HIV infection and aging of the innate immune system

The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.     

Immunologic versus toxicologic mechanisms in airway responses

There is now considerable evidence that T lymphocytes play an important role in generating the IgE-mediated immune response of classical allergic asthma. An immune response can be generated by other routes, including IgG- and cell-mediated mechanisms, as well. Regardless of the mechanism, it is clear that allergic asthma is an inflammatory disease, with activated T lymphocytes, eosinophils, mast cells, and other leucocytes all playing a role. Recently, an irritant asthma called reactive airway dysfunction syndrome also has emerged. It appears to be due to direct irritant or toxic effects, but shares many features of allergic asthma. Thus, several different pathways lead to the inflammatory changes and nonspecific airway responsiveness underlying asthma.     

Vagus nerve participates in regulation of the airways: inflammatory response and hyperreactivity induced by occupational asthmogens

An initial recognition of occupational asthmogens present in dust, fume or aerosol particles is carried out by a specialized subset of immune cells, dendritic cells and macrophages, present in the airway tissues. When activated by asthmogens these cells release proinflammatory molecular signals and not only send them to other cells of the innate immunological system, but also activate sensory pathways that relay information to the central nervous system (CNS). The precise mechanisms by which the peripheral immune system can signal to the CNS the airway injury has been the subject of much debate. Recently, a new pathway of the CNS-mediated regulation of the peripheral immune response has been found. The efferent vagus nerve was proposed as an immune-to-brain pathway and it was suggested that acetycholine, the principal vagal neurotransmitter, may directly modulate the airway immune response to pathogenic invasion or to injury by irritant asthmogens. Sensory innervation of the airways by ascending fibres traveling in the vagus nerve as well as by pain sensory pathways, provides an important input about the status of injurious challenges in the inflammation zone of the airway compartments. These neural inflammation-sensing pathways can function at low thresholds of detection and can activate responses even when inflammatory agents are present in the airway tissues in quantities that are not high enough to reach the brain through the bloodstream. The cholinergic vagus nerves participate not only in the regulation of the airways inflammatory response. The airways function in response to spastic stimuli such as irritants, allergens, and inflammatory mediators is also controlled, in a larger part, by efferent vagal endings present in the airway smooth muscles. Cholinergic mechanisms represent the predominat constrictor neural pathway in human airways. Differences in expression of muscarinic acetylcholine receptors in asthma suggest that cholinergic system may participate in the molecular framework influencing the airway functions in occupational asthma.     

趋化因子在哮喘中的作用及研究进展

哮喘是一种气道的慢性炎症性疾病,其主要病理特点是气道炎症反应,气道高反应性和气道重塑。在炎症过程中有多种细胞(如嗜酸性粒细胞,肥大细胞,T细胞,中性粒细胞,气道上皮细胞等)参与,其中嗜酸性粒细胞浸润是其主要特征,而对这些炎症细胞的活化和向气道迁移的过程中,趋化因子则发挥着重要作用。随着大量的趋化因子和其受体的发现以及对其与哮喘发生机制的研究,趋化因子和趋化因子受体有可能成为抗炎治疗的靶点。本文意在讨论趋化因子与这些炎症细胞的关系,以及是否可以通过调节哮喘发病过程中趋化因子及趋化因子受体来作用于TH1/TH2的平衡,以达到治疗哮喘的目的 。     

RNA干扰技术在支气管哮喘研究中的应用

支气管哮喘(Bronchial Asthma,简称哮喘),是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症。目前已知这些细胞都可产生炎症介质,其包括组胺、前列腺素、白三烯、内皮素-1等。如果我们能利用RNA干扰技术从源头上让致病基因"沉默",减轻甚至阻断多种炎症细胞、炎症介质和细胞因子的产生及其相互作用,以减轻气道慢性炎症,从而达到缓解哮喘症状甚至治疗哮喘的目的。本文就RNA干扰技术在哮喘研究中的应用的综述。     

肠道菌群通过短链脂肪酸参与过敏性哮喘气道高反应机制研究进展

支气管哮喘(简称哮喘)是一种以可逆性气流阻塞和气道高反应性为特点的气道慢性炎症疾病;短链脂肪酸(SCFAs)是肠道益生菌发酵不易消化的碳水化合物如膳食纤维、抗性淀粉等生成的产物,不仅是机体重要的能量来源,还是重要的免疫信号分子,血液中SCFAs浓度升高对肺部过敏性炎症起保护作用。大量研究表明哮喘发生与肠道菌群变化密切相关。本文从ERK1/2信号通路、TGF-β1/Smads信号传导通路、GPR41 和 GPR43的表达三个方面综述了肠道菌群通过短链脂肪酸参与哮喘气道高反应的可能发生分子机制,为哮喘的治疗提供潜在的新靶点。     

