CD4~+CD25~+调节性T细胞与Th17细胞在寻常型银屑病中的表达

目的:检测外周血中CD4~+CD25~+调节性T细胞(简称Treg细胞)与Th17细胞在寻常型银屑病(PV)中的表达。方法:34例寻常型银屑病患者,18例正常人作为对照。采用流式细胞术检测外周血中Treg细胞、FOXP3~+Treg细胞及Th17细胞的表达水平。结果:PV患者外周血中Treg细胞比例和FOXP3~+Treg细胞比例分别为(3.68±1.22)%和(0.53±0.19)%,低于正常对照组的(6.63±1.00)%和(0.76±0.14)%(P0.05)。Th17细胞比例为(2.20±0.78)%,高于正常对照组的(0.65±0.22)%(P0.05)。PV患者外周血中Treg细胞的表达与FOXP3~+Treg细胞的表达呈正相关(r=0.563,P0.05),而Treg细胞的表达与Th17细胞的表达呈负相关(r=-0.522,P0.05);Treg细胞和Th17细胞二者与PASI评分无相关性,与病程亦无相关性。结论:Treg细胞表达的减少及Th17细胞应答的增强,可能是导致PV免疫失衡的重要原因。     

Nasal tolerance in experimental autoimmune myasthenia gravis (EAMG): induction of protective tolerance in primed animals

Nasal administration of μg doses of acetylcholine receptor (AChR) is effective in preventing the development of B cell-mediated EAMG in the Lewis rat, a model for human MG. In order to investigate whether nasal administration of AChR modulates ongoing EAMG, Lewis rats were treated nasally with AChR 2 weeks after immunization with AChR and Freund's complete adjuvant. Ten-fold higher amounts of AChR given nasally (600 μg/rat) were required to ameliorate the manifestations of EAMG compared with the amounts necessary for prevention of EAMG. In lymph node cells from rats receiving 600 μg/rat of AChR, AChR-induced proliferation and interferon-gamma (IFN-γ) secretion were reduced compared with control EAMG rats receiving PBS only. The anti-AChR antibodies in rats treated nasally with 600 μg/rat of AChR had lower affinity, reduced proportion of IgG2b and reduced capacity to induce AChR degradation. Numbers of AChR-reactive IFN-γ and tumour necrosis factor-alpha (TNF-α) mRNA-expressing lymph node cells from rats treated nasally with 600 μg/rat of AChR were suppressed, while IL-4, IL-10 and transforming growth factor-beta (TGF-β) mRNA-expressing cells were not affected. Collectively, these data indicate that nasal administration of AChR in ongoing EAMG induced selective suppression of Th1 functions, i.e. IFN-γ and IgG2b production, but no influence on Th2 cell functions. The impaired Th1 functions may result in the production of less myasthenic anti-AChR antibodies and contribute to the amelioration of EAMG severity in rats treated with AChR 600 μg/rat by the nasal route.     

T helper 17 cells play a critical pathogenic role in lung cancer

Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17–producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-ras^G12D), frequently found in human lung cancer, is restrictedly expressed in lung epithelial cells [via Clara cell secretory protein (CCSP^cre)]. In this model, Th17 and Treg but not Th1 cells were found enriched at the tumor tissues. When CCSP^cre/K-ras^G12D mice were weekly challenged with a lysate of nontypeable Haemophilus influenza (NTHi), which induces COPD-type inflammation and accelerates the tumor growth, they showed greatly enhanced Th17 cell infiltration in the lung tissues. Lack of IL-17, but not IL-17F, resulted in a significant reduction in lung tumor numbers in CCSP^cre/K-ras^G12D mice and also those treated with NTHi. Absence of IL-17 not only resulted in reduction of tumor cell proliferation and angiogenesis, but also decreased the expression of proinflammatory mediators and reduced recruitment of myeloid cells. Depletion of Gr-1⁺CD11b⁺ myeloid cells in CCSP^cre/K-ras^G12D mice suppressed tumor growth in lung, indicating Gr-1⁺CD11b⁺ myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease.Inflammation plays an important role in tumor development (1, 2). Although targeting inflammation and tumor microenvironment has been considered as a new direction of cancer therapy, the mechanisms underlying cancer-associated inflammation have not been well understood. Lung cancer is a leading cause of death in the world. Accumulating evidence has shown that inflammation is associated with pathogenesis of lung cancer, especially those induced by cigarette smoke (3). The primary risk factor among smokers to develop lung cancer is the presence of chronic obstructive pulmonary disease (COPD) (4), which is characterized by chronic pulmonary inflammation, airway remodeling and destruction of lung parenchyma. Human lung cancers are inflicted with alterations in various subsets of lymphocytes and myeloid cells (5, 6), reminiscent of immune activation during chronic inflammation. Several studies have shown NFκB signaling as a mechanistic link between inflammation and lung cancer using a mouse model of lung adenocarcinoma (7, 8). However, the specific inflammatory cell types or molecules potentiating lung cancer are not understood clearly.We and others have identified a novel subset of CD4 helper T cells that produce IL-17 and are referred as Th17 cells (9, 10). Th17 cells have been associated with inflammatory diseases such as rheumatoid arthritis, asthma, lupus, and allograft rejection. An important function of IL-17 is to promote tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines (11). Consistently, we have shown that transgenic overexpression of IL-17 in the lungs resulted in chemokine up-regulation and tissue infiltration by leukocytes, although mice treated with neutralizing IL-17–specific antibody were also found to be resistant to the induction of experimental autoimmune encephalomyelitis (9). These and other studies collectively demonstrated that IL-17 and Th17 cells play nonredundant function in promoting inflammation.Increased frequencies of IL-17 and Th17 cells have been reported in patients with different types of tumors (12), including lung adenocarcinoma (13). The density of intratumoral IL-17–positive cells in primary human nonsmall cell lung cancer was inversely correlated with patient outcome and correlated with smoking status of the patients (14). Th17 cells specific for a common tumor antigen were found in lung cancer patients as part of their spontaneous immune response to the autologous tumor (15). However, the function of Th17 cells and IL-17 in the development of lung cancer remains to be shown. Animal model studies have revealed contrasting roles of IL-17 in various tumors (16). Tumor-promoting effect of IL-17 was shown in some models such as colon cancer (17–20), whereas in others, IL-17 supported anti-tumor immunity, including in B16 melanoma model (21–24). Thus, the role of IL-17 could be complex and tumor-specific.To properly evaluate the role of IL-17 in inflammation-associated lung cancer, we used a model of oncogenic K-ras mutation expressed only in the lung. Mice expressing K-ras mutation in Clara cells (CCSP^cre/K-ras^G12D mice) spontaneously develop lung adenocarcinoma (25). In addition, we induced COPD-type lung inflammation by challenging mice with lysates of nontypeable Haemophilus influenza (NTHi). Inflammation driven by NTHi can promote tumor growth in CCSP^cre/K-ras^G12D mice (25). These experiments collectively indicate a tumorigenic role of IL-17–mediated inflammation in the development of lung cancer.     

