自然杀伤细胞在创伤性脑损伤中的变化研究
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摘要
研究目的：
通过测定创伤性脑损伤(Traumatic Brain Injury,TBI)患者外周血中自然杀伤(Natural Killer cells, NK cells)细胞表型的变化,探讨伤后不同时间NK细胞水平与不同程度TBI的关系。
研究内容：
TBI是导致我国青壮年死亡的主要原因之一,有极高的致死率和伤残率,构成重大的公共卫生和社会经济问题。新研究发现神经损伤的程度似乎与固有免疫活动规模和活性程度相关,细胞和体液免疫系统在TBI的损伤机制中起到的关键作用。NK细胞是与T、B细胞并列的第三类群淋巴细胞,是免疫监视的第一道防线,可以调控适应性免疫的发生,具有极强的免疫学调节功能。本研究以不同程度TBI患者外周血中NK细胞变化为研究内容,为进一步探讨脑损伤与免疫反应的关系,探明TBI的发病机制,为探寻新的TBI治疗方式提供参考。
研究方法：
选择30例于天津医科大学总医院神经创伤监护中心收治的闭合性颅脑外伤患者,根据格拉斯哥昏迷评分(Glasgow Coma Scale, GCS)评定脑损伤程度,选择轻、中、重不同程度TBI患者各10例。分别于脑损伤后1、3、7、14、21天采集外周血样,应用流式细胞仪检测方法分析外周血CD3-CD56+NK细胞百分比和绝对值数量变化。同步收集性别,年龄等一般临床资料与TBI患者相对照的20例正常健康志愿者外周血标本。统计不同程度TBI患者感染类型、感染率,测定中重TBI患者清晨血清皮质醇浓度,随访伤后3和6个月格拉斯哥预后评分(Glasgow Outcome Scale,GOS)评价神经功能预后,进一步探讨伤后不同时间NK细胞与GCS、GOS评分关系,明确感染与NK细胞变化的关系,初步探讨TBI后固有免疫变化机制。
研究结果：
1、与健康对照组相比,轻度TBI患者NK细胞的百分比和绝对值数量在伤后第1天和第3天呈显著下降,伤后7天,NK细胞的百分比和绝对值数量恢复至正常范围水平；中度TBI患者相同的时间点的CD3-CD56+NK细胞的百分比和绝对值数量的变化趋势并不完全相同,伤后7天,NK细胞的百分比和绝对值数量与对照组比较均明显降低,外周血NK细胞的绝对值数量于伤后21天已恢复正常范围；重度TBI患者外周血中最低NK细胞百分比和绝对值数量被发现在伤后3-7天,此外,NK细胞百分比和绝对值数量在伤后21天仍没有恢复正常水平。
2、TBI患者感染发生率较高,最常见的感染并发症为肺部感染、尿路感染和败血症。感染组与非感染组TBI患者在伤后3-7天左右出现NK细胞的统计学差异,感染组NK细胞相对非感染组呈显著下降趋势。
3、TBI组患者伤后7、14和21天NK细胞与GCS评分呈正相关：伤后3、6个月,TBI后7、14天NK细胞与GOS评分呈正相关；感染组和非感染组TBI组患者伤后7天NK细胞与GCS评分呈正相关；感染组外周血NK细胞百分比和绝对值数量和3、6个月的GOS评分无明显相关；非感染组在伤后7天外周血NK细胞和GOS评分相关性有统计学意义。
研究结论：
1、本研究调查了不同程度TBI患者外周血中NK细胞百分比和绝对值数量的变化。结果提示脑损伤后伴随着外周血中NK细胞的比例和数目的减少,脑损伤愈严重,NK细胞减少愈明显,呈先下降后缓慢复原的趋势。研究揭示了创伤性脑损伤可以诱发外周血NK细胞的减少。
2、脑损伤后常伴有严重的颅外全身系统并发症,原因与免疫失衡和中枢神经系统诱发的免疫缺陷相关。常见并发症为严重的肺部感染、尿路感染和败血症等。我们发现不同程度TBI患者罹患颅外感染的几率不同,在TBI疾病发展过程中,外周血固有免疫反应的主要效应细胞—NK细胞发生了戏剧性的变化,其变化趋势与感染发生规律有相关性。
3、NK细胞可能在某种程度上对TBI患者的神经功能和预后产生一定影响。严重TBI后常伴随下丘脑-垂体-肾上腺轴功能衰竭及中枢性免疫抑制的发生,我们选定中重度TBI患者检测清晨外周血清皮质醇浓度,进一步探讨TBI患者合并外周血NK细胞减少的机制。改善中枢神经损伤后NK细胞功能可能会对控制感染和改善预后起到帮助,但同时避免NK细胞对自体细胞的识别和过度对获得性免疫的调控也是进一步思考的课题。总之,TBI诱导NK细胞病理变化原因可能是复杂和多方面的,尚需进一步的探索和研究。
Objective:
To investigate the relationship between natural killer (NK) cells and traumatic brain injury (TBI), we explored the phenotype of circulating NK cells in patients with different grades of TBI at different time points.
