RNA sequencing of whole blood in dogs with primary immune-mediated hemolytic anemia (IMHA) reveals novel insights into disease pathogenesis.
RNA sequencing of whole blood in dogs with primary immune-mediated hemolytic anemia (IMHA) reveals novel insights into disease pathogenesis.
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DOI：
10.1371/journal.pone.0240975
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Friedenberg SG
中科院分区：
文献类型：
--
作者：
Borchert C;Herman A;Roth M;Brooks AC;Friedenberg SG
免疫介导的溶血性贫血（IMHA）是一种危及生命的自身免疫性疾病，其特征是对循环红细胞的自我介导攻击。这种疾病自然发生在狗和人身上，但在狗身上更为普遍。由于跨物种的共同特征，狗为研究人类的IMHA提供了一个自然发生的模型。在这项研究中，我们使用treatment-naïve狗的全血RNA测序来研究新诊断动物与健康对照组相比基因表达的转录组范围变化。我们在中性粒细胞功能、凝血和造血相关的通路中发现了许多过度表达的基因。特别是，在这些病例中，高表达的基因是磷脂酶超燃酶，它介导磷脂酰丝氨酸从细胞膜的内叶向外叶的外化。这个基因家族已被证明对红细胞的程序性细胞死亡以及凝血级联的启动至关重要。出乎意料的是，我们发现许多与淋巴细胞功能相关的基因明显表达不足。我们还确定了与感染犬的炎症反应和红细胞再生高度相关的基因组。我们没有发现任何基因来区分活下来的狗和那些在诊断后30天死亡的狗，我们也没有在受影响动物的血液中发现任何相关的微生物基因组特征。未来的研究需要验证这些发现，并评估它们对开发新的治疗方法对患有IMHA的狗和人的意义。
Immune-mediated hemolytic anemia (IMHA) is a life-threatening autoimmune disorder characterized by a self-mediated attack on circulating red blood cells. The disease occurs naturally in both dogs and humans, but is significantly more prevalent in dogs. Because of its shared features across species, dogs offer a naturally occurring model for studying IMHA in people. In this study, we used RNA sequencing of whole blood from treatment-naïve dogs to study transcriptome-wide changes in gene expression in newly diagnosed animals compared to healthy controls. We found many overexpressed genes in pathways related to neutrophil function, coagulation, and hematopoiesis. In particular, the most highly overexpressed gene in cases was a phospholipase scramblase, which mediates the externalization of phosphatidylserine from the inner to the outer leaflet of cell membranes. This family of genes has been shown to be critically important for programmed cell death of erythrocytes as well as the initiation of the clotting cascade. Unexpectedly, we found marked underexpression of many genes related to lymphocyte function. We also identified groups of genes that are highly associated with the inflammatory response and red blood cell regeneration in affected dogs. We did not find any genes that distinguished dogs that lived vs. those that died at 30 days following diagnosis, nor did we find any relevant genomic signatures of microbial organisms in the blood of affected animals. Future studies are warranted to validate these findings and assess their implication in developing novel therapeutic approaches for dogs and humans with IMHA.
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