Molecular and immmunological analyses of cytokines and γδT cells in intracellular infection of Salmonella

摘要人类对沙门氏菌的宿主免疫应答知之甚少。本研究对沙门氏菌病患者外周血中Th1和Th-1细胞因子及T细胞反应进行了研究，发现沙门氏菌病患者急性期血清Th-1和Th-1细胞因子水平升高。此外，系统性沙门氏菌病患者血清IL-15、IL-18水平明显高于胃肠炎型患者。经系列检测，胃肠炎型患者血清干扰素-γ、IL-12、IL-15、IL-18水平较系统性胃肠炎患者更容易恢复正常，且干扰素-γ水平与IL-12、IL-18水平呈显著正相关。IL-15水平与IL-18水平呈显著正相关。体外沙门氏菌刺激后，沙门氏菌、卡介苗或大肠杆菌刺激均可产生IL-15和IL-18，而沙门氏菌刺激可优先产生IL-12和干扰素-γ。抗IL-12单抗和抗IL-18单抗均能显著抑制沙门氏菌诱导的干扰素-γ的产生，而抗IL-15单抗对其无明显抑制作用。系统性胃肠炎患者的HLADR+T细胞、CD69+T细胞、γδT细胞和HLADR+γδT细胞明显高于胃肠炎患者。HLA-DR+T细胞数与血清干扰素-γ、IL-15、IL-18水平呈正相关。HL A-DR+γδT细胞数与IL-15水平呈负相关。在系统性和胃肠炎中，分选的γδT细胞的干扰素-γ水平明显高于αβT细胞。综上所述，IL-12、IL-18和IL-15在复杂的相互作用下，似乎参与了整个T细胞的激活和γδT细胞的扩增，从而产生干扰素以保护人类免受沙门氏菌感染。

AbstractKnowledge of the host immune response against Salmonella is not sufficient in humans. In the present study, Th1- and Th-1 including cytokines and T cell response were investigated in salmonellosis.Serum Th-1 and Th-1including cytokine levels at acute phase in patients with salmonellosis were elevated. In addition, serum levels of IL-15 and IL-18 in patients with systematic form of salmonellosis were significantly higher than those in patients gastroenteritis form. By serial determination, serum IFN-γ ,IL-12, IL-15 and IL-18 levels in gastroenteritis form returned to normal levels easier than those in systematic form.IFN-γ level was significantly correlated with IL-12 and IL-18 levels. In addition, IL-15 level was significantly correlated with IL-18 level. Furthermore, IFN-γ , IL-15 and IL-18 levels were significantly correlated with duration with fever.Upon stimulation with Salmonella in vitro, IL-15 and IL-18 were produced by Salmonella, BCG or E. coli stimulation in both salmonellosis and controls, while IL-12 and IFN-γ were preferentially produced upon stimulation with Salmonella in Salmonellosis. A significant inhibition of Salmonella -induced IFN-γ production by anti-IL-12 mAb or anti-IL-18 mAb but not by anti-IL 15 mAb.HLA-DR+T cells, CD69+T cells, γδT cells and HLA-DR+γδT cells were significantly elevated in systematic form than in gastroenteritis from. HLA-DR+T cell-number tended to correlate with serum IFN-γ, IL-15 and IL-18 levels. HLA-DR+γδT cell-number was marginally associated with IL-15 levels. Sorted γδT cells contained significantly higher levels of IFN-γ mRNA than αβT cells both in systemic and gastroenteritis formsIn summary, IL-12, IL-18, and IL-15, with complex mutual interactions , appear to be involved in total T cell activation as well as γδT cell-expansion, resulting in IFN- production for the protection against Salmonella infection in humans.