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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 163 records · Page 9Linked to original sources

bioRxiv2018

Genetic evidence that the latency III stage of Epstein-Barr Virus infection is a therapeutic target for Multiple Sclerosis

Genome wide association studies have identified >200 susceptibility loci accounting for much of the heritability of Multiple Sclerosis (MS). Epstein Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS, with evidence for disease causation. The molecular and immunological basis for this has not been established. LCL proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. We show that the CD40 ligand, CD40L, potentially through competitive signalling with LMP1, reduces LCL proliferation (p<0.001). The MS risk variants of the LMP1 signalling inhibitor, TRAF3, had altered expression in B cells and LCLs. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2. We have investigated transcriptomes of B cells and EBV infected B cells at Latency III (LCLs) and identified 47 MS risk genes with altered expression, associated with the risk genotype. Overall these MS risk SNPs were overrepresented in target loci of the EBV transcription factor EBNA2 (p<10-16), in genes dysregulated between B and LCLs (p<10-5), and as targets for EBV miRNAs (p<10-4). The risk gene ZC3HAV1 is the putative target for multiple EBV miRNAs. It amplifies the interferon response, and was shown to have reduced expression in LCLs for the risk allele. These data indicate targeting EBV EBNA2, miRNAs, and MS risk genes on the LMP1/LMP2 pathways, and the pathways themselves, may be of therapeutic benefit in MS.

genomics↗

bioRxiv2018

Unstable Angina is a syndrome correlated to Th17 inflammatory disorder

PurposeUnstable angina is common clinical manifestation of atherosclerosis. However, the detailed pathogenesis of unstable angina is still not known. Here, I propose that unstable angina is a TH17 dominant inflammatory disorder.\n\nMethodsMicroarray dataset from unstable angina patients from Gene Expression Omnibus publicly available website is used for further analysis compared to healthy control.\n\nResultsI find out that TH17 related cytokine, cytokine receptor, chemokines, complement, immune-related transcription factors, anti-bacterial genes, Toll-like receptors, and heat shock proteins are all up-regulated in peripheral leukocytes of unstable angina. In addition, H+-ATPase, glycolytic genes, platelet and RBC related genes are also up-regulated in peripheral leukocytes of during unstable angina. Pathway analysis also supports that TH17 immunological pathway is over-represented in the unstable angina dataset.\n\nConclusionsThis finding implies that atherosclerosis is correlated to TH17 inflammatory disease. If we know the etiology of unstable angina as well as atherosclerosis better, we can have better methods to control and prevent this detrimental illness.

bioinformatics↗

bioRxiv2018

Endogenous viral elements are widespread in arthropod genomes and commonly give rise to piRNAs

Arthropod genomes contain sequences derived from integrations of DNA and non-retroviral RNA viruses. These sequences, known as endogenous viral elements (EVEs), have been acquired over the course of evolution and have been proposed to serve as a record of past viral infection. Recent evidence indicates that EVEs can function as templates for the biogenesis of PIWI-interacting RNAs (piRNAs) in some mosquito species and cell lines, raising the possibility that EVEs may function as a source of immunological memory in these organisms. However, whether EVEs are capable of acting as templates for piRNA production in other arthropod species is unknown. Here we used publically available genome assemblies and small RNA sequencing datasets to characterize the repertoire and function of EVEs across 48 arthropod genomes. We found that EVEs are widespread in arthropod genomes and primarily correspond to unclassified ssRNA viruses and viruses belonging to the Rhabdoviridae and Parvoviridae families. Additionally, EVEs were enriched in piRNA clusters in a majority of species and we found that production of primary piRNAs from EVEs is common, particularly for EVEs located within piRNA clusters. While we found evidence suggesting that piRNAs mapping to a number of EVEs are produced via the ping-pong cycle, potentially pointing towards a role for EVE-derived piRNAs during viral infection, limited nucleotide identity between currently described viruses and EVEs identified here likely limits the extent to which this process plays a role during infection with known viruses.

microbiology↗

bioRxiv2018

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

Hypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, [≥]70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.

