Woehrle Tobias, Du Weidong, Goetz Achim, Hsu Hsin-Yun, Joos Thomas O, Weiss Manfred, Bauer Ute, Brueckner Uwe B, Marion Schneider E
University of Ulm, Experimental Anesthesiology, Department of Anesthesiology, Steinhoevelstr. 9, Ulm 89075, Germany.
Cytokine. 2008 Mar;41(3):322-9. doi: 10.1016/j.cyto.2007.12.006. Epub 2008 Jan 30.
Toll-like receptors (TLRs) are crucial pattern-recognition receptors (PRRs) for activation of innate and adapted immunity. TLR2 heterodimerizes with TLR1 or TLR6 to recognize multiple pathogen-associated molecular patterns (PAMPs) of fungi, Gram-positive pathogens, and mycobacteria. Receptor activation culminates in monocyte, T-helper (Th)1, and Th2 cytokine release. Single nucleotide polymorphisms (SNPs) Arg753Gln and Arg677Trp affect TLR2 responsiveness and may contribute to the course of sepsis, which is associated with substantial morbidity and mortality during intensive care treatment. We genotyped 325 critically ill patients with septic shock, and performed a detailed clinical follow-up with 47 of these patients. Here, we investigated whether distinct sepsis episodes result in defined plasma cytokine patterns, and whether cytokine profiles may be linked to the TLR2 polymorphisms. Blood sampling was done daily and microbiological testing was performed on a routine basis. DNA was extracted from whole blood and TLR2 SNPs were typed by pyrosequencing. Cytokines were measured by multiplexed array technologies and the leukocyte phenotype was determined by flow cytometry. Among the 325 ICU patients, 17 individuals (5.2%) were heterozygous for Arg753Gln. The SNP Arg677Trp was not found in any patient. Episodes of Gram-negative, Gram-positive, and Candida sepsis were recorded. During Gram-positive sepsis, the cytokine pattern did not differ between Arg753Gln heterozygous patients and wild type patients. By contrast, during Candida sepsis, the Arg753Gln heterozygous patients showed biomarker patterns that differed from wild type patients with elevated TNF-alpha plasma concentrations, but reduced IFN-gamma and IL-8 levels. In conclusion, TLR2 SNP Arg753Gln results in altered cytokine release in response to Candida but not to Gram-positive sepsis.
Toll样受体（TLRs）是激活固有免疫和适应性免疫的关键模式识别受体（PRRs）。TLR2与TLR1或TLR6形成异二聚体，以识别真菌、革兰氏阳性病原体和分枝杆菌的多种病原体相关分子模式（PAMPs）。受体激活最终导致单核细胞、辅助性T（Th）1和Th2细胞因子释放。单核苷酸多态性（SNP）Arg753Gln和Arg677Trp影响TLR2反应性，并可能导致脓毒症的病程发展，脓毒症在重症监护治疗期间与高发病率和死亡率相关。我们对325例感染性休克的重症患者进行了基因分型，并对其中47例患者进行了详细的临床随访。在此，我们研究了不同的脓毒症发作是否会导致特定的血浆细胞因子模式，以及细胞因子谱是否可能与TLR2多态性相关。每天进行血液采样，并定期进行微生物检测。从全血中提取DNA，通过焦磷酸测序对TLR2 SNPs进行分型。通过多重阵列技术测量细胞因子，并通过流式细胞术确定白细胞表型。在325例ICU患者中，17例个体（5.2%）为Arg753Gln杂合子。在任何患者中均未发现SNP Arg677Trp。记录了革兰氏阴性、革兰氏阳性和念珠菌脓毒症发作情况。在革兰氏阳性脓毒症期间，Arg753Gln杂合子患者和野生型患者之间的细胞因子模式没有差异。相比之下，在念珠菌脓毒症期间，Arg753Gln杂合子患者表现出与野生型患者不同的生物标志物模式，其血浆TNF-α浓度升高，但IFN-γ和IL-8水平降低。总之，TLR2 SNP Arg753Gln导致对念珠菌而非革兰氏阳性脓毒症的细胞因子释放改变。
