Healthcare Research Institute of Hospital 12 de Octubre, Madrid, Spain.
INOVA Diagnostics, San Diego, CA, United States.
Front Immunol. 2019 May 7;10:1031. doi: 10.3389/fimmu.2019.01031. eCollection 2019.
Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with presence of anti-phospholipid antibodies (aPL). The APS classification criteria only consider the aPL of IgG/IgM isotype, however testing of aPL of IgA isotype is recommended when APS is suspected and consensus aPL are negative. IgA anti-βeta-2 glycoprotein-I (B2GP1) has been clearly related with occurrence of thrombotic events. Antibodies anti-B2GP1 of IgG/M isotypes recognize an epitope in Domain 1 (R39-G43), the epitopes that recognize IgA anti-B2GP1 antibodies are not well-identified. To determine the zones of B2GP1 recognized by antibodies of IgA isotype from patients with APS symptomatology and positive for IgA anti-B2GP1. IgA antibodies to Domain-1(D1) and Domain-4/5(D4/5) of B2GP1 (ELISA) and epitope mapping on oligopeptide arrays of B2GP1 were evaluated in sera from a group of 93 patients with at least one thrombotic and with isolated positivity for IgA anti-B2GP1 antibodies (negative for other aPL). A total of 47 patients (50.5%) were positive for anti-D4/5 and 23(25%) were positive for anti-D1. When peptide arrays were analyzed, three zones of B2GP1 reactivity were identified for more than 50% of patients. The center of these zones corresponds to amino acids 140(D3), 204(D4), and 264(D5). The peptides recognized on D3 and D4 contain amino acid sequences sharing high homology with proteins of microorganism that were previously related with a possible APS infectious etiology. In the three-dimensional structure of B2GP1, the three peptides, as the R39-G43 epitope, are located on the right side of the molecule (L-shape). The left side (J-shape) does not bind the antibodies. Patients with thrombotic APS clinical-criteria, and isolated IgA anti-B2GP1 positivity appear to preferentially bind, not to the D1 or D4/5 domains of B2GP1, but rather to three sites in D3, D4, and D5. The sites on D3 and D4 were previously described as the target identified by human monoclonal antibodies derived from patients that were capable of inducing APS in animal models. The localization of these epitopes opens a new route to explore to increase understanding of the patholophysiology of the APS and to propose new alternatives and therapeutic targets.
抗磷脂综合征（APS）的特征是血栓形成和/或妊娠并发症，同时存在抗磷脂抗体（aPL）。APS 分类标准仅考虑 IgG/IgM 同种型的 aPL，但是当怀疑存在 APS 且共识 aPL 为阴性时，建议检测 IgA 同种型的 aPL。IgA 抗β2-糖蛋白 I（B2GP1）与血栓事件的发生明显相关。IgG/M 同种型的抗-B2GP1 抗体识别表位位于结构域 1（R39-G43），而识别 IgA 抗-B2GP1 抗体的表位尚未明确。本研究旨在确定具有 APS 症状且 IgA 抗-B2GP1 阳性的患者中 IgA 同种型的 B2GP1 所识别的区域。通过 ELISA 检测了来自 93 例至少有一次血栓形成且单独存在 IgA 抗-B2GP1 抗体阳性（其他 aPL 阴性）患者的 B2GP1 结构域 1（D1）和结构域 4/5（D4/5）的 IgA 抗体，并对 B2GP1 寡肽阵列上的表位作图。共有 47 例（50.5%）患者抗-D4/5 阳性，23 例（25%）患者抗-D1 阳性。当分析肽阵列时，确定了 3 个超过 50%患者具有反应性的 B2GP1 区域。这些区域的中心对应于氨基酸 140（D3）、204（D4）和 264（D5）。在 D3 和 D4 上识别的肽包含与先前与可能的 APS 感染病因学相关的微生物蛋白具有高度同源性的氨基酸序列。在 B2GP1 的三维结构中，这三个肽，与 R39-G43 表位一样，位于分子的右侧（L 形）。左侧（J 形）不与抗体结合。具有血栓形成 APS 临床标准和孤立性 IgA 抗-B2GP1 阳性的患者似乎更倾向于结合，而不是 B2GP1 的 D1 或 D4/5 结构域，而是结合 D3、D4 和 D5 上的三个位点。D3 和 D4 上的这些位点之前被描述为源自能够在动物模型中诱导 APS 的患者的人单克隆抗体所识别的靶标。这些表位的定位开辟了一条新的途径，可以增加对 APS 病理生理学的理解，并提出新的治疗选择和治疗靶点。
