Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands.
GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
Immunogenetics. 2024 Jun;76(3):155-164. doi: 10.1007/s00251-024-01336-w. Epub 2024 Mar 13.
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-A23, A24, 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 (C1C2Bw4) 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）是一种血液系统恶性肿瘤，由骨髓中恶性浆细胞的克隆性扩张引起。骨髓瘤细胞易被自然杀伤（NK）细胞杀伤，但 NK 细胞未能控制疾病进展，提示存在免疫抑制。NK 效应功能的激活阈值受 KIR 与自身 HLA Ⅰ类之间的相互作用调节，这一过程称为“教育”，以确保自身耐受。NK 细胞可以根据缺乏 HLA Ⅰ类表达来响应病变细胞（“缺失自身”假说）。HLA 和 KIR 谱极为多样化；因此，本研究旨在描述 MM 患者与健康对照者之间 HLA Ⅰ类 NK 表位和 KIR 基因型组成的潜在差异。在 172 例 MM 患者和 195 例健康对照者中分析了 KIR 和 HLA 的基因型表达（HLA-C 组-C1/C2 和 Bw4 基序（包括 HLA-A23、A24、A*32）。与健康对照者相比，我们没有观察到 MM 患者中更高发生率的特定 KIR 基因或基因型，或 HLA NK 表位。所有三种 HLA NK 表位（C1C2Bw4）的存在与 MM 的发生无关。然而，MM 患者更可能同时存在 C1/C2/Bw4（p=0.049，OR 1.996）。与此一致的是，MM 患者中 Bw4 和 KIR3DL1 的遗传共发生呈增加趋势（p=0.05，OR 1.557）。此外，MM 患者更可能同时遗传表达 C2/KIR2DL1 和 Bw4/KIR3DL1（p=0.019，OR 2.453）。我们的研究结果揭示了与 MM 发生相关的 HLA NK 表位组合。没有特定的 KIR 基因型与 MM 相关。