维生素A与支气管哮喘的关系

研究发现哮喘患者体内维生素A水平显著低于健康人群，维生素A对哮喘的气道炎症、自主神经受体及免疫功能等方面产生有利影响；维生素A维护上皮细胞和抗氧化的功能也共同参与了调节哮喘发病的过程。本文主要综述维生素A与支气管哮喘的关系。     

Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study

Background  

Asthma is the most common chronic disease in childhood, characterized by chronic airway inflammation. There are problems with the diagnosis of asthma in young children since the majority of the children with recurrent asthma-like symptoms is symptom free at 6 years, and does not have asthma. With the conventional diagnostic tools it is not possible to differentiate between preschool children with transient symptoms and children with asthma. The analysis of biomarkers of airway inflammation in exhaled breath is a non-invasive and promising technique to diagnose asthma and monitor inflammation in young children. Moreover, relatively new lung function tests (airway resistance using the interrupter technique) have become available for young children. The primary objective of the ADEM study (Asthma DEtection and Monitoring study), is to develop a non-invasive instrument for an early asthma diagnosis in young children, using exhaled inflammatory markers and early lung function measurements. In addition, aetiological factors, including gene polymorphisms and gene expression profiles, in relation to the development of asthma are studied.     

CD4^＋CD25^＋调节性T细胞对哮喘大鼠气道炎症的影响

目的观察CD4^＋CD25^＋调节性T细胞（CD4^＋CD25^＋Treg）对哮喘大鼠气道炎症的影响。方法将卵白蛋白（OVA）免疫耐受大鼠CD4^＋CD25^＋Treg细胞过继转移给哮喘大鼠,然后观察支气管肺泡灌洗液（BALF）中细胞计数及分类,ELISA检测BALF中IL-4、IL-5和IFN-1及血清OVA特异性IgE含量,HE染色观察肺组织的病理改变。结果与哮喘组比较,过继转移CD4^＋CD25^＋Treg细胞后哮喘大鼠BALF中细胞总数、中性粒细胞和淋巴细胞百分率降低（P〈0．05）,嗜酸性粒细胞（Eos）百分率明显降低（P〈0．01）;BALF中IL4和IL-5含量明显降低,IFN-1含量明显升高,血清OVA特异性IgE含量明显降低（P〈0．05）;气道炎症明显减轻。结论过继转移OVA免疫耐受大鼠CD4^＋CD25^＋Treg细胞可以明显抑制哮喘的慢性气道炎症。     

Inhibition of IFN-γ promotes anti-asthma effect of Mycobacterium bovis Bacillus Calmette-Guerin neonatal vaccination: A murine asthma model

Objective

The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) neonatal vaccination inhibits allergy-induced pathologic changes. However, the mechanisms underlying this process are unclear. This study aimed to investigate the role of interferon (IFN)-γ and interleukin (IL)-17 in the protective effects of the BCG neonatal vaccination on allergic pulmonary inflammation and airway hyperresponsiveness (AHR).

Methods

Wild type (WT)-neonate and IL-17 knock out (KO) neonate mice were vaccinated with BCG. A murine asthma model was developed by sensitization and then challenging with ovalbumin (OVA). Recombinant IL-17 or recombinant IFN-γ was delivered to the airway to overexpress IL-17 or IFN-γ. An anti-IFN-γ neutralizing antibody was used to block the effects of IFN-γ.

Results

We found exogenous IL-17 delivered to the airway reversed the anti-asthma effects of the neonatal BCG vaccination. BCG neonatal vaccination further reduced OVA-induced inflammation and AHR in IL-17 KO mice. Inhibition of IFN-γ in BCG neonatal vaccinated OVA-induced asthma model mice led to a further reduction in airway inflammation and AHR. In addition, airway inflammation and AHR were robust following treatment with exogenous IFN-γ. Neutralizing IL-17 was not sufficient to block OVA-induced airway inflammation and AHR. In IL-17 KO mice, airway inflammation and AHR did not occur following treatment with an anti-IFN-γ neutralizing antibody.

Conclusions

In an OVA-induced murine asthma model, inhibition of IFN-γ enhanced the anti-asthma effects of BCG neonatal vaccination.     