Background:
TBI is the leading cause of neurological disability, especially among young persons. It leads to a large public health problem and enormously financial burden throughout the world. The extent of neuronal damage seems to correlate with the degree of innate immune activity and numerous studies have demonstrated the critical role of the cellular and humoral immune system in TBI. NK cells are large granular cells and being third in lineage among lymphocytes after B and T cells. The role of NK cells is the first line of defense to combat infections and one of the earliest cell types to arrive at target organs of inflammation. NK cells can affect the initiation of autoimmunity and regulate inflammation. Herein, we aimed to investigate the change of circulating NK cells in patients with mild, moderate and severe TBI quantitatively. In addition, we explored the relationship between NK cells and neurologic outcome, and tried to take a step toward understanding the pathogenesis of immunodepression after TBI.
Method:
The consecutive30patients who treated in the Neurotrauma Intensive Care Unit at Department of Neurosurgery of General Hospital, Tianjin Medical University, China were enrolled. Patients with TBI were graded as mild, moderate or severe on the basis of the level of GCS score on admission. Peripheral blood samples of all enrolled patients were examined on first, third, seventh, fourteenth and twenty-first days after TBI and evaluated for immunological analysis. The rates and types of infection of different extent TBI were analyzed. The hormone assays were performed at different days after trauma in moderate and severe group. The primary neurologic outcome was assessed with the Glasgow Outcome Scale (GOS).
Result:
1. The percentage and absolute number of NK cells in mild group within7days of injury restore to the level obtained in healthy volunteers. The percentage and absolute number of NK cells were significantly lower in moderate TBI patients than controls on the7day after injury. The absolute number of peripheral blood CD3-CD56+NK cells of moderate TBI return to normal by day21. In patients with severe TBI, the lowest percentage and absolute number of CD3-CD56+NK cells were noticed on day3to7as comparison with other days and control group. In addition, the percentage and absolute number of peripheral blood CD3-CD56+NK cells did not returned to normal by day21.
2. TBI patients showed high susceptibility to infections such as pneumonia, urinary tract infections and septicaemia. On post-injury day3to7, the percentage and absolute number of NK cells in infective group dropped significantly compared with the noninfective group.
3. The lower NK cells were independently associated with the lower Glasgow Coma Scale score in some time point investigated. In addition, the positive correlation between NK cells at some time point and Glasgow Outcome Scale score was calculated.
Conclusion:
1. The magnitude of NK cell reduction correlated with different severity of TBI at different time points. Our results indicate that TBI induce reduction of NK cells, and the magnitude of such reduction appears correlated with severity of TBI.
2. Severe TBI have serious systemic complications outside the brain. One of such complications is the impact on the immune system and the induction of immune deficiency. The alterations of NK cells during the course of TBI and revealed a dramatic change of those innate immune cells. We further analyzed the correlation of NK cell alteration with clinical infection of TBI.
3. Neurological damage induces a disturbance between central nervous system and the immune system, and leads to central nervous system injury-induced immunodepression and the dysfunction of the Hypothalamic Pituitary Adrenal axis. We checked the morning serum cortisol concentrations on the different days after trauma in moderate and severe TBI group. Our experimental evidence indicates that NK cells may contribute to the amplification of drastic immunodepression after TBI. Measuring NK cells expressing CD3-CD56+post-TBI may have novel prognostic and therapeutic implications for TBI. Extensive monitoring of the NK-cell phenotype in TBI patients might aid future NK-based immuno-interventions. More work is yet needed to elucidate roles of NK cells on immune responses in the TBI patients.
