Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia
Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia
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DOI：
10.1182/blood-2011-07-365189
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发表时间：
2011-12-15
期刊：
影响因子：
20.3
通讯作者：
Nakao, Shinji
中科院分区：
文献类型：
--
作者：
Katagiri, Takamasa;Sato-Otsubo, Aiko;Nakao, Shinji
特发性再生障碍性贫血（AA）是获得性骨髓衰竭的常见原因。虽然对造血祖细胞的自身免疫被认为是其发病机制的原因，但对这种自身免疫的分子基础知之甚少。在这里，我们表明，一个相当大的比例的AA患者港口克隆造血的特点是存在获得性拷贝数中性杂合性丢失（CNN-LOH）的6p武器（6pLOH）。6pLOH通常涉及HLA位点，导致一种HLA单倍型的丢失。流式细胞术证实所有6例pLOH（+）病例均存在多系白细胞HLA-A表达缺失。令人惊讶的是，6个pLOH（+）克隆中缺失的HLA等位基因明显偏向于特定等位基因，包括HLA-A*02：01、A*02：06、A*31：01和B*40：02。一项对各种血液病患者HLA等位基因的大规模流行病学研究显示，4种HLA等位基因在再障患者的生殖系中具有较高的代表性。这些发现表明，在AA中发现的6pLOH（+）造血代表了从自身免疫中“逃逸”的造血，其由细胞毒性T细胞介导，所述细胞毒性T细胞通过这些I类HLA靶向造血祖细胞上呈递的相关自身抗原。我们的研究结果为AA发病机制的遗传基础提供了新的见解。（血。2011;118（25）：6601-6609）
Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-Aexpression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02: 01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes" hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant autoantigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA. (Blood. 2011;118(25):6601-6609)