Formation of immune proteasomes and development of immune system in ontogenesis of mammals

Current concepts of the structure of immune proteasomes and their role in immune response have been considered. The main attention has been paid to the formation of immune proteasomes in secondary lymphoid and nonlymphoid organs during ontogenesis of mammals. The causes of ineffective formation of immune system in early postnatal development have been discussed.     

七鳃鳗鳃黏膜免疫系统类淋巴细胞免疫应答遗传基础

近年来,在无颌类脊椎动物七鳃鳗体内发现了以可变淋巴细胞受体(Variable lymphocyte receptors, VLR)为基础的抗原识别机制。为揭示七鳃鳗鳃黏膜免疫系统中类淋巴细胞适应性免疫应答的遗传基础,探索无颌类与有颌类脊椎动物在适应性免疫应答机制上的进化关系,本文构建了日本七鳃鳗(Lampetra japonica)鳃囊组织免疫前后cDNA文库并进行了高通量转录组测序及分析。通过对组装得到的88 525个独立基因(Unigene)进行功能注释,分别有21 704和9769个unigene在GO(Gene Ontology)和KEGG(Kyoto Encyclopedia of Genes and Genomes)数据库得到注释。999个unigene参与免疫系统的多个通路,其中184个与高等脊椎动物TCR(T cell receptor)和BCR(B cell receptor)信号通路的51个分子具有较高的同源关系,说明七鳃鳗体内存在高等脊椎动物适应性免疫应答信号通路的相关分子。本文还发现5个VLRA、7个VLRB和4个VLRC分子,说明七鳃鳗鳃黏膜免疫组织内至少分布3种类淋巴细胞亚群。实时荧光定量PCR结果显示,Lck、Fyn和Zap70基因在免疫激发后表达量显著上调,而Syk、Btk和Blnk基因表达没有显著变化,说明七鳃鳗鳃组织受到抗原刺激后,类似T淋巴细胞的信号转导途径被激活。本研究初步证明,尽管无颌类和有颌类脊椎动物的适应性免疫系统在抗原识别机制上存在不同,但具有共同的遗传基础。研究结果为探讨七鳃鳗VLRA⁺、VLRB⁺和VLRC⁺淋巴细胞免疫应答信号传导过程提供了有价值的线索。     

Discovering dominant tumor immune archetypes in a pan-cancer census

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Learning ability of young rats is unaffected by repeated exposure to a static electromagnetic field in early life

Infant albino rats were exposed to a static electromagnetic field of 0.0 Tesla (control) or 0.5 Tesla (experimental) for 14 postnatal days. Following a 1-month rest period, the experimental (13 males and 10 females) and control (11 males and 14 females) rats were trained on four successive reversals of a position habit in a single-unit enclosed T-maze that was adapted for the use of escape-avoidance of mild foot shock as a motive. There was no significant difference in learning ability between the experimental and control groups in terms of total (initial combined with repetitive) errors committed over the four reversal problems. While the females tended to make more errors than the males, this difference was likewise insignificant.     

Species comparison of anatomical and functional immune system development

The components of the immune system have not been traditionally emphasized as potential target organs in standard developmental and reproductive toxicity (DART) protocols. A number of workshops have been organized in recent years to examine scientific questions that underlie developmental immunotoxicity tests, and the interpretation of results as they relate to human risk assessment. A key question that must be addressed is to determine the most appropriate species and strains to model the developing human immune system. The objective of this review is to compare the anatomical and functional development of the immune system in several species important to either preclinical studies for drug development or safety assessments for chemicals, with what is known in humans. The development of the immune system in humans will be compared to what is known in mice, rats, dogs and nonhuman primates.     

Ecological immunology: life history trade-offs and immune defense in birds

There has been considerable recent interest in the effects oflife-history decisions on immunocompetence in birds. If immunocompetenceis limited by available resources, then trade-offs between investmentin life-history components and investment in immunocompetencecould be important in determining optimal life-history traits.For this to be true: (1) immunocompetence must be limited byresources, (2) investment in life-history components must benegatively correlated with immunocompetence, and (3) immunocompetencemust be positively correlated with fitness. To gather such empiricaldata, ecologists need to be able to measure immunocompetence.We review techniques used to measure immunocompetence and howthey are applied by ecologists. We also consider the componentsof the immune system that constitute immunocompetence and evaluatethe possible consequences of measuring immunocompetence in differentways. We then review the empirical evidence for life-historytrade-offs involving immune defense. We conclude that thereis some evidence suggesting that immunocompetence is limitedby resources and that investment in certain life-history componentsreduces immunocompetence. However, the evidence that immunocompetenceis related to fitness is circumstantial at present, althoughconsistent with the hypothesis that immunocompetence and fitnessare positively correlated. We argue that future work needs toexamine the fitness effects of variation in immunocompetenceand suggest that artificial selection experiments offer a potentiallyimportant tool for addressing this issue.     

