Immunology and immunogenetics insights最新文献

英文中文

The Immune System as Drug Target 免疫系统作为药物靶点

Immunology and immunogenetics insights

Pub Date : 2013-01-01 DOI: 10.4137/III.S12145

D. Flower

The immune system is perhaps the largest yet most diffuse and distributed somatic system in vertebrates. It plays vital roles in fighting infection and in the homeostatic control of chronic disease. As such, the immune system in both pathological and healthy states is a prime target for therapeutic interventions by drugs–-both small-molecule and biologic. Comprising both the innate and adaptive immune systems, human immunity is awash with potential unexploited molecular targets. Key examples include the pattern recognition receptors of the innate immune system and the major histocompatibility complex of the adaptive immune system. Moreover, the immune system is also the source of many current and, hopefully, future drugs, of which the prime example is the monoclonal antibody, the most exciting and profitable type of present-day drug moiety. This brief review explores the identity and synergies of the hierarchy of drug targets represented by the human immune system, with particular emphasis on the emerging paradigm of systems pharmacology.

免疫系统可能是脊椎动物中最大但最分散和分布的躯体系统。它在对抗感染和慢性疾病的体内平衡控制中起着至关重要的作用。因此，病理和健康状态下的免疫系统是小分子和生物药物治疗干预的主要目标。人体免疫系统包括先天免疫系统和适应性免疫系统，充满了潜在的未开发的分子靶点。主要的例子包括先天免疫系统的模式识别受体和适应性免疫系统的主要组织相容性复合体。此外，免疫系统也是许多当前和未来药物的来源，其中最主要的例子是单克隆抗体，这是当今药物中最令人兴奋和最有利可图的类型。这篇简短的综述探讨了以人体免疫系统为代表的药物靶点层次的身份和协同作用，特别强调了系统药理学的新兴范式。

引用次数: 3

Sequence of Rabbit (Oryctolagus Cuniculus) DNA from the OryCun2.0 Donor does not Confirm a Frameshift in Exon 2 of IL4 来自OryCun2.0供体的兔(Oryctolagus Cuniculus) DNA序列未确认IL4外显子2的移码

Immunology and immunogenetics insights

Pub Date : 2012-01-01 DOI: 10.4137/III.S9557

R. Mage, M. Mage

This note follows up on an observation concerning a possible frameshift in the DNA sequence of exon 2 of rabbit interleukin 4 (IL4) made in a comparative study of the rabbit Th2 cytokine region sequences from two different rabbits. One was from the tuberculosis-susceptible Thorbecke strain, whose whole genome was sequenced at Broad Institute (OryCun2.0), and the other a normal NZW rabbit studied as part of the ENCODE project. If present, a frameshift could have resulted in exon skipping and production of IL4δ2 protein. We resequenced DNAs of the Thorbecke OryCun2.0 donor rabbit, another rabbit of the same strain, and a third rabbit of the inbred B/J strain in the region in question. All three had sequences identical to the normal NZW in the ENCODE ENm002 assembly in that region and hence no frameshift. The sequence information was submitted to GenBank and assigned accession numbers JQ687218 and JX073284.

本文是对兔白细胞介素4 (il - 4)外显子2的DNA序列中可能存在的移码的后续研究，该移码是在对两只不同的兔的Th2细胞因子区域序列进行比较研究时发现的。其中一种来自对结核病敏感的Thorbecke菌株，其全基因组在Broad研究所(OryCun2.0)进行了测序，另一种是作为ENCODE项目的一部分研究的正常的NZW兔。如果存在，移码可能导致外显子跳跃并产生IL4δ2蛋白。我们对Thorbecke OryCun2.0供体兔、同一菌株的另一只兔和该地区近亲繁殖的B/J菌株的第三只兔的dna进行了重新测序。这三个序列都与ENCODE ENm002组装区的正常NZW序列相同，因此没有移码。序列信息提交到GenBank，登记号为JQ687218和JX073284。

引用次数: 4

Bioinformatics-Based Predictions of Peptide Binding to Disease-Associated HLA Proteins Suggest Explanation for Shared Autoimmunity 基于生物信息学的多肽结合疾病相关HLA蛋白的预测为共同自身免疫提供了解释

