Cell-mediated Immune Responses in Chronic Liver Diseases

Studies of the cell-mediated response to liver antigens, using the leucocyte migration test, in 163 patients with various liver disorders showed that abnormal responses were almost confined to active chronic hepatitis (53% abnormal), primary biliary cirrhosis (64%), and cryptogenic cirrhosis (29%). The test was also abnormal in five out of seven patients with jaundice due to drug hypersensitivity and in one patient with acute infectious hepatitis at a time when mitochondrial antibodies were present in the serum. More of those with active chronic hepatitis on prednisone or azathioprine had normal tests than of those who were untreated, and in 8 out of 10 examined serially during therapy there was an accompanying improvement in leucocyte migration. Abnormal responses to salivary gland or kidney antigens were also found in nearly half of those with features of Sjögren''s syndrome or renal tubular acidosis as part of a multisystem involvement—this, though occurring in cryptogenic cirrhosis, was found with greater frequency in active chronic hepatitis and primary biliary cirrhosis. These cell-mediated immune responses, perhaps triggered by the initial damage to the liver from viral or other agents, may be responsible both for the perpetuation of the liver disease and, because of common surface antigens, for the damage to other organs.     

心血管疾病在他汀类药物多效性中的获益

心血管疾病是危害人类健康的严重疾病,是造成死亡的重要原因。随着社会的发展,人们生活水平的提高,人口的老龄化,心血管疾病已经成为仅次于肿瘤的第二大杀手。他汀类药物在心血管疾病特别是冠状动脉粥样硬化性心脏病的防治中意义重大,其对血脂的的确切调节作用已经被大家所认可,并被公认为是此类药物临床获益的首要机制。然而,随着他汀类药物的广泛应用与基础、临床研究的不断深入,越来越多的证据表明除了对血脂的调节作用,他汀类药物还有抗炎症反应、抗氧化应激、减轻血管内皮损伤、改善心肌重塑、抑制血栓形成和抗血小板聚集、保护肾功能等其他作用,这些独立于降脂作用的其他作用统称为他汀类药物的多效性。他汀类药物多效性的发现进一步增加了其在心血管疾病防治中的临床应用价值。本文就几种常见心血管疾病在他汀类药物多效性中的获益做一简单介绍。     

Identification of Potential Pleiotropic Genes for Immune and Skeletal Diseases Using Multivariate MetaCCA Analysis

BackgroundImmune and skeletal systems physiologically and pathologically interact with each other. Immune and skeletal diseases may share potential pleiotropic genetics factors, but the shared specific genes are largely unknown.ObjectiveThis study aimed to investigate the overlapping genetic factors between multiple diseases (including rheumatoid arthritis (RA), psoriasis, osteoporosis, osteoarthritis, sarcopenia, and fracture).MethodsThe canonical correlation analysis (metaCCA) approach was used to identify the shared genes for six diseases by integrating genome-wide association study (GWAS)-derived summary statistics. The versatile Gene-based Association Study (VEGAS2) method was further applied to refine and validate the putative pleiotropic genes identified by metaCCA.ResultsAbout 157 (p<8.19E-6), 319 (p<3.90E-6), and 77 (p<9.72E-6) potential pleiotropic genes were identified shared by two immune diseases, four skeletal diseases, and all of the six diseases, respectively. The top three significant putative pleiotropic genes shared by both immune and skeletal diseases, including HLA-B, TSBP1, and TSBP1-AS1 (p<E-300), were located in the major histocompatibility complex (MHC) region. Nineteen of 77 putative pleiotropic genes identified by metaCCA analysis were associated with at least one disease in the VEGAS2 analysis. Specifically, the majority (18) of these 19 putative validated pleiotropic genes were associated with RA.ConclusionThe metaCCA method identified some pleiotropic genes shared by the immune and skeletal diseases. These findings help to improve our understanding of the shared genetic mechanisms and signaling pathways underlying immune and skeletal diseases.     