Evaluation of chronic immune system stimulation models in growing pigs

Two experiments (EXPs) were conducted to evaluate models of immune system stimulation (ISS) that can be used in nutrient metabolism studies in growing pigs. In EXP I, the pig's immune response to three non-pathogenic immunogens was evaluated, whereas in EXP II the pig's more general response to one of the immunogens was contrasted with observations on non-ISS pigs. In EXP I, nine growing barrows were fitted with a jugular catheter, and after recovery assigned to one of three treatments. Three immunogens were tested during a 10-day ISS period: (i) repeated injection of increasing amounts of Escherichia coli lipopolysaccharide (LPS); (ii) repeated subcutaneous injection of turpentine (TURP); and (iii) feeding grains naturally contaminated with mycotoxins (MYCO). In EXP II, 36 growing barrows were injected repeatedly with either saline (n = 12) or increasing amounts of LPS (n = 24) for 7 days (initial dose 60 μg/kg body weight). Treating pigs with TURP and LPS reduced feed intake (P < 0.02), whereas feed intake was not reduced in pigs on MYCO. Average daily gain (ADG; kg/day) of pigs on LPS (0.50) was higher than that of pigs on TURP (0.19), but lower than that of pigs on MYCO (0.61; P < 0.01). Body temperature was elevated in pigs on LPS and TURP, by 0.8°C and 0.7°C, respectively, relative to pre-ISS challenge values (39.3°C; P < 0.02), but remained unchanged in pigs on MYCO. Plasma concentrations of interleukin-1β were increased in pigs treated with LPS and TURP (56% and 55%, respectively, relative to 22.3 pg/ml for pre-ISS; P < 0.01), but not in MYCO-treated pigs. Plasma cortisol concentrations remained unchanged for pigs on MYCO and TURP, but were reduced in LPS-treated pigs (30% relative to 29.8 ng/ml for pre-ISS; P < 0.05). Red blood cell glutathione concentrations were lower in TURP-treated pigs (13% relative to 1.38 μM for pre-ISS; P < 0.05), but were unaffected in pigs on LPS and MYCO. In EXP I, TURP caused severe responses including skin ulceration and substantial reductions in feed intake and ADG, whereas MYCO did not induce effective ISS. In EXP II, ISS increased relative organ weights, eye temperature, white blood cell count and plasma acute-phase proteins (P < 0.05), confirming that repeated injection with increasing amounts of LPS induced chronic and relatively mild ISS. Repeated injection with increasing amounts of LPS is a suitable model for studying nutrient metabolism and evaluating the efficacy of nutritional intervention during chronic ISS in growing pigs.     

Chronic mTOR inhibition in mice with rapamycin alters T,B, myeloid,and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

The mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.     

免疫系统区室化与上皮细胞局部微环境中的免疫调节作用

近年来,免疫系统区室化（compartmentalization of immune system）的概念逐渐引起了人们的重视。对各类免疫及非免疫器官中的免疫区室化现象进行深入研究,有助于进一步了解机体免疫系统、免疫应答以及免疫相关疾病的发病机制,并可提供新的应对策略。上皮细胞体内广泛分布,承载机体多种重要生理功能。它作为免疫防御首道防线参与免疫系统区室化形成,并在免疫反应局部微环境中,既可与免疫细胞相互作用发挥固有免疫调节作用,亦可通过自身转分化调节后续适应性免疫应答,在抵御及清除病原体入侵、调控局部炎症免疫反应以及促进组织损伤修复中,发挥了不可或缺的重要作用。病理状态下,上皮细胞又可能是免疫稳态失衡甚或肿瘤发生发展的关键因素。结合免疫系统区室化,对上皮细胞在局部微环境中的免疫调节作用作一综述,为免疫相关疾病的研究以及临床诊疗提供新的思路和策略。     

Scale-free dynamics of somatic adaptability in immune system

The long-time dynamics of somatic adaptability in immune system is simulated by a simple physical model defined in the shape space. The immune system described by the model exhibits a scale free behavior as is observed in living systems. The balance between the positive and negative feedbacks of the model leads to a robust immune system where the positive one corresponds to the formation of memory cells and the negative one to immunosuppression. Also the immunosenescence of the system is discussed based on the time-dependence of the epigenetic landscape of the adaptive immune cells in the shape space.     

