Th1/Th2细胞失衡在不稳定型心绞痛发病机制中的作用

目的:通过与超敏C反应蛋白(hsCRP)检测对比,探讨Th1相关的白细胞介素(IL)-12、IL-18和Th2相关的IL-10与不稳定型心绞痛的关系。方法:临床及冠状动脉造影确诊的50例不稳定型心绞痛患者作为病例组(男40例,女10例),30例非冠心病者作为对照组(男23例,女7例)。采用ELISA法检测血清中IL-10,IL-12及IL-18水平,乳胶增强免疫比浊法检测血清hsCRP水平。结果:病例组中,IL-12,IL-18水平增高,IL-10水平降低,均差异有统计学意义。对照组中上述指标没有显著改变。病例组中,hsCRP水平与IL-12,IL-18水平呈正相关,而与IL-10水平呈负相关。IL-12与IL-18水平呈正相关而两者均与IL-10水平呈负相关。结论:在不稳定型心绞痛患者的炎性反应中,Th2细胞活性降低,Th1细胞活性升高,导致了Th1/Th2的失衡。     

Role of T lymphocytes in secretory response to an enteric nematode parasite

Athymic (nude) rats have been used to assess the role of thymus-dependent T cells in the control of the intestinal response following infection with the enteric parasite,Nippostrongylus brasiliensis. Tissues from infected rats were excised on days 4, 7, 10, and 21 postinfection (p-i) for physiological and morphological studies; uninfected (day 0) rats served as controls. In response to the worm burden, jejunal tissues displayed a secretory response, indicated by an elevated baseline short-circuit current (I _sc ) on days 7 and 10 p-i, and were more responsive to histamine than control tissues. Despite this enhanced secretory response, 35% of the worm burden was still present on day 21 p-i (compared with expulsion of >95% by day 14 p-i in normal rats). Mast cell activation and hyperplasia, increased goblet cell (implying increased mucus synthesis) and intraepithelial leukocyte numbers, and abnormalities inI _sc responses after electrical stimulation of enteric nerves were identified following infection. These events in nude rats were attenuated or delayed in onset as compared with conventional immunocompetent rats. Our results support the postulate that thymus-dependent T cells regulate the timing and/or nature of the mucosal response to enteric parasitic infections. However, ion secretion was not altered in the absence of T cells and, therefore, is more likely to be a consequence of mast cell activation.This work was conducted with financial support from The Canadian Medical Research Council and the National Institutes of Health (NS 29536).     

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these pattern-recognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4(+) Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c(+) cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4(+) Th2 effector function. Finally, we found that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1-mediated disease, such as Crohn's disease.     

Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an alpha-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast to IFN-gamma production, which was only transiently decreased under such stimulation. Notably, EBI3-/- mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function.     

Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice.

Parasitic helminths typically induce components of immediate-type hypersensitivity, including elevated serum IgE, eosinophilia, and mucosal mast cells. These responses are T-cell-dependent and associated with rapid expulsion of parasitic worms from a sensitized host; existing experimental systems have failed to define the precise role of cytokines in these responses. We report here that anti-interleukin 4 or anti-interleukin 4 receptor antibodies block the polyclonal IgE response to a parasitic nematode, Heligmosomoides polygyrus, and abrogate protective immunity to the infection. In contrast, anti-interleukin 5 antibody prevented H. polygyrus-induced eosinophilia but did not prevent protection. These data provide evidence that a specific cytokine affects the physiology and survival of a parasitic nematode in the host.     

Impaired survival of T helper cells in the absence of CD4

Signal transduction in response to ligand recognition by T cell receptors regulates T cell fate within and beyond the thymus. Herein we examine the involvement of the CD4 molecule in the regulation of T helper cell survival. T helper cells that lack CD4 expression are prone to apoptosis and show diminished survival after adoptive transfer to irradiated recipients. The helper lineage in CD4(-/-) animals shows a higher than normal apparent rate of cell division and is also enriched for cells exhibiting a memory cell phenotype. Thus the data point to a necessary role for CD4 in the regulation of T helper cell survival and homeostasis.     

