低氧微环境下内质网应激及其相关疾病

内质网应激是细胞应激的重要组成部分,是真核细胞的一种保护性反应。氧分压改变（如低氧）是重要的应激条件,显著影响细胞的生物学表型及细胞行为（生存、迁移及侵袭等）。细胞通过内质网应激降低胞内未折叠蛋白的浓度,抑制未折叠蛋白凝集的发生。近来发现内质网应激与肿瘤、糖尿病及炎症等多种疾病的发生、发展密切相关,组织局部的低氧微环境是这些疾病的特征之一。因此对低氧导致的内质网应激的发生及其机制的研究,对肿瘤、心血管疾病及糖尿病等疾病治疗新策略的发展具有重要意义。     

ILC 细胞与自身炎症性疾病

固有淋巴细胞(ILCs)是一群参与固有免疫的异质性淋巴细胞,多分布于黏膜屏障部位,接受局部微环境细胞因子的信号后,通过分泌细胞因子及其他介质,发挥早期的免疫监视和免疫调节作用。ILCs细胞多为组织驻留淋巴细胞,参与黏膜免疫的形成,在淋巴细胞的发育、组织损伤的修复及上皮屏障的维持方面发挥重要作用。但由于其数量或功能异常,将参与炎症、自身免疫性疾病、代谢性疾病、哮喘、过敏等多种疾病的发生发展。鉴于不同ILC亚群在免疫监视、组织修复、稳态维持和炎症应答中的重要作用,ILCs细胞有望成为免疫治疗或炎症相关疾病治疗的靶点。本文就ILC细胞亚群的表型、发育和功能特点、ILCs细胞在炎症、组织稳态和修复中的作用、与自身炎症性疾病发生发展的关系及相关治疗策略等新进展做一综述。     

胶质瘤微环境中髓源性抑制细胞的作用研究进展

胶质瘤是人类大脑中最常见的原发性肿瘤,预后不良,由胶质瘤细胞引发形成的局部和全身免疫抑制环境使其能够逃避免疫监视。在人体的免疫抑制系统中,髓源性抑制细胞(MDSCs)是非常重要的组成部分,由早期髓系祖细胞和前体细胞共同组成,是一种异质性细胞群,这些细胞虽在表型和功能上具多样性,但是都表现出了很强的免疫抑制特点。在胶质瘤组织中,存在MDSCs的广泛浸润,它们在胶质瘤微环境中发挥着极为重要的免疫抑制作用,导致肿瘤的免疫疗效大大降低。本文将回顾总结脑胶质瘤微环境中MDSCs的表型特征及其在胶质瘤进展中的作用机制,对更好地了解胶质瘤的发病机制并探索有效的综合治疗方案具有积极的意义。     

固有淋巴细胞研究进展

固有淋巴细胞(innate lymphoid cells,ILC)是一群来源于共同淋巴前体(common lymphoid progenitor,CLP),具有固有类细胞特征的淋巴细胞。ILC由多种细胞亚群构成,主要包含NK细胞、Th2ILC和RORγt+ILC,参与组织构建、修复和再生,维持组织稳态,参与固有免疫应答,抗致病菌、寄生虫感染。本文就各类ILC的表型、功能及其与疾病的关系作一综述。     

组织定居巨噬细胞在维持免疫稳态中的研究进展

组织定居巨噬细胞是维持免疫稳态以及参与炎症反应的重要免疫细胞,其在组织微环境中高度的异质性和活化状态的可塑性既能用于机体免疫功能的调节,也能被病原体或病理过程利用而损害机体。近年的研究发现,组织定居巨噬细胞在响应不同微环境刺激下,可以改变其活化状态及细胞表型,进而调控感染性疾病、肿瘤和自身免疫病等疾病的发生发展。因此,揭示组织定居巨噬细胞的起源、活化及其免疫调控机制,可望为多种疾病的干预和治疗提供新思路。     

