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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 199 records · Page 11Linked to original sources
bioRxiv2015

Effect of Poli I:C in murine model of autoimmune thyroiditis

Hashimotos thyroiditis is one of the most common autoimmune diseases in humans and, similar to other autoimmune diseases, is multifactorial in nature. Moreover, the expression of TLRs has been implicated in the pathogenesis of autoimmune and inflammatory diseases, such as diabetes and insulinitis. The TLRs are a family of at least 10 receptors associated with innate immunity that are present in monocytes, macrophages, and dendritic cells, which recognize highly conserved patterns of the surface of microorganisms, such as LPS, peptidoglycan, and dsRNA and CpG sequences.\n\nThe aim of this study was to evaluate mRNA of the TLR3, TLR9 and cytokines (IFN-beta, TNF and IL-1) in thyroid follicular cells obtained of mice with autoimmune experimental thyroiditis (EAT). For that C57BL/6 mice were immunized with Tg plus complete Freunds adyuvant and treated or not with Poli I:C. Anti-thyroglobulin autoantibodies level was determined by indirect ELISA. Also isolated thyroid follicles were treated in vitro with Poli IC. The results show that TLR3 receptors and some cytokines (IFN-beta, TNF and IL-10) are more highly expressed in thyroid follicular cells treated with Poli I:C. and in the animals with TAE, which present humoral autoimmune response. Taken together, these results suggest that TLR3 expression in thyroid follicular cells induces signaling mechanisms to enhanced IL-1, TNF and IFN-{beta} levels during pathogen infections and that could trigger of autoimmune thyroiditis.

Immunology↗
bioRxiv2016

A novel polymorphism in nitric oxide synthase interacting protein (NOSIP) modulates nitric oxide synthesis and influences mortality in human sepsis

Nitric oxide, synthesised by three isoforms of Nitric Oxide synthases viz., nNOS by neurons, eNOS by endothelial cells and iNOS by phagocytes, performs a wide variety of biological functions in neurons, vascular endothelial cells and immune cells. Interaction between inducible nitric oxide synthase (iNOS) and Nitric oxide synthase interacting protein (NOSIP) was observed both in human monocytes and mouse macrophages and in cell free systems by biophysical methods. A novel mutation in nitric oxide synthase interacting protein (NOSIP) determined NO levels produced by human monocytes and was associated with disease severity in Sepsis patients. The study reveals NOSIP as an important regulator of inflammation by virtue of its ability to influence nitric oxide production both in mice and in humans and opens up novel avenues for therapeutic strategies against acute inflammation. While the influence of this novel NOSIP polymorphism in cardio-vascular and neuronal functions could be a subject of future investigations, its role in determining disease severity and mortality of the ongoing Covid 19 pandemic will be of immediate relevance.

Immunology↗
bioRxiv2016

Reinvestigating the role of ERK5: kinase activity is not required for cellular immune response or proliferation

Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal and tissue-restricted deletions have profound effects on erythroid development, cardiac function and neurogenesis. In addition, depletion of ERK5 is anti-inflammatory and anti-tumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a non-catalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity, and delineate which can be pharmacologically targeted.

Immunology↗
bioRxiv2016

Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires

The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a \"public\" repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pregnancy, and survive over long periods, providing the basis of the public repertoire.

