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Results for “Immunology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 91 records · Page 5Linked to original sources

bioRxiv2018

The CD56bright CD62L+ NKG2A+ immature cell subset is dominantly expanded in human cytokine-induced memory-like NK cells

Recent studies have revealed immunological memory of NK cells. Short-term in vitro cytokine stimulation also induces NK cell memory, but heterogeneous cell subsets within the cytokine-induced memory-like (CIML) NK cells has not been elucidated. Here we found that the dominant cell subset in human CIML NK cells are immature CD56bright CD62L+cells, and they were selectively expanded CD56bright CD16- CD62L+ NK cells. Although these cells acquired KIR expression after the cytokine stimulation, sustained NKG2A expression inhibits cytotoxicity against HLA-E+ target cells. In contrast, another checkpoint molecule LAG-3 is induced mainly on KIR+ NKG2C+ minor CIML NK cells. Our findings imply targeting NKG2A and LAG-3 should be considered for CIML NK cell-based immunotherapy.

immunology↗

bioRxiv2018

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other difficult pathogens, due to the significant immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine needle aspirates, we found that two independent methods of slow delivery immunization of rhesus macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified differential IgV gene usage between slow delivery immunized and conventional bolus immunized animals. The most immunodominant IgV gene used by conventionally immunized animals was associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb development by altering GCs and modulating immunodominance of non-neutralizing epitopes.

immunology↗

bioRxiv2018

TCR-pMHC bond length controls TCR ligand discrimination

T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses1-4. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered question in immunology. Here we show that a TCR discriminates between closely related peptides by forming TCR-pMHC bonds with different lengths, which precisely control the accessibility of CD3{zeta} immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation. Using in situ fluorescence resonance energy transfer (FRET)3,5, we measured the intermolecular length of single TCR-pMHC bonds and the intramolecular distance of individual TCR-CD3{zeta} complexes at the membrane of live primary T cells. We found that an agonist forms a short TCR-pMHC bond to pull the otherwise sequestered CD3{zeta} off the inner leaflet of the plasma membrane, leading to full exposure of its ITAMs for strong phosphorylation. By contrast, a structurally similar weaker peptide forms a longer bond with the TCR, resulting in partial dissociation of CD3{zeta} from the membrane and weak phosphorylation. Furthermore, we found that TCR-pMHC bond length determines 2D TCR binding kinetics and affinity, T-cell calcium signaling and T-cell proliferation, governing the entire process of signal reception, transduction and regulation. Thus, our data reveal the fundamental mechanism by which a TCR deciphers the structural differences between foreign antigens and self-peptides via TCR-pMHC bond length to initiate different TCR signaling for ligand discrimination.

immunology↗

bioRxiv2018

Immune profiling of cord blood after prolonged rupture of membranes.

We hypothesised that foetal immune responses to an infectious challenge may be detected by genome-wide transcriptional profiling of cord blood. In order to test this hypothesis, we sought to identify transcriptomic changes in post-natal cord blood samples following prolonged pre-labour rupture of membranes (PROM) as a surrogate for increased risk of infection. By comparison to controls we found increased levels of blood transcripts in a subset of prolonged PROM cases, significantly enriched for innate immune system signalling pathways. These changes were idiosyncratic, suggesting qualitative and quantitative variation in foetal immune responses which may reflect differences in exposure and/or in host genetics. Our data support the view that PROM represents an infection risk to the foetus. In addition, we propose that cord blood transcriptional profiling offers exciting opportunities to identify immune correlates of clinical outcome following potential in utero exposures to infection. These may be used to elucidate the mechanisms of immunological protection and pathology in the foetus and identify biomarkers to stratify the risk of adverse outcomes.