Immunology and immunogenetics insights

Pub Date : 2011-01-01 DOI: 10.4137/III.S6558

J. Glutting, P. Reche, M. Fridkis-Hareli

Aim This study was designed to examine the immunogenetic basis for shared autoimmunity, resulting in autoantigen presentation that leads to the production of two or more disease-specific autoantibodies. Methods A bioinformatics approach based on peptide binding predictions to disease-associated HLA determinants has been developed and tested here using 11 disease associations between autoimmune systemic and mucocutaneous blistering disorders. Various HLAs associated with antigens within a given “disease model” (set of HLA class II and protein sequences known to be associated with a specific autoimmune disease) were tested and ranked against the antigenic proteins, first with proteins they are known to associate with and then with proteins known to be implicated in a second disease model. In every case binding predictions were compared for different proteins binding to the same HLA. Subsequently, disease-related autoantigens have been tested for their binding affinity against each disease-specific HLA class II protein. Results For a single HLA haplotype, several binders have been generated from a related autoantigen with the variable binding score. In most cases, the binding score corresponding to the interactions between the autoantigen-derived epitope and the HLA associated with one disease was similar or lower than the interactions between the epitope from proteins associated with the second disease and the same HLA. Notably, there was no compelling promiscuity in peptide binding to each of the HLA molecules, in spite of the promiscuous nature of HLA class II binding. Conclusions The data suggest that, in susceptible individuals, shared autoimmunity might be initiated by two types of HLA/peptide interaction; first between an autoantigen-derived epitope and its disease-associated HLA molecules, and second, between a different peptide of the same autoantigen and HLA proteins specific for the second disease.

目的:本研究旨在探讨共同自身免疫的免疫遗传学基础，共同自身免疫导致自身抗原呈递，从而产生两种或多种疾病特异性自身抗体。方法一种基于多肽结合预测疾病相关HLA决定因素的生物信息学方法已经开发出来，并在这里使用自身免疫系统和粘膜皮肤水泡疾病之间的11种疾病关联进行了测试。在给定的“疾病模型”(一组已知与特定自身免疫性疾病相关的HLA II类和蛋白质序列)中检测与抗原相关的各种HLA，并根据抗原蛋白进行排序，首先与已知与它们相关的蛋白质进行排序，然后与已知与第二种疾病模型相关的蛋白质进行排序。在每种情况下，结合预测比较不同的蛋白质结合到相同的HLA。随后，疾病相关的自身抗原已被检测其对每种疾病特异性HLA II类蛋白的结合亲和力。结果对于单个HLA单倍型，从相关的自身抗原中产生了多种结合物，其结合分数不同。在大多数情况下，自身抗原衍生表位与一种疾病相关的HLA相互作用对应的结合评分与第二种疾病相关蛋白的表位与相同HLA的相互作用相似或更低。值得注意的是，尽管HLA II类结合具有混杂性，但肽与每个HLA分子的结合没有明显的混杂性。结论:在易感人群中，共享自身免疫可能由两种类型的HLA/肽相互作用启动;首先是自身抗原衍生表位与其疾病相关的HLA分子之间的差异，其次是同一自身抗原的不同肽与第二种疾病特异性的HLA蛋白之间的差异。

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引用次数: 0

Comparative analysis of genome sequences of the Th2 cytokine region of rabbit (Oryctolagus cuniculus) with those of nine different species. 兔(Oryctolagus cuniculus) Th2细胞因子区基因组序列与9个不同物种的比较分析。

Immunology and immunogenetics insights

Pub Date : 2011-01-01 DOI: 10.4137/III.S7236

E Michael Gertz, Richa Agarwala, Rose G Mage, Alejandro A Schäffer

The regions encoding the coordinately regulated Th2 cytokines IL5, IL4 and IL13 are located on chromosomes 5 of man and 11 of mouse. They have been intensively studied because these interleukins have protective roles in helminth infections, but may lead to detrimental effects such as allergy, asthma, and fibrosis in lung and liver. We added to previous studies by comparing sequences of syntenic regions on chromosome 3 of the rabbit (Oryctolagus cuniculus) genome OryCun 2.0 assembly from a tuberculosis-susceptible strain, with the corresponding region of ENCODE ENm002 from a normal rabbit as well as with 9 other mammalian species. We searched for rabbit transcription factor binding sites in putative promoter and other non-coding regions of IL5, RAD50, IL13 and IL4. Although we identified several differences between the two donor rabbits in coding and non-coding regions of potential functional significance, confirmation awaits additional sequencing of other rabbits.