Pleiotropic Models of Quantitative Variation

It is widely held that each gene typically affects many characters, and that each character is affected by many genes. Moreover, strong stabilizing selection cannot act on an indefinitely large number of independent traits. This makes it likely that heritable variation in any one trait is maintained as a side effect of polymorphisms which have nothing to do with selection on that trait. This paper examines the idea that variation is maintained as the pleiotropic side effect of either deleterious mutation, or balancing selection. If mutation is responsible, it must produce alleles which are only mildly deleterious (s approximately 10(-3)), but nevertheless have significant effects on the trait. Balancing selection can readily maintain high heritabilities; however, selection must be spread over many weakly selected polymorphisms if large responses to artificial selection are to be possible. In both classes of pleiotropic model, extreme phenotypes are less fit, giving the appearance of stabilizing selection on the trait. However, it is shown that this effect is weak (of the same order as the selection on each gene): the strong stabilizing selection which is often observed is likely to be caused by correlations with a limited number of directly selected traits. Possible experiments for distinguishing the alternatives are discussed.     

外泌体及其抗肿瘤作用机制

外泌体是由细胞分泌到胞外的囊泡状小体,体内多种细胞可以分泌外泌体,来源于树突状细胞（DC）和肿瘤细胞的外泌体表面表达MHC分子和抗原肽,体内外实验证明其具有抗肿瘤的作用,因此外泌体作为抗肿瘤疫苗被广泛研究。该文介绍外泌体的发现、蛋白质组成、体内抗肿瘤的机制,以及DC与肿瘤来源的外泌体的基础及临床研究。     

Pleiotropic Overdominance and the Maintenance of Genetic Variation in Polygenic Characters

A model of selection is described in which optimizing phenotypic selection is combined with pleiotropic overdominance. Thus, the role that mutation commonly plays in models of phenotypic evolution is replaced by balancing selection. Expressions are provided for the equilibrium genetic variance in phenotype and for the heterozygosity. An approximate analysis of the transient properties of the model shows that, in certain circumstances, the behavior is quite similar to that of models based on the interaction of mutation and selection.     

Individual Variation in Influenza A Virus Infection Histories and Long-Term Immune Responses in Mallards

Wild dabbling ducks (genus Anas) are the main reservoir for influenza A virus (IAV) in the Northern Hemisphere. Current understanding of disease dynamics and epidemiology in this virus-host system has primarily been based on population-level surveillance studies and infection experiments conducted in laboratory settings. Using a combined experimental-natural approach with wild-strain captive mallards (Anas platyrhynchos), we monitored individual IAV infection histories and immunological responses of 10 birds over the course of 15 months. This is the first detailed study to track natural IAV infection histories over several seasons amongst the same individuals growing from juvenile to adults. The general trends in the infection histories of the monitored birds reflected seasonal variation in prevalence at the population level. However, within the study group there were significant differences between individuals in infection frequency as well as in short and long term anti-IAV antibody response. Further observations included individual variation in the number of infecting virus subtypes, and a strong tendency for long-lasting hemagglutinin-related homosubtypic immunity. Specifically, all infections in the second autumn, except one, were of different subtypes compared to the first autumn. The variation among birds concerning these epidemiologically important traits illustrates the necessity for IAV studies to move from the level of populations to examine individuals in order to further our understanding of IAV disease and epidemiology.     

