BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken
BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken
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DOI：
10.1073/pnas.0906776106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Miller, Marcia M.
中科院分区：
文献类型：
--
作者：
Goto, Ronald M.;Wang, Yujun;Miller, Marcia M.
假定病原体选择驱动抗原呈递位点的MHC等位基因多样性。然而，在大多数物种中，明显的MHC感染性疾病关联是罕见的。MHC-B单倍型和病毒诱导的鸡肿瘤的发生之间的强联系提供了一种手段，用于定义病原体选择和MHC多态性之间的关系。在这里，我们验证了两种密切相关的重组MHC-B单倍型对原鸡疱疹病毒-2（GaHV-2）诱导的淋巴瘤（马立克氏病）的抗性存在显着差异。我们映射的交叉断点，区分这些单倍型的高度多态性的BG 1位点。BG 1编码一种Ig超家族I型跨膜受体样蛋白，其含有基于免疫受体酪氨酸的抑制基序（ITIM），该基序经历磷酸化并被含Src同源2结构域的蛋白酪氨酸磷酸酶（SHP-2）识别。重组单倍型是相同的，除了在BG 1 3 '-非翻译区（3'-UTR）内的差异。与淋巴瘤增加相关的BG 1等位基因的3 '-UTR含有逆转录病毒来源的225-bp插入片段，与其他等位基因相比，对荧光素酶报告基因翻译的抑制作用更大。这些研究结果表明，BG 1可以通过调节淋巴细胞对感染的反应性来影响GaHV-2感染的结果，这是GaHV-2复制的关键条件，其中MHC-B单倍型先前已被牵连。这项工作提供了一种机制，MHC-B区遗传学有助于GaHV-2诱导的鸡恶性淋巴瘤的发病率，并邀请考虑类似的机制可能会影响与其他致癌病毒感染相关的淋巴瘤的发病率。
Pathogen selection is postulated to drive MHC allelic diversity at loci for antigen presentation. However, readily apparent MHC infectious disease associations are rare in most species. The strong link between MHC-B haplotype and the occurrence of virally induced tumors in the chicken provides a means for defining the relationship between pathogen selection and MHC polymorphism. Here, we verified a significant difference in resistance to gallid herpesvirus-2 (GaHV-2)-induced lymphomas (Marek's disease) conferred by two closely-related recombinant MHC-B haplotypes. We mapped the crossover breakpoints that distinguish these haplotypes to the highly polymorphic BG1 locus. BG1 encodes an Ig-superfamily type I transmembrane receptor-like protein that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), which undergoes phosphorylation and is recognized by Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2). The recombinant haplotypes are identical, except for differences within the BG1 3'-untranslated region (3'-UTR). The 3'-UTR of the BG1 allele associated with increased lymphoma contains a 225-bp insert of retroviral origin and showed greater inhibition of luciferase reporter gene translation compared to the other allele. These findings suggest that BG1 could affect the outcome of GaHV-2 infection through modulation of the lymphoid cell responsiveness to infection, a condition that is critical for GaHV-2 replication and in which the MHC-B haplotype has been previously implicated. This work provides a mechanism by which MHC-B region genetics contributes to the incidence of GaHV-2-induced malignant lymphoma in the chicken and invites consideration of the possibility that similar mechanisms might affect the incidence of lymphomas associated with other oncogenic viral infections.