bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves
Authors: Guerra-Maupome Mariana , McGill Jodi L. 
Published: January 2023

Abstract
M. bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine for use against tuberculosis (TB). BCG is known to reduce childhood mortality from infections other than TB. The unspecific protection induced by BCG has been associated with the induction of memory-like traits identified as ‘trained’ immunity. In humans and mice, in vitro and in vivo BCG training leads to enhanced production of proinflammatory cytokines in response to secondary unrelated pathogens. While BCG nonspecific protective effects have been studied extensively in humans and mice, it has not been defined in agricultural species. Here, we show that in vitro BCG training induces increased transcription of proinflammatory cytokines upon restimulation with the TLR agonists. Importantly, in vivo, aerosol BCG vaccination of calves induced a ‘trained’ phenotype in PBMCs, that lead to a significantly enhanced TLR-induced proinflammatory cytokine response compared to PBMCs from unvaccinated calves. Similar to the long-term training effects of BCG reported in humans, our results suggest that in young calves, the effects of BCG induced innate training last for at least 3 months in circulating immune cells. Interestingly, however, aerosol BCG vaccination did not ‘train’ innate cells at the mucosal level, as alveolar macrophages from aerosol BCG vaccinated calves did not mount an enhanced inflammatory response to secondary stimulation, compared to cells isolated from control calves. Together, our results suggest that, like mice and humans, the innate immune system of calves can be ‘trained’; and that BCG vaccination could be used as an immunomodulatory strategy to reduce disease burden in juvenile food animals before the adaptive immune system has fully matured.
A comprehensive map of the human dendritic cell HIV-response transcriptional network
Authors: Johnson Jarrod S , De Veaux Nicholas , Rives Alexander W , Lahaye Xavier , Lucas Sasha Y , Pérot Brieuc , Luka Marine , Amon Lynn M , Watters Aaron , Aderem Alan , Manel Nicolas , Littman Dan R , Bonneau Richard , Ménager Mickaël M 
Published: January 2023

Abstract
Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral type I interferon and DC maturation. Here, we have developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we have inferred a gene regulatory network that links 542 transcription factors (TFs) with 21,862 target genes. Through genetic perturbation and drug treatments we identify PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting the complexity and cooperativity in the regulatory circuit controlling the DC response to HIV-1 infection.
Crosseactivity of flaviviruses specific CD8+T cell responses across different viral species
Authors: Grifoni Alba , Voic Hannah , Sidney John , de Silva Aruna D , Durbin Anna , Diehl Sean A , Harris Eva , Sette Alessandro , Weiskopf Daniela 
Published: January 2023

Abstract
Several flaviviruses, including Dengue Virus (DENV), Zika Virus (ZIKV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV), and Yellow Fever Virus (YFV), share significant sequence homology and often circulate in the same geographical regions. Significant levels of cross-reactivity could in turn result in pre-existing T cell immunity modulating T cell responses to subsequent flavivirus infections or vaccination. Whether and to what extent cross-reactivity at the level of CD8 responses is detected is currently unclear. Thus we designed pools of epitopes and predicted HLA binding peptides derived from DENV, ZIKV, JEV, WNV and YFV. We then used PBMC of individuals vaccinated with DENV or YF to test their potential to recall antigen specific CD8 memory T cell response in an Intracellular Cytokine Staining (ICS) assay. Significant cross-reactivity of CD8 T cell responses against several of the pools was observed both in the case of DENV and YF vaccinees, but the extent of cross-reactivity varied as a function of the flavivirus species considered, and the cross-reactive responses were significantly lower than the responses to the autologous virus. Phenotypic analyses showed a suboptimal expression of activation markers in cross-reactive responses. We are currently characterizing cross-reactive responses at the single epitope level, and in PBMCs from donors naturally exposed to flaviviruses. Characterization of the extent and functionality of CD8 cross-reaction across different flaviviruses will contribute to the understanding of immunity in the natural infection, and has particular implications for vaccine efficacy and safety in endemic settings.
Targeted protein degradation via NEDD8 conjugation does not enhance direct MHC class I antigen presentation
Authors: Vijayasimha Kartikeya , Leestemaker-Palmer Amy L. , Gibbs James S. , Yewdell Jonathan W , Dolan Brian P 
Published: January 2023