cancer biology↗

bioRxiv2018

Bayesian Trees for Automated Cytometry Data Analysis

Cytometry is an important single cell analysis technology in furthering our understanding of cellular biological processes and in supporting clinical diagnoses across a variety hematological and immunological conditions. Current data analysis workflows for cytometry data rely on a manual process called gating to classify cells into canonical types. This dependence on human annotation significantly limits the rate, reproducibility, and scope of cytometrys use in both biological research and clinical practice. We develop a novel Bayesian approach for automated gating that classifies cells into different types by combining cell-level marker measurements with an informative prior. The Bayesian approach allows for the incorporation of biologically-meaningful prior information that captures the domain expertise of human experts. The inference algorithm results in a hierarchically-structured classification of individual cells in a manner that mimics the tree-structured recursive process of manual gating, making the results readily interpretable. The approach can be extended in a natural fashion to handle data from multiple different samples by the incorporation of random effects in the Bayesian model. The proposed approach is evaluated using mass cytometry data, on the problems of unsupervised cell classification and supervised clinical diagnosis, illustrating the benefits of both incorporating prior knowledge and sharing information across multiple samples.

bioinformatics↗

bioRxiv2018

Bioluminscent Mycobacterium ulcerans, a tool to study host-pathogen interactions in a murine tail model of Buruli ulcer

Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans. In this study we used a previously reported strain of M. ulcerans, genetically engineered to constitutively produce bioluminescence, to follow the progression of Buruli ulcer in mice using an in-vivo imaging (IVIS(R)) system. We aimed to characterize a mouse tail infection model for pathogenesis, as well as for pre-clinical vaccine and drug development research for Buruli ulcer. Immune parameters, such as antibody titers and cytokine levels, were determined throughout the course of the infection and histology specimens were examined for comparison with human pathology. Nine out of ten (90%) BALB/c mice infected subcutaneously with 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection over the course of the experiment indicating M. ulcerans growth in-vivo. Five out of ten (50%) animals developed clinical signs of disease. Antibody titers were overall low and their onset was late, as measured by responses to both heterogenous (bacterial whole cell lysate) and single antigen (Hsp18) targets. IFN-{gamma}, and IL-10 are reported to play a vital role in host control of Buruli ulcer and these cytokines were elevated in animals with pathology. For mice with advanced pathology, histology revealed clusters of acid-fast bacilli within subcutaneous tissue 300-400 m beneath the epidermis of the tail, with macrophage infiltration and granuloma-formation resembling human Buruli ulcer. This study has shown the utility of using bioluminescent M. ulcerans and IVIS(R) in a mouse tail infection model to study Buruli ulcer infection.\n\nAuthor summaryBuruli ulcer is one of the so called neglected tropical diseases. It is an infectious disease, mainly occurring in West Africa but also in Australia. It manifests as skin lesion and ulcer. Up to date, the way of transmission is inadequately understood. Also, there is no vaccine to protect against the disease. Buruli ulcer is treatable with a course of antibiotics that need to be given for the duration of two months. More laboratory research is needed to elucidate the mechanism of transmission, develop a vaccine and improve and shorten antibiotic therapy. For this, animal (mouse) models of disease are used. The aim of this study was to refine and improve the mouse tail infection model of Buruli ulcer. For this, we used a genetically modified Mycobacterium ulcerans strain that emits light. After infection of animals, light emitted from the bacteria was read out with an in-vivo imaging (IVIS) camera. This allowed us to monitor the location of bacteria in the living animal over time without the need to kill the animal. We also measured parameters of the immune system such as antibodies and cytokines as a baseline for future studies into immunology, vaccine development and pathology of Buruli ulcer. We successfully improved and characterized the mouse tail infection model in Buruli ulcer with the use of modern technology using light emitting bacteria and the IVIS camera.

microbiology↗

bioRxiv2018

Evidence that poor HAART adherence has a great impact on HIV/AIDS treatment failure more than severity of illness and opportunity of infection in Ethiopia: Systematic review and meta-analysis