通过测定创伤性脑损伤(Traumatic Brain Injury,TBI)患者外周血中自然杀伤(Natural Killer cells, NK cells)细胞表型的变化,探讨伤后不同时间NK细胞水平与不同程度TBI的关系。
研究内容：
TBI是导致我国青壮年死亡的主要原因之一,有极高的致死率和伤残率,构成重大的公共卫生和社会经济问题。新研究发现神经损伤的程度似乎与固有免疫活动规模和活性程度相关,细胞和体液免疫系统在TBI的损伤机制中起到的关键作用。NK细胞是与T、B细胞并列的第三类群淋巴细胞,是免疫监视的第一道防线,可以调控适应性免疫的发生,具有极强的免疫学调节功能。本研究以不同程度TBI患者外周血中NK细胞变化为研究内容,为进一步探讨脑损伤与免疫反应的关系,探明TBI的发病机制,为探寻新的TBI治疗方式提供参考。
研究方法：
选择30例于天津医科大学总医院神经创伤监护中心收治的闭合性颅脑外伤患者,根据格拉斯哥昏迷评分(Glasgow Coma Scale, GCS)评定脑损伤程度,选择轻、中、重不同程度TBI患者各10例。分别于脑损伤后1、3、7、14、21天采集外周血样,应用流式细胞仪检测方法分析外周血CD3-CD56+NK细胞百分比和绝对值数量变化。同步收集性别,年龄等一般临床资料与TBI患者相对照的20例正常健康志愿者外周血标本。统计不同程度TBI患者感染类型、感染率,测定中重TBI患者清晨血清皮质醇浓度,随访伤后3和6个月格拉斯哥预后评分(Glasgow Outcome Scale,GOS)评价神经功能预后,进一步探讨伤后不同时间NK细胞与GCS、GOS评分关系,明确感染与NK细胞变化的关系,初步探讨TBI后固有免疫变化机制。
研究结果：
1、与健康对照组相比,轻度TBI患者NK细胞的百分比和绝对值数量在伤后第1天和第3天呈显著下降,伤后7天,NK细胞的百分比和绝对值数量恢复至正常范围水平；中度TBI患者相同的时间点的CD3-CD56+NK细胞的百分比和绝对值数量的变化趋势并不完全相同,伤后7天,NK细胞的百分比和绝对值数量与对照组比较均明显降低,外周血NK细胞的绝对值数量于伤后21天已恢复正常范围；重度TBI患者外周血中最低NK细胞百分比和绝对值数量被发现在伤后3-7天,此外,NK细胞百分比和绝对值数量在伤后21天仍没有恢复正常水平。
2、TBI患者感染发生率较高,最常见的感染并发症为肺部感染、尿路感染和败血症。感染组与非感染组TBI患者在伤后3-7天左右出现NK细胞的统计学差异,感染组NK细胞相对非感染组呈显著下降趋势。
3、TBI组患者伤后7、14和21天NK细胞与GCS评分呈正相关：伤后3、6个月,TBI后7、14天NK细胞与GOS评分呈正相关；感染组和非感染组TBI组患者伤后7天NK细胞与GCS评分呈正相关；感染组外周血NK细胞百分比和绝对值数量和3、6个月的GOS评分无明显相关；非感染组在伤后7天外周血NK细胞和GOS评分相关性有统计学意义。
研究结论：
1、本研究调查了不同程度TBI患者外周血中NK细胞百分比和绝对值数量的变化。结果提示脑损伤后伴随着外周血中NK细胞的比例和数目的减少,脑损伤愈严重,NK细胞减少愈明显,呈先下降后缓慢复原的趋势。研究揭示了创伤性脑损伤可以诱发外周血NK细胞的减少。
2、脑损伤后常伴有严重的颅外全身系统并发症,原因与免疫失衡和中枢神经系统诱发的免疫缺陷相关。常见并发症为严重的肺部感染、尿路感染和败血症等。我们发现不同程度TBI患者罹患颅外感染的几率不同,在TBI疾病发展过程中,外周血固有免疫反应的主要效应细胞—NK细胞发生了戏剧性的变化,其变化趋势与感染发生规律有相关性。
3、NK细胞可能在某种程度上对TBI患者的神经功能和预后产生一定影响。严重TBI后常伴随下丘脑-垂体-肾上腺轴功能衰竭及中枢性免疫抑制的发生,我们选定中重度TBI患者检测清晨外周血清皮质醇浓度,进一步探讨TBI患者合并外周血NK细胞减少的机制。改善中枢神经损伤后NK细胞功能可能会对控制感染和改善预后起到帮助,但同时避免NK细胞对自体细胞的识别和过度对获得性免疫的调控也是进一步思考的课题。总之,TBI诱导NK细胞病理变化原因可能是复杂和多方面的,尚需进一步的探索和研究。
Objective:
To investigate the relationship between natural killer (NK) cells and traumatic brain injury (TBI), we explored the phenotype of circulating NK cells in patients with different grades of TBI at different time points.
