Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR β and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.

中文翻译：

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II 类 HLA 基因型的相似性定义了特发性骨髓衰竭疾病的自身反应模式。

特发性再生障碍性贫血 (IAA) 是一种罕见的自身免疫性骨髓衰竭 (BMF) 疾病，由人类白细胞抗原 (HLA) 限制性 T 细胞对未知抗原的反应引发。与其他自身免疫性疾病一样，对某些 HLA 谱的偏好似乎代表了一个病因因素。然而，这种疾病的自我呈现所涉及的结构功能模式仍不清楚。在此，我们通过深入剖析 300 名 IAA 患者和近 3000 名健康人和疾病对照者的 HLA 复合物的分子状况，深入剖析他们的基因型配置、功能差异、自身抗原结合能力和 T 细胞受体 (TCR) 库特异性。具体来说，对 HLA 基因型（HED）进化差异的分析表明，IAA 患者携带 II 类 HLA 分子，其抗原结合位点具有高度的结构同源性，仅部分由特定风险等位基因谱解释。这种模式意味着 HLA 结合能力降低，这一点已通过造血干细胞 (HSC) 衍生自肽的结合分析得到证实。IAA 表型与 DRB1 分子肽结合沟内特定位置的几个氨基酸的富集有关，影响 HLA-抗原-TCR β 界面，并可能构成 T 细胞功能障碍和自身反应性的基础。在分析与临床结果的关联时，低 HED 与恶性进展的风险和较差的生存率相关，这可能是清除来自克隆造血机制的潜在新抗原的肿瘤监测减少的原因。我们的数据揭示了与 IAA 病因学和克隆进化相关的免疫遗传学风险，以及可能涉及其他自身免疫性疾病的一般病理生理学机制。