Lactobacillus gasseri suppresses Th17 pro-inflammatory response and attenuates allergen-induced airway inflammation in a mouse model of allergic asthma

Probiotics are normal inhabitants of the gastrointestinal tract of man and are widely considered to exert a number of beneficial effects in many diseases. But the mechanism by which they modulate the immune system is poorly understood. The present study was planned to explore the anti-allergic effect of Lactobacillus gasseri on a mouse model of allergic asthma. Dermatophoides pteronyssinus (Der p) sensitised and challenged BALB/c mice were orally administered via oral administration with three different doses of L. gasseri (low, 1 × 10(6) colony-forming units (CFU); medium, 2 × 10(6) CFU; high, 4 × 10(6) CFU), in 700 μl of PBS daily, starting from 2 weeks before Der p sensitisation for 4 weeks. After the allergen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage (BAL) fluids and splenocytes culture were assessed. Our results showed that oral administration of a high dose of L. gasseri (4 × 10(6) CFU) decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airways and reduced the levels of TNF-α, thymus and activation-regulated chemokine (TARC) and IL-17A in BAL fluids of Der p-sensitised and -challenged mice. Moreover, L. gasseri decreased IL-17A production in transforming growth factor-α and IL-6 stimulated splenocytes and cell numbers of IL-17 producing alveolar macrophages in L. gasseri-treated mice as compared to non-treated, Der p-sensitised and -challenged mice. In conclusion, oral administration with L. gasseri can attenuate major characteristics of allergen-induced airway inflammation and IL-17 pro-inflammatory immune response in a mouse model of allergic asthma, which may have clinical implication in the preventive or therapeutic potential in allergic asthma.     

Immunosénescence et infections,mythe ou réalité ?

The susceptibility of elderly people to infectious diseases is usually associated to increasing risk factors found in young adults. However, the role of immune function ageing is associated with the decline of immune function but this decline is not homogenous. Some functions such as the cellular immune system are altered but others are enhanced such as innate immunity. The important events of immune ageing are modifications of lymphocyte subsets with accumulation of memory cells, decrease in proliferative response, and a chronic inflammatory state. The chronic antigenic load throughout life is responsible for gaps in the antigenic system with a greater sensitivity to new antigens. These immune system changes are all the more important that diseases are severe and that denutrition is associated. These diseases will speed up the ageing process. The interaction between immunosenescence and pathology is an important phenomenon to consider. This review outlines the immune system changes due to ageing, their relationship with diseases of the aged patient, and the consequences of these modifications on vaccination effectiveness.     

Immunometabolism in Obese Asthmatics: Are We There Yet?

Obesity is now recognised as a worldwide epidemic. The recent International Association for the Study of Obesity/International Obesity Taskforce (IASO/IOTF) analysis estimates that approximately 1.0 billion adults are currently overweight and a further 475 million are obese. Obesity has huge psychosocial impact with obese children and adolescents facing discrimination and stigmatization in many areas of their lives leading to body dissatisfaction, low self-esteem and depression. Indeed, obesity is recognised as an important risk factor for the development of several chronic diseases such as hypertension, cancer, asthma and metabolic syndrome. Chronic low grade systemic inflammation is considered as a hallmark of obesity and may possibly explain the link between obesity and chronic disease, in particular the increased incidence, prevalence and severity of asthma in obese individuals. There is now strong evidence for infiltration of immune and inflammatory cells into adipose tissue that drives systemic inflammation and subsequent end organ damage. In addition to adipocytes, the key adipose tissue resident immune cells are macrophages and mast cells. Immunometabolism, as an emerging field of investigation, explores the pivotal role of these immune cells in translating immunological changes to metabolic effects in obesity. Abundance of free fatty acids, along with other inflammatory cytokines shift the balance of metabolic homeostasis to pro-inflammatory status by influencing the development of inflammatory cell lineage, which, further exhibits distinct functional phenotypes. There is emerging evidence for macrophage activation and functional polarization of an anti-inflammatory M₂ phenotype towards a pro-inflammatory M₁ phenotype of macrophages in obese adipose tissue. Similarly, studies in both obese humans and murine models reveal the pathognomic presence of an increased number of mast cells in visceral adipose tissue. These suggest a possible contribution of mast cells to the unique metabolome of obese asthma. This review examines proposed multilevel interactions between metabolic and immune systems in obese asthmatics that underlie the negative effects of obesity and may offer significant therapeutic promise.     