Abstract
MHC class I molecules present peptide antigens derived from proteins synthesized and degraded within the antigen presenting cell. An understanding the protein degradation pathways that contribute to peptide generation is necessary for developing next generation immunotherapies. We recently discovered that conjugation of the ubiquitin-like molecule NEDD8 to the N-terminus of a protein can result in the rapid degradation of the target protein by either the ubiquitin-proteasome system (UPS) and the autophagy pathway. To determine if protein NEDDylation increased peptide presentation, we fused NEDD8 to the N-terminus of a cytosolic form of ovalbumin (OVA) and measured presentation of the SIINFEKL peptide via the murine MHC class I molecule Kb using a monoclonal antibody specific for the Kb-SIINFEKL complex. Like other constructs we have characterized, NEDDylated OVA was rapidly degraded by the UPS and autophagy pathways. While proteasome inhibition prevented presentation of SIINFEKL peptides, inhibiting autophagy did not affect antigen presentation. We then compared presentation of NEDDylated OVA to ubiquitin conjugated OVA and found that ubiquitin conjugation was far more effective at generating antigenic peptides. These data demonstrate that rapid degradation per se of an antigenic protein is not sufficient to enhance antigen presentation but rather the precise manner in which a protein is degraded governs the efficiency of peptide generation. Our findings are consistent with the idea that protein degradation is organized in some way to optimize generation the immunopeptidome for immunosurveillance.
Isoflavone Rich Diet Ameliorates Experimental Autoimmune Encephalomyelitis (EAE) through Modulation of Gut Bacteria Depleted in Multiple Sclerosis Patients
Authors: Freedman Samantha N , Shahi Shailesh K , Zarei Kasra , Gupta Arnav , Guseva Natalya V , Bossler Aaron D , Legge Kevin L , Mangalam Ashutosh K 
Published: January 2023

Abstract
Multiple sclerosis (MS), an autoimmune disease of the central nervous system, has been shown to be influenced by gut bacteria. We and others have shown that MS patients have depletion of isoflavone-metabolizing bacteria compared to healthy individuals. We hypothesize that gut bacteria-mediated isoflavone metabolism induces an anti-inflammatory state and reduction/depletion of these gut bacteria might predispose to MS development and/or severity. To test this, we placed mice on a diet with or without isoflavones and induced EAE, an animal model of MS. Mice on an isoflavone diet developed milder disease compared to those on an isoflavone-free diet. This phenomenon was dependent on the presence of isoflavone-metabolizing gut bacteria as confirmed by antibiotic depletion and bacterial reconstitution. Mice on an isoflavone diet exhibited altered peripheral immune responses, CNS cellular infiltration, and CNS pathology post EAE induction compared to mice on an isoflavone-free diet. Additionally, the gut microbiome of mice on an isoflavone diet and an isoflavone-free diet closely resembles the gut microbiota of healthy individuals and MS patients, respectively. Thus our results suggest that dietary isoflavone metabolites produced with the help of gut bacteria can influence the disease through modulation of the immune system.
A newly discovered dual expresser lymphocyte that clonally expanded in Type 1 diabetes (T1D) patients secretes a public antibody that recognize public TCR in T1D
Authors: Ahmed Rizwan , Omidian Zahra , Giwa Adebola , Karakus Kagan E , Majety Neha , Yang Angela , Zhang Hao , Rabb Hamid , Jie Chunfa , Donner Thomas , Hamad Abdel R.A. 
Published: January 2023

Abstract

PURPOSE
We have recently discovered a new lymphocyte that co-express BCR and TCR (Ahmed et al, Cell, 2019: 177:11583) and referred as X cell to denote its crossover phenotype. Importantly, X cells express a public BCR that also encodes a potent autoantigen in its CDR3 sequence that is 10 fold more potent than native insulin peptide (InsB:9–23) in binding to DQ8 and activating autologous CD4 T cells. The x-autoantigen cross-activate insulin specific CD4 T cells as a peptide in the context of HLA-DQ8 molecules or as a soluble intact mAb (x-mAb). The goal of this study is to characterize autoreactive CD4 T cells that are responsive to x-mAb to determine their phenotype, cytokine profile and TCR repertoire and whether they express public TCRs.

