Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease

Autophagy contributes to cellular homeostasis in the face of nutrient deprivation and other cellular stresses. Cell type-specific functions for autophagy are critical in maintaining homeostasis at both the tissue level and at the whole-organism level. Recent work has highlighted the ways in which human genetic variants modulate autophagy to alter epithelial and immune responses in inflammatory bowel disease.     

ROS介导的自噬及其在相关疾病中的作用

传统观念认为,活性氧类(reactive oxygen species,ROS)只是一类损伤细胞的毒性物质,近年的研究发现ROS作为一种信号分子参与细胞的增殖、分化及凋亡等多个生理过程.自噬是一种溶酶体依赖性的细胞内大分子物质和细胞器的降解过程,不仅在生理情况下发挥重要作用且参与一些疾病的发生发展[1-3].最新的研究表明ROS,特别是线粒体源性ROS,作为信号分子参与自噬的调节.本文集中讨论了ROS和自噬的关系以及ROS介导的自噬在疾病发生发展中的作用,从而为疾病的治疗提供新的靶点和策略.     

Interleukin-13 in asthma pathogenesis

Summary: Bronchial asthma is a complex disorder that is thought to arise as a result of aberrant T‐lymphocyte responses to noninfectious environmental antigens. In particular, the symptoms of asthma are closely associated with the presence of activated T‐helper 2 cell (Th2) cytokine‐producing cells [interleukin (IL)‐4, IL‐5, IL‐9, and IL‐13] in the airway wall. Although each of the Th2 cytokines likely contributes to the overall immune response directed against environmental antigens, a substantial body of evidence points to a singular role for IL‐13 in the regulation of the allergic diathesis. Initial studies in animal models of disease provided compelling evidence that IL‐13, independently of other Th2 cytokines, was both necessary and sufficient to induce all features of allergic asthma. The importance of IL‐13 in allergic disorders in humans is supported by consistent associations between tissue IL‐13 levels and genetic variants in the IL‐13 gene with asthma and related traits. With the preponderance of evidence continuing to support a pivotal role for IL‐13 in allergic disorders, attention is now turned toward understanding the mechanisms by which this cytokine may mediate the pathophysiological features of allergic disease. The emerging paradigm is that IL‐13 induces features of the allergic response via a complex array of actions on resident airway cells rather than through traditional effector pathways involving eosinophils and immunoglobulin E‐mediated events. In light of these recent developments, this review explores our current understanding of the singular role of IL‐13 in the pathogenesis of asthma, with a particular focus on new insights into the mechanisms by which IL‐13 mediates various features of asthma.     

IgE regulation and roles in asthma pathogenesis

Asthma and the predisposition to produce IgE are inherited as linked traits in families. In patients IgE levels correlate with asthma severity and bronchial hyperresponsiveness. The concept that IgE plays a critical role in asthma pathogenesis has driven the development of IgE blockers, which are currently being introduced into clinical use. This review focuses on the mechanisms whereby IgE participates both in immediate hypersensitivity responses in the airways and in the induction of chronic allergic bronchial inflammation. The molecular genetic events that give rise to IgE production by B cells and the cellular and cytokine factors that support IgE production in the bronchial mucosal microenvironment are discussed. It is clear that much remains to be learned regarding the roles of IgE in asthma and the genetic and environmental influences that lead to its production. Over the next few years, the emerging experience with anti-IgE in patients will provide a more complete understanding of the mechanisms whereby IgE contributes to disease, as well as the therapeutic potential of its inhibition.     

Dual role of autophagy in HIV-1 replication and pathogenesis

ABSTRACT: Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.     

Genetic basis of toxin production and pathogenesis in Vibrio cholerae: evidence against phage conversion.

The pathogenicity of Vibrio cholerae strains "cured" of "Kappa-type" phage was not significantly altered relative to that of their "Kappa" lysogenic parental strains. Unlike Corynebacterium diphtheriae, the capacity of V. cholerae to produce exotoxin was not stimulated as a consequence of active phage multiplication. Toxin production in cultures in which Kappa-type phage multiplication was initiated either by inducing Kappa lysogens or by infecting naturally occurring or "cured" Kappa-sensitive strains was greatly reduced compared to normally growing control cultures. Kappa-sensitive El Tor strain Mak 757 and a Kappa lysogen derived from it did not differ in their capacity to colonize ligated rabbit ileal loops nor in their sensitivites to ultraviolet radiation, acidic pH, or osmotic shock. We conclude that Kappa-type phages do not directly affect the pathogenicity of these V. cholerae strains.     