immunology↗

bioRxiv2018

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

Eradication of tuberculosis (TB), the worlds leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in preclinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guerin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFN{gamma}, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.\n\nAuthor summaryTuberculosis (TB) causes more deaths than any other single infectious disease, and a new, improved vaccine is needed to control the epidemic. Many new TB vaccine candidates are in clinical development, but only one or two can be advanced to expensive efficacy trials. In this study, we compared magnitude and functional attributes of memory T cell responses induced in recently conducted clinical trials by six TB vaccine candidates, as well as BCG. The results suggest that these vaccines induced CD4 and CD8 T cell responses with similar functional attributes, but that one vaccine, M72/AS01E, induced the largest responses. This finding may indicate a lack of diversity in T cell responses induced by different TB vaccine candidates. A repertoire of vaccine candidates that induces more diverse immune response characteristics may increase the chances of finding a protective vaccine against TB.

immunology↗

bioRxiv2013

A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction

Graphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC=\"FIGDIR/small/000380_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@197f26org.highwire.dtl.DTLVardef@1eac3f3org.highwire.dtl.DTLVardef@1e698f1org.highwire.dtl.DTLVardef@42fb4b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe model the cholesterol biosynthesis pathway and its regulation\nC_LIO_LIThe innate immune response leads to a suppression of flux through the pathway\nC_LIO_LIStatin inhibitors show a different mode of suppression to the immune response\nC_LIO_LIStatin inhibitor suppression is less robust and less specific than immune suppression\nC_LI\n\nAsbtractThe cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalyzing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus infection or treated with IFN{gamma}, we show that, under these assumptions, coordinate down regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses.

Systems Biology↗

bioRxiv2014

Immune stimulation reduces sleep and memory ability in Drosophila melanogaster

Psychoneuroimmunology studies the increasing number of connections between neurobiology and immunology. We establish Drosophila melanogaster as a tractable model in this field by demonstrating the effects of the immune response on two fundamental behaviours: sleep and memory ability.\n\nWe used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. Importantly, by stimulating the immune system of adult flies in the absence of infection we have avoided the added complications of developmental and disease effects that have confounded other studies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep.\n\nImmune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. The effects on sleep were more pronounced for day compared to night sleep. Immune stimulated flies also showed a reduction in memory abilities.\n\nThese are important results as they establish Drosophila as a model for immune-neural interactions and provide a possible role for sleep in the interplay between the immune response and memory.

Zoology↗

bioRxiv2014

Quantitative comparison of single-cell sequencing methods using hippocampal neurons

Single-cell genomic analysis has grown rapidly in recent years and will find widespread applications in various fields of biology, including cancer biology, development, immunology, pre-implantation genetic diagnosis, and neurobiology. In this study, we amplified genomic DNA from individual hippocampal neurons using one of three single-cell DNA amplification methods (multiple annealing and looping-based amplification cycles (MALBAC), multiple displacement amplification (MDA), and GenomePlex whole genome amplification (WGA4)). We then systematically evaluated the genome coverage, GC-bias, reproducibility, and copy number variations among individual neurons. Our results showed that single-cell genome sequencing results obtained from the MALBAC and WGA4 methods are highly reproducible and have a high success rate. Chromosome-level and subchromosomal-level copy number variations among individual neurons can be detected.

Genomics↗

bioRxiv2014

Quantitative comparison of single-cell sequencing methods using hippocampal neurons

Genomics↗

bioRxiv2014

Extensive capsule locus variation and large-scale genomic recombination within the Klebsiella pneumoniae clonal complex 258/11.

Klebsiella pneumoniae clonal complex (CC) 258/11, comprising sequence types (STs) 258, 11 and closely related STs, is associated with dissemination of the K. pneumoniae carbapenemase (KPC). Hospital outbreaks of KPC CC258/11 infections have been observed globally and are very difficult to treat. As a consequence there is renewed interest in alternative infection control measures such as vaccines and phage or depolymerase treatments targeting the K pneumoniae polysaccharide capsule. To date, 78 immunologically distinct capsule variants have been described in K. pneumoniae. Previous investigations of ST258 and a small number of closely related strains suggested capsular variation was limited within this clone; only two distinct ST258 capsular synthesis (cps) loci have been identified, both acquired through large-scale recombination events (>50 kbp). Here we report comparative genomic analysis of the broader K. pneumoniae CC258/11. Our data indicate that several large-scale recombination events have shaped the genomes of CC258/11, and that definition of the complex should be broadened to include ST395 (also reported to harbour KPC). We identified 11 different cps loci within CC258/11, suggesting that capsular switching is actually common within the complex. We also observed several insertion sequences (IS) within the cps loci, and show further diversification of two loci through IS activity. These findings suggest the capsular loci of clinically important K. pneumoniae are under diversifying selection, which alters our understanding of the evolution of this important clone and has implications for the design of control measures targeting the capsule.

Genomics↗

bioRxiv2015

Partitioning heritability by functional category using GWAS summary statistics

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

Genetics↗

bioRxiv2015

Mediated pleiotropy between psychiatric disorders and autoimmune disorders revealed by integrative analysis of multiple GWAS

Epidemiological observations and molecular-level experiments have indicated that brain disorders in the realm of psychiatry may be influenced by immune dysregulation. However, the degree of genetic overlap between immune disorders and psychiatric disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies (GWAS) of 18 complex human traits/diseases (five psychiatric disorders, seven autoimmune disorders, and others) and multiple genomewide annotation resources (Central nervous system genes, immune-related expressionquantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell-lines). We detected pleiotropy in 24 of the 35 psychiatric-autoimmune disorder pairs, with statistical significance as strong as p=3.9e-285 (schizophrenia-rheumatoid arthritis). Strong enrichment (>1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and autoimmune disorders were detected. The MHC region on chromosome 6 appears to be the most important (and it was indeed previously noted (1-3) as a confluence between schizophrenia and immune disorder risk regions), with many other regions, such as cytoband 1p13.2. We also found that most alleles shared between schizophrenia and Crohns disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohns disease. Our results offer a novel birds-eye view of the genetic relationship and demonstrate strong evidence for mediated pleiotropy between psychiatric disorders and autoimmune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk.

Genomics↗

bioRxiv2015

The relationship between interpregnancy interval (IPI) and mother’s preceding pregnancies (PP)

IntroductionFollowing the investigation of the mothers preceding pregnancies on fetal development and postnatal survival of the neonate, we turned our attention to an earlier period, that is the interval separating the onset of the current pregnancy from the end of the preceding one. The objectives of this study is to investigate the variations of interpregnancy interval length associated to the mothers preceding pregnancies.\n\nMethodsA population of 7773 neonates, alive at the time of hospital discharge, were divided into cohorts according to the current neonates sex and number and sex of the mothers preceding pregnancies. Interpregnancy interval average of each cohort of same neonates sex and mothers parity, but different configuration of preceding pregnancies, were measured and compared.\n\nResultsA positive association was found between mothers preceding pregnancies and length of interpregnancy interval when current pregnancy and preceding pregnancy were of the same sex, and a negative association when they were of opposite sex.\n\nDiscussionInterpregnancy interval length follows a pattern regarding the gravidas preceding pregnancy similar to the other early life indicators pattern, birth weight, placenta weight, gestation length and neonatal survival. Our results confirm and complete an immunological explanation of the indicators variations associated to the gravidas preceding pregnancy.

Developmental Biology↗

bioRxiv2015

Robust Estimates of Overall Immune-Repertoire Diversity from High-Throughput Measurements on Samples

The diversity of a persons B- and T-cell repertoires is both clinically important and a key measure of immunological complexity. However, diversity is hard to estimate by current methods, due to inherent uncertainty in the number of B- and T-cell clones that will be missing from a blood or tissue sample by chance (the missing-species problem), inevitable sampling bias, and experimental noise. To solve this problem we developed Recon, a modified maximum-likelihood method that outputs the overall diversity of a repertoire from measurements on a sample. Recon outputs accurate, robust estimates by any of a vast set of complementary diversity measures, including species richness and entropy, at fractional repertoire coverage. It also outputs error bars and power tables, allowing robust comparisons of diversity between individuals and over time. We apply Recon to in silico and experimental immune-repertoire sequencing datasets as proof of principle for measuring diversity in large, complex systems.