The role of the maternal immune system in the regulation of human birthweight

Human birthweight is subject to stabilizing selection. Large babies are at risk of obstetric complications such as obstructed labour, which endangers both mother and child. Small babies are also at risk with reduced survival. Fetal growth requires remodelling of maternal spiral arteries to provide an adequate maternal blood supply to the placenta. This arterial transformation is achieved by placental trophoblast cells, which invade into the uterine wall. Under-invasion is associated with fetal growth restriction; but if invasion is excessive large babies can result. A growing body of evidence suggests that this process is controlled by interactions between killer-cell immunoglobulin-like receptors (KIRs) expressed on maternal uterine natural killer cells (uNK) and their corresponding human leukocyte antigen-C (HLA-C) ligands on invading trophoblast. Mothers with the KIR AA genotype and a fetus with a paternal HLA-C2 allele tend to have small babies, because this combination inhibits cytokine secretion by uNK. Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases secretion of cytokines that enhance trophoblast invasion. We conclude that specific combinations of the highly polymorphic gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birthweight between two extremes.     

From the urban metabolism to the urban immune system

Urban areas face mounting risks from many sources. Cities pursue myriad tactics to resist, recover from and adapt to shocks and stresses, but little is known about how these approaches relate across the scales of a city nor how cities compare in their abilities. Part of the challenge in addressing these gaps is that the risk to cities is typically studied with an emphasis on one or a few hazards or through the lens of a singular sector. This paper proposes a framework, dubbed the Urban Immune System (UIS) to coalesce and expand industrial ecology research on urban risk management. In the same way that Urban Metabolism (UM) is a unifying framework for urban environmental sustainability, UIS can be a unifying framework for urban resilience, especially related to climate change. Herein, UIS is defined, its many capabilities are dissected and linked to disparate studies; and opportunities for application of the concept are provided. The paper concludes by examining the relationship between UIS and climate change and by identifying those attributes of the UIS that are expected to be of increasing importance under climate change.     

Behavioural conditioning as the mediator of placebo responses in the immune system

Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have been demonstrated in experimental animals, healthy subjects and patients. The physiological mechanisms responsible for this 'learned immune response' are not yet fully understood, but some relevant afferent and efferent pathways in the communication between the brain and the peripheral immune system have been identified. In addition, possible benefits and applicability in clinical settings have been demonstrated where behaviourally conditioned immunosuppression attenuated the exacerbation of autoimmune diseases, prolonged allograft survival and affected allergic responses. Here, we summarize data describing the mechanisms and the potential clinical benefit of behaviourally conditioned immune functions, with particular focus on learned placebo effects on allergic reactions.     

早期口服益生菌对早产儿免疫系统及消化系统的影响

目的探讨出生后早期口服益生菌对早产儿免疫系统及消化系统的影响,为临床合理应用益生菌提供参考。方法选取2018年4月至2018年10月入住武汉同济医院新生儿科的40例早产儿(胎龄28～34周,出生体质量2 500 g)为研究对象,按单双号编号法随机分为观察组(20例)和对照组(20例),观察组患儿出生后第1天起给予鼠李糖乳杆菌溶液(Lactobacillus rhamnosus GG,LGG,4×10~9 CFU/mL, 0.25 mL/d),对照组患儿给予等量的LGG空白溶液(玉米油)口服,疗程30 d。抽取两组患儿生后第1天和第42天时2 mL血液检测免疫球蛋白(IgM、IgG)及T淋巴细胞亚群(B淋巴细胞百分比、CD3~+ T细胞百分比、CD4~+ T细胞百分比、CD8~+ T细胞百分比、CD4~+T/CD8~+T比值)水平,并记录患儿胃潴留、腹胀、呕吐、喂养不耐受、坏死性小肠结肠炎的发生情况及患儿生长情况。结果最终观察组和对照组均有16例患儿完成了研究。出生后第1天,两组患儿血液IgG、IgM和T淋巴细胞亚群水平差异无统计学意义。出生后第42天,观察组患儿CD8~+T细胞百分比低于对照组、CD4~+T/CD8~+T比值高于对照组,差异均有统计学意义(均P0.05)。与对照组相比,治疗后观察组患儿胃潴留(18.8%vs 50.0%)、腹胀(6.25%vs 18.8%)、呕吐(12.5%vs 18.8%)、喂养不耐受(25.0%vs 56.3%)及坏死性小肠结肠炎(0例vs 2例)的发生率均较低。两组患儿出院体质量及出生后第42天体质量差异无统计学意义(均P0.05)。结论出生后早期口服益生菌能够提高早产儿的细胞免疫功能,并且在增强早产儿胃肠动力、降低喂养不耐受及坏死性小肠结肠炎发病率方面发挥一定的作用。     