自噬作用在阿尔茨海默病中的分子机制

自噬在清除异常积聚的蛋白、长寿命蛋白以及受损细胞器、维持细胞内稳态和细胞生存中扮演重要角色,其基本分子机制及调控信号传导通路非常复杂。近年来的研究显示自噬对于β-淀粉样蛋白(Aβ)和细胞骨架相关tau蛋白的生成和神经元的存活与凋亡都有密切的关系。明确自噬在阿尔茨海默病(AD)发病和病程中的分子信号机制可能有助于发现更为有效的治疗靶点。     

Genetic polymorphism in allergy and asthma

The impact of genetic factors on the pathogenesis of allergy and asthma is currently an area of intense investigation. Although epidemiological studies find more and more genes that are likely to contribute to allergic inflammation, functional studies of the mechanisms that link genetic variation with dysregulation of gene expression and function are hindered by the high frequency of natural variation. The interplay between genes and environment adds another layer of complexity to the determination of allergic phenotypes. The complexity emerging from these studies warrants novel experimental strategies and bolder conceptual paradigms.     

Airway remodelling in the pathogenesis of asthma

The inflammatory and remodelling processes that underlie asthma result from a highly complex interaction between various cell types. Apart from inflammatory cells, such as eosinophils, activated T cells, mast cells and macrophages, structural tissue cells such as epithelial cells, fibroblasts and smooth muscle cells can also play an important effector role through the release of a variety of mediators, cytokines and chemokines. This results in an acute inflammatory response that is characterized by vascular leakage, mucus hypersecretion, epithelial shedding and widespread airway narrowing. At the same time, through the release of mediators, cytokines, chemokines and growth factors, epithelial and mesenchymal cells cause persistence of the inflammatory infiltrate and induce structural changes in the airway wall, such as increased thickness of the basement membrane, increased collagen deposition, changes in bronchial microcirculation, and smooth muscle hypertrophy and hyperplasia. The end result of airway inflammation and remodelling is an increased thickness of the airway wall, leading to a reduced baseline airway calibre and exaggerated airway narrowing.     

New insights into asthma pathogenesis and treatment

Although national asthma guidelines help organize standards for asthma care, current asthma management is still primarily symptom based. Recent reports provide insights on how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. Despite many significant gains in managing asthma, we must now find improved strategies to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care. Perhaps new directions in personalized medicine including a systems biology approach, along with improved health care access and communication will lead to better methods to alleviate the burden of asthma. This review will discuss the benefits and limitations of the current approach to asthma management, new studies that could impact new directions in asthma management, and new insights related to mechanisms of asthma and allergic airways inflammation that could eventually lead to improved asthma control.     

No evidence for aluminum in etiology and pathogenesis of alzheimer's disease

The review by Crapper McLachlan provides a one sided view in support of the possible role of aluminum in Alzheimer's disease without going into the biology, pathology and biochemistry of the disease or the disease process. Aluminum has been implicated as a cause or an important factor in Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ALS-parkinsonism dementia and dialysis dementia. However, outside of the dialysis dementia syndrome, to date there is no evidence that aluminum has a role in the observed pathological changes, signs and symptoms in any of these diseases.     

Genetic risks and childhood-onset asthma

Recent large-scale genome-wide association studies have successfully identified several genetic loci that influence asthma susceptibility. The loci thus far identified confer a high population attributable risk for childhood-onset disease and have provided a better understanding of the primary mechanisms underlying asthma and a clear focus for new therapies to treat the disease. The loci are of limited utility for diagnostic or predictive genetic testing. This review considers different aspects of genetic risk, including individual, population, and familial risks, and explores how these different measures interact and how the next generation of genetic studies might be best designed.     

自噬在缺血性心脏病发病机制中的作用

在心肌缺血再灌注过程中可以通过多种因素诱导细胞的自噬活动,心肌细胞自噬可以保护细胞,减少细胞损失,但是自噬也可导致心肌细胞死亡。