Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
Crit Care Med. 2010 Oct;38(10):2003-10. doi: 10.1097/CCM.0b013e3181eb9ed6.
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.
利用动物模型检验以下假说，即女性 X 染色体炎症基因表达的镶嵌现象是否会导致宿主反应过程中的性别二态性反应。X 染色体连锁的遗传多态性提供了一种独特的生物学条件，因为女性在每个细胞中均表现出杂合性细胞镶嵌现象，这是由于在女性中，要么是来自母亲的 X 染色体，要么是来自父亲的 X 染色体在每个细胞中失活。这与男性的情况形成对比，男性只携带来自母亲的 X 染色体。
前瞻性、随机、实验室研究。
大学研究实验室。
缺乏 X 连锁 gp91phox 的雌性小鼠、杂合子（镶嵌）或 WT。
我们比较了杂合子（镶嵌）、WT 和纯合子缺乏的动物在体内脂多糖（大肠杆菌，20mg/kg 体重）反应中选择的炎症标志物。为了测试多形核中性粒细胞反应的个体镶嵌亚群，我们还开发了一种流式细胞术测定法，该方法使用 gp91phox 表达作为标记，确定单个细胞中的活性母系 X 染色体。
杂合子镶嵌小鼠的白细胞迁移模式与 WT 小鼠相似，尽管镶嵌动物中的缺乏亚群显示出细胞激活增加，表现为中性粒细胞 CD11b 表达升高和脾脏浸润。镶嵌动物还显示脾脏中性粒细胞浸润，偏向于缺乏亚群。脾脏 T 细胞耗竭和脂多糖后白细胞介素 10 反应的观察结果表明，镶嵌动物的炎症反应并不是简单地表现出缺乏和 WT 反应的平均值，而是镶嵌动物表现出独特的特征性反应。
该研究支持这样一种观点，即女性 X 染色体多态性基因表达的镶嵌现象代表一种独特的情况，可能导致炎症反应的性别二态性特征。X 连锁多态性的镶嵌现象可能具有临床意义，并且在遗传关联或性别相关的临床研究中需要考虑。
