Female X-chromosome mosaicism for gp91phox expression diversifies leukocyte responses during endotoxemia.
Female X-chromosome mosaicism for gp91phox expression diversifies leukocyte responses during endotoxemia.
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DOI：
10.1097/ccm.0b013e3181eb9ed6
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发表时间：
2010-10
影响因子：
8.8
通讯作者：
Spolarics Z
中科院分区：
文献类型：
--
作者：
Chandra R;Federici S;Haskó G;Deitch EA;Spolarics Z
为了检验这一假设，我们使用动物模型来研究炎症基因表达的女性 X 染色体嵌合是否会导致宿主反应期间的性别二态性反应。 X染色体连锁的遗传多态性呈现出独特的生物学状况，因为女性表现出杂合的细胞嵌合体，这是由于母本或父本X染色体在女性的每个个体细胞中失活的事实。这与仅携带母体 X 染色体的男性的情况形成鲜明对比。前瞻性、随机、实验室研究。大学研究实验室。 X 连锁 gp91phox 缺陷、杂合（马赛克）或 WT 的雌性小鼠。我们比较了杂合子（马赛克）、WT 和纯合缺陷动物中选定的炎症标志物对体内脂多糖（大肠杆菌，20 毫克/千克体重）的反应。为了测试多形核中性粒细胞反应的个体嵌合亚群，我们还开发了一种流式细胞术测定法，使用 gp91phox 表达作为标记来识别个体细胞中的活性亲本 X 染色体。杂合嵌合小鼠表现出与 WT 小鼠中观察到的白细胞运输模式相似，尽管嵌合动物中的缺陷亚群表现出细胞活化增加，如中性粒细胞 CD11b 表达升高和脾脏浸润所反映。镶嵌动物还表现出脾脏中性粒细胞浸润，这偏向于缺陷亚群。对脾 T 细胞耗竭和脂多糖白细胞介素 10 后反应的观察表明，嵌合体动物的炎症反应并不简单地表现出缺陷反应和 WT 反应的平均值，但嵌合体受试者表现出独特的特征性反应。该研究支持这样的观点，即多态性基因表达的女性 X 染色体嵌合代表了一种独特的条件，这可能导致炎症反应的性别二态性特征。 X连锁多态性的嵌合现象可能具有临床意义，需要在遗传关联或性别相关的临床研究中考虑。
To test the hypothesis, using an animal model, whether female X-chromosome mosaicism for inflammatory gene expression could contribute to the gender dimorphic response during the host response. X-chromosome-linked genetic polymorphisms present a unique biological condition because females display heterozygous cellular mosaicism, due to the fact that either the maternal or the paternal X chromosomes are inactivated in each individual cell in females. This is in contrast with the conditions in males who carry exclusively the maternal X chromosome. Prospective, randomized, laboratory investigation. University research laboratory. Female mice deficient, heterozygous (mosaic) or WT for the X-linked gp91phox. We compared selected inflammatory markers among heterozygous (mosaics), WT and homozygous deficient animals in response to in vivo lipopolysaccharide (Escherichia coli, 20 mg/kg body weight). To test individual mosaic subpopulations of polymorphonuclear neutrophil responses, we also developed a flow cytometry assay that identifies the active parental X chromosomes in individual cells, using gp91phox expression as a marker. Heterozygous mosaic mice presented white blood cell trafficking patterns similar to that observed in WT mice, despite the fact that the deficient subpopulation in mosaic animals displayed increased cell activation as reflected in elevated neutrophil CD11b expression and splenic infiltration. Mosaic animals also displayed splenic neutrophil infiltration, which was skewed toward the deficient subpopulation. Observations on splenic T-cell depletion and post lipopolysaccharide interleukin-10 responses indicated that the inflammatory response in mosaic animals does not simply display an average of the deficient and WT responses, but the mosaic subjects display a uniquely characteristic response. The study supports the notion that female X chromosome mosaicism for polymorphic gene expression represents a unique condition, which may contribute to the gender dimorphic character of the inflammatory response. Mosaicism for X-linked polymorphisms may have clinical significance and needs consideration in genetic association or gender-related clinical studies.