BackgroundThe pooled burden of HIV treatment failure and its associated factors in Ethiopian context is required to provide evidence towards renewed ambitious future goal.\n\nMethodsPubMed, Web of Science, Scopus, Google Scholar, and Ethiopian Universities (University of Gondar and Addis Ababa University) online repository library were used to get the research articles. I-squared statistics was used to see heterogeneity. Publication bias was checked by Eggers regression test. A meta-analysis using the DerSimonian-Laird random-effects model was employed to estimate the overall prevalence of treatment failure. Subgroup analyses based on the geographical location of the study, age of study population, type of treatment failure, and study design were conducted to see variation in outcomes. The sensitivity analysis was also employed to see whether an outlier result found in the included studies.\n\nResultsOverall HIV treatment failure found to be 15.9% (95% CI: 11.6%-20.1%). HIV treatment failure was 10.2% (6.9%-13.6%) using immunological definition, 5.6% (95% CI: 2.9%-8.3%) using virological definition, and 6.3% (4.6%-8.0%) using clinical definition. Poor HAART adherence (AOR= 8.5; 95% CI: 4.1-12.8), severity of illness (as measured by WHO clinical stage III/IV (AOR=1.9; 95% CI: 1.3-2.6), and presence of opportunistic infections (AOR=1.8; 95% CI: 1.2-2.4) were significantly associated with HIV treatment failure.\n\nConclusionsHIV treatment failure in Ethiopia found to be high and differed by adherence level, severity of illness, and presence of opportunistic infection. HIV intervention programs, such as behavioral intervention is required to sustain HIV treatment adherence and improve treatment success as a result.\n\nProtocol RegistrationIt has been registered in the PROSPERO database (CRD42018100254).

epidemiology↗

bioRxiv2018

Differential immune gene expression associated with contemporary range expansion of two invasive rodents in Senegal

BackgroundBiological invasions are major anthropogenic changes associated with threats to biodiversity and health. What determines the successful establishment of introduced populations still remains unsolved. Here we explore the appealing assertion that invasion success relies on immune phenotypic traits that would be advantageous in recently invaded sites. ResultsWe compared gene expression profiles between anciently and recently established populations of two major invading species, the house mouse Mus musculus domesticus and the black rat Rattus rattus, in Senegal. Transcriptome analyses revealed respectively 364 and 83 differentially expressed genes along the mouse and rat invasion routes. Among them, 20.0% and 10.6% were annotated with functions related to immunity. All immune-related genes detected along the mouse invasion route were over-expressed in recently invaded sites. Genes of the complement activation pathway were over-represented. Results were less straightforward when considering the black rat as no particular immunological process was over-represented. ConclusionsWe revealed changes in transcriptome profiles along invasion routes. Patterns differed between both invasive species. These changes potentially be driven by increased infection risks in recently invaded sites for the house mouse and stochastic events associated with colonization history for the black rat. These results provide a first step in identifying the immune ecoevolutionary processes potentially involved in invasion success.

ecology↗

bioRxiv2018

Correlation between the oral microbiome and brain resting state connectivity in smokers

Recent studies have shown a critical role of the gastrointestinal microbiome in brain and behavior via the complex gut-microbiome-brain axis, however, the influence of the oral microbiome in neurological processes is much less studied, especially in response to the stimuli in the oral microenvironment such as smoking. Additionally, given the complex structural and functional networks in brain system, our knowledge about the relationship between microbiome and brain function in specific brain circuits is still very limited. In this pilot work, we leveraged next generation microbial sequencing with functional neuroimaging techniques to enable the delineation of microbiome-brain network links as well as their relationship to cigarette smoking. Thirty smokers and 30 age- and sex- matched non-smokers were recruited for measuring both microbial community and brain functional networks. Statistical analyses were performed to demonstrate the influence of smoking on the abundance of the constituents within the oral microbial community and functional network connectivity among brain regions as well as the associations between microbial shifts and the brain functional network connectivity alternations. Compared to non-smokers, we found a significant decrease in beta diversity (p = 6x10-3) in smokers and identified several classes (Betaproteobacteria, Spirochaetia, Synergistia, and Mollicutes) as having significant alterations in microbial abundance. Taxonomic analyses demonstrate that the microbiota with altered abundance are mainly involved in pathways related to cell processes, DNA repair, immune system, and neurotransmitters signaling. One brain functional network connectivity component was identified to have a significant difference between smokers and nonsmokers (p = 0.033), mainly including connectivity between brain default network and other task-positive networks. The brain functional component was also significantly associated with some smoking related oral microbiota, suggesting a potential link between smoking-induced oral microbiome dysbiosis and brain functional connectivity, possibly through immunological and neurotransmitter signaling pathways. This work is the first attempt to link oral microbiome and brain functional networks, and provides support for future work in characterizing the role of oral microbiome in mediating smoking effects on brain activity.

