Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called “education” to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression (“Missing-self” hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1⁺C2⁺Bw4⁺) was not associated with MM occurrence. However, MM patients were more likely to be C1^-/C2⁺/Bw4⁺ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.

多发性骨髓瘤（MM）是一种由骨髓中恶性浆细胞克隆性扩张引起的血液恶性肿瘤。骨髓瘤细胞容易被自然杀伤 (NK) 细胞杀死，但 NK 细胞无法控制疾病进展，这表明存在免疫抑制。NK 效应器功能的激活阈值通过 KIR 与自身 HLA I 类之间的相互作用进行调节，在一个称为“教育”的过程中确保自我耐受。NK 细胞可以基于 HLA I 类表达的缺失（“自我缺失”假说）对患病细胞做出反应。HLA 和 KIR 的功能极其多样化；因此，本研究旨在表征 MM 患者和健康对照之间 HLA I 类 NK 表位和 KIR 基因型组成的潜在差异。分析了 172 名 MM 患者和 195 名健康对照者中 KIR 和 HLA（HLA-C 组 - C1/C2 和 Bw4 基序（包括 HLA-A*23、A*24、A*32）的基因型表达。与健康对照相比，我们没有观察到特定的KIR基因或基因型，或者MM患者中患病率较高的HLA NK表位。所有三个HLA NK表位（C1 ⁺ C2 ⁺ Bw4 ⁺）的存在与MM的发生无关。然而，MM患者更有可能是 C1 ^- /C2 ⁺ /Bw4 ⁺ ( p = 0.049, OR 1.996)。与此一致，MM 患者中 Bw4 和 KIR3DL1 的遗传共现率有增加的趋势 ( p = 0.05, OR 1.557）。此外，MM 患者更有可能同时表达 C2/KIR2DL1 和 Bw4/KIR3DL1（p = 0.019，OR 2.453）。我们的结果揭示了与 MM 发生相关的 HLA NK 表位组合。无特异性KIR 基因型与 MM 相关。