编码协调调节的Th2细胞因子IL5、IL4和IL13的区域位于人类的5号染色体和小鼠的11号染色体上。它们已被深入研究，因为这些白细胞介素在蠕虫感染中具有保护作用，但可能导致有害影响，如过敏、哮喘、肺和肝纤维化。我们将兔(Oryctolagus cuniculus)基因组OryCun 2.0组装体3号染色体上的同序列序列与正常兔以及其他9种哺乳动物的ENCODE ENm002对应区域进行了比较。我们在IL5、RAD50、IL13和IL4的推定启动子和其他非编码区寻找兔转录因子结合位点。虽然我们发现了两个供体兔在编码区和非编码区潜在功能意义上的一些差异，但还需要其他兔的进一步测序才能得到证实。

引用次数: 9

Cytokine-mediated Regulation of CX3CL1 in Osteoblasts from Patients with Rheumatoid Arthritis 细胞因子介导的CX3CL1在类风湿关节炎患者成骨细胞中的调节作用

Immunology and immunogenetics insights

Pub Date : 2010-01-01 DOI: 10.4137/III.S4970

T. Isozaki, Michihito Sato, R. Takahashi, K. Wakabayashi, T. Odai, N. Yajima, Y. Miwa, Masakazu Tezuka, T. Kasama

Introduction CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and migration of leukocytes, is involved in the recruitment of cells to tissues undergoing inflammatory responses. To explore the regulation of CX3CL1 in inflammatory bone diseases, we examined CX3CL1 expression in osteoblasts. Methods Human osteoblasts isolated from the femora of rheumatoid arthritis patients were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay (ELISA). The expression of CX3CL1 mRNA transcripts in osteoblasts was examined using the quantitative TaqMan real-time polymerase chain reaction. Results The combination of tumor necrosis factor (TNF)-α and interferon (IFN)-γ induced dramatic increases in levels of both soluble CX3CL1 protein and mRNA transcripts. CX3CL1 expression in osteoblasts was decreased by the addition of interleukin(IL)-4 or IL-17 but was increased when stimulation by IFN-γ and IL-17 was supplemented with IL-1β In addition, expression was decreased when TNF-α was added. Conclusions Multiple cytokines, including IL-17, are able to either increase or decrease the expression of CX3CL1 by human osteoblasts.

CX3CL1 (fractalkine)是一种膜结合趋化因子，可诱导白细胞的粘附和迁移，参与细胞向炎症反应组织的募集。为了探讨CX3CL1在炎性骨病中的调控作用，我们检测了CX3CL1在成骨细胞中的表达。方法从类风湿关节炎患者股骨分离成骨细胞，在不同炎症刺激存在或不存在的情况下培养。收集培养上清，用酶联免疫吸附试验(ELISA)测定可溶性CX3CL1水平。采用定量TaqMan实时聚合酶链反应检测成骨细胞中CX3CL1 mRNA转录本的表达。结果肿瘤坏死因子(TNF)-α和干扰素(IFN)-γ联合使用诱导可溶性CX3CL1蛋白和mRNA转录物水平显著升高。CX3CL1在成骨细胞中的表达在添加白细胞介素(IL)-4或IL-17时降低，在IFN-γ和IL-17同时添加IL-1β时升高，在添加TNF-α时表达降低。结论包括IL-17在内的多种细胞因子可增加或降低人成骨细胞CX3CL1的表达。

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引用次数: 0

In Vitro and In Vivo Phagocytic Ability of Mouse B-1 Cells 小鼠B-1细胞体内外吞噬能力的研究

Immunology and immunogenetics insights

Pub Date : 2010-01-01 DOI: 10.4137/III.S6156

R. N. E. Brito, B. Cortéz, GM Machado-Santelli, P. Xander, B. De Lorenzo, H. Oliveira, F. Thies, E.S. Kioshima, J. Maricato, J. Lopes, M. Mariano

B-1 cells are a peculiar subpopulation of B cells found in the peritoneal and pleural cavities in mice. These cells are typically IgM+ and CD11b+. B-1 cells are able to migrate from the peritoneal cavity to non-specific inflammatory sites in mice. In addition, they can differentiate into mononuclear phagocyte-like cells in vitro; however, it is still unknown whether B-1 cells are capable of performing phagocytosis in vivo. Here we further characterized B-1 cells as phagocytes in vitro, and we investigated their ability to phagocytose apoptotic cells and bacteria in vivo. Our results demonstrate that B-1 phagocytes are able to uptake apoptotic thymocytes and Escherichia coli bacteria, both in vitro and in vivo. These findings indicate that along with macrophages, B-1 phagocytic cells might play a role in fundamental processes such as tissue remodeling, resolution of inflammation and pathogen clearance.