血浆凝血因子XⅢ、IL-17水平与脑梗死相关性及预后的研究

目的：探讨血浆凝血因子XⅢ（FXⅢ）、IL-17水平与脑梗死患者病程进展及预后的相关性。方法：①对50例脑梗死患者根据头部CT或MRI病灶大小,梗死体积按Pullicino公式（长×宽×层数／2）计算进行分组：大梗死组（病灶体积〉10cm3）,中梗死组（病灶体积4～10cm3）,小梗死组（病灶体积〈4cm3）;健康对照组20例,神经功能受损程度按照NIHSS进行评分。分别在24h内、第3天、第7天、第14天采集脑梗死组抗凝血标本。采用酶联免疫双抗体夹心法检测FXⅢ、IL-17含量。②根据脑梗死组发病24h内和第14天的NIHSS评分进行近期预后分型比较。结果：①大梗死组发病24h内FXⅢ、IL-17水平明显高于对照组（P〈0．01）,中、小梗死组发病24h内FXⅢ、IL-17水平高于对照组（P〈0．05）。②大梗死组FXⅢ、IL-17水平与小梗死组比较差异有统计学意义（P〈0．05）。③随着梗死病情好转,FXⅢ、IL=17水平有下降趋势（P〉0．05）。④脑梗死组患者近期预后与FXⅢ水平下降呈正相关（r=0．33）,与IL-17水平下降呈正相关（r=0．31）。结论：脑梗死患者血浆FXⅢ、IL-17水平与病程及预后呈正相关,其水平变化可作为脑梗死治疗及预后的判断指标。     

Th17细胞与皮肤病

Th17细胞亚群是近年来发现的一类CD4+T细胞亚群,产生白介素-17、6、22和肿瘤坏死因子-α而不产生干扰素-γ和白介素-4,可介导慢性炎症反应、自身免疫性疾病、肿瘤和移植排斥等,在机体免疫调节、免疫病理和宿主防御反应中发挥重要作用.白介素-17是一种强大的促炎因子,可发挥与Toll样受体激动剂相似的作用激活固有免疫,同时也是炎症反应的微调因子,能与多种细胞因子产生协同作用,放大炎性效应,促进许多自身免疫性疾病的发生和发展.研究表明,系统性红斑狼疮、银屑病、蕈样肉芽肿及特应性皮炎等患者相关血清因子水平异常,提示Th17细胞与T细胞介导的皮肤慢性炎症及自身免疫性疾病有关.     

Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk

Summary:  The Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of non-receptor tyrosine kinases consists of five members: Tec, Bruton's tyrosine kinase (Btk), inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and bone marrow-expressed kinase (Bmx/Etk). Although their functions are probably best understood in antigen receptor signaling, where they participate in the phosphorylation and regulation of phospholipase C-γ (PLC-γ), it is now appreciated that these kinases contribute to signaling from many receptors and that they participate in multiple downstream pathways, including regulation of the actin cytoskeleton. In T cells, three Tec kinases are expressed, Itk, Rlk/Txk, and Tec. Itk is expressed at highest amounts and plays the major role in regulating signaling from the T-cell receptor. Recent studies provide evidence that these kinases contribute to multiple aspects of T-cell biology and have unique roles in T-cell development that have revealed new insight into the regulation of conventional and innate T-cell development. We review new findings on the Tec kinases with a focus on their roles in T-cell development and mature T-cell differentiation.     