Genetic mapping of a murine locus controlling development of T helper 1/T helper 2 type responses.

Genetic background of the T cell can influence T helper (Th) phenotype development, with some murine strains (e.g., B10.D2) favoring Th1 development and others (e.g., BALB/c) favoring Th2 development. Recently we found that B10.D2 exhibit an intrinsically greater capacity to maintain interleukin 12 (IL-12) responsiveness under neutral conditions in vitro compared with BALB/c T cells, allowing for prolonged capacity to undergo IL-12-induced Th1 development. To begin identification of the loci controlling this genetic effect, we used a T-cell antigen receptor-transgenic system for in vitro analysis of intercrosses between BALB/c and B10.D2 mice and have identified a locus on murine chromosome 11 that controls the maintenance of IL-12 responsiveness, and therefore the subsequent Th1/Th2 response. This chromosomal region is syntenic with a locus on human chromosome 5q31.1 shown to be associated with elevated serum IgE levels, suggesting that genetic control of Th1/Th2 differentiation in mouse, and of atopy development in humans, may be expressed through similar mechanisms.     

滤泡辅助性T细胞在实验性免疫性不育小鼠中的表达

目的检测滤泡辅助性T细胞在实验性免疫性不育小鼠中的表达,探讨滤泡辅助性T(T follicular helper,Tfh)细胞在免疫性不育发病中的作用。方法用同种小鼠精子及完全福氏佐剂免疫BALB/c雄性小鼠获得免疫性不育动物模型,同时设立正常对照组给予生理盐水。流式细胞仪检测免疫性不育小鼠和正常对照小鼠脾脏淋巴细胞中CD4^+CXCR5^+ICOS^+T(Tfh)细胞和CD3^-CD19^+B细胞表达水平,并进行相关性分析。结果人工免疫后的雄性小鼠血清抗精子抗体均为阳性,正常对照小鼠均为阴性。流式分析结果显示,免疫性不育小鼠脾脏淋巴细胞中Tfh细胞和B细胞[分别为(4.15±1.03)%和(8.05±1.97)%]表达水平显著高于对照组[分别为(1.05±0.25)%和(2.81±0.473)%]小鼠(P<0.0001),Tfh细胞与B细胞比例呈显著正相关(r=0.58,P<0.05)。结论滤泡辅助性T细胞和B细胞的增加与免疫性不育的发生有关。     

T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice

BACKGROUND & AIMS: Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases. METHODS: Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness. RESULTS: The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro. CONCLUSIONS: These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.     

Protective immunity to Schistosoma japonicum infection depends on the balance of T helper cytokine responses in mice vaccinated with gamma-irradiated cercariae

Although the strain difference in protection of mice to Schistosoma mansoni infection has been described, limited information is available in the case of Schistosoma japonicum. In the present study, we compared the protective immunity to S. japonicum infection and cytokine production in various strains of mice vaccinated with gamma-irradiated cercariae. A significant reduction in worm recovery was observed in male and female mice of DBA/2 at a 6-week interval between vaccination and a challenge infection, whereas vaccinated mice of C57BL/6, C57BL/10, (C57BL/6 x DBA/2) F1 (B6D2F1) and (C57BL/10 x DBA/2) F1 (B10D2F1) showed no detectable level of protection. No sex-linked difference in development of resistance was observed in any of the strains so far examined. Vaccination with gamma-irradiated cercariae twice with a 3-week interval also induced significant protection against a challenge infection in DBA/2 but not in BALB/c or C57BL/6 strains. Further studies demonstrated that spleen cells of vaccinated C57BL/6 mice produced lower levels of IFN-gamma compared to the cells of vaccinated BALB/c and DBA/2. On the other hand, production of IL-10 by spleen cells was relatively higher in BALB/c mice than in the other two strains. Macrophages that had been stimulated with spleen cell culture supernatants derived from vaccinated DBA/2 damaged schistosomula more effectively than cells stimulated with supernatants derived from the other strains. These results suggest that different levels of protection observed among strains of mice depend on the balance of cytokine responses which consequently activate or suppress macrophage-mediated damage to schistosomula.     