microbiology↗

bioRxiv2018

The genome of the plague-resistant great gerbil reveals species-specific duplication of an MHCII gene

The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious diseases and is defined as a key reservoir species for plague (Yersinia pestis). Studies from the wild have shown that the great gerbil is largely resistant to plague but the genetic basis for resistance is yet to be determined. Here, we present a highly contiguous annotated genome assembly of great gerbil, covering over 96 % of the estimated 2.47 Gb genome. Comparative genomic analyses focusing on the immune gene repertoire, reveal shared gene losses within TLR gene families (i.e. TLR8, TLR10 and all members of TLR11-subfamily) for the Gerbillinae lineage, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes. The great gerbil genome provides new insights into the genomic landscape that confers immunological resistance towards plague. The high affinity for Yersinia epitopes could be key in our understanding of the high resistance in great gerbils, putatively conferring a faster initiation of the adaptive immune response leading to survival of the infection. Our study demonstrates the power of studying zoonosis in natural hosts through the generation of a genome resource for further comparative and experimental work on plague survival and evolution of host-pathogen interactions.

genomics↗

bioRxiv2018

Bacterial T6SS Effector EvpP Inhibits Neutrophil Recruitment via Jnk-Caspy Inflammasome Signaling In vivo

The type VI secretion system (T6SS) comprises dynamic complex bacterial contractile nanomachines and is used by many bacteria to inhibit or kill other prokaryotic or eukaryotic cells. Previous studies have revealed that T6SS is constitutively active in response to various stimuli, or fires effectors into host cells during infection. It has been proposed that the T6SS effector EvpP in Edwardsiella piscicida can inhibit NLRP3 inflammasome activation via the Ca2+-dependent JNK pathways. Here, we developed an in vivo infection model by microinjecting bacteria into the tail vein muscle of 3-day-post-fertilized zebrafish larvae, and found that both macrophages and neutrophils are essential for bacterial clearance. Further study revealed that EvpP plays a critical role in promoting the pathogenesis of E. piscicida via inhibiting the phosphorylation of Jnk signaling to reduce the expression of cxcl8a, mmp13 and IL-1{beta} in vivo. Subsequently, by utilizing Tg (mpo:eGFP+/+) zebrafish larvae for E. piscicida infection, we found that the EvpP-inhibited Jnk-caspy inflammasome signaling axis significantly suppressed the recruitment of neutrophils to infection sites, and the caspy- or IL-1{beta}-MO knockdown larvae were more susceptible to infection and failed to restrict bacterial colonization in vivo.\n\nIMPORTANCEInnate immunity is regulated by phagocytic cells and is critical for host control of bacterial infection. In many bacteria, T6SSs can affect bacterial virulence in certain environments, but little is known about the mechanisms underlying T6SS regulation of innate immune responses during infection in vivo. Here, we investigated the role of an E. piscicida T6SS effector EvpP in manipulating the reaction of neutrophils in vivo. We show that EvpP inhibits the activation of Jnk-caspy inflammasome pathway in zebrafish larvae, and reveal that macrophages are essential for neutrophil recruitment in vivo. This interaction improves our understanding about the complex and contextual role of a bacterial T6SS effector in modulating the action of myeloid cells during infection, and offers new insights into the warfare between bacterial weapons and host immunological surveillance.

microbiology↗

bioRxiv2026

Multiscale modelling of drug-host-pathogen interaction: quantifying drug and immune contributions to treatment response

