基），与人类蛋白质组的冗余性较低。序列比对显示，人类桥粒芯糖蛋白1和3共享REW-KFAK-RE序列作为共同基序，残基一致性为75%。
本研究1）验证了与自身蛋白质组的序列冗余是塑造桥粒芯糖蛋白肽免疫原性的主要因素；2）为分析两种天疱疮形式所表现出的自身免疫反应的共性提供了分子机制基础；3）指出了天疱疮疾病可能的肽免疫治疗方法。