Inducible costimulator is required for type 2 antibody isotype switching but not T helper cell type 2 responses in chronic nematode infection

Inducible costimulator (ICOS) has been suggested to perform an important role in T helper cell type 2 (Th2) responses, germinal center formation, and isotype switching. The role of ICOS in chronic Th2 responses was studied in a nematode model with the filarial parasite, Brugia malayi. Contrary to expectations, we did not observe a significant defect in IL-4-producing Th2 cells in ICOS-/- mice or in eosinophil recruitment. We also found that ICOS was not required for the differentiation of alternatively activated macrophages (AAMPhi) that express Ym1 and Fizz1. Although the production of IgE was slightly reduced in ICOS-/- mice, this was not as significant as in CD28-/- mice. In contrast to live infection, the primary response of ICOS-/- mice immunized with soluble B. malayi antigen and complete Freund's adjuvant resulted in significantly fewer IL-4-producing cells in the lymph nodes. As previously reported, we observed a defect in antibody isotype switching toward the IgG1 isotype in ICOS-/- mice during live infection. Interestingly, there was a significant enhancement of parasite-specific IgG3 isotype antibodies. CD28-/- and MHC class II-/- mice also had enhanced parasite-specific IgG3 isotype antibodies. Our results suggest that ICOS is not required to maintain a chronic cellular Th2 response. The primary role of ICOS in a chronic helminth infection could be to drive antibodies toward type 2 isotypes. T-independent antibody response to the parasite could be enhanced in the absence of costimulation and T cell help.     

T helper type-2 cells induce ileal villus atrophy,goblet cell metaplasia,and wasting disease in T cell-deficient mice

BACKGROUND & AIMS: T helper (Th) 1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4(+)CD45RB(Hi) (RB(Hi)) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2-deficient (RAG(-/-)) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. METHODS: RB(Hi) T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-gamma-defective [IFN-gamma(-/-)]) with or without B cells were transferred to T cell receptor (TCR)-beta and delta-chain-defective (TCR(-/-)) or SCID mice. RESULTS: Transfer of Wt RB(Hi) T cells induced wasting disease with severe colitis in the TCR(-/-) mice. In contrast, IFN-gamma(-/-) RB(Hi) T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-gamma(-/-) RB(Hi) T cells for ileal lesions to develop. Treatment of TCR(-/-) recipients of IFN-gamma(-/-) RB(Hi) T cells with anti-IL-4 mAb abrogated both the wasting disease and the villus atrophy. CONCLUSIONS: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells.     

Single dose of OCH improves mucosal T helper type 1/T helper type 2 cytokine balance and prevents experimental colitis in the presence of valpha14 natural killer T cells in mice

BACKGROUND AND AIMS: Valpha14 natural killer T (NKT) cells seem to play important roles in the development of various autoimmune diseases. However, the pathophysiologic role of NKT cells in inflammatory bowel disease remains unclear. To clarify the mechanism by which the activation of NKT cells mediates protection against intestinal inflammation, we investigated the antiinflammatory role of specifically activated Valpha14 NKT cells by glycolipids in a mouse experimental model of colitis induced by dextran sulfate sodium (DSS). METHODS: Colitis was induced in C57BL/6 mice by the oral administration of 1.5% DSS for 9 days. A single dose of OCH or alpha-galactosylceramide, a ligand for NKT cells, was administered on day 3 after the induction of colitis. Body weights and colonic mucosal injury were assessed in each glycolipid-treated group. Interferon-gamma and interleukin-4 levels in the supernatants from colonic lamina propria lymphocytes (LPLs) were measured by enzyme-linked immunosorbent assay. RESULTS: The administration of a single dose of OCH attenuated colonic inflammation, as defined by body weights and histologic injury. The protective effects of OCH could not be observed in Valpha14 NKT cell-deficient mice. In vivo treatment with OCH had improved the interferon-gamma/interleukin-4 ratio from colonic LPLs on day 9 after DSS treatment. CONCLUSION: The present data indicated that the activation of Valpha14 NKT cells by OCH plays a pivotal role in mediating intestinal inflammation via altered mucosal T-helper type 1/type 2 responses. Therapeutic strategies that are designed to activate specifically Valpha14 NKT cells may prove to be beneficial in treating intestinal inflammation.     

