肠道M细胞的功能与疾病的研究进展

M细胞(microfold cell,M cell)来源于肠隐窝Lgr5+干细胞,成熟的M细胞基底膜向上突起,呈“囊袋状”.M细胞分布广泛,在肠道相关淋巴组织(gut associated lymphoid tissue, GALT)、鼻咽相关淋巴组织(nasopharyngeal lymphoid tissue,NA...     

黏膜疫苗及其佐剂的研究进展

黏膜疫苗可以通过激活机体黏膜和系统的免疫应答而阻止病原微生物的入侵 ,还可通过诱导抗原特异性的黏膜耐受而选择性地治疗自身免疫性疾病、变态反应性疾病及感染性的免疫病理紊乱等。无论是感染性疾病的预防还是自身免疫性疾病的免疫治疗 ,黏膜疫苗都离不开黏膜佐剂或抗原运输载体。该文从黏膜部位的基本结构出发 ,探讨了设计黏膜疫苗所必需之处 ,重点介绍了黏膜佐剂或抗原运输载体的最新研究状况     

肠道微生物与肝肠疾病研究进展

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溃疡性结肠炎与肠道微生物关系研究进展

溃疡性结肠炎(ulcerative colitis,UC)是炎症性肠病(inflammatory bowel disease,IBD)中最常见的类型之一,目前在我国已成为消化系统的常见病,高复发率是UC重要临床特征,但UC的发生与发展机制现尚不十分明确,可能涉及遗传异质性、免疫学、肠道微生物、饮食因素等多个方面,较为复...     

肠道M细胞研究进展

消化道的粘膜属于机体的第一道防线.抗原物质如细菌、病毒及大分子异物需通过这层屏障结构,刺激位于消化道壁的淋巴组织以引起免疫反应.Owen等发现回肠Peyer淋巴集结表面覆盖一种特殊的上皮细胞,因其游离面为不规则的微皱褶而非微绒毛,命名为微皱褶细胞(microfold cell),简称为M细胞.随后对M细胞的形态和功能进行了广泛研究.从而     

心肌M细胞的电生理特性和临床意义

心肌Ｍ细胞的电生理特性和临床意义鲁端Ｍ细胞（ｍｉｄｍｙｏｃａｒｄｉａｌｃｅｌｓ）是指位于心室肌中层一组独特的细胞亚群，近年来被发现其与其他部位的心室肌细胞有着完全不同的电生理特性，因而受到众多学者的关注［１～４］。自从１９９１年Ｓｉｃｏｕｒｉ和Ａｎｔ...     

肠道微生态系统与肠道黏膜屏障

人体微生态学是研究微生物与其宿主相互关系的科学,主要包括口腔、胃肠道、泌尿系统、皮肤四个生态领域,其中对胃肠道微生态学的研究历史最为悠久,资料最为丰富。人体胃肠道中有大量细菌,包括革兰氏隐性杆菌、球菌及厌氧     

肠黏膜屏障损伤与保护分子机制研究进展

介绍肠黏膜屏障损伤因素的分子机制,如内毒素及氧自由基、炎症介质和细胞因子如白细胞介素（interleukin）、肿瘤坏死因子-α（TNF-α）、核转录因子kappa B、TOLL样受体（TLRs）和NOD受体通路、高迁移率族蛋白B1、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）等。对肠黏膜屏障的保护分子机制如肠上皮紧密连接蛋白、白介素家族、其它保护性调控因子等作出介绍。     

黏膜免疫系统和黏膜疫苗

局部及全身的黏膜免疫反应,特别是黏膜表面的分泌型IgA,对抵御经呼吸道、消化道或泌尿生殖道等黏膜表面入侵的病原体有着非常重要的作用。诱导黏膜免疫应答最有效的方式就是将抗原直接接种到黏膜表面,但是这种直接接种并不容易诱导具有保护效果的免疫应答。到目前为止,仅有少数几种黏膜疫苗获准在人体应用。本文简述了黏膜免疫系统的结构及功能,并对现有的及正在研发中的黏膜疫苗进行了总结概括。     

肠道微生物与动脉粥样硬化的研究进展

动脉粥样硬化是一种慢性进行性动脉管腔狭窄,其发生发展与脂质代谢失衡,内皮细胞功能障碍、炎性细胞聚集以及血小板反应性增高等密切相关[1].近年来,研究发现肠道微生物可通过影响上述途径参与动脉粥样硬化的发展.肠道微生物是指定居在肠道中的细菌、病毒、真菌、古生菌等数量庞大的微生物群落[2].肠道微生物群可调节肠道粘膜屏障、营...     

