Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T-cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined the somatic loss of HLA class I alleles and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In 2 patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late-onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.

中文翻译：

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HLA 关联、HLA 表达的体细胞缺失以及免疫再生障碍性贫血的临床结果。

免疫性再生障碍性贫血 (AA) 的特点是骨髓细胞上 HLA I 类等位基因表达的体细胞丧失，这与逃避 T 细胞介导的造血干细胞和祖细胞破坏的机制一致。HLA 异常的临床意义尚未得到很好的表征。我们检查了 544 名 AA 患者的 HLA I 类等位基因的体细胞丢失，并将 HLA 丢失和突变相关的 HLA 基因型与临床表现和免疫抑制治疗后的结果相关联。在 412 名接受测试的患者中，有 92 名 (22%) 检测到 HLA I 类等位基因丢失，其中有 393 例体细胞 HLA 基因突变和 40 例杂合性丢失。最常受影响的是 HLA-B*14:02，其次是 HLA-A*02:01、HLA-B*40:02、HLA-B*08:01 和 HLA-B*07:02。HLA-B*14:02、HLA-B*40:02 和 HLA-B*07:02 在 AA 中的比例也过高。高风险克隆进化与 HLA 丢失、HLA-B*14:02 基因型和年龄相关，从而产生了有效的预测模型。在 2 名患者中，我们追踪了来自携带 HLA-A*02:01 和 HLA-B*40:02 体细胞突变的现有克隆的单体 7 克隆进化。HLA-B*40:02 的丢失与较高的血细胞计数相关。HLA-B*07:02 和 HLA-B*40:01 基因型及其缺失与迟发性 AA 相关。我们的结果表明分子发病机制的特定免疫机制的存在具有临床意义。HLA 基因分型和 HLA 缺失筛查可能对免疫 AA 的治疗有价值。该研究在 ClinicalTrials.gov 上注册为 NCT00001964、NCT00061360、NCT00195624、NCT00260689、NCT00944749、NCT01193283 和 NCT01623167。