The Fermented Soy Product ImmuBalanceTM Suppresses Airway Inflammation in a Murine Model of Asthma

The fermented soy product ImmuBalance contains many active ingredients and its beneficial effects on some allergic diseases have been reported. We hypothesized that ImmuBalance could have potential effects on airway inflammation in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts and levels of cytokines. Lung tissues were examined for cell infiltration and mucus hypersecretion. Oral administration of ImmuBalance significantly inhibited ovalbumin-induced eosinophilic inflammation and decreased Th2 cytokine levels in bronchoalveolar lavage fluid (p < 0.05). In addition, lung histological analysis showed that ImmuBalance inhibited inflammatory cell infiltration and airway mucus production. Our findings suggest that supplementation with ImmuBalance may provide a novel strategy for the prevention or treatment of allergic airway inflammation.     

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models

Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.     

Are there causal relationships between the development of the inflammatory diseases amyotrophic lateral sclerosis and asthma?

Amyotrophic lateral sclerosis (ALS) and asthma are inflammatory diseases. ALS is a fatal progressive, neurodegenerative disease with inflammation around the upper and lower motor neurons leading to their degeneration, muscle atrophy, paralysis, and death. Asthma is a chronic inflammatory disease with reversible airway obstruction and nonspecific airway hyper-reactivity. The local release of sensory neuropeptides from capsaicin-sensitive primary afferents causes motor neuron pathophysiology and airway inflammation and hyper-reactivity. While there is no cure for ALS, asthma is managed according to its symptoms and severity, to decrease the symptoms, improve pulmonary function, and reduce morbidity. To determine whether understanding asthma may provide insights into how to clinically deal with ALS, the authors examined the etiologies of ALS and asthma, and the factors that exacerbate the symptoms. Although no direct correlations were found, the similar multifactorial triggers, and the critical roles of neuronal inflammation, suggest that one or more exists.     

Nutrients, nuclear receptors, inflammation, immunity lipids, PPAR, and allergic asthma

The peroxisome proliferator-activated receptors (PPARs) belong to the larger superfamily of steroid/thyroid nuclear receptors. PPARgamma is expressed in a number of hematopoietic cells, including dendritic cells, eosinophils, macrophages, and T cells. A number of lipids and synthetic compounds interact with PPARgamma, that, depending on the cell type, results in the regulation of specific genes. There is now a large body of data indicating that allergic asthma is the result of a predominant type-2 helper T cell immune response including IL-4, -5 and -13, eosinophilic inflammation in the lungs, mucous production, and airway hyperresponsiveness (AHR). Targeting the production of these type-2 helper T cell mediated cytokines has been proposed as a way to regulate this disease. Because PPARgamma ligands can affect T cell cytokine production in vitro, we have examined whether these ligands affect symptoms of allergic asthma in a murine model of this disease. We discuss data showing that ciglitazone and GW1929, two agonistic ligands for PPARgamma, significantly inhibited airway inflammation during allergic asthma induction. Oral treatment with ciglitazone and GW1929 inhibited airway inflammation, with less of an effect on AHR. By contrast, intranasal exposure to GW1929 significantly reduced AHR following exposure to allergen, while GW9662, a PPARgamma antagonist, had no effect. In vitro, T cells from ciglitazone-treated mice secreted significantly less IL-4 and IFN-gamma in response to restimulation. These data suggest that PPARgamma agonists may be useful for the treatment of allergic asthma.     

磷酸酰肌醇-3激酶抑制剂对小鼠气道炎症影响的实验研究

目的观察磷酸酰肌醇-3激酶(PI3K)抑制剂LY294002对卵白蛋白(OVA)诱导哮喘小鼠气道炎症的影响。方法Balb/c小鼠30只,随机分为三组,每组10只:PI3K抑制剂治疗组(LY组),OVA组和正常对照组(NC组)。通过OVA多次腹腔注射致敏和反复雾化激发,建立哮喘小鼠模型。末次抗原激发后48h收集支气管肺泡灌洗液(BALF)和骨髓标本,计数细胞总数和嗜酸性粒细胞(Eos),并行肺组织学检查。结果与OVA组比较,LY组BALF中细胞总数及Eos绝对数明显减少(p<0.05);肺组织中细支气管、血管周围Eos浸润得到控制,气道粘液分泌减少。结论PI3K抑制剂(LY294002)对卵白蛋白(OVA)致敏的哮喘小鼠气道炎症具有抑制作用。