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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 217 records · Page 12Linked to original sources

bioRxiv2016

Heterologous protection against Asian Zika virus challenge in rhesus macaques

Zika virus (ZIKV) isolates are genetically diverse, but belong to two recognized lineages, termed \"African\" and \"Asian.\" Asian ZIKV infection during pregnancy causes fetal abnormalities including microcephaly. Developing an effective preventative Zika virus vaccine that protects pregnant women is essential for minimizing fetal abnormalities; at least 18 groups are developing ZIKV vaccines (Hayden, 2016). The genetic and antigenic variability of many RNA viruses limits the effectiveness of vaccines, and the degree to which immunity against one ZIKV strain could provide protection against another is unknown. Here we show that rhesus macaques infected with East African ZIKV strain MR766 are completely protected from subsequent infection with heterologous Asian ZIKV. MR766 is more genetically divergent from all known Asian ZIKV strains than Asian ZIKV strains are from one another. Therefore, ZIKV strain selection is unlikely to compromise vaccine effectiveness.\n\nHighlightsO_LIAfrican Zika virus (ZIKV) strain MR766 productively infects macaques (68 characters)\nC_LIO_LIImmunity elicited by MR766 protects macaques against heterologous Asian ZIKV (77 characters)\nC_LIO_LIIn vivo restoration of a putative N-linked glycosylation site in MR766 (70 characters)\nC_LIO_LIImmunogen selection is unlikely to adversely affect the breadth of vaccine protection (85 characters)\nC_LI\n\neTOCAn effective Zika virus vaccine is needed to prevent infection-associated fetal abnormalities. Macaques whose immune responses are primed by infection with East African ZIKV are completely protected from reinfection with heterologous Asian ZIKV. Any Asian ZIKV immunogen that protects against homologous challenge will likely confer protection against all other Asian ZIKV strains.

Immunology↗

bioRxiv2016

Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection

In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contribution of cytokines remain largely unclear.\n\nIn the current study, mathematical modelling on in vivo experimental data highlight IFN-{gamma} as a decisive candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. Moreover, we found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was however not as distinct as for IFN-{gamma}. Importantly, our results furthermore challenge current beliefs that the TNF- response or the increased availability of nutrients modulated by IAV infection have a central role to the bacterial outgrowth. Ultimately, our findings contribute to a detailed understanding of the mechanisms underlying impaired bacterial clearance following influenza infection.

Immunology↗

bioRxiv2016

A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells

A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the germinal center reaction. Finally, we demonstrate that clonal expansion upon return to the germinal center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone.

Immunology↗

bioRxiv2016

Signal Transduction Through a DNA-Based T Cell Receptor

T cells mount an immune response by measuring the binding strength of its T cell receptor (TCR) for peptide-loaded MHCs (pMHC) on an antigen-presenting cell. How T cells convert the lifetime of the extracellular TCR-pMHC interaction into an intracellular signal remains unknown. Here, we developed a synthetic signaling system in which the extracellular domains of the TCR and pMHC were replaced with short hybridizing strands of DNA. Remarkably, T cells can discriminate between DNA ligands differing by a single base pair. Single molecule imaging reveals that signaling is initiated when single ligand-bound receptors are converted into clusters, a time-dependent process requiring ligands with longer bound times. A computation model reveals that receptor clustering serves a kinetic proofreading function, enabling ligands with longer bound times to have disproportionally greater signaling outputs. These results suggest that spatial reorganization of receptors plays an important role in ligand discrimination in T cell signaling.

Immunology↗

bioRxiv2016

A compound interest approach to HIV cure

In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4+ T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone.

Immunology↗

bioRxiv2016

Persistent activation of interlinked Th2-airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic atopic asthmatics

RationaleAtopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced Th2-associated airways inflammation. However, the vast majority of atopics do not develop asthma-related wheeze, despite ongoing exposure to aeroallergens to which they are strongly sensitized, indicating that additional pathogenic mechanism(s) operate in conjunction with Th2 immunity to drive asthma pathogenesis.\n\nObjectivesEmploy systems level analyses to identify inflammation-associated gene networks operative at baseline in sputum-derived RNA from house dust mite-sensitized (HDMs) subjects with/without wheezing history; identify networks characteristic of the ongoing asthmatic state. All subjects resided in the constitutively-HDMhigh Perth environment.\n\nMethodsGenome wide expression profiling by RNASeq followed by gene coexpression network analysis.\n\nMeasurements/ResultsHDMs-nonwheezers displayed baseline gene expression in sputum including IL-5, IL-13 and CCL17. HDMs-wheezers showed equivalent expression of these classical Th2-effector genes but their overall baseline sputum signatures were more complex, comprising hundreds of Th2-associated and epithelial-associated genes, networked into two separate coexpression modules. The first module was connected by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3, and contained genes that control mucociliary clearance.\n\nConclusionsOur findings provide new insight into the inflammatory mechanisms operative at baseline in the airway mucosal microenvironment in atopic asthmatics undergoing natural perennial aeroallergen exposure. The molecular mechanism(s) that determine susceptibility to asthma amongst these subjects involve interactions between Th2-and epithelial function-associated genes within a complex co-expression network, which is not operative in equivalently sensitized/exposed atopic non-asthmatics.\n\nFundingThis study was funded by the Asthma Foundation WA, the Department of Health WA, and the NHMRC. AB is funded by a BrightSpark Foundation McCusker Fellowship. GLH is a NHMRC Fellow. AG is supported by the McCusker Charitable Foundation Bioinformatics Centre. ACJ is a recipient of an Australian Postgraduate Award and a Top-Up Award from the University of Western Australia.

Immunology↗

bioRxiv2016

Protection against maternal infection-associated fetal growth restriction - proof-of-concept with a microbial-derived immunomodulator OM85: safety and efficacy data

Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction and/or miscarriage. Treatment strategies for protection of at-risk mothers are limited to a narrow range of vaccines, which do not cover the bulk of the common pathogens most frequently encountered. Employing mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85TM), currently used clinically for attenuation of infection-associated airway inflammatory symptoms in infants-adults, markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial LPS or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress, notably high levels of RANTES, MIP-1a, CCL2, IL-8 and G-CSF in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses conducted in parallel employing RNASeq revealed that OM85 pretreatment selectively tunes LPS-induced activation in maternal gestational tissues for attenuated expression of TNF-, IL1-, and IFNg-driven that drive production of these pro-inflammatory cytokines, without constraining Type1-IFN-associated networks central to first-line anti-microbial defense. This study suggests that broad-spectrum protection-of-pregnancy against infection-associated inflammatory stress, without compromising capacity for efficient pathogen eradication, represents an achievable therapeutic goal.\n\nDisclosureThis study was funded principally by Nation Health and Medical Research Council (NHMRC) of Australia with supplementary support provided by OM Pharma (Geneva, Switzerland).\n\nCP is an employee of OM Pharma (Vifor Pharma). The other authors declare that they have no conflict of interest.

Immunology↗

bioRxiv2016

A qualitative model for the integration of conflicting exogenous and endogenous signals by dendritic cells

Cells of the immune system are confronted with opposing pro-and anti-inflammatory signals. Dendritic cells (DC) integrate these cues to make informed decisions whether to initiate an immune response. Confronted with exogenous microbial stimuli, DC endogenously produce both anti-(IL-10) and pro-inflammatory (TNF) cues whose joint integration controls the cell's final decision. We combine experimental measurements with theoretical modeling to quantitatively describe the integration mode of these opposing signals. We propose a two step integration model that modulates the effect of the two types of signals: an initial bottleneck integrates both signals (IL-10 and TNF), the output of which is later modulated by the anti-inflammatory signal. We show that the anti-inflammatory IL-10 signaling is long ranged, as opposed to the short-ranged pro-inflammatory TNF signaling. The model suggests that the population averaging and modulation of the pro-inflammatory response by the anti-inflammatory signal is a safety guard against excessive immune responses.

Immunology↗

bioRxiv2016

A generalized quantitative antibody homeostasis model: regulation of B-cell development by BCR saturation and novel insights into bone marrow function

In a pair of articles we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this first paper we describe the cycles of B-cell expansion and differentiation driven by B-cell receptor engagement.\n\nThe fate of a B cell is determined by the signals it receives via its antigen receptor at any point of its lifetime. We express BCR engagement as a function of apparent affinity and free antigen concentration, using the range of 10-14 to 10-3 M for both factors. We assume that for keeping their BCR responsive B cells must maintain partial BCR saturation, which is a narrow region defined by [Ag]{approx}KD. To remain in this region, B cells respond to changes in [Ag] by proliferation or apoptosis and modulate KD by changing BCR structure. We apply this framework to various niches of B-cell development, such as the bone marrow, blood, lymphoid follicles and germinal centers. We propose that clustered B cells in the bone marrow and in follicles present antigen to surrounding B cells by exposing antigen captured on complement and Fc receptors. The model suggests that antigen-dependent selection in the bone marrow results in 1) effector BI cells, which develop in blood as a consequence of the inexhaustible nature of soluble antigens, 2) memory cells that survive in antigen rich niches, identified as marginal zone B cells. Finally, the model implies that memory B cells could derive survival signals from abundant non-cognate antigens.

Immunology↗

bioRxiv2016

Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease

The association between human cytomegalovirus (hCMV) reactivation and the development of graft-versus-host-disease (GVHD) has been observed in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV-derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive ([≥]6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8 {+/-} 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 {+/-} 16121.8 matched MUD DRP peptides (Students T-test, p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins expressed at [≥]10 RPKM). hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset with a subset analysis of 7 instances of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute + chronic GVHD (n=2) indicating cross reactive peptide expression within affected organs. We propose that based on our analysis and preliminary clinical correlations that hCMV immune cross-reactivity may cause antigenic mimicry of human alloreactive peptides triggering GVHD.

Immunology↗

bioRxiv2016

Temporal Stability and Molecular Persistence of the Bone Marrow Plasma Cell Antibody Repertoire

Plasma cells in human bone marrow (BM PCs) are thought to be intrinsically long-lived and to be responsible for sustaining lifelong immunity through the constitutive secretion of antibody--but the underlying basis for this serological memory remains controversial. Here, we analyzed the molecular persistence of serological immunity by an examination of BM PC immunoglobulin heavy-chain (IGH) transcripts derived from serial bone marrow specimens obtained during a span of several years. Using high-throughput sequence analysis of the same individual for 6.5 years, we show that the BM PC repertoire is remarkably stable over time. We find that the bias in IGH V, D, and J individual gene usage and also the combinatorial V-D, V-J, D-J, and V-D-J usage across time to be nearly static. When compared to a second donor with time points 2 years apart, these overall patterns are preserved, and surprisingly, we find high correlation of gene usage between the two donors. Lastly, we report the persistence of numerous BM PC clonal clusters (~2%) identifiable across 6.5 years at all time points assayed, supporting a model of serological memory based, at least in part, upon intrinsic longevity of human PCs. We anticipate that this longitudinal study will facilitate the ability to differentiate between healthy and diseased antibody repertoire states, by serving as a point of comparison with future deep-sequencing studies involving immune intervention.

Immunology↗

bioRxiv2016

Heme concentration-dependently modulates the production of specific antibodies in murine

Free heme is an endogenous danger signal to provoke innate immunity. Active innate immunity is a precondition of an effective adaptive immune response. However, heme catabolites, CO, biliverdin and bilirubin trigger immunosuppression. Furthermore, free heme induces the expression of heme oxygenase-1 to reinforce the production of CO, biliverdin and bilirubin. As such, free heme can drive two antagonistic mechanisms to affect adaptive immunity. What is the outcome of animal immune response to an antigen in the presence of free heme? The question remains to be explored. Here we report the immunization results by intraperitoneal injection of the formulations containing BSA and heme. When the used heme concentrations were about less than 1 {micro}M, the production of anti-BSA IgG and IgM was unaffected; when the used heme concentrations were about more than 1 {micro}M but less than 5 {micro}M, the production of anti-BSA IgG and IgM was enhanced; when the used heme concentrations were about more than 5 {micro}M, the production of anti-BSA IgG and IgM was suppressed. The results demonstrate that heme can modulate adaptive immunity (at least humoral immunity) by the mode of double concentration-thresholds. If heme concentrations are below the first threshold, there is no effect on adaptive immunity; if between the first and second thresholds, there is promotive effect; if over the second threshold, there is inhibitive effect. A hypothesis is also presented here to explain the mode.

Immunology↗

bioRxiv2016

Characterization of the pscC (Type III secretion) gene of Pseudomonas aeruginosa (PA01) and assessment of immunogenicity of pscC protein in rats

Proteins associated with the bacterial membrane can be recruited for application as antigens for the development of vaccines. This preliminary study was directed towards evaluating the antigenic properties of the Pseudomonas aeruginosa (PA01) pscC protein which is a component of the Type III secretion system. Gene specific primers were designed to isolate the pscC gene which was isolated, ligated onto the multiple cloning site of vector pGS21(a), cloned and expressed in Escherichia coli (BL21). The molecular weight of the expressed pscC protein was determined by SDS-PAGE (10% sodium dodecyl sulphate-polyacrylamide gel electrophoresis) and was found to be around 57 KDa and purified by the size exclusion chromatography. Finally, the purified pscC protein was injected subcutaneously into adult Sprague Dawley(R) rats with a range of concentrations (50, 100 and 150 {micro}g per rat) respectively. Recombinant pscC antigen induced a specific humoral immune response against the antigen, which was validated by Enzyme-linked immunosorbent assay (ELISA). The results concluded that anti-pscC antibody was elicited in the animal model.

Immunology↗

bioRxiv2016

Architecture of a minimal signalling pathway explains the T cell response to a 1,000,000-fold variation in antigen affinity and dose

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map pMHC affinity onto T cell responses have produced inconsistent patterns of responses preventing formulations of canonical models of T cell signalling. Here, a systematic analysis of T cell responses to 1,000,000-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signalling incorporating kinetic proofreading with limited signalling coupled to an incoherent feed forward loop (KPL-IFF), that reproduces these observations. We show that the KPL-IFF model correctly predicts the T cell response to antigen co-presentation. Our work offers a general approach for studying cellular signalling that does not require full details of biochemical pathways.\n\nSignificance statementT cells initiate and regulate adaptive immune responses when their T cell antigen receptors recognise antigens. The T cell response is known to depend on the antigen affinity/dose but the precise relationship, and the mechanisms underlying it, are debated. To resolve the debate, we stimulated T cells with antigens spanning a 1,000,000-fold range in affinity/dose. We found that a different antigen (and hence different affinity) produced the largest T cell response at different doses. Using model identification algorithms, we report a simple mechanistic model that can predict the T cell response from the physiological low affinity regime into the high affinity regime applicable to therapeutic receptors.

Immunology↗

bioRxiv2016

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immunity

The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analysed gene conservation of all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared to other immune cell populations, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA-Sequencing of lck:GFP cells in zebrafish to obtain the first transcriptome of specific immune cell types in a non-mammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T-cells, a novel type of NK-like cells and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune cell specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed a higher gene turnover and lower conservation of trans-membrane proteins in NK cells compared to T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates.

Immunology↗

bioRxiv2016

Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune-Responses

It is currently unknown whether and how mammalian pathogen-recognition receptors (PRR) respond to biophysical patterns of pathogen-associated molecular danger-signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large-viruses, we have discovered that the quality and quantity of Toll-like-receptor-9 (TLR9)-signaling by CpG in mouse dendritic cells (mDC) is uniquely dependent on biophysical attributes, specifically the surface-density of CpG and size of the presenting PLP. These physical patterns control DC-programming by regulating kinetics and magnitude of MyD88-IRAK4 signaling, NF{kappa}B-driven responses, and STAT3 phosphorylation, which in turn controls differential T cell responses and in vivo immune-polarization, especially T-helper 1 (Th1) versus T-helper 2 (Th2) antibody responses. Our findings suggest that innate immune cells can sense and respond not only to molecular, but also pathogen-associated physical patterns (PAPPs), broadening the tools for modulating immunity, helping to better understand innate response mechanisms to pathogens and develop new and improved vaccines.

Immunology↗

bioRxiv2016

ImSig: A resource for the identification and quantification of immune signatures in blood and tissue transcriptomics data

The outcome of many diseases is commonly correlated with the immune response at the site of pathology. The ability to monitor the status of the immune system in situ provides a mechanistic understanding of disease progression, a prognostic assessment and a guide for therapeutic intervention. Global transcriptomic data can be deconvoluted to provide an indication of the cell types present and their activation state, but the gene signatures proposed to date are either disease-specific or have been derived from data generated from isolated cell populations. Here we describe an improved set of immune gene signatures, ImSig, derived based on their co-expression in blood and tissue datasets. ImSig includes validated lists of marker genes for the main immune cell types and a number of core pathways. When used in combination with network analysis, ImSig is an accurate and easy to use approach for monitoring immune phenotypes in transcriptomic data derived from clinical samples.

Immunology↗

bioRxiv2016

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

immunology↗