Presence of preexisting antibodies mediates survival in sepsis.
Presence of preexisting antibodies mediates survival in sepsis.
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DOI：
10.1097/shk.0b013e3182356f3e
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发表时间：
2012-01
期刊：
影响因子：
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通讯作者：
Remick DG
中科院分区：
文献类型：
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作者：
Moitra R;Beal DR;Belikoff BG;Remick DG
败血症是世界范围内医院死亡的主要原因之一。即使采用最佳治疗，严重的脓毒症也会导致50%的死亡率，这表明个体对治疗的反应是不同的。我们假设，在盲肠结扎和穿孔(CLP)诱导的小鼠脓毒症发生之前，血液中存在预先存在的抗体，这是造成它们存活率差异的原因。用血浆增强杀伤试验(PEK)计算血浆的PEK容量，即血浆增强PMN杀灭细菌的能力。PEK计算为PEK=(1/log(N))×100，其中N=存活细菌数；PEK越高，杀菌效果越好。在CLP前收集的小鼠血浆中的一系列PEK被观察到，证明了细菌杀灭能力的个体差异。根据CLP后24小时的血浆IL-6水平预测死亡率。与携带PEK>；16的小鼠相比，预计将会死亡的小鼠(Die-P)在败血症后24小时的PEK(<；14)较低，而腹膜细菌计数较高。与PEK>；16组相比，携带PEK<；14的小鼠死亡的可能性高3.1倍。为了了解预先存在的抗体的防御机制，用流式细胞仪记录了IgM或IgG与肠道细菌的结合。为了确定Ig M或Ig G的相对贡献，从原始血浆样本中特异性地去除免疫球蛋白，并测量耗尽血浆的PEK。与单纯血浆相比，去除IgM对PEK无明显影响。然而，耗尽免疫球蛋白使PEK增加，这表明抑制的免疫球蛋白结合到细菌的抗原部位，阻止了细菌的最佳调理。这些数据表明，在CLP之前，在CLP脓毒症模型中，存在循环抑制性IgG抗体，可以防止PMN杀死细菌。
Sepsis is one of the leading causes of death in hospitals worldwide. Even with optimal therapy, severe sepsis results in 50% mortality, indicating variability in the response of individuals towards treatment. We hypothesize that the presence of pre-existing antibodies present in the blood before the onset of sepsis induced by cecal ligation and puncture (CLP) in mice, accounts for the differences in their survival. A Plasma Enhanced Killing (PEK) assay was performed to calculate the PEK capacity of plasma i.e. the ability of plasma to augment PMN killing of bacteria. PEK was calculated as PEK= (1/log (N)) × 100; where N= number of surviving bacteria; a higher PEK indicated better bacterial killing. A range of PEK in plasma collected from mice prior to CLP was observed, documenting individual differences in bacterial killing capacity. Mortality was predicted based on plasma IL-6 levels at 24 hr post CLP. Mice predicted to die (Die-P) had a lower PEK (<14) and higher peritoneal bacterial counts 24 hr post sepsis compared to those predicted to live (Live-P) with a PEK>16. Mice with PEK<14 were 3.1 times more likely to die compared to the PEK>16 group. To understand the mechanism of defense conferred by the pre-existing antibodies, binding of IgM or IgG to enteric bacteria was documented by flow cytometry. To determine the relative contribution of IgM or IgG, the immunoglobulins were specifically immuno-depleted from the naïve plasma samples and the PEK of the depleted plasma measured. Compared to naïve plasma, depletion of IgM had no effect on the PEK. However, depletion of IgG increased PEK suggesting that an inhibitory IgG binds to antigenic sites on bacteria preventing optimal opsonization of the bacteria. These data demonstrate that prior to CLP; circulating inhibitory IgG antibodies exist that prevent bacterial killing by PMNs in a CLP model of sepsis.