Immunology↗
bioRxiv2016

Cryopreservation of human mucosal leukocytes

BackgroundUnderstanding how leukocytes in the cervicovaginal and colorectal mucosae respond to pathogens, and how medical interventions affect these responses, is important for developing better tools to prevent HIV and other sexually transmitted infections. An effective cryopreservation protocol for these cells following their isolation will make studying them more feasible.\n\nMethods and findingsTo find an optimal cryopreservation protocol for mucosal mononuclear leukocytes, we compared cryopreservation media and procedures using human vaginal leukocytes and confirmed our results with endocervical and colorectal leukocytes. Specifically, we measured the recovery of viable vaginal T cells and macrophages after cryopreservation with different cryopreservation media and handling procedures. We found several cryopreservation media that led to recoveries above 75%. Limiting the number and volume of washes increased the fraction of cells recovered by 10-15%, possibly due to the small cell numbers in mucosal samples. We confirmed that our cryopreservation protocol also works well for both endocervical and colorectal leukocytes.\n\nCryopreserved leukocytes had slightly increased cytokine responses to antigenic stimulation relative to the same cells tested fresh. Additionally, we tested whether it is better to cryopreserve endocervical cells on the cytobrush or in suspension.\n\nConclusionsLeukocytes from cervicovaginal and colorectal tissues can be cryopreserved with good recovery of functional, viable cells using several different cryopreservation media. The number and volume of washes has an experimentally meaningful effect on the percentage of cells recovered. We provide a detailed, step-by-step protocol with best practices for cryopreservation of mucosal leukocytes.

Immunology↗
bioRxiv2016

Times to Key Events in the Course of Zika Infection and their Implications for Surveillance: A Systematic Review and Pooled Analysis

BackgroundEvidence suggests that Zika virus has driven a 10-fold increase in babies born with microcephaly in Brazil, prompting the WHO to declare a Public Health Emergency of International Concern. However, little is known about the natural history of infection. These data are critical for implementing surveillance and control measures such as protecting the blood supply.\n\nMethodsWe conducted a systematic review and pooled analysis to estimate the distribution of times from Zika infection to symptom onset, seroconversion, and viral clearance, and analyzed their implications for surveillance and blood supply safety.\n\nResultsBased on 25 cases, we estimate the median incubation period of Zika virus infection is 5.9 days (95% CI: 4.4-7.6), and that 95% of those who do develop symptoms will do so by 11.1 days post-infection (95% CI: 7.6-18.0). On average seroconversion occurs 9.0 days (95% CI, 7.0-11.6) after infection, and virus is detectable in blood for 9.9 days (95% CI: 6.8-21.4). In 5% of cases detectable virus persists for over 18.9 days (95% CI: 12.6-79.5). The baseline (no screening) risk of a Zika infected blood donation increases by approximately 1 in 10,000 for every 1 per 100,000 person-days increase in Zika incidence. Symptom based screening reduces this by 7% (RR 0.93, 95% CI 0.86-0.99), and antibody screening by 29% (RR 0.71, 95% CI: 0.28-0.88).\n\nConclusionsSymptom or antibody-based surveillance can do little to reduce the risk of Zika contaminated blood donations. High incidence areas may consider PCR testing to identify lots safe for use in pregnant women.

Immunology↗
bioRxiv2016

Diurnal variation of circulating interleukin-6 in humans: a meta-analysis

The pleiotropic cytokine interleukin-6 (IL-6) has been proposed to contribute to circadian regulation of sleepiness by increasing in the blood at night to signal for sleepiness. Earlier studies have reported diurnal variations of IL-6, but phase estimates are conflicting. We have therefore performed a meta-analysis on the diurnal variation of circulating IL-6. Studies were included if they reported circulating levels of IL-6 recorded at least twice within 24 hours in the same individual. A systematic search resulted in the inclusion of 43 studies with 56 datasets, for a total of 1100 participants. Individual participant data were available from 4 datasets with a total of 56 participants. Mixed-effects meta-regression modelling confirmed that IL-6 varied across the day, the most conspicuous effect being a trough in the morning. These results stand in contrast to earlier findings of a peak in the evening or night, and suggest that diurnal variation should be taken into account in order to avoid confounding in studies of IL-6 in plasma or serum.

Immunology↗
bioRxiv2016

Association between use of the progestin Depot Medroxyprogesterone Acetate and Female Cervicovaginal Lavage Proinflammatory Cytokines among HIV-1 and HSV-2 co-infected African women: a case control study

BackgroundUse of the progestin contraceptive Depot Medroxyprogesterone Acetate (DMPA) by HIV 1 infected women is associated with increased female to male transmission of HIV. Mucosal innate immune activation has been proposed as a likely mechanism. To establish the effect of DMPA upon mucosal immune activation, this study sought to evaluate the concentrations of 5 proinflammatory and the regulatory cytokine IL 10 in cervicovaginal lavage fluid.\n\nMethodsThis was a case control study, 70 participants were recruited, comprising of 35 asymptomatic ART naive HIV positive women on DMPA recruited as cases and 35 age matched asymptomatic ART naive HIV positive women not on contraceptives recruited as controls. Peripheral blood CD4 and total lymphocyte counts, High vaginal swab microscopy, endocervical smears and cervical cytology were performed for each participant. Concentrations of six proinflammatory cytokines were measured on cervicovaginal lavage by multiplex cytometric bead array.\n\nResultsThe mean age of cases was 26.8 years and 30 years for controls. Total lymphocyte counts and CD4 cell counts were significantly higher among cases (p=0.02 and 0.004 respectively). HSV 2 prevalence as determined by ELISA was higher (p=0.034 among cases. The concentrations of the cytokines IL 1{beta}, IL 6, IL 8, IL 12p70 and TNF were lower among cases, with IL 1{beta} being statistically significant (p=0.046). Concentrations of IL 10 was higher among cases (p=0.022). On multivariate analysis, reduction in IL 1{beta} and IL 8 were associated with the duration of DMPA use (p=0.015 and 0.041 respectively). Inclusion of HSV 2 into the multivariate models showed elevation of all cytokines measured (p=<0.001).\n\nConclusionDMPA use is associated with reduction of proinflammatory cytokines and elevation of the regulatory cytokine IL 10. This may explain increased female to male transmission of HIV infection by modulation of male genital tract mucosa in the absence of increased HIV 1 genital shedding.

Immunology↗
bioRxiv2016

Quantifying lymphocyte receptor diversity

To recognize pathogens, B and T lymphocytes are endowed with a wide repertoire of receptors generated stochastically by V(D)J recombination. Measuring and estimating the diversity of these receptors is of great importance for understanding adaptive immunity. In this chapter we review recent modeling approaches for analyzing receptor diversity from high-throughput sequencing data. We first clarify the various existing notions of diversity, with its many competing mathematical indices, and the different biological levels at which it can be evaluated. We then describe inference methods for characterizing the statistical diversity of receptors at different stages of their history: generation, selection and somatic evolution. We discuss the intrinsic difficulty of estimating the diversity of receptors realized in a given individual from incomplete samples. Finally, we emphasize the limitations of diversity defined at the level of receptor sequences, and advocate the more relevant notion of functional diversity relative to the set of recognized antigens.

Immunology↗
bioRxiv2016

Dengue Virus Antibodies Enhance Zika Virus Infection

BackgroundFor decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases endemic in the same regions. Recent reports of severe disease associated with ZIKV, including Guillain-Barre syndrome and severe fetal abnormalities, have greatly heightened awareness. Given its recent history of rapid spread in immune naive populations, it is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent Aedes mosquito vectors are found. Globally, dengue virus (DENV) is the most common mosquito-transmitted human flavivirus and is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through a mechanism known as antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. However, response to DENV antibodies has not yet been investigated.\n\nMethodology / Principal FindingsWe tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection.\n\nConclusions / SignificanceOur results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.\n\nAuthor SummaryRecent reports of severe disease, including developmental problems in newborns, have greatly heightened public health awareness of Zika virus (ZIKV), a mosquito-transmitted virus for which there is no vaccine or treatment. It is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent mosquitoes are found. Dengue virus (DENV), a closely related mosquito-transmitted virus is well-established in regions of recent ZIKV introduction and spread. It is increasingly common that individuals living in these regions may have had a prior DENV infection or may be infected with DENV and ZIKV at the same time. However, very little is known about the impact of DENV infections on ZIKV disease severity. In this study, we tested the ability of antibodies against DENV to prevent or enhance ZIKV infection in cell culture-based assays. We found that DENV antibodies can greatly enhance ZIKV infection in cells.\n\nOur results suggest that ZIKV infection in individuals that had a prior DENV infection may experience more severe clinical manifestations. The results of this study provide a better understanding of the interplay between ZIKV and DENV infections that can serve to inform public health responses and vaccine strategies.

Immunology↗
bioRxiv2016

C19ORF66 is an Interferon-Stimulated Gene (ISG) which Inhibits Human Immunodeficiency Virus-1

Innate immunity is the first line of defense against invading microbes1. The type I interferon (IFN) pathway plays a key role in controlling Human Immunodeficiency Virus type 1 (HIV-1) replication2,3. We identified an IFN- stimulated gene C19ORF66 that we term Suppressor of Viral Activity (SVA). Full length SVA-1 protein inhibits HIV-1 by blocking virion production. SVA splice variants truncated at the C-terminus and/or disrupted at the nuclear export signal (NES) lose antiviral activity and localize to nucleus, while full length SVA-1 co-localizes with HIV-1 p24 protein in the cytoplasmic compartment of infected cells. SVA-1 is structurally and functionally conserved across species, including mouse and chimpanzee. We provide the first description of the effector function of the gene SVA/C190RF66 as an innate immune factor with anti-HIV-1 activity.

Immunology↗
bioRxiv2016

50-valent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques

As the predominant etiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. We approached this problem straightforwardly. We tested the hypothesis that increasing virus input titers in polyvalent inactivated HRV vaccine will result in broad nAb responses. Here, we show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. We for the first time generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types.

Immunology↗
bioRxiv2016

T-cell activation and HLA-regulated response to smoking in the deep airways of patients with multiple sclerosis

1. Introduction 1. Introduction 2. Material and methods 3. Results 4. Discussion 6 References Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS) [1], with a largely unknown aetiology. International efforts have defined over 100 genetic loci modifying the risk for MS [2]. However, these genes only explain a fraction of the disease risk, suggesting an important contributory role of environmental factors [3]. One of the most established environmental risk factors for MS is cigarette smoking, with an estimated odds ratio (OR) of 1.51 for daily smokers compared to nonsmokers [4]. This risk factor is also shared with other autoimmune diseases, including rheumatoid arthritis (RA), where a risk increase of a similar magnitu ...

Immunology↗
bioRxiv2016

EXPERIMENTAL GRANULOMATOUS PULMONARY NOCARDIOSIS in BALB/c MICE

Pulmonary nocardiosis is a granulomatous disease with high mortality that affects both immunosuppressed and immunocompetent patients. The mechanisms leading to the establishment and progression of the infection are currently unknown. An animal model to study these mechanisms is sorely needed. We report the first in vivo model of granulomatous pulmonary nocardiosis that closely resembles human pathology. BALB/c mice infected intranasally with two different doses of GFP-expressing Nocardia brasiliensis ATCC700358 (NbGFP), develop weight loss and pulmonary granulomas. Mice infected with 109 CFUs progressed towards death within a week while mice infected with 108 CFUs died after five to six months. Histological examination of the lungs revealed that both the higher and lower doses of NbGFP induced granulomas with NbGFP clearly identifiable at the center of the lesions. Mice exposed to 108 CFUs and subsequently to 109 CFUs were not protected against disease severity but had less granulomas suggesting some degree of protection. Attempts to identify a cellular target for the infection were unsuccessful but we found that bacterial microcolonies in the suspension used to infect mice were responsible for the establishment of the disease. Small microcolonies of NbGFP, incompatible with nocardial doubling times starting from unicellular organisms, were identified in the lung as early as six hours after infection. Mice infected with highly purified unicellular preparations of NbGFP did not develop granulomas despite showing weight loss. Finally, intranasal delivery of nocardial microcolonies was enough for mice to develop granulomas with minimal weight loss. Taken together these results show that Nocardia brasiliensis microcolonies are both necessary and sufficient for the development of granulomatous pulmonary nocardiosis in mice.