Spatial distribution of LTi-like cells in intestinal mucosa regulates type 3 innate immunity

Lymphoid tissue inducer (LTi)-like cells are tissue resident innate lymphocytes that rapidly secrete cytokines that promote gut epithelial integrity and protect against extracellular bacterial infections.Here, we report that the retention of LTi-like cells in conventional solitary intestinal lymphoid tissue (SILT) is essential for controlling LTi-like cell function and is maintained by expression of the chemokine receptor CXCR5. Deletion of Cxcr5 functionally unleashed LTi-like cells in a cell intrinsic manner, leading to uncontrolled IL-17 and IL-22 production. The elevated production of IL-22 in Cxcr5-deficient mice improved gut barrier integrity and protected mice during infection with the opportunistic pathogen Clostridium difficile. Interestingly, Cxcr5^−/− mice developed LTi-like cell aggregates that were displaced from their typical niche at the intestinal crypt, and LTi-like cell hyperresponsiveness was associated with the local formation of this unconventional SILT. Thus, LTi-like cell positioning within mucosa controls their activity via niche-specific signals that temper cytokine production during homeostasis.

Lymphoid tissue inducer (LTi)-like cells belong to a family of tissue resident innate lymphocytes that lack rearranged antigen-specific receptors and act as a first line of defense at barrier tissues. LTi-like cells, along with other group 3 innate lymphoid cells (ILC3), maintain intestinal homeostasis by producing the cytokines IL-22 and IL-17A, which promote gut epithelial cell proliferation, anti-microbial peptide production, and tight junction protein abundance (1, 2). The conditioning of epithelial cells by these cytokines contributes to balanced interactions between the host and commensal microbiota under steady-state conditions, and LTi-like cell-derived IL-22 promotes barrier integrity and protective immunity during infection with the enteric pathogenic bacteria (3).In addition to providing effector functions, LTi-like cells and their fetal LTi counterparts are required for early steps in lymphoid tissue development. Fetal LTi induce lymph node and Peyer’s patch development during gestation by activating lymphoid tissue organizer cells at primordial lymphoid organs with lymphotoxin (LT)-α1β2 (4–6). Similarly, LTi-like cells are required for the postnatal development of cryptopatches, small lymphoid aggregates in the intestine that have the potential to mature into isolated lymphoid follicles (ILF) in response to signals from microbes (7, 8). In line with their roles in lymphoid tissue organogenesis and maturation, LTi-like cells in adult mouse intestines preferentially localize in solitary intestinal lymphoid tissue (SILT). The microenvironments of these highly specialized niches are expected to support and regulate LTi-like cells; however, their impact on LTi-like cell behavior has not been fully explored.LTi-like cells express multiple G protein–coupled receptors that facilitate their migration in tissue (9–12). Among these, CXCR5 has a predominant role in the migration of LTi to developing lymphoid structures, with Cxcr5^−/− mice exhibiting defects in lymph node and Peyer’s patch development (13). Mice deficient in CXCR5 or its ligand CXCL13 also have delayed cryptopatch development and fail to convert cryptopatches to mature ILF because of impaired recruitment of B cells to these structures (14–16). Dendritic cells (DCs) have been shown to be a local source of CXCL13 in SILT (16) and thus likely retain B cells and LTi-like cells at these structures under homeostatic conditions via the CXCL13–CXCR5 signaling axis. The retention of LTi-like cells in SILT is expected to bring these cells in close proximity to activating and inhibitory signals provided by specialized myeloid cells, neurons that express the vasoactive intestinal peptide (VIP), and lymphocyte populations localized at these sites (17–20). However, the impact of CXCR5 on functions of LTi-like cells beyond those associated with lymphoid tissue maintenance and development remains unknown.In the current study, we show that CXCR5 expression regulates LTi-like cell function. Deletion of Cxcr5 led to increased numbers of LTi-like cells in the small intestine (SI) and enhanced their ability to produce IL-17A and IL-22. Cxcr5 regulated LTi-like cells via a cell-intrinsic mechanism that did not involve direct suppression by CXCL13. Heightened LTi-like cell activity in Cxcr5-deficient mice was associated with the development of abnormal LTi-like cell aggregates in the SI that were localized in villus lamina propria instead of at the intestinal crypt base. Importantly, augmented production of IL-22 in Cxcr5^−/− mice was protective during acute infection with the opportunistic pathogen Clostridium difficile. These data reveal that CXCR5-dependent migration can control innate type 3 immunity by altering the niche of LTi-like cells in intestinal lamina propria.     

