Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
J Thromb Haemost. 2023 Mar;21(3):616-628. doi: 10.1016/j.jtha.2022.09.002. Epub 2022 Dec 22.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare autoimmune disorder caused by autoantibodies against ADAMTS13. A strong association of DRB1∗11 with iTTP and DRB1∗11-restricted T-cell epitopes in ADAMTS13 have been reported in Europeans, whereas we previously found DRB1∗08:03 as a susceptible allele in Japanese.
The limited information is available regarding a susceptible allele and its T-cell epitopes in Japanese patients with iTTP.
We conducted a reanalysis on iTTP-predisposing alleles using 3 distinct Japanese control groups. Subsequently, a novel human leukocyte antigen (HLA)-peptide expression assay (MHC-density assay) was used to identify the presentation of 24 ADAMTS13-derived peptides, including the regions that were identified previously by MHC-peptidome analysis and/or T-cell assays or predicted by NetMHCIIpan-4.0, to DRB1∗08:03 and DRB1∗11:01.
We reconfirmed the strong association of DRB1∗08:03 with iTTP, as well as the absence of the secondary risk alleles and protective alleles in Japanese iTTP, which altogether reveal that the HLA association pattern is completely different between the European and Japanese iTTP. MHC-density assay found the 3 ADAMTS13-derived peptides in the spacer domain as a potential strong binder to DRB1∗08:03. Moreover, 6 peptides in the metalloprotease, spacer, sixth thrombospondin-1 repeat, and CUB domains in ADAMTS13 showed increased presentation by both DRB1∗08:03 and DRB1∗11:01.
Altogether, the findings of distinct HLA-DR association with iTTP across populations and the presentation of common peptides by DRB1∗08:03 and DRB1∗11:01 suggest that the same ADAMTS13-derived peptides might be presented and trigger the activation of autoreactive CD4 T cells, leading to production of anti-ADAMTS13 autoantibodies by autoreactive B cells.
免疫介导性血栓性血小板减少性紫癜（iTTP）是一种由抗 ADAMTS13 自身抗体引起的超罕见自身免疫性疾病。在欧洲人中，已经报道了 DRB1∗11 与 iTTP 以及 ADAMTS13 中的 DRB1∗11 限制性 T 细胞表位之间存在强烈关联，而我们之前在日本人中发现了 DRB1∗08:03 作为易感等位基因。
关于日本人 iTTP 患者的易感等位基因及其 T 细胞表位，目前信息有限。
我们使用 3 个不同的日本对照组对 iTTP 易感性等位基因进行了重新分析。随后，使用新型人类白细胞抗原（HLA）-肽表达测定法（MHC 密度测定法）来鉴定包括先前通过 MHC-肽组分析和/或 T 细胞测定鉴定的区域或由 NetMHCIIpan-4.0 预测的 24 个 ADAMTS13 衍生肽在 DRB1∗08:03 和 DRB1∗11:01 上的呈递。
我们重新证实了 DRB1∗08:03 与 iTTP 之间的强烈关联，以及日本人 iTTP 中不存在次要风险等位基因和保护等位基因，这表明欧洲人和日本人 iTTP 之间的 HLA 关联模式完全不同。MHC 密度测定法发现间隔区中的 3 个 ADAMTS13 衍生肽是与 DRB1∗08:03 结合的潜在强配体。此外，ADAMTS13 中的金属蛋白酶、间隔区、第六个血小板反应蛋白-1 重复和 CUB 结构域中的 6 个肽显示出由 DRB1∗08:03 和 DRB1∗11:01 增强的呈递。
总的来说，不同人群中 HLA-DR 与 iTTP 的关联以及由 DRB1∗08:03 和 DRB1∗11:01 呈递的常见肽的发现表明，相同的 ADAMTS13 衍生肽可能被呈递并触发自身反应性 CD4 T 细胞的激活，从而导致自身反应性 B 细胞产生抗 ADAMTS13 自身抗体。