Immunology↗
bioRxiv2016

Differential modulation of the cellular and humoral immune responses in Drosophila is mediated by the endosomal ARF1-Asrij axis

How multicellular organisms maintain immune homeostasis across various organs and cell types is an outstanding question in immune biology and cell signaling. In Drosophila, blood cells (hemocytes) respond to local and systemic cues to mount an immune response. While endosomal regulation of Drosophila hematopoiesis is reported, the role of endosomal proteins in cellular and humoral immunity is not well-studied. Here we demonstrate a functional role for endosomal proteins in immune homeostasis. We show that the ubiquitous trafficking protein ADP Ribosylation Factor 1 (ARF1) and the hemocyte-specific endosomal regulator Asrij differentially regulate humoral immunity. ARF1 and Asrij mutants show reduced survival and lifespan upon infection, indicating perturbed immune homeostasis. The ARF1-Asrij axis suppresses the Toll pathway anti-microbial peptides (AMPs) by regulating ubiquitination of the inhibitor Cactus. The Imd pathway is inversely regulated-while ARF1 suppresses AMPs, Asrij is essential for AMP production. Several immune mutants have reduced Asrij expression, suggesting that Asrij co-ordinates with these pathways to regulate the immune response. Our study highlights the role of endosomal proteins in modulating the immune response by maintaining the balance of AMP production. Similar mechanisms can now be tested in mammalian hematopoiesis and immunity.

Immunology↗
bioRxiv2016

To what extent are the terminal stages of sepsis, septic shock, SIRS, and multiple organ dysfunction syndrome actually driven by a prion/amyloid form of fibrin? bioRxiv preprint.

A well-established development of increasing disease severity leads from sepsis through septic shock, SIRS, multiple organ dysfunction syndrome and cellular and organismal death. We argue that a chief culprit is the LPS-induced anomalous coagulation of fibrinogen to produce a form of fibrin that is at once inflammatory, resistant to fibrinolysis, and underpins the disseminated intravascular coagulation commonly observed in sepsis. In particular, we argue that the form of fibrin produced is anomalous because much of its normal -helical content is transformed to {beta}-sheets, as occurs in established amyloidogenic and prion diseases. We hypothesise that these processes play a major role in the passage along the above pathways to organismal death, and that inhibiting them would be of great therapeutic value, a claim for which there is emerging evidence.

Immunology↗
bioRxiv2016

Complement receptor 2 and IL-8 production identifies in adults and neonates naive T cells recently arising from the thymus

The adaptive immune system utilizes multiple mechanisms linked to innate immune cell functions to respond appropriately to pathogens and commensals. Here we discover further aspects of this connectivity by demonstrating that naive T cells as they emerge from the thymus (recent thymic emigrants, RTEs) express complement receptors (CR1 and CR2), the bacterial pathogen recognition receptor TLR1 and an enzyme that deactivates bacterial lipopolysaccharide (AOAH) and following activation secrete the anti-microbial cytokine IL-8. CR2+ naive T cells also express a selection of genes associated with tissue migration, consistent with the hypothesis that following emigration from the thymus RTEs seed peripheral compartments where some pursue their anti-microbial potential by becoming IL-8-producing CR2+ memory cells while others undergo homeostatic expansion. CR2+ naive and memory cells are abundant in children but decrease with age, coinciding with the involution of the thymus. The ability of CR2, which is also a receptor for Epstein-Barr Virus (EBV), to identify recent thymic emigrants will facilitate assessment of thymic function during aging and aid investigations of multiple clinical areas including the occurrence of T cell lymphomas caused by EBV.

Immunology↗