Centre for Haematology, Imperial College London, London, UK.
University College Hospital, London, UK.
J Thromb Haemost. 2024 Apr;22(4):1069-1079. doi: 10.1016/j.jtha.2023.12.028. Epub 2023 Dec 30.
Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) have anti-ADAMTS-13 immunoglobulin G (IgG) autoantibodies that enhance ADAMTS-13 clearance and/or inhibit its function. ADAMTS-13 normally circulates in a closed conformation, which is manifested by the interaction of the CUB domains with the central spacer domain. Disruption of the spacer-CUB interaction opens ADAMTS-13, which augments its proteolytic function but may also expose cryptic autoimmune epitopes that promote further autoantibody recognition.
To explore differences in autoantibody binding to ADAMTS-13 in its closed or open conformations in patients with iTTP and to correlate these differences with disease-related parameters.
We developed a novel assay to measure autoantibodies binding to closed and open ADAMTS-13. Autoantibody titer and IgG subclass binding to open or closed ADAMTS-13 were measured in 70 iTTP first presentation samples and correlated with clinical data, remission, and relapse.
In 70 patients with iTTP, the mean autoantibody titer against open ADAMTS-13 was, on average, approximately 2-fold greater than that against closed ADAMTS-13, suggesting that ADAMTS-13 opening increases epitope exposure and immune complex formation. Autoantibody titer against closed/open ADAMTS-13 and IgG subclass did not correlate with ADAMTS-13 antigen at presentation. Two patients with iTTP and persistent autoantibodies lost specificity for closed ADAMTS-13 in remission. Recognition of closed/open ADAMTS-13 and autoantibody IgG subclass between the first and second iTTP episodes were very similar.
ADAMTS-13 autoantibody binding is highly influenced by ADAMTS-13 conformation. Although this does not appear to modify the pathogenicity of autoantibodies, the autoantibody signature at relapse suggests that relapse represents re-emergence of the original autoimmune response rather than de novo presentation.
免疫介导性血栓性血小板减少性紫癜（iTTP）患者存在抗 ADAMTS-13 免疫球蛋白 G（IgG）自身抗体，该抗体增强 ADAMTS-13 的清除率和/或抑制其功能。ADAMTS-13 通常以封闭构象循环，这表现为 CUB 结构域与中心间隔结构域的相互作用。间隔-CUB 相互作用的破坏使 ADAMTS-13 开放，从而增强其蛋白水解功能，但也可能暴露潜在的自身免疫表位，从而促进进一步的自身抗体识别。
探讨 iTTP 患者 ADAMTS-13 封闭和开放构象中自身抗体结合的差异，并将这些差异与疾病相关参数相关联。
我们开发了一种新的测定法来测量封闭和开放 ADAMTS-13 上的自身抗体结合。在 70 例 iTTP 首次就诊样本中测量了自身抗体滴度和 IgG 亚类与开放或封闭 ADAMTS-13 的结合，并与临床数据、缓解和复发相关联。
在 70 例 iTTP 患者中，针对开放 ADAMTS-13 的平均自身抗体滴度平均比针对封闭 ADAMTS-13 的高约 2 倍，这表明 ADAMTS-13 开放增加了表位暴露和免疫复合物形成。在首次就诊时，针对封闭/开放 ADAMTS-13 的自身抗体滴度和 IgG 亚类与 ADAMTS-13 抗原不相关。两名 iTTP 患者和持续性自身抗体在缓解期失去了对封闭 ADAMTS-13 的特异性。在第一次和第二次 iTTP 发作之间，对封闭/开放 ADAMTS-13 和自身抗体 IgG 亚类的识别非常相似。
ADAMTS-13 自身抗体结合受 ADAMTS-13 构象的强烈影响。尽管这似乎不会改变自身抗体的致病性，但在复发时的自身抗体特征表明复发代表了原始自身免疫反应的再次出现，而不是新的发作。
