Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.
PLoS One. 2011 Jan 28;6(1):e16582. doi: 10.1371/journal.pone.0016582.
The major histocompatibility complex (MHC) is the most important genomic region that contributes to the risk of graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Matching of MHC class I and II genes is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology of GVHD by mRNA expression profiling.
METHODOLOGY/PRINCIPAL FINDINGS: To reduce the complexity of the task, we used genetically well-defined rat inbred strains and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR), to analyze the expression of MHC, natural killer complex (NKC), and other genes in cutaneous GVHR. We observed a statistically significant and strong up or down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in GVHD-affected skin lesions of transplanted rats and in human skin explant assays.
CONCLUSIONS/SIGNIFICANCE: We identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2, AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in patients.
主要组织相容性复合体（MHC）是导致造血干细胞移植后移植物抗宿主病（GVHD）风险的最重要基因组区域。MHC 类 I 和 II 基因的匹配对于移植的成功至关重要。然而，MHC 还包含其他基因，这些基因也会增加发生急性 GVHD 的风险。由于该区域存在连锁不平衡，仅通过遗传关联研究很难识别这些基因。因此，我们旨在通过 mRNA 表达谱鉴定参与 GVHD 病理生理学的 MHC 基因和其他基因。
方法/主要发现：为了降低任务的复杂性，我们使用遗传上定义良好的大鼠近交系和大鼠皮肤外植体测定，一种移植物抗宿主反应（GVHR）的体外模型，分析皮肤 GVHR 中 MHC、自然杀伤细胞复合物（NKC）和其他基因的表达。我们观察到 11 个 MHC、6 个 NKC 和其他基因组区域编码的 168 个基因的表达呈统计学上显著且强烈的上调或下调，分别占测试基因的 4.9%、14.0%和 2.6%。通过定量实时 PCR 和独立的皮肤外植体测定验证了 7 个选定的 MHC 和 3 个 NKC 基因的调节。此外，在移植大鼠的 GVHD 受累皮肤病变和人类皮肤外植体测定中观察到大多数选定基因的类似调节。
结论/意义：我们鉴定了大鼠和人类 MHC 和 NKC 基因，这些基因在皮肤外植体测定中在 GVHR 期间受到调节，因此可以作为 GVHD 的生物标志物。几个相应的人类基因，包括 HLA-DMB、C2、AIF1、SPR1、UBD 和 OLR1，是多态性的。这些候选基因可能因此导致患者 GVHD 的遗传风险。