A Pleiotropic Nonadditive Model of Variation in Quantitative Traits

A model of mutation-selection-drift balance incorporating pleiotropic and dominance effects of new mutations on quantitative traits and fitness is investigated and used to predict the amount and nature of genetic variation maintained in segregating populations. The model is based on recent information on the joint distribution of mutant effects on bristle traits and fitness in Drosophila melanogaster from experiments on the accumulation of spontaneous and P element-induced mutations. These experiments suggest a leptokurtic distribution of effects with an intermediate correlation between effects on the trait and fitness. Mutants of large effect tend to be partially recessive while those with smaller effect are on average additive, but apparently with very variable gene action. The model is parameterized with two different sets of information derived from P element insertion and spontaneous mutation data, though the latter are not fully known. They differ in the number of mutations per generation which is assumed to affect the trait. Predictions of the variance maintained for bristle number assuming parameters derived from effects of P element insertions, in which the proportion of mutations with an effect on the trait is small, fit reasonably well with experimental observations. The equilibrium genetic variance is nearly independent of the degree of dominance of new mutations. Heritabilities of between 0.4 and 0.6 are predicted with population sizes from 10(4) to 10(6), and most of the variance for the metric trait in segregating populations is due to a small proportion of mutations (about 1% of the total number) with neutral or nearly neutral effects on fitness and intermediate effects on the trait (0.1-0.5σ(P)). Much of the genetic variance is contributed by recessive or partially recessive mutants, but only a small proportion (about 10%) of the genetic variance is dominance variance. The amount of apparent selection on the trait itself generated by the model is very small. If a model is assumed in which all mutation events have an effect on the quantitative trait, the majority of the genetic variance is contributed by deleterious mutations with tiny effects on the trait. If such a model is assumed for viability, the heritability is about 0.1, independent of the population size.     

Comparative Genomics Reveal That Host-Innate Immune Responses Influence the Clinical Prevalence of Legionella pneumophila Serogroups

Legionella pneumophila is the primary etiologic agent of legionellosis, a potentially fatal respiratory illness. Amongst the sixteen described L. pneumophila serogroups, a majority of the clinical infections diagnosed using standard methods are serogroup 1 (Sg1). This high clinical prevalence of Sg1 is hypothesized to be linked to environmental specific advantages and/or to increased virulence of strains belonging to Sg1. The genetic determinants for this prevalence remain unknown primarily due to the limited genomic information available for non-Sg1 clinical strains. Through a systematic attempt to culture Legionella from patient respiratory samples, we have previously reported that 34% of all culture confirmed legionellosis cases in Ontario (n = 351) are caused by non-Sg1 Legionella. Phylogenetic analysis combining multiple-locus variable number tandem repeat analysis and sequence based typing profiles of all non-Sg1 identified that L. pneumophila clinical strains (n = 73) belonging to the two most prevalent molecular types were Sg6. We conducted whole genome sequencing of two strains representative of these sequence types and one distant neighbour. Comparative genomics of the three L. pneumophila Sg6 genomes reported here with published L. pneumophila serogroup 1 genomes identified genetic differences in the O-antigen biosynthetic cluster. Comparative optical mapping analysis between Sg6 and Sg1 further corroborated this finding. We confirmed an altered O-antigen profile of Sg6, and tested its possible effects on growth and replication in in vitro biological models and experimental murine infections. Our data indicates that while clinical Sg1 might not be better suited than Sg6 in colonizing environmental niches, increased bloodstream dissemination through resistance to the alternative pathway of complement mediated killing in the human host may explain its higher prevalence.     

Strain Dependent Variation of Immune Responses to A. fumigatus: Definition of Pathogenic Species

For over a century microbiologists and immunologist have categorized microorganisms as pathogenic or non-pathogenic species or genera. This definition, clearly relevant at the strain and species level for most bacteria, where differences in virulence between strains of a particular species are well known, has never been probed at the strain level in fungal species. Here, we tested the immune reactivity and the pathogenic potential of a collection of strains from Aspergillus spp, a fungus that is generally considered pathogenic in immuno-compromised hosts. Our results show a wide strain-dependent variation of the immune response elicited indicating that different isolates possess diverse virulence and infectivity. Thus, the definition of markers of inflammation or pathogenicity cannot be generalized. The profound understanding of the molecular mechanisms subtending the different immune responses will result solely from the comparative study of strains with extremely diverse properties.     