METHODS
We used EBV-lymphoblastoid X cell clone as a source of x-mAb (IgM) and FACS based protocol to identify IgM reactive CD4 T cells (referred as IgMpos) and their functional properties. ImmunoSEQ assay used to characterize TCR repertoires.

RESULTS
Preliminary data show that frequency of IgMpos CD4 T cells is significantly higher in T1D as compared to Healthy subjects. In addition, IgMpos CD4 T cells exhibit an activated phenotype as compared to autologous IgMneg CD4 T cells, including expression of CD45RO, CD44, and CD69. Analysis of TCRVβ repertoire shows that IgMpos CD4 T cells are enriched for public clonally expanded TCRs as compared to IgMneg counterparts.

CONCLUSIONS
X cells in T1D patients are predominated by a single public BCR and that the secreted version of this BCR (x-mAb) is autoreactive against a specific subset of CD4 T cells that predominated by few clonotypes that express public TCRs. Our results are revealing previously unknown mechanism that appears to be a play critical role in pathogenesis of T1D.
Functions and mechanisms of chondroitin disaccharide-induced miRNAs in the regulation of CD44 expression involved in the development of experimental autoimmune encephalomyelitis
Authors: Zhou Juhua , Ma Xinting , Li Yanmin , Zhong Yin , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the central nervous system (CNS). In this study, we investigated the effects of chondroitin disaccharide and its induced miR-29b and miR-199b on CD44 expression in mouse lymphocytes, as well as the effects of miR-29b and miR-199b on the development and progression of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of MS. The effects of chondroitin sulfate disaccharide on the changes in cellular immunity were investigated in EAE induced in mice by MOG and PTX. Real-time PCR and flow cytometry were used to investigate the effects of the anti-miRs and mimics of miR-29b and miR-199b on CD44 expression in mouse splenocytes after electroporation. After the transduction of antai-miRs and mimics of miR-29b and miR-199b into splenocytes, they were adoptively transferred into mice intravenously and the changes in immune cells and cytokines were analyzed by flow cytometry and ELISA. Our studies revealed that chondroitin disaccharide significantly up-regulated several specific miRNAs such as miR-29b and miR-199b, and thus dramatically inhibited EAE in mice. In vitro and in vivo studies demonstrated that miR-29b and miR-199b could down-regulate the expression of CD44 and modulate the expression of IL-17 and IL-4 in the lymphocytes from EAE mice. Therefore, miR-29b and miR-199b could inhibit the expression of CD44, modulate the expression of IL-4 and IL-17, and thus suppress lymphocyte proliferation and migration, leading to significant inhibition of EAE development. Thus, miR-29b and miR-199b could also be used as therapeutic targets for EAE and MS.
Induced lymphatic circulation decreases IL-17 expression in the lymph nodes of rats in adjuvant-induced arthritis
Authors: Volin Michael V , Zanotti Brian , Hager Denver , Lai LinhChi , Gober Calley , Pulpulaan Paul Anthony , Incrocci Ryan , Swanson-Mungerson Michelle Anne 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation mediated by Th-17 cells. Rat adjuvant-induced arthritis (AIA) is a Th-17-dependent RA model with dysfunctional lymphatic circulation. We hypothesized that induction of lymphatic circulation would attenuate arthritic inflammation. We utilized Lymphatic Pump Treatment (LPT), an osteopathic lymphatic manipulation, to determine if inducing lymphatic flow would alleviate arthritic inflammation. LPT was accomplished on AIA rats by gradually increasing compression on the chest wall for 5 seