Genetics of the immune response to gluten in coeliac disease

Accumulating evidence indicates that coeliac disease (CD) is a multifactorial disorder where several heritable factors in conjunction with environmental factors are involved in the disease development. Gluten proteins are a critical environmental factor as the presence of disease in affected individuals is strictly dependent on dietary gluten exposure. Most likely coeliac patients have genetically shaped immune responses to gluten proteins that cause intestinal pathology. Many of the CD genes thus supposedly encode variants of proteins with immune functions. HLA has been identified as a major genetic factor, but yet no further genes have been identified. There probably exist several predisposing non-HLA genes, but available data indicate that the heritable contribution by each of them can be small. Combined genetic and functional studies will hopefully identify additional predisposing genes in the future.     

非洛地平对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块及烟酰胺腺嘌呤二核苷酸氧化酶的影响

目的:探讨钙通道阻断剂(CCB)非洛地平对载脂蛋白E基因敲除(apoEKO)小鼠动脉粥样硬化斑块及烟酰胺腺嘌呤二核苷酸[NAD(P)H]氧化酶的影响。方法:apoEKO小鼠随机分为普通饮食组、高胆固醇饮食组、高胆固醇饮食加非洛地平组。无创血压系统测小鼠血压;内眦动脉取血检测血清TC和TG水平;冷冻切片光镜下定位主动脉根部,油红O染色评估斑块大小;实时定量PCR和Western blot方法检测主动脉中NAD(P)H氧化酶亚基p47phox和Rac-1表达。结果:高胆固醇饮食组小鼠血压没有明显变化,血脂明显升高(P<0.01),且斑块面积明显高于普食组(P<0.01);非洛地平可以明显减小斑块面积(P<0.01),同时还可以降低NAD(P)H氧化酶亚基p47phox和Rac-1表达(P<0.01)。结论:非洛地平可能通过阻断氧化应激反应抑制动脉粥样硬化发生发展。     

Age-dependent antileukemic action and suppression of immune response by 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) in mice

The antineoplastic activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) against murine leukemia P388 was found to be markedly reduced in 12- and 18-month-old mice as compared to young animals. The immune response against sheep red blood cells (SRBC), a T cell-dependent antigen, was also strongly diminished in tumor-free old mice and was further suppressed after ambazone treatment. Since the antileukemic effect of ambazone disappeared more or less in congenitally athymic nude mice, in neonatally thymectomized or silica-pretreated animals, it has been concluded that the action of the compound seems to be limited to young adult immunocompetent tumor-bearing hosts. Therefore immunosenescence, primarily of T cell functions of old tumor-bearers, may represent a decisive factor influencing the antileukemic, especially curative effect of ambazone in aged animals. A combined treatment with ambazone and immunomodulators (thymalin or a splenopentin derivative) failed to improve the antileukemic effect in young and old leukemia P388-bearing mice.     

The presence of Syphacia obvelata in laboratory mice (BALB/c) — parasite antigens in immune response

Summary In conventional mice colonies, mouse pinworm, Syphacia obvelata is found very often. Several studies indicate that infection with this parasite can modulate the immune system of the host and can affect experimental final results. The aim of our study was to investigate the most immunogenic proteins of S. obvelata inducing both local and systemic immune response in naturally infected laboratory mice. Protein extracts of S. obvelata were analysed by Western blotting to examine their antigenic character. The antigens were probed with serum and mucosa of S. obvelata naturally infected mice. Surface and somatic antigens were recognized by serum and mucosal IgG, IgA and IgM antibodies. The most immunogenic and dominant proteins were observed. Proteins of Mw ∼ 70, 65 and 48 kDa showed the most evident reaction with serum and mucosa antibodies of infected animals. Surface and somatic antigens of nematode S. obvelata eliciting immune response in laboratory mice may be useful in development of a diagnostic test which could be applied for the infection control prior the experiments.     

The analysis of somatic antigens extracted from Aspiculuris tetraptera (Oxyuridae) and their role in eliciting immune response in laboratory mice

BACKGROUND: The aim of this study was isolation and examination of Aspiculuris tetraptera somatic proteins and somatic antigens role in eliciting of immune response in laboratory mice. MATERIAL AND METHODS: In our investigation 40 laboratory mice (BALB/c strain) were used. To extract the somatic proteins Tris-HCl buffer with NaCl and Triton X-100 was used. The analysis of somatic antigens was undertaken by Western blotting. RESULTS: The study showed the presence of 14 protein bands ranging from approximately 82 to 28 kDa. Glicoproteins detection revealed 13 bands in range between approximately 70 to 30 kDa. There was no reaction observed with immunoglobulins IgA. Comparision of these results with earlier studies concerning S. obvelata somatic antigens show that there are proteins and glicoproteins with the same molecular weights for both species. It is also observed that S. obvelata somatic extract is more diversed and have higher antigenicity than A. tetraptera. Hence, we may suppose this fact could favour easier colonization of the host by A. tetraptera.     

Aging and immune response in chronic human schistosomiasis

There has been no systematic study of the immune response of individuals over 60 residing in areas endemic for Schistosoma mansoni infection although senescence is reportedly associated with susceptibility to infection and progressive decline in immune function. We have shown previously, in two endemic areas in Minas Gerais, Brazil, that the frequency of individuals over 60 with chronic schistosomiasis is no longer negligible. Several aging-related immunological alterations are already described in medical literature, mostly in the T-cell compartment. Since aging is associated with a decline in T-cell function, it is not surprising that individuals over 60 would be more susceptible to infection. However, not all aged individuals in endemic areas have high intensity of infection; some of them display a negative stool-screening test for the presence of schistosome eggs and low levels of serum antibodies reactive with S. mansoni antigens indicating they are not infected. Non-infected, negative individuals may develop compensatory mechanisms to cope with immune dysfunction and to generate protective responses against the constant threat of infection in these areas. Herein, we reviewed previous reports from our group showing that two mechanisms contribute to distinguish between infected and egg negative aged individuals. First, egg negative aged individuals develop innate immune responses to replace the decline in T-cell function that is observed with aging. Second, chronically activated regulatory T cells, that may impair protective immune responses, are more vigorous in infected aged individuals. We propose that egg negative individuals may be considered as an example of healthy aging in areas endemic for infectious disease.     

致敏小鼠抗原激发后肺局部免疫反应的研究

目的：探讨抗原致敏和激发后肺局部免疫反应的变化。方法：以抗原钥孔嘁血兰素（KLH）经气管内滴注致敏小鼠，2－4周后进行激发，期间分别收集支气管肺泡灌洗液（BALF）和外周血，对肺、肺相关淋巴结（LALN）和脾组织细胞悬液进行培养并收集上清液，以酶联免疫吸附试验（ELISA）测定总IgA、抗KLHIgA及白蛋白。结果：KLH致敏和激发均引起BALF中抗KLHIgA反应。抗原致敏和激发后BALF中抗KLHIgA／白蛋白比率明显高于血清；抗原致敏激发后肺和LALN细胞悬液在体外均可释放抗KLHIgA，而脾细胞悬液仅释放低水平抗KLHIgA。结论：气管内滴注抗原致敏小鼠可诱导肺局部抗原特异IgA反应，抗原激发后反应加强，肺局部积聚的抗KLHIgA并非由血中渗漏而来，而是局部产生的结果，肺和LALN中的淋巴细胞是抗原特异IgA的主要来源。     

The peripheral immune response of mice infected with a neuropathogenic schistosome

Trichobilharzia regenti (Schistosomatidae) percutaneously infects birds and mammals and invades their central nervous system (CNS). Here, we characterized the peripheral immune response of infected mice and showed how it was influenced by the parasite-induced inflammation in the skin and the CNS. As revealed by flow cytometry, T cells expanded in the spleen and the CNS-draining lymph nodes 7-14 days post-infection. Both T-bet+ and GATA-3+ T cells were markedly elevated suggesting a mixed type 1/2 immune response. However, it dropped after 7 dpi most likely being unaffected by the neuroinflammation. Splenocytes from infected mice produced a high amount of IFN-γ and, to a lesser extent, IL-10, IL-4 and IL-17 after in vitro stimulation by cercarial homogenate. Nevertheless, it had only a limited capacity to alter the maturation status of bone marrow-derived dendritic cells (BMDCs), contrary to the recombinant T. regenti cathepsin B2, which also strongly augmented expression of Ccl5, Cxcl10, Il12a, Il33 and Il10 by BMDCs. Taken together, mice infected with T. regenti developed the mixed type 1/2 immune response, which was driven by the early skin inflammation rather than the late neuroinflammation. Parasite peptidases might play an active role in triggering the host immune response.     

海洋生物活性成份(HQS-V)对免疫受抑小鼠免疫机能的影响

采用液-液分配色谱等方法对海洋生物-被囊类动物进行萃取分离,得到不同组分的活性提取物,观察HQS-V成分对免疫低下小鼠部分免疫功能指标的影响。通过环磷酰胺造成小鼠免疫功能低下,HQS-V按每日100mg/kg、200mg/kg、400mg/kg分成三组。结果显示100mg/kg及200mg/kg两组对免疫抑制小鼠腹腔巨噬细胞的吞噬功能影响更明显(模型组OD值为0。070±0.015,100mg/kg组0.417±0.184,20mg/kg组0.348±0.145,400mg/kg组0.168±0.120),而对脾T淋     

The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice

Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPARdelta) in the pathogenesis of atherosclerosis. Administration of synthetic PPARdelta agonists to obese rhesus monkeys elevates serum high-density lipoprotein (HDL) cholesterol as a result of increased reverse cholesterol transport whilst in vitro studies have suggested a role for PPARdelta in lipid uptake into macrophages. Recent studies have found that PPARdelta depletion from macrophages in LDL receptor (LDLR(-/-)) mice decreases lesion area via modulation of the inflammatory status of the macrophage, an effect also seen on pharmacological activation of PPARdelta in vitro. We demonstrate here that the PPARdelta agonist, GW0742X has potent anti-atherogenic activity in the LDLR(-/-) mouse, decreasing lesion area by up to 50%. Administration of GW0742X had no effect on total cholesterol, HDL or LDL cholesterol and modest effects on very low-density lipoprotein (VLDL). Treatment with GW0742X resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and intracellular adhesion moleculae 1 (ICAM-1) in the aortae of treated mice. In addition, GW0742X decreased tumour necrosis factor-alpha (TNFalpha) expression in peritoneal macrophages, aortae and adipose tissue in comparison with control animals. Changes in gene expression were reflected in decreased plasma levels of MCP-1. These observations support an atheroprotective effect of PPARdelta agonists in vivo.     

Calorie restriction (CR) reduces age-dependent decline of non-homologous end joining (NHEJ) activity in rat tissues

Even though CR has shown to enhance base excision repair (BER) and nucleotide excision repair (NER) capacities, it has not been reported whether CR can enhance non-homologous end joining (NHEJ) activity. To examine the effect of CR on NHEJ activity, ad libitum (AL)- and calorie restricted (CR)-dieted rats were used. Age-dependent decline of NHEJ activity was apparent in the lung, liver, and kidney and appeared to be slightly decreased in spleen. CR reduced age-dependent decline of NHEJ activity in all tissues, even though the extent of recovery was variable among tissues. Moreover, CR appeared to reduce age-dependent decline of XRCC4 protein level. These results suggest that CR could reduce age-dependent decline of NHEJ activity in various tissues of rats possibly through up-regulation of XRCC4.