Maintenance versus growth: investigating the costs of immune activation among children in lowland Bolivia

Immune function is a central component of maintenance effort, and it provides critical protection against the potentially life threatening effects of pathogens. However, immune defenses are energetically expensive, and the resources they consume are not available to support other activities related to growth and/or reproduction. In our study we use a life history theory framework to investigate tradeoffs between maintenance effort and growth among children in a remote area of Amazonian Bolivia. Baseline concentrations of C-reactive protein (CRP) were measured in 309 2- to 10-year olds as an indicator of immune activation, and height was measured at baseline and three months later. Elevated CRP at baseline predicts smaller gains in height over the subsequent three months, with the costs to growth particularly high for 2- to 4-year olds and for those with low energy reserves (in the form of body fat) at the time of immunostimulation. These results provide evidence for a significant tradeoff between investment in immunity and growth in humans, and highlight an important physiological mechanism through which maintenance effort may have lasting effects on child growth and development.     

Viruses and the immune system: their roles in seizure cascade development

Viral encephalitis affects approximately 7.5 people/100 000 and carries a high rate of morbidity and mortality. Most patients with viral encephalitis will develop some form of seizure during the infectious process, and of those who survive encephalitic disease, approximately 4–20% will develop epilepsy. Arthropod-borne (arbo)viruses are the leading cause of viral encephalitis in the world today, with between 10% and 35% of patients infected with these viruses displaying some form of seizure. Several neurotropic DNA viruses, including Herpes and cytomegalovirus also commonly cause seizures in infected patients. In the clinical setting, the cause of seizures seen during viral encephalitis is usually attributed to acute febrile responses. However, it has become apparent that the mechanisms behind seizure generation during viral encephalitis are likely to be much more complicated. For example, CD4⁺ and CD8⁺ T cells possibly through their secretion of interferon-γ, appear to play an important role in determining neuronal responses when challenged with kainic acid. In addition, the ability of the human immunodeficiency virus, transactivating protein to modulate NMDA signaling possibly triggering seizures, highlights the fact that elements of the antiviral response and even virally derived proteins are capable of directly manipulating neuronal function. Understanding the complex relationships between the CNS, the immune system, and invading pathogens is a critical step in understanding the pathogenesis of seizures seen during viral infections and informing the development of novel therapies.     

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Dimethyl fumarate (DMF) is an important oral treatment option for various autoimmune diseases, such as multiple sclerosis (MS) and psoriasis. DMF and its dynamic metabolite, monomethyl fumarate (MMF) are the major compounds that exert therapeutic effects on several pathologic conditions in part, through downregulation of immune responses. The exact mechanism of DMF is yet to be fully understood even though its beneficial effects on the immune system are extensively studied. It has been shown that DMF/MMF can affect various immune cells, which can get involved in both the naive and adaptive immune systems, such as T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells. It is suggested that DMF/MMF may exert their effect on immune cells through inhibition of nuclear factor-κB translocation, upregulation of nuclear factor erythroid-derived 2(E2)-related factor antioxidant pathway, and activation of hydroxyl carboxylic acid receptor 2. In this review, the mechanisms underlying the modulatory functions of DMF or MMF on the main immune cell populations involved in the immunopathogenesis of MS are discussed.     

A quasispecies approach to viral evolution in the context of an adaptive immune system

A deeper understanding of the mechanisms that determine viral evolution in the context of an adaptive immune system is vital for the development of efficient strategies to defeat viral infections. The problem of describing these mechanisms is discussed using the concept of quasispecies. Conditions for both an optimal immune response and for highest viral viability are derived from theoretical models and are supported by empirical data.     

Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation

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