Paiardini Alessandro, Pascarella Stefano
Dipartimento di Scienze Biochimiche A, Rossi Fanelli, Sapienza-Università di Roma, Roma, 00185, Italy.
Theor Biol Med Model. 2013 Apr 10;10:25. doi: 10.1186/1742-4682-10-25.
Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis. A subgroup of AIH patients presents specific autoantibodies to soluble liver antigen/liver-pancreas (SLA/LP) protein, which is regarded as a highly specific diagnostic marker. Autoantigenic SLA/LP peptides are targeted by CD4+ T cells, and restricted by the allele HLA-DRB1*03:01, which confers disease susceptibility in Europeans and Americans. A positively charged residue at position 71 has been indicated as critical for AIH susceptibility in all of the HLA alleles identified to date. Though the exact molecular mechanisms underlying pathogenesis of AIH are not clear, molecular mimicry between SLA/LP and viral/bacterial antigens has been invoked.
The immunodominant region of SLA/LP was used as query in databank searches to identify statistically significant similarities with viral/bacterial peptides. Homology modeling and docking was used to investigate the potential interaction of HLA-DRB1*03:01 with the identified peptides. By molecular mechanics means, the interactions and energy of binding at the HLA binding site was also scrutinized.
A statistically significant structural similarity between the immunodominant regions of SLA/LP and a region of the surface antigen PS 120 from Rickettsia spp. has been detected. The interaction of the SLA/LP autoepitope and the corresponding Rickettsia sequence with the allele HLA-DRB103:01 has been simulated. The obtained results predict for both peptides a similar binding mode and affinity to HLA-DRB103:01. A "hot spot" of interaction between HLA-DRB1*03:01 and PS 120 is located at the P4 binding pocket, and is represented by a salt bridge involving Lys at position 71 of the HLA protein, and Glu 795 of PS120 peptide.
These findings strongly support the notion that a molecular mimicry mechanism can trigger AIH onset. CD4+ T cells recognizing peptides of SLA/LP could indeed cross-react with foreign Rickettsia spp. antigens. Finally, the same analysis suggests a molecular explanation for the importance of position 71 in conferring the susceptibility of the allele HLA-DRB1*03:01 to AIH. The lack of a positive charge at such position could prevent HLA alleles from binding the foreign peptides and triggering the molecular mimicry event.
自身免疫性肝炎（AIH）是一种慢性进行性肝病，其特征为持续的肝细胞炎症和坏死。一部分AIH患者会出现针对可溶性肝抗原/肝-胰腺（SLA/LP）蛋白的特异性自身抗体，该蛋白被视为一种高度特异性的诊断标志物。自身抗原性SLA/LP肽段是CD4+ T细胞的靶标，并受等位基因HLA-DRB1*03:01的限制，该等位基因在欧美人群中赋予疾病易感性。在迄今鉴定出的所有HLA等位基因中，第71位的带正电荷残基已被表明对AIH易感性至关重要。尽管AIH发病机制的确切分子机制尚不清楚，但已有人提出SLA/LP与病毒/细菌抗原之间存在分子模拟。
以SLA/LP的免疫显性区域作为查询序列在数据库中进行搜索，以鉴定与病毒/细菌肽段具有统计学显著相似性的序列。采用同源建模和对接技术研究HLA-DRB1*03:01与鉴定出的肽段之间的潜在相互作用。通过分子力学方法，还对HLA结合位点处的相互作用和结合能进行了仔细研究。
已检测到SLA/LP的免疫显性区域与立克次氏体属表面抗原PS 120的一个区域之间存在统计学显著的结构相似性。模拟了SLA/LP自身表位和相应立克次氏体序列与等位基因HLA-DRB103:01的相互作用。所得结果预测这两种肽段与HLA-DRB103:01具有相似的结合模式和亲和力。HLA-DRB1*03:01与PS 120之间的相互作用“热点”位于P4结合口袋，由涉及HLA蛋白第71位赖氨酸和PS120肽段第795位谷氨酸的盐桥表示。
这些发现有力地支持了分子模拟机制可引发AIH发病的观点。识别SLA/LP肽段的CD4+ T细胞确实可能与外来的立克次氏体属抗原发生交叉反应。最后，同样的分析为第71位在赋予等位基因HLA-DRB1*03:01对AIH易感性方面的重要性提供了分子解释。该位置缺乏正电荷可能会阻止HLA等位基因结合外来肽段并引发分子模拟事件。