Determinants of reovirus interaction with the intestinal M cells and absorptive cells of murine intestine

Reovirus type 1 penetrates the gastrointestinal tract in suckling mice via specialized epithelial cells, designated membranous cells, or M cells, located in the epithelium overlying Peyer's patches. We have examined whether the interaction of reovirus with murine mucosa of in situ closed ileal loops is influenced by mouse age or strain or reovirus serotype. Neither mouse age (suckling or adult), strain (C3H/HeJ or Balb/cJ), nor reovirus serotype (types 1 and 3) affected reovirus adherence to and transport through M cells. In all conditions, reovirions adhered to the M-cell surface and were transported across M cells in endocytic vesicles. The adherence to and endocytosis by M cells of type 1 reovirus and reassortants with the viral hemagglutinin of type 1 were selective in suckling mice; type 1 virus was not adherent to nor endocytosed by absorptive cells. In adult mice, type 1 reovirions adhered to the surface of a minority of absorptive cells but were never seen within absorptive cell cytoplasm. In contrast, type 3 reovirus and reassortants with the viral hemagglutinin of type 3 adhered to and were endocytosed not only by M cells but also by absorptive cells of suckling mice. Virions accumulated within lysosomelike bodies in absorptive cells but transport of virions across absorptive cells was not observed. These studies indicate that (a) adherence of reovirus to the apical surface of and transcellular transport by M cells is independent of viral serotype or viral surface proteins, (b) adherence of reovirus to and transcellular transport by M cells is independent of mouse age after 9 days and comparable in two mouse strains, and (c) adherence of reovirus to and their endocytosis by absorptive cells of suckling mice is determined by the viral hemagglutinin (sigma 1 protein).     

Phospholipid turnover in the inflamed intestinal mucosa: Arachidonic acid-rich phosphatidyl/plasmenyl-ethanolamine in the mucosa in inflammatory bowel disease

Cytosolic phospholipase A2 (PLase A2) is activated by low Ca²⁺ concentrations and translocates from the cytosol to the cell membrane, releasing arachidonic acid; the arachidonic acid cascade then leads to the production of many inflammatory mediators. The aim of this study, accordingly, was to investigate the role of phospholipid metabolism in the intestinal mucosa in inflammatory bowel disease (IBD). Surgically resected specimens from patients with Crohn's disease (CD), ulcerative colitis (UC), and colrectal cancer (non-cancerous tissue; as a control) were submitted to phospholipid analysis and a PLase A2 assay, which measures the degradation of endogenous mucosal phospholipids. A high percentage of plasmenylethanolamine (plas.E) was detected in the glycerophospholipid fraction of CD mucosa. The arachidonic acid content of the phosphatidylethanolamine plus plas.E subfraction was higher in inflamed than in intact mucosa in CD. PLaseA2 activity, resulting in lysophosphatidyl ethanolamine production, was detected only in inflamed mucosa from CD and UC patients, but not in normal mucosa from controls. PLaseA2 activity was highest in moderately inflamed mucosa adjacent to a severely ulcerated area. The PLaseA2 that reacts with endogenous phosphatidylcholine (PC) to form lysoPC was found irrespective of the presence of inflammation. The PLaseA2 that reacts with ethanolamine-containing phospholipids is more closely related to inflammation than other PLaseA2 isoenzymes in IBD mucosa. (Received Mar. 19, 1998; accepted July 24, 1998)     

Protective mechanisms against the intestinal nematode Strongyloides venezuelensis in Schistosoma japonicum-infected mice

Mice infected with Schistosoma japonicum were resistant to the intestinal nematode, Strongyloides venezuelensis. The numbers of adult S. venezuelensis recovered from mice were significantly decreased when infections were given from 6 weeks after S. japonicum infection. Larval recovery from the lungs showed that significant numbers of subcutaneously inoculated S. venezuelensis larvae were eliminated by 3 days in S. japonicum-infected mice (P < 0.0001), while histology revealed that this was associated with massive eosinophilic infiltration in the lungs. In addition, adult S. venezuelensis worms implanted in the duodenum of S. japonicum-infected mice could not establish in the intestine. This failure was associated with mucosal mastocytosis. Activation of eosinophils and intestinal mast cells was correlated with elevated expression of mRNA for interleukin (IL)-3, IL-4, and IL-5 in S. japonicum-infected mice. Sera from S. japonicum-infected mice recognized S. venezuelensis larva antigens as strongly as those from S. venezuelensis-infected mice, although transfer of sera from S. japonicum-infected mice to normal recipient mice did not protect them from S. venezuelensis challenge infection. It was concluded that the mechanisms for larval killing and adult worm expulsion of S. venezuelensis in S. japonicum-infected mice were identical to those seen in infections with S. venezuelensis only.     

Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa

The intestinal mucosa squares the circle by allowing efficient nutrient absorption while generating a firm barrier toward the enteric microbiota, enteropathogenic microorganisms and high luminal concentrations of potent immunostimulatory molecules. The mucus layer together with local antimicrobial and anti-inflammatory peptides significantly contribute to this ability. Here we summarize the recent progress made to better understand the critical importance of this dynamic, complex and highly structured anti-inflammatory and antimicrobial barrier.     

Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa

The intestinal mucosa squares the circle by allowing efficient nutrient absorption while generating a firm barrier toward the enteric microbiota, enteropathogenic microorganisms and high luminal concentrations of potent immunostimulatory molecules. The mucus layer together with local antimicrobial and anti-inflammatory peptides significantly contribute to this ability. Here we summarize the recent progress made to better understand the critical importance of this dynamic, complex and highly structured anti-inflammatory and antimicrobial barrier.     

Selective effector mechanisms for the expulsion of intestinal helminths

In the middle of the era of molecular biology, much less attention is paid to in vivo phenomena. However, carefully designed experimental systems in vivo still can provide valuable information as to the mechanisms underlying the establishment and maintenance of host-parasite relationships. In this review we describe the advantage of using concurrent infections with appropriately chosen combinations of different genera or different maturation stages of parasites to segregate the cellular responses of the host. By means of simple experimental approaches we have found that mucosal mast cells and goblet cells, both of which have long been considered as non-specific effectors, are in fact highly selective and specific effector cells of the host defence mechanisms capable of acting on the establishment and the expulsion of intestinal helminths.     

Adhesion of probiotic strains to the intestinal mucosa and interaction with pathogens

Probiotic lactic acid strains are live micro-organisms that, when consumed in adequate amounts as part of food, confer a health benefit on the host. The scientific basis for the use of selected probiotic strains has only recently been firmly established, and appropriate and well-conducted experimental in vitro and in vivo studies, as well as clinical studies, are now beginning to be published, especially with regard to the effectiveness of probiotic strains in antagonizing pathogens. In particular, experimental data have allowed new insights into selected probiotic strains that express strain-specific probiotic properties and into the mechanism of action of these strains. The objective of this review is to analyse the in vitro or in vivo experimental studies in which the antimicrobial activity of selected Lactobacillus and Bifidobacterium strains has been documented.     

肠易激综合征患者肠黏膜肥大细胞与神经纤维的关联

目的　探讨肠黏膜肥大细胞与神经纤维之间的关联及其与肠易激综合征 (IBS)发病的关系。方法　应用电镜和免疫组化双重染色技术 ,对 5 6例符合罗马Ⅱ标准的腹泻型IBS患者和 12例非IBS对照组患者末端回肠和直肠 乙状结肠交界部位肠黏膜内的肥大细胞与神经纤维的关联进行了检测。结果　IBS患者和对照组肠黏膜内多数肥大细胞与神经纤维紧邻。患者末端回肠、直肠 乙状结肠交界处黏膜内神经元特异性烯醇化酶 (NSE)、P物质、5 羟色胺 (5 HT)的表达明显高于对照组 (P <0 .0 5 ) ,肥大细胞周围NSE、P物质、降钙素基因相关肽 (CGRP)、5 HT的表达也明显增强。IBS患者末端回肠黏膜内肥大细胞的数目 (10 .98± 2 .96 )与对照组 (6 .0 5± 0 .5 1)相比明显增多 (P <0 .0 1)。IBS患者与对照组相比 ,末端回肠内NSE(6 .73± 1.0 2比 4 .2 5± 0 .5 0 )、P物质 (6 .84± 0 .85比 4 .2 8± 0 .4 0 )、CGRP(6 .73± 0 .82比 4 .33± 0 .5 4 )、5 HT(6 .72± 0 .81比 4 .0 0± 0 .6 3)阳性神经纤维紧邻的肥大细胞数目亦明显增多 (P <0 .0 1)。结论　IBS患者肠黏膜内肥大细胞数量的增多及其周围神经肽表达的增强表明 :免疫系统与肠神经丛之间通路的活化可能与IBS的发病有关。