机体在病毒感染、肿瘤等病理因素下产生的大量坏死细胞需要细胞毒性T淋巴细胞(CTL)的靶向杀伤作用来清除.人外周血BDCA3+树突状细胞上的Clec9A能特异性识别与结合坏死细胞暴露的纤维状肌动蛋白(F-actin),激活胞内脾酪氨酸激酶Syk.Clec9A作为F-actin的受体,不仅内吞坏死细胞,同时将坏死细胞相关抗原交叉提呈至CD8+T细胞,活化CTL,启动机体获得性免疫应答.CTL释放的穿孔素及颗粒酶特异性杀伤靶细胞,导致体内感染细胞或肿瘤细胞进一步被清除.因此,Clec9A在机体抗病毒感染、肿瘤治疗中具有潜在的应用前景.

Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on “NLRP3 inflammasome-NETs” inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1β and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8−/− diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1β, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8−/− neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1β/IL-18 were significantly elevated in Mfge8−/− macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the “NLRP3 inflammasome-NETs” inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.

Hippo-YAP通路是由一种癌基因和多种抑癌基因所组成的高度保守的信号转导通路,能抑制细胞增殖、促进细胞凋亡、控制器官生长发育和调节细胞接触性抑制.YAP是Hippo-YAP通路的主要效应因子,YAP过表达或Hippo-YAP通路异常会引发多种疾病,进而导致肿瘤的产生.YAP可作为肿瘤治疗的有效靶点,目前虽没有YAP的直接抑制剂,但可通过抑制YAP活性来进行药物治疗.本文综述了Hippo-YAP通路的组成、调控机制、与肿瘤的关系及针对Hippo-YAP通路的靶向治疗.

肌动蛋白是细胞骨架微丝系统的主要组成成分,在细胞膜完整性受损的情况下,肌动蛋白被释放到细胞外成为危险相关分子模式的一员.目前已发现的胞外肌动蛋白有三种存在形式:与细胞膜外表面连接、存在于细胞外基质或是游离于循环体液中.胞外肌动蛋白参与多种疾病病理生理过程,作为一种自身抗原也参与许多自身免疫性疾病的发生发展.循环游离肌动蛋白、抗肌动蛋白免疫球蛋白以及肌动蛋白清除系统相关组分均可以作为生物标志物,用于多种疾病的预后判断.

Alarmins known as danger associated molecular patterns(DAMPs) are released into the extracellular endogenous bi-ological mediate by white blood cells and epithelial cells when body in a state of tissue injury and inflammation or physiological stress. Immunological and adaptive immune responses are activated and strengthened by chemotaxis and activation of antigen presenting cells(APC). They are closely associated with the disease development and outcome,and have important guiding significance for clinical diagnosis and treatment.

Objective To investigate the value of F-actin autoantibodies in the serum of patients with systemic lupus erythematosus (SLE),and to explore the relationships between F-actin autoantibodies and other clinical indicators.Methods ELISA was established to detect serum levels of F-actin autoantibodies in 93 inpatients with SLE from March 2017 to January 2018 (case group,n=93),72 patients with rheumatoid arthritis (RA) (disease control group) and 83 healthy subjects (healthy control group) were included during the same period.The positive rates of F-actin autoantibodies between the case group and the two control group were compared.Clinical data including SLE disease activity index (SLEDAI),immuno-globulin (lg)G,erythrocyte sedimentation rate (ESR),anti-dsDNA,and antinuclear antibody (ANA) of 93 patients with SLE were collected and the correlation analysis between F-actin autoantibodies units was applied respectively.The diagnostic performance of F-actin autoantibodies in SLE was analyzed by using the receiver operating characteristic curve (ROC).T test,Chi-square test and Spearman/Pearson correlation analysis were applied for statistical analysis.Results The serum levels of F-actin autoantibodies in the SLE case group,disease control group,and healthy control group were (18±13),(12±6),and (11±5) U,respectively,the differences between SLE case group and disease control group,and healthy control group were significant (t=3.163,P=0.001 9;t=4.436,P＜0.01).The positive rates of F-actin autoantibodies were 33％(31/93) in patients with SLE,10％(7/72) in disease control group,and 4％(3/83) in healthy control group.The F-actin autoanti-bodies units in SLE were correlated with SLEDAI,IgG,ESR,anti-dsDNA,and ANA (r=0.273 7,P=0.008 3;r=0.558 7,P＜0.01;r=0.419 9,P=0.000 1,r=0.351 4,P=0.001 1,r=0.460 9,P＜0.01),in which F-actin autoantibodies units showed significant correlation with IgG and ANA.In the ROC curve,the area under the curve(AUC) was 0.62 [95％CI(0.54,0.70)],P=0.001 3.which was statistically significant.When the cut-off value of the F-actin autoantibodies was 14.04 U,the Youden's index (YI) was the largest (YI=0.30),and the sen-sitivity for the diagnosis of SLE was 0.77,the specificity was 0.53.Conclusion The positive rate of F-actin autoantibodies in the serum of patients with SLE is higher than that of RA and healthy controls,so it has certain diagnostic value for SLE.The F-actin autoantibodies units is correlated with both SLEDAI,ESR,and anti-dsDNA,suggesting that F-actin autoantibodies units may be a new biomarker for disease activity assessment of SLE patients.

机体每时每刻都有大量细胞凋亡,及时清除凋亡细胞对维持机体的免疫平衡至关重要,凋亡细胞被吞噬细胞清除过程分为:招募、识别和吞噬消化3个阶段.凋亡细胞清除表现为没有炎性反应或者一个已经存在的促炎反应在吞噬发生后被下调.当机体处于组织损伤和炎性反应状态或生理应激时,细胞发生凋亡或坏死,若凋亡细胞不能及时清除也会继发性坏死,细胞坏死释放内源性危险信号分子,也称为危险相关分子模式(DAM Ps).DAM Ps在结构和功能上与侵入机体的外源性的保守的微生物即病原体相关分子模式的表面结构具有相似性,可被病原体识别受体(PRRs)识别,激活相关信号通路,产生自身抗体或活化其他免疫细胞,导致自身免疫性疾病或炎性反应.

Objective To investigate the application value of acute phase reactants serum amyloid A (SAA) and C-reactive protein (CRP) in the monitoring of inflammatory diseases.Methods Datas of SAA and CRP of 1020 cases of patients with clinically suspected infection as experimental group and 111 healthy subjects as normal control group were collected and analyzed.Experimental group was divided into 6 groups according to the types of disease:diabetes mellitus (DM) with complication,cardiovascular diseases,multiple myeloma,traumatic fractures,other tumors and skin diseases.The SAA and CRP experimental data of each group were analyzed by ROC curve area,and the diagnostic value of two independent tests and parallel tests for each disease was determined.Results The analysis of experimental data showed that,SAA and CRP changes in the trend of inconsistent patients accounted for 44.6％,the proportion was relatively large,especially SAA increased,while CRP patients were normal.Compared the two indicators in the same disease in the increase,the former was higher than the latter,and through the experimental data calculated SAA compared to CRP higher sensitivity to the disease.By calculating the area under the ROC curve of various diseases,it could be found that joint detection generally had more area under the curve.Conclusion Compared with CRP,SAA may be more clinically valuable in monitoring inflammatory diseases.In clinical practice,attention should be paid to abnormal elevated SAA levels in patients with normal CRP.Choosing two kinds of indexes for joint detection under conditioned circumstance is more valuable in clinical diagnosis