Background and Objective: Predicting treatment outcomes in infectious diseases requires accounting for the interplay between drug effects, pathogen dynamics, and host immunity. Integrating pharmacological and immunological approaches into a single simulation environment remains a fundamental challenge in both theory and practice. We aimed to develop and validate a multiscale in silico framework coupling these processes, and to quantify their respective contributions to bacterial clearance. Methods: We present the Drug-Host-Pathogen Interaction (DHPI) framework, combining three independent mechanistic components: a physiologically based pharmacokinetic model of drug disposition, a pharmacokinetic-pharmacodynamic model of drug-induced bacterial killing, and a stochastic agent-based model of the immune response. Continuous concentration profiles are time-averaged onto the agent-based time grid, assigned to bacterial phenotypic states, and converted into per-agent killing probabilities, so that drug-mediated and immune-mediated death events are recorded separately at each step. The framework was applied to simulate symptomatic pulmonary tuberculosis. Phenotype-specific drug-efficacy parameters were inferred using Approximate Bayesian Computation from historical clinical data on eight weeks of 600 mg rifampicin monotherapy, and validated against independent early bactericidal activity data over a disjoint time window. Results: The calibrated framework reproduced the observed decline in bacterial load, and matched reported early bactericidal activity over the first week. In a virtual cohort of symptomatic patients, drug-mediated killing accounted for 81-88% and immune-mediated killing for 12-19% of total bacterial elimination over the 60-day treatment course, while the dormant, granuloma-contained fraction rose from 0.20-0.29 in the first week to 0.85-0.89 at treatment completion. Over a follow-up of up to 50 years, patients reaching clinical cure had accumulated more memory lymphocytes during treatment than those progressing to clinical failure or death; moreover, the final outcome depended on the immune changes occurring during therapy rather than on the initial disease stage. Conclusions: The results show that the DHPI framework can reproduce treatment dynamics observed in patients and enable the analysis of how therapy reshapes host immune responses and subsequent disease trajectories. By explicitly representing drug-host-pathogen interactions, it provides a mechanistic basis for in silico treatment simulations and for the study of long-term immune consequences of antimicrobial therapy.

systems biology↗

bioRxiv2013

Lack of evidence for the presence of an interferon in invertebrate

In vertebrates, the interferon (IFN) response is the primary form of innate antiviral defense. Previously (2005), a partial cDNA which could encode an interferon-like protein (IntlP) is reported in shrimp, later Rosa et al. (2008) argue that this partial cDNA should encode a portion of insect mitochondrial ATP synthase (MAS) B-chain. Recently (2009), it is demonstrated IntlP also possess antibacterial activity beside antiviral activity reported before. Lacking of a consensus opinion to the question of whether this gene encodes IntlP or MAS, we try to provide more evidences to identify this gene exactly. Here we obtain the full length cDNAs of IntlP/ MAS in Litopenaeus vannamei, and perform the tissue distribution and induced expression analysis. Our results confirm that IntlP is coded by a mistaken ORF and the actual protein indeed is a L. vannamei mitochondrial ATP synthase (LvMAS) whose function is unknown in antiviral responses.

Immunology↗

bioRxiv2013

Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders

Despite decades of research, thousands of studies and numerous advances, the etiologies of Alzheimers Disease (AD), Parkinsons Disease (PD), Huntingtons Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD-U), Creutzfeldt-Jakob Disease (CJD), Reactive Systemic Amyloidosis (RSA) and many other neurodegenerative and systemic amyloid diseases have not been defined, nor have the pathogenic mechanisms leading to cellular death and disease. Moreover, the biological functions of APP/amyloid-{beta} (A{beta}), tau, -synuclein, huntingtin, TAR DNA-binding protein 43 (TDP-43), prion protein (PrP), amyloid A (AA) and some of the other primary proteins implicated in amyloid diseases are not known. And, there are no successful preventive or therapeutic approaches. Based on a comprehensive analysis and new interpretation of the existing data in context of an evolutionary framework, it is proposed that: (i) A{beta}, tau, -synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system, (ii) the isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire, and (iii) the immune reactions and activities associated with the function of these proteins in innate immunity lead to AD, PD, HD, ALS, CJD, RSA and other related diseases, which are innate immunity disorders.

Immunology↗

bioRxiv2014

VgeneRepertoire.org identifies and stores variable genes of immunoglobulins and T-cell receptors from the genomes of jawed vertebrates

The VgeneRepertoire.org platform (http://vgenerepertoire.org) is a new public database repository for variable (V) gene sequences that encode immunoglobulin and T-cell receptor molecules. It identifies the nucleic and amino acid sequences of more than 20,000 genes, providing their exon location in either the contig, scaffold, or chromosome region, as well as locus information for more than 100 jawed vertebrate taxa whose genomes have been sequenced. This web repository provides support to immunologists interested in these molecules and aids in comparative phylogenetic studies.