A new nematode (allantonematidae) parasite of Heliophilus (T diptera, syrphidae)]

For the second time, the authors have found a new entomophagous nematode parasitic in Syrphidae. The first species, which was described as Syrphonematidae nov. fam., is living in the duct of various aphidophagous species of Syrphidae. This one has been found in the hemocoel of adults of Helophilus trivittatus Fabricius and H. pendulus Linneaus (Eristalinae with aquatic rat tailed larvae). It seems to belong to the genus Iotonchium (Allantonematidae), which was known as yet only by the free-living stages. This work could bring the proof that the genus Iotonchium is really parasite of insect as it was supposed by T. GOODEY and J. B. GOODEY. The three distinct forms which are living in the body cavity of the host are briefly described. The life cycle, which differs from those of all other Allantonematidae, is discussed. This species requires further studies, especially on the free-living stages which have to be obtained for the comparative study of the morphology of the various forms and for life history.     

阿托伐他汀调节急性冠状动脉综合征患者外周血辅助性T细胞亚群失衡的研究

目的观察急性冠状动脉综合征(acute coronary,syndromes,ACS)患者应用阿托伐他汀后外周血中1型辅助性T细胞(Th1)和2型辅助性T细胞(Th2)的频率及其相关细胞因子的变化,探讨他汀类药物对ACS患者辅助性T细胞分化的影响。方法选择ACS患者73例,随机分为安慰剂组(36例)和阿托伐他汀组(37例),入选实验后即刻,1、3、14天抽取外周血,检测Th1和Th2频率及其相关细胞因子的浓度,其中Th1相关细胞因子为干扰素γ、白细胞介素2,Th2相关细胞因子为白细胞介素4、白细胞介素10。结果安慰剂组与阿托伐他汀组即刻外周血Th1和Th2频率及其相关细胞因子水平比较,差异无统计学意义(P0.05);阿托伐他汀组外周血1、3、14天Th1相关细胞因子干扰素γ、白细胞介素2水平较安慰剂组明显降低(P0.05),而Th2相关细胞因子白细胞介素10水平较安慰剂组明显升高(P0.05);阿托伐他汀组1、3、14天Th1频率较安慰剂组明显降低(P0.05),而Th2频率两组间差异无统计学意义(P0.05)。结论阿托伐他汀通过调节Th1和Th2亚群分化失衡,抑制炎性反应,提示他汀类药物对ACS患者有更广泛的保护作用。     

Systematic review and meta-analysis of survival outcomes in T2a and T2b gallbladder cancers

BackgroundThe 8th edition of AJCC TNM staging of Gallbladder cancer subdivided T2 stage into T2a and T2b based on tumour location. This meta-analysis aimed to investigate the long-term outcomes in T2a and T2b gallbladder cancers.MethodsLiterature search of Medline, Web of science, Embase and Cochrane databases was performed. Study characteristics, survival and recurrence data were extracted for meta-analysis of effect estimates and of individual patient data.ResultsFifteen retrospective studies (2531 patients, T2a = 1332, T2b = 199) were included in the meta-analysis. Overall survival (OS) was significantly worse in patients with T2b compared to T2a tumours (HR 2.18, 95% CI 1.67–2.86, p < 0.0001). Meta-analysis of individual patient data (n = 629) showed similar results (HR 1.92, 95% CI 1.43–2.58, p < 0.00001). Patients with T2b tumours had higher risk of recurrence compared to T2a (OR 3.19, 95% CI 1.40–7.28, p = 0.006) and were more likely to receive adjuvant chemotherapy (OR 1.76, 95% CI 1.12–2.84, p = 0.014). Liver resection improved OS in T2b tumours (HR 2.99, CI 1.73–5.16, p < 0.0001).ConclusionT2b gallbladder tumours have worse overall survival and increase risk of recurrence compared to T2a. Liver resection appears to improve OS in patients with T2b tumours. However, high quality multicenter data is required to confirm these results.