Systems Biology↗

bioRxiv2015

Immunosequencing reveals diagnostic signatures of chronic viral infection in T cell memory

B and T cells expand clonally in response to pathogenic infection, and their descendants, which share the same receptor sequence, can persist for years, forming the basis of immunological memory. While most T cell receptor (TCR) sequences are seen very rarely, public TCRs are present in many individuals.\n\nUsing a combination of high throughput immunosequencing, statistical association of particular TCRs with disease status, and machine learning, we identified of a set of public TCRs that discriminates cytomegalovirus (CMV) infection status with high accuracy. This pathogen-specific diagnostic tool uses a very general assay that relies only on a training cohort coupled with immunosequencing and sophisticated data analysis. Since all memory T cell responses are encoded in the common format of somatic TCR rearrangements, a key advantage of reading T cell memory to predict disease status is that this approach should apply to a wide variety of diseases. The underlying dataset is the largest collection of TCRs ever published, including [~]300 gigabases of sequencing data and [~]85 million unique TCRs across 640 HLA-typed individuals, which constitutes by far the largest such collection ever published. We expect these data to be a valuable public resource for researchers studying the TCR repertoire.

Genomics↗

bioRxiv2015

Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to five autoimmune diseases

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia, and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to five diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify six immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Genetics↗

bioRxiv2016

Explaining Missing Heritability Using Gaussian Process Regression

For many traits and common human diseases, causal loci uncovered by genetic association studies account for little of the known heritable variation. Such missing heritability may be due to the effect of non-additive interactions between multiple loci, but this has been little explored and difficult to test using existing parametric approaches. We propose a Bayesian non-parametric Gaussian Process Regression model, for identifying associated loci in the presence of interactions of arbitrary order. We analysed 46 quantitative yeast phenotypes and found that over 70% of the total known missing heritability could be explained using common genetic variants, many without significant marginal effects. Additional analysis of an immunological rat phenotype identified a three SNP interaction model providing a significantly better fit (p-value 9.0e-11) than the null model incorporating only the single marginally significant SNP. This new approach, called GPMM, represents a significant advance in approaches to understanding the missing heritability problem with potentially important implications for studies of complex, quantitative traits.

Genetics↗

bioRxiv2016

Comparison of Clustering Methods for High-Dimensional Single-Cell Flow and Mass Cytometry Data

Recent technological developments in high-dimensional flow cytometry and mass cytometry (CyTOF) have made it possible to detect expression levels of dozens of protein markers in thousands of cells per second, allowing cell populations to be characterized in unprecedented detail. Traditional data analysis by \"manual gating\" can be inefficient and unreliable in these high-dimensional settings, which has led to the development of a large number of automated analysis methods. Methods designed for unsupervised analysis use specialized clustering algorithms to detect and define cell populations for further downstream analysis. Here, we have performed an up-to-date, extensible performance comparison of clustering methods for high-dimensional flow and mass cytometry data. We evaluated methods using several publicly available data sets from experiments in immunology, containing both major and rare cell populations, with cell population identities from expert manual gating as the reference standard. Several methods performed well, including FlowSOM, X-shift, PhenoGraph, Rclusterpp, and flowMeans. Among these, FlowSOM had extremely fast runtimes, making this method well-suited for interactive, exploratory analysis of large, high-dimensional data sets on a standard laptop or desktop computer. These results extend previously published comparisons by focusing on high-dimensional data and including new methods developed for CyTOF data. R scripts to reproduce all analyses are available from GitHub (https://github.com/lmweber/cytometry-clustering-comparison), and pre-processed data files are available from FlowRepository (FR-FCM-ZZPH), allowing our comparisons to be extended to include new clustering methods and reference data sets.

Bioinformatics↗