人类肝脏NK 细胞与肝脏疾病

肝脏疾病的发生发展与免疫反应密切相关。自然杀伤(NK)细胞是固有免疫系统的重要淋巴细胞,在肝脏内的含量十分丰富。人类肝脏NK细胞与外周循环NK细胞的表型和功能差异较大,含有组织驻留特性的NK细胞亚群。NK细胞在抵御病毒感染与肿瘤免疫监视中发挥重要作用。近来研究表明,慢性肝脏疾病中NK细胞表型发生改变,且功能紊乱,不能有效控制病毒感染和肿瘤发展。本文总结了人类肝脏NK细胞的特性和亚群组成,探讨其与固有淋巴细胞(ILC)之间的联系,以及与肝脏疾病的关系,为肝脏疾病的治疗展现新思路。     

肿瘤微环境中的基质细胞在转移形成中的角色

传统观念认为癌症的进展仅仅是由癌细胞基因和表型变化的多个过程所致.但最近20年的研究显示肿瘤微环境(tumor microenvironment,TME)对于肿瘤行为的影响是同等重要的.TME的组成包括局部的基质细胞,如定植的成纤维细胞(cancer-associated fibroblasts,CAF)和巨噬细胞,远处招募的细胞如内皮细胞、免疫细胞包括髓系和淋巴系细胞、骨髓来源的前体细胞和循环中的血小板.TME能够分泌影响并调控肿瘤表型的分子,如能揭示成瘤细胞与微环境之间的关系,必定能够为肿瘤的发生发展及治疗等一系列难题提供全新的视角.     

细胞损伤修复及相关药物研发现状

组织损伤的本质是大量细胞死亡导致的组织结构改变和功能失常，严重情况下还可能进一步发展为器官的损伤。目前对组织损伤的处理更偏重于改善微环境和促进细胞新生，但对细胞的损伤修复不够重视，易导致疾病进展并迁延难愈。因此，治疗组织损伤应该以修复细胞为基础。为了系统的掌握细胞损伤修复的研究现状和药物开发情况，本文从 DNA损伤、RNA损伤、蛋白质损伤、线粒体损伤、膜损伤以及细胞死亡等方面对损伤原因、修复机制、药物发展进行了系统综述，期望能有助于促进修复类药物的研究发展。     

人卵巢上皮癌组织中树突状细胞表型抗原的免疫组织化学研究

目的：观察人卵巢上皮癌中CD1c、S－100树突状阳性细胞数和表达强度及癌局部微环境中细胞表型抗原的变化,探讨其与卵巢上皮癌发生、发展的关系,为临床生物治疗提供实验依据。方法：采用ABC免疫组织化学技术和图像分析。结果：在卵巢上皮癌中,CD1c^ 、S－100^ 细胞数明显减少,与正常卵巢组织相比较具有显著性差异,与临床分期和病理分级无关;卵巢上皮癌中D1c、S－100阳性细胞表达强度与正常卵巢组织相比较明显减弱,具有显著性差异（P＜0．01）,与临床分期和病理 分级相关。结论：人卵巢上皮癌局部微环境中,树突状细胞表型抗原表达总量下降,说明树突状细胞在抗卵巢上皮癌的免疫应答中具有重要作用。     

固有淋巴细胞研究进展

长期以来,自然杀伤(NK)细胞被认为是固有免疫系统中唯一属于淋巴谱系的细胞群体,然而近来研究揭示人和小鼠体内存在着多种类型的固有淋巴细胞(ILC)。这些新发现的ILC群体主要分布于黏膜屏障部位,尽管数量较少,但在抵抗病原体入侵和维持组织器官稳态等方面发挥重要作用。ILC发育分化早期存在着共同前体,但在后期阶段受不同转录因子调控,成为表型和功能不同的ILC成员。不同ILC亚群有着不同的细胞因子分泌谱,依据辅助性T细胞亚群的分类方法,ILC家族可以分成三类。ILC多样性的发现极大地丰富了固有免疫的内涵,也为我们研究固有免疫和适应性免疫之间的联系开辟了新途径。     

Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes

Eosinophil granulocytes are intriguing members of the innate immunity system that have been considered important defenders during parasitic diseases as well as culprits during allergy‐associated inflammatory diseases. Novel studies have, however, found new homoeostasis‐maintaining roles for the cell. Recent clinical trials blocking different Th2 cytokines have uncovered that asthma is heterogeneous entity and forms different characteristic endotypes. Although eosinophils are present in allergic asthma with early onset, the cells may not be essential for the pathology. The cells are, however, likely disease causing in asthma with a late onset, which is often associated with chronic rhinosinusitis. Assessment of eosinophilia, fraction exhaled nitric oxide (FeNO) and periostin are markers that have emerged useful in assessing and monitoring asthma severity and endotype. Current scientific knowledge suggests that eosinophils are recruited by the inflammatory environment, activated by the innate interleukin (IL)‐33 and prevented from apoptosis by both lymphocytes and innate immune cells such as type two innate immune cells. Eosinophils contain four specific granule proteins that exhibit an array of toxic and immune‐modulatory activates. The granule proteins can be released by different mechanisms. Additionally, eosinophils contain a number of inflammatory cytokines and lipid mediators as well as radical oxygen species that might contribute to the disease both by the recruitment of other cells and the direct damage to supporting cells, leading to exacerbations and tissue fibrosis. This review aimed to outline current knowledge how eosinophils are recruited, activated and mediate damage to tissues and therapies used to control the cells.     

Cross-roads in the lung: immune cells and tissue interactions as determinants of allergic asthma

Allergic asthma is a chronic disease of the lung characterized by underlying Th2- and IgE-mediated inflammation, structural alterations of the bronchial wall, and airway hyperresponsiveness. Initial allergic sensitization and later development of chronic disease are determined by close interactions between lung structural cells and the resident and migratory immune cells in the lung. Epithelial cells play a crucial role in allergic sensitization by directly influencing dendritic cells induction of tolerant or effector T cells and production of type 2 cytokines by innate immune cells. During chronic disease, the bronchial epithelium, stroma, and smooth muscle become structurally and functionally altered, contributing to the perpetuation of tissue remodeling. Thus, targeting tissue-driven pathology in addition to inflammation may increase the effectiveness of asthma treatment.     

Host defense genes in asthma and sepsis and the role of the environment

PURPOSE OF REVIEW: There is growing evidence that innate immunity genes contribute to asthma pathogenesis. At the core of the innate immune response are ubiquitous, soluble fragments of bacterial lipopolysaccharide or endotoxin, and chronic exposure to domestic endotoxin has been shown to influence asthma severity. Asthmatic and atopic individuals are more sensitive to endotoxin than nonallergic individuals, suggesting a role for genetics in the innate immunity response, and the potential for gene-environment interactions. Variants in genes associated with classic innate immunity-related disorders, such as sepsis, may be unique candidates for asthma susceptibility. RECENT FINDINGS: Candidate genes for asthma and allergic diseases co-associated with sepsis including innate immunity receptors and related molecules (CD14, TLR4 and AOAH) and novel genes such as MYLK provide good examples of pleitropic effects of innate immunity genes, where variants conferring risk to specific traits (i.e. sepsis) under one set of genetic and environmental circumstances confer a reduced risk in a different (but possibly related) clinical outcome (i.e. allergic asthma), and support the 'common variant/multiple disease' hypothesis. SUMMARY: Collectively, these observations suggest a greater role for the innate immunity response in allergic asthma than previously assumed, and implicate host defense genes in disease pathology.     

Dangerous allergens: innate immunity,dendritic cells and allergic asthma

Immune responses can be compartmentalized into innate versus adaptive components. This relatively recent dichotomy positioned the innate immune system at the interface between the host and the external environment, and provided a new conceptual framework with which to view allergic diseases, including asthma. Among the cells of the innate immune system, antigen-presenting dendritic cells are now thought to be intimately involved in allergen recognition, as well as modulating allergic immune responses. This review summarizes current thinking regarding the role of dendritic cells in allergic asthma and concludes with a summary of emerging concepts in the field.     

Epithelium: at the interface of innate and adaptive immune responses

Several diseases of the airways have a strong component of allergic inflammation in their cause, including allergic rhinitis, asthma, polypoid chronic rhinosinusitis, eosinophilic bronchitis, and others. Although the roles played by antigens and pathogens vary, these diseases have in common a pathology that includes marked activation of epithelial cells in the upper airways, the lower airways, or both. Substantial new evidence indicates an important role of epithelial cells as both mediators and regulators of innate immune responses and adaptive immune responses, as well as the transition from innate immunity to adaptive immunity. The purpose of this review is to discuss recent studies that bear on the molecular and cellular mechanisms by which epithelial cells help to shape the responses of dendritic cells, T cells, and B cells and inflammatory cell recruitment in the context of human disease. Evidence will be discussed that suggests that secreted products of epithelial cells and molecules expressed on their cell surfaces can profoundly influence both immunity and inflammation in the airways.     

Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm.

The concept that airway inflammation leads to airway disease has led to a widening search for the types of cellular and molecular interactions responsible for linking the initial stimulus to the final abnormality in airway function. It has not yet been possible to integrate all of this information into a single model for the development of airway inflammation and remodeling, but a useful framework has been based on the behavior of the adaptive immune system. In that paradigm, an exaggeration of T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli leads to airway inflammatory disease, especially asthma. In this review, we summarize alternative evidence that the innate immune system, typified by actions of airway epithelial cells and macrophages, may also be specially programmed for antiviral defense and abnormally programmed in inflammatory disease. Furthermore, this abnormality may be inducible by paramyxoviral infection and, in the proper genetic background, may persist indefinitely. Taken together, we propose a new model that highlights specific interactions between epithelial, viral, and allergic components and so better explains the basis for airway immunity, inflammation, and remodeling in response to viral infection and the development of long-term disease phenotypes typical of asthma and other hypersecretory airway diseases.     

Interaction Between Helminths and Toll-Like Receptors: Possibilities and Potentials for Asthma Therapy

Toll-like receptors (TLRs) are essential components of the innate immune system. They play an important role in the pathogenesis of allergic diseases, especially asthma. Since TLRs significantly orchestrate innate and adaptive immune response, their manipulation has widely been considered as a potential approach to control asthma symptoms. It is well established that helminths have immunoregulatory effects on host immune responses, especially innate immunity. They release bioactive molecules such as excretory-secretory (ES) products manipulating TLRs expression and signaling. Thus, given the promising results derived from preclinical studies, harnessing helminth-derived molecules affecting TLRs can be considered as a potential biological therapy for allergic diseases. Prospectively, the data that are available at present suggest that, in the near future, it is possible that helminth antigens will offer new therapeutic strategies and druggable targets for fighting allergic diseases. This review describes the interactions between helminths and TLRs and discusses the potential possibilities for asthma therapy. In this opinion paper, the authors aimed to review the updated literatures on the interplay between helminths, TLRs, and asthma with a view to proposing helminth-based asthma therapy.     

Toll-like receptors and their function in innate and adaptive immunity

Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.     

Asthma: The importance of dysregulated barrier immunity

Chronic asthma is an inflammatory disease of the airway wall that leads to bronchial smooth muscle hyperreactivity and airway obstruction, caused by inflammation, goblet cell metaplasia, and airway wall remodeling. In response to allergen presentation by airway DCs, T‐helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of IL‐4, IL‐5, IL‐13, IL‐17, and IL‐22, and these are counterbalanced by cytokines produced by Treg cells. Many cells of the innate immune system such as mast cells, basophils, neutrophils, eosinophils, and innate lymphoid cells also play an important role in disease pathogenesis. Barrier epithelial cells are being ever more implicated in disease pathogenesis than previously thought, as these cells have in recent years been shown to sense exposure to allergens via pattern recognition receptors and to activate conventional and inflammatory‐type DCs and other innate immune cells through the secretion of thymic stromal lymphopoietin, granulocyte‐macrophage colony stimulating factor, IL‐1, IL‐33, and IL‐25. Understanding this cytokine crosstalk between barrier epithelial cells, DCs, and immune cells provides important insights into the mechanisms of allergic sensitization and asthma progression as discussed in this review.     

Basophils in allergic immune responses

Basophils are rare effector cells of the innate immune system. They are generally associated with type 2 immune responses that develop during helminth infections and allergic reactions. The role of basophils for initiation and execution of allergic immune responses is not well understood. Over the past few years new tools have been generated to study the function of basophils in mouse models. Depending on the experimental systems used conflicting results were obtained with regard to the role of basophils for initiation and execution of immune responses against allergens and helminths. This review highlights the current knowledge about basophil in vivo functions with a focus on the role of basophils for allergic responses like asthma, allergic skin diseases and anaphylaxis.