Immunology↗

bioRxiv2014

Genomic V-gene repertoire in reptiles

Reptiles and mammals diverged over 300 million years ago, creating two parallel evolutionary lineages amongst terrestrial vertebrates. In reptiles, two main evolutionary lines emerged, one gave rise to Squamata, while the other gave rise to Testudines, Crocodylia and birds. In this study, we determined the genomic variable (V)-gene repertoire in reptiles corresponding to the three main immunoglobulin (Ig) loci and the four main T-cell receptor (TCR) loci. We show that squamata lack the TCR{gamma} /{delta} genes and snakes lack the V{kappa} genes. In representative species of testudines and crocodiles, the seven major Ig and TCR loci are maintained. As in mammals, genes of the Ig loci can be grouped into well-defined clans through a multi-species phylogenetic analysis. We show that the reptile VH and V{lambda} genes are distributed amongst the established mammalian clans, while their V{kappa} genes are found within a single clan, nearly exclusive from the mammalian sequences. The reptile and mammal V-genes of the TRA locus cluster into six common evolutionary clans. In contrast, the reptile V-genes from the TRB locus cluster into three clans, which have few mammalian members. In this locus, the V-gene sequences from mammals appear to have undergone different evolutionary diversification processes that occurred outside these shared reptile clans.

Immunology↗

bioRxiv2014

Quantifying selection in immune receptor repertoires

The efficient recognition of pathogens by the adaptive immune system relies on the diversity of receptors displayed at the surface of immune cells. T-cell receptor diversity results from an initial random DNA editing process, called VDJ recombination, followed by functional selection of cells according to the interaction of their surface receptors with self and foreign antigenic peptides. To quantify the effect of selection on the highly variable elements of the receptor, we apply a probabilistic maximum likelihood approach to the analysis of high-throughput sequence data from the {beta}-chain of human T-cell receptors. We quantify selection factors for V and J gene choice, and for the length and amino-acid composition of the variable region. Our approach is necessary to disentangle the effects of selection from biases inherent in the recombination process. Inferred selection factors differ little between donors, or between naive and memory repertoires. The number of sequences shared between donors is well-predicted by the model, indicating a purely stochastic origin of such \"public\" sequences. We find a significant correlation between biases induced by VDJ recombination and our inferred selection factors, together with a reduction of diversity during selection. Both effects suggest that natural selection acting on the recombination process has anticipated the selection pressures experienced during somatic evolution.

Immunology↗

bioRxiv2014

Lack of association between Toll Like Receptor-2 & Toll Like Receptor-4 Gene Polymorphisms and Iranian Asthmatics risk or features

BackgroundAsthma as chronic inflammatory airway disease is considered to be the most common chronic disease that is involving genetic and environmental factors. Toll like receptors (TLRs) and other inflammatory mediators are important in modulation of inflammation. In this study we evaluated the role of TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms in the asthma susceptibility, progress, control levels and lung functions in Iranian subjects.\n\nMethodsOn 99 asthmatic patients and 120 normal subjects, TLR2 Arg753Gln and TLR4 Asp299Gly polymorphism were evaluated by PCR-RFLP method recruiting Msp1 and Nco1 restriction enzymes, respectively. IgE serum levels by ELISA technique were determined and asthma diagnosis, treatment and control levels were considered using standard schemes and criteria.\n\nResultsOur results indicated that the genotype and allele frequencies of the TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were not significantly different between control subjects and asthmatics (p > 0.05) or even in asthma features such as IgE levels, asthma history and pulmonary factors (p > 0.05).\n\nConclusionsMeanwhile some previous studies indicated TLRs and their polymorphisms role in asthma incidence and features, our data demonstrated that TLR2 Arg753Gln and TLR4 Asp299Gly gene variants were not risk factor of asthma or its features in Iranian patients. Genetic complexity, ethnicity, influence of other genes or polymorphisms may overcome these polymorphisms in our asthmatics.

Immunology↗