Dendritic cell-mediated T cell polarization

Effective defense against diverse types of micro-organisms that invade our body requires specialized classes of antigen-specific immune responses initiated and maintained by distinct subsets of effector CD4⁺ T helper (Th) cells. Excessive or detrimental (e.g., autoimmune) responses by effector T cells are controlled by regulatory T cells. The optimal balance in the development of the different types of effector and regulatory Th cells is orchestrated by dendritic cells (DC). This review discusses the way DC adapt the T cell response to the type of pathogen, focusing on the tools that DC use in this management of the T cell response.     

声门上型喉癌手术治疗与Th1/Th2监测的临床意义

目的探讨声门上型喉癌患者手术前是否存在Th1／Th2免疫失衡及根治性切除肿瘤后能否使Th1／Th2恢复平衡。方法用流式细胞仪检测48例根治切除的声门上型喉癌患者术前、术后不同时期外周血淋巴细胞亚群中各种细胞因子表达。结果能代表Th1功能的IL-2、IL-12和IFN-γ术后的表达水平较术前明显升高（P〈0．01）；能代表Th2功能的IL-4和IL-10术前的表达水平远高于术后，差别均具有显著意义（P〈0．01）。如IL-4和IL-10术后的表达水平与术前无差异，提示癌瘤复发或转移的可能性大。结论声门上型喉癌患者手术前即存在Th1／Th2免疫失衡，行根治性肿瘤切除可解除免疫抑制，改善患者细胞免疫功能而促使TH1/TH2免疫恢复平衡。     

Maternal peripheral T helper 1-type and T helper 2-type immunity in women during the first trimester of twin pregnancy

Introduction This study investigated the T helper Th1:Th2 balance in twin pregnancies compared with singleton pregnancies during the first trimester.Methods Blood samples were taken from 24 women with a singleton pregnancy and 14 women with twin pregnancy at 8–9 weeks gestation to examine the ratios of Th1:Th2 and serum human chorionic gonadotropin (hCG) and progesterone levels.Results The average ratio of Th1:Th2 in the twin pregnancies was significantly lower than that in singleton pregnancies (7.3±2.3 vs. 10.5±2.2, p<0.05). There were negative correlations between the Th1:Th2 ratio and serum hCG levels (mIU/ml) (Th1:Th2 ratio = 14.5–4.52×10^–5×hCG, r²=0.41, p<0.05) and between the Th1:Th2 ratio and serum progesterone levels (ng/dl; Th1:Th2 ratio = 23.0–0.63 × progesterone, r²=0.36, p<0.05).Conclusion Our findings show marked predominance of Th2 type cytokines occurring in twin pregnancies is related to the increase in trophoblasts during the first trimester.     

Is there a relation between vitamin D,interleukin-17, and bone mineral density in patients with inflammatory bowel disease?

IntroductionIn inflammatory bowel diseases (IBD), osteopenia and osteoporosis constitute a significant medical problem. Cytokines, especially IL-17, play an important role in the pathogenesis of IBD and osteoporosis. Vitamin D is a regulator of bone metabolism, and helps maintain immune system homeostasis.Material and methodsThe research sample consisted of 208 persons: 83 patients (age 35 ±11.99 years) with Crohn’s disease (CD); 86 patients (age 39.58 ±14.74 years) with ulcerative colitis (UC); and 39 persons (age 30.74 ±8.63 years) in the control group (CG). Clinical data on bone mineral density of the lumbar spine (L2-L4), bone mineral density of the femoral neck (FN), and body mass index (BMI) were collected. 25OHD and IL-17 serum concentrations were also measured.ResultsBody mass index (kg/m²) results: in CD, 21.51 ±3.68; in UC, 23.31 ±4.38; and in CG, 24.57 ±3.45 (p < 0.01). Densitometry results for L2–L4 T-score SD: in CD –0.83 ±1.45; in UC –0.47 ±1.15; in CG 0.09 ±0.70. Densitometry results for FN T-score SD: in CD –0.62 ±1.26; in UC –0.29±1.17; in CG 0.41 ±1.03 25OHD (ng/ml) serum concentrations: in CD, 21.33±12.50; in UC, 22.04±9.56; in CG, 21.56±9.11 (ns). IL-17 (pg/ml) serum concentrations: in CD, 8.55±10.99; in UC, 11.67±12.97; in CG, 5.16±9.11 (ns).ConclusionsInflammatory bowel diseases patients and persons from the CG did not differ in vitamin D or IL-17 levels. Patients with a mild course of the disease had a higher vitamin D concentration and bone mineral density. In UC, higher vitamin D concentrations were associated with lower IL-17 concentrations. The IBD patients with a severe course of the disease had a lower body mass than those in the CG and the patients with a mild course of the disease.