B-1细胞是在小鼠腹膜和胸膜腔中发现的一种特殊的B细胞亚群。这些细胞通常是IgM+和CD11b+。小鼠的B-1细胞能够从腹腔迁移到非特异性炎症部位。此外，它们在体外可分化为单核吞噬细胞样细胞;然而，B-1细胞在体内是否具有吞噬能力尚不清楚。在此，我们进一步在体外将B-1细胞定性为吞噬细胞，并在体内研究其吞噬凋亡细胞和细菌的能力。我们的研究结果表明，B-1吞噬细胞能够在体外和体内摄取凋亡的胸腺细胞和大肠杆菌。这些发现表明，B-1吞噬细胞可能与巨噬细胞一起在组织重塑、炎症消退和病原体清除等基本过程中发挥作用。

引用次数: 18

Relationship between Celiac Disease Markers and Gastrointestinal Disease in Children with Autism 自闭症儿童乳糜泻标志物与胃肠道疾病的关系

Immunology and immunogenetics insights

Pub Date : 2010-01-01 DOI: 10.4137/III.S3662

A.J. Russo

Aim This study was designed to determine if there is a relationship between celiac disease (CD) and the presence of gastrointestinal disease (GI) disease in children with autism. Subjects and Methods One hundred twenty-two children were tested for IgG and IgA anti-transglutaminase autoantibodies (55 autistic children with GI disease, 28 non autistic children with no GI disease, 30 autistic children with no GI disease, and 9 non autistic children with GI Disease). We also compared the presence/level of these autoantibodies to presence of anti-neutrophil cytoplasmic antibodies (ANCA) and level of Alpha-1 Antitrypsin (AAT). Results We did not find a significant difference in the level of anti-transglutaminase IgG or IgA in autistic children with GI disease compared to controls. However, we found a significant relationship between the presence of ANCA and low-level IgG anti-transglutaminase IgG in children with autism and GI disease. Discussion Although there appears to be no relationship between these celiac disease markers and the presence of GI disease in autistic children, these results suggest a possible association between sub diagnostic levels of anti-transglutaminase IgG and the presence of ANCA, and therefore, supports the hypothesis that there is a generalized autoimmune dysfunction in autistic children with GI disease.

目的本研究旨在确定自闭症儿童乳糜泻(CD)与胃肠道疾病(GI)之间是否存在关系。研究对象和方法对122例儿童进行IgG和IgA抗谷氨酰胺酶自身抗体检测，其中有胃肠道疾病的自闭症儿童55例，无胃肠道疾病的非自闭症儿童28例，无胃肠道疾病的自闭症儿童30例，有胃肠道疾病的非自闭症儿童9例。我们还比较了这些自身抗体的存在/水平与抗中性粒细胞胞浆抗体(ANCA)的存在和α -1抗胰蛋白酶(AAT)的水平。结果与对照组相比，患有胃肠道疾病的自闭症儿童抗转谷氨酰胺酶IgG或IgA水平无显著差异。然而，我们发现在自闭症和胃肠道疾病儿童中，ANCA的存在与低水平IgG抗谷氨酰胺酶IgG之间存在显著关系。虽然这些乳糜泻标志物与自闭症儿童的胃肠道疾病之间似乎没有关系，但这些结果表明，抗转谷氨酰胺酶IgG亚诊断水平与ANCA的存在之间可能存在关联，因此，支持自闭症儿童胃肠道疾病中存在全局性自身免疫功能障碍的假设。

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引用次数: 1

Chronic Periodontitis as a Risk Marker for Systemic Diseases with Reference to Cardiometabolic Disorders: Common Pathways in their Progression 慢性牙周炎是与心脏代谢紊乱相关的全身性疾病的危险标志:其进展的共同途径