Background:
TBI is the leading cause of neurological disability, especially among young persons. It leads to a large public health problem and enormously financial burden throughout the world. The extent of neuronal damage seems to correlate with the degree of innate immune activity and numerous studies have demonstrated the critical role of the cellular and humoral immune system in TBI. NK cells are large granular cells and being third in lineage among lymphocytes after B and T cells. The role of NK cells is the first line of defense to combat infections and one of the earliest cell types to arrive at target organs of inflammation. NK cells can affect the initiation of autoimmunity and regulate inflammation. Herein, we aimed to investigate the change of circulating NK cells in patients with mild, moderate and severe TBI quantitatively. In addition, we explored the relationship between NK cells and neurologic outcome, and tried to take a step toward understanding the pathogenesis of immunodepression after TBI.
Method:
The consecutive30patients who treated in the Neurotrauma Intensive Care Unit at Department of Neurosurgery of General Hospital, Tianjin Medical University, China were enrolled. Patients with TBI were graded as mild, moderate or severe on the basis of the level of GCS score on admission. Peripheral blood samples of all enrolled patients were examined on first, third, seventh, fourteenth and twenty-first days after TBI and evaluated for immunological analysis. The rates and types of infection of different extent TBI were analyzed. The hormone assays were performed at different days after trauma in moderate and severe group. The primary neurologic outcome was assessed with the Glasgow Outcome Scale (GOS).
Result:
1. The percentage and absolute number of NK cells in mild group within7days of injury restore to the level obtained in healthy volunteers. The percentage and absolute number of NK cells were significantly lower in moderate TBI patients than controls on the7day after injury. The absolute number of peripheral blood CD3-CD56+NK cells of moderate TBI return to normal by day21. In patients with severe TBI, the lowest percentage and absolute number of CD3-CD56+NK cells were noticed on day3to7as comparison with other days and control group. In addition, the percentage and absolute number of peripheral blood CD3-CD56+NK cells did not returned to normal by day21.
2. TBI patients showed high susceptibility to infections such as pneumonia, urinary tract infections and septicaemia. On post-injury day3to7, the percentage and absolute number of NK cells in infective group dropped significantly compared with the noninfective group.
3. The lower NK cells were independently associated with the lower Glasgow Coma Scale score in some time point investigated. In addition, the positive correlation between NK cells at some time point and Glasgow Outcome Scale score was calculated.
Conclusion:
1. The magnitude of NK cell reduction correlated with different severity of TBI at different time points. Our results indicate that TBI induce reduction of NK cells, and the magnitude of such reduction appears correlated with severity of TBI.
2. Severe TBI have serious systemic complications outside the brain. One of such complications is the impact on the immune system and the induction of immune deficiency. The alterations of NK cells during the course of TBI and revealed a dramatic change of those innate immune cells. We further analyzed the correlation of NK cell alteration with clinical infection of TBI.
3. Neurological damage induces a disturbance between central nervous system and the immune system, and leads to central nervous system injury-induced immunodepression and the dysfunction of the Hypothalamic Pituitary Adrenal axis. We checked the morning serum cortisol concentrations on the different days after trauma in moderate and severe TBI group. Our experimental evidence indicates that NK cells may contribute to the amplification of drastic immunodepression after TBI. Measuring NK cells expressing CD3-CD56+post-TBI may have novel prognostic and therapeutic implications for TBI. Extensive monitoring of the NK-cell phenotype in TBI patients might aid future NK-based immuno-interventions. More work is yet needed to elucidate roles of NK cells on immune responses in the TBI patients.
引文
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