CpG对乙型肝炎基因重组(CHO细胞)疫苗免疫效果的影响

为了研究CpG-寡脱氧核苷酸(CpG-OPN)作为佐剂对乙型肝炎基因重组(CHO细胞)疫苗(简称乙肝疫苗)免疫效果的影响,以乙肝疫苗加Al(OH)3、疫苗加CpG和疫苗加Al(OH)3与CpG3三种配伍方式,通过腹腔、皮下或肌内3种不同途径免疫Balb/c小鼠,观察不同免疫途径和不同配伍的免疫效果.同时又将疫苗与CpG混合后在4℃存放6个月再免疫小鼠,观察CpG的稳定性.结果表明:①3种免疫途径中以肌内注射效果最好,这在使用CpG的实验组尤为明显,在该组肌内免疫的ED50比腹腔的低了10倍,而诱发的抗体滴度提高了3倍;②疫苗与CpG、Al(OH)3联合使用的免疫效果最好,在肌内免疫时联合使用的免疫效果比疫苗+Al(OH)3提高4倍,比疫苗+CpG提高7倍;③疫苗+Al(OH)3免疫时,表现为IgG1抗体亚型占优势,而再加入CpG后则IgG1和IgG2a均升高,以IgG2a最显著;④疫苗与CpG混合后4℃保存半年,不影响其活性.     

Pleiotropic Effects of Suppressor Mutations in Bacillus subtilis

Isogenic strains of Bacillus subtilis carrying sup-1 (26), sup-3 (10), or their wild-type alleles were constructed in three genetic backgrounds. The patterns of suppression at 37 and 43.5 C, identity of mapping site, effects of the suppressor genes on growth rate, sporulation, and production of altered enzymes were examined. The similarity of the suppression pattern by sup-1 and sup-3 suggests that the suppressors are of the same type. They do not, however, represent mutations in the same gene, since, based on differences in temperature sensitivity of phage mutants in suppressor-containing hosts, sup-1 and sup-3 insert different amino acids and can coexist within the same cell. The ability to produce slow-migrating forms of enzymes of the type described in the accompanying paper was co-transferred with either of the suppressor genes during transformation, was lost on reversion of the suppressor mutations, and was independent of the genetic background. Similarly, transformation and reversion studies indicate that the additional pleiotropic properties such as slow growth rate and inability to attain competence or to yield plaques with phi105C4, which are characteristic of the Okubo sup-1 strain (HA101B) but not its early sporulation defect, result from the presence of the suppressor mutation. The possible mechanisms by which altered enzyme forms and the additional pleiotropic effects are produced in suppressor strains are discussed. In addition, a newly recognized suppressor phenotype is described and partially characterized.     

Effects of Starvation and Refeeding on Glucose Metabolism and Immune Responses in Macrobrachium rosenbergii

Marine Biotechnology - Starvation is a common challenge for aquatic animals in both natural and cultured environments. To investigate the effects of starvation and refeeding on glucose metabolism...     

The Adverse Effects of Se Toxicity on Inflammatory and Immune Responses in Chicken Spleens

Selenium (Se) is an essential trace element, but excessive intake of Se could induce Se poisoning, and result in various health problems. NF-κB regulated many molecules of the immune response and the inflammatory response, and Th1/Th2 balance played a key in the regulation of immune response. The aim of this study is to investigate the role of NF-κB pathway and Th1/Th2 imbalance in the adverse influence of Se poisoning on chicken spleens. In the current study, 90 chickens were randomly divided into two groups (n?=?45 per group). The chickens were maintained either on a basal diet (the control group) containing 0.2 mg/kg Se or a high supplemented diet (the Se group) containing 15 mg/kg Se for 45 days. Then, we observed the pathohistology of spleen cells and detected NO content, iNOS activity, and the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, Foxp3, IL-4, and IFN-γ in chicken spleens. In chicken spleens of the Se group, the result showed typical characteristics of inflammation: the content of NO and the activity of iNOS were increased, and the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, and IL-4 was enhanced and that of Foxp3 and IFN-γ was decreased. Our study showed that Se toxicity could promote inflammation via NF-κB pathway, impairing the immune function, and changing Th1/Th2 balance in the chicken spleens.