Immunology and immunogenetics insights

Pub Date : 2010-01-01 DOI: 10.4137/III.S5795

M. Soory

Periodontitis, an inflammatory condition of the supporting structures of teeth resulting from dental plaque biofilm attached to tooth surfaces is potentially an important nidus of systemic inflammation and its sequelae. Relevant risk markers common to periodontitis co-existing with coronary heart disease and diabetes mellitus play an important role in their pathogeneses and abate in response to treatment. An over-exuberant host-response to periodontal pathogen- mediated inflammation, triggers a cycle of events which is not dissimilar to an autoimmune response in a cohort of susceptible individuals. Some variation in documented findings regarding correlations with co-morbidities and periodontitis could be explained by the lack of uniformity in studies with regard to stipulation of periodontal inflammatory status in the context of risk factors examined. There are several genetic and environmental factors which influence the progression of inflammatory periodontitis in response to plaque biofilm, also relevant to associated cardiometabolic disorders in the same subject. Some common mechanisms in the pathogeneses of periodontitis and cardiometabolic disorders based on regulation of inflammation are addressed in this review. There is some evidence of an improved systemic inflammatory profile in response to periodontal treatment which emphasizes the importance of periodontal management for systemic health in relevant cases.

牙周炎是一种由附着在牙齿表面的牙菌斑生物膜引起的牙齿支撑结构的炎症状态，是潜在的系统性炎症及其后遗症的重要病灶。牙周炎合并冠心病和糖尿病的相关危险标志物在其发病机制中起重要作用，并随治疗效果减弱。宿主对牙周病原体介导的炎症反应过度旺盛，会引发一系列事件，这与易感个体的自身免疫反应没有什么不同。文献中关于合并症和牙周炎相关性的研究结果存在一些差异，这可以解释为在检查的危险因素背景下，关于牙周炎症状态的研究缺乏一致性。有几个遗传和环境因素影响炎症性牙周炎对菌斑生物膜的反应，也与同一受试者的相关心脏代谢疾病有关。本文综述了基于炎症调节的牙周炎和心脏代谢紊乱的一些常见发病机制。有一些证据表明，在对牙周治疗的反应中，全身炎症状况得到改善，这强调了牙周管理对相关病例全身健康的重要性。

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引用次数: 9

Characteristics of Activated Monocyte Phenotype Support R5-Tropic Human Immunodeficiency Virus. 激活单核细胞表型支持r5 -回归线人类免疫缺陷病毒的特征。

Immunology and immunogenetics insights

Pub Date : 2009-01-01 DOI: 10.4137/iii.s2011

Sody M Munsaka, Melissa Agsalda, David Troelstrup, Ningjie Hu, Qigui Yu, Bruce Shiramizu

BACKGROUND: Microbial translocation has been recognized as an important factor in monocyte activation and contributing to AIDS pathogenesis with elevated plasma lipopolysaccharide (LPS) levels, as a marker for microbial translocation, seen in advanced HIV disease. Therefore, the current study was undertaken to assess monocyte activation in vitro by LPS and to determine its impact on monocyte phenotype. METHODS: Monocytes from non-HIV-infected donors were analyzed for CD14, CD16, CD69, TNFα, and CCR5 by flow cytometry pre- and post-stimulation with LPS. In-vitro cultures were then set up to expose non-activated and activated monocytes to R5-, X4-, and dual (R5/X4)-tropic viruses; and the amount of HIV present on the cells was assayed. RESULTS: Non-HIV-infected monocytes, after LPS stimulation, were confirmed to have an activated phenotype with increase in CD16 and CD69 surface expressions (p<0.05). The activation phenotype was supported by increase in TNFα production, p<0.05. The activated monocytes had increased surface CCR5 (from 21% to 98%; p=0.05); and were found to have more R5-tropic virus than non-activated monocytes (p<0.05). CONCLUSIONS: Following activation by LPS, non-HIV-infected monocytes were found to have increase in surface CCR5. These activated monocytes, when exposed to R5-tropic virus, were found to have more virus compared to non-activated monocytes. The significance of the findings could lie in explaining how microbial translocation plays a role in HIV progression; and possibly promoting CCR5-directed strategies in treating HIV.

背景:微生物易位已被认为是单核细胞活化的一个重要因素，并促进了艾滋病的发病机制，血浆脂多糖(LPS)水平升高是HIV晚期疾病中微生物易位的标志。因此，本研究旨在评估LPS在体外对单核细胞的激活，并确定其对单核细胞表型的影响。方法:通过流式细胞术分析来自非hiv感染供者的单核细胞在LPS刺激前后的CD14、CD16、CD69、TNFα和CCR5。然后建立体外培养，将非活化和活化的单核细胞暴露于R5、X4和双(R5/X4)向病毒;并检测细胞上存在的HIV的数量。结果:非hiv感染的单核细胞，在LPS刺激后，被证实具有活化的表型，CD16和CD69表面表达增加(p

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引用次数: 15

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