Spec Andrej, Shindo Yuichiro, Burnham Carey-Ann D, Wilson Strother, Ablordeppey Enyo A, Beiter Evan R, Chang Katherine, Drewry Anne M, Hotchkiss Richard S
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
Crit Care. 2016 Jan 20;20:15. doi: 10.1186/s13054-016-1182-z.
Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40%. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections.
Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated.
Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1).
Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.
尽管进行了适当的治疗，念珠菌血流感染的死亡率仍约为40%。在动物模型中，T细胞耗竭导致的免疫功能受损与真菌败血症死亡率有关。本研究的目的是通过对微生物学确诊的念珠菌血流感染患者的循环T淋巴细胞进行免疫表型分析，确定真菌诱导免疫抑制的潜在机制。
对血培养中任何念珠菌属阳性的患者进行研究。无细菌或真菌感染证据的非脓毒症重症患者作为对照。通过流式细胞术分析T细胞的细胞活化情况以及阳性和阴性共刺激分子的表达。对表达特定免疫表型标志物的细胞百分比以及几何平均荧光强度（GMFI，一种衡量每个细胞受体或配体数量表达的指标）进行定量分析。
研究了27例念珠菌血流感染患者和16例对照患者。与对照患者相比，念珠菌血症患者的CD8 T细胞有细胞活化的证据，表现为CD69表达增加，而CD4 T细胞主要阳性共刺激分子CD28的表达降低。念珠菌血症患者的CD4和CD8 T细胞表达了T细胞耗竭的典型标志物，表现为程序性细胞死亡1（PD-1）或其配体（PD-L1）的百分比增加或MFI增加。
念珠菌血症患者的循环免疫效应细胞表现出与免疫抑制一致的免疫表型，T细胞耗竭和阳性共刺激分子的同时下调证明了这一点。这些发现可能有助于解释为什么真菌败血症患者尽管接受了适当的抗真菌治疗仍有高死亡率。开发能够逆转T细胞耗竭并增强宿主免疫力的免疫佐剂可能是改善这种高致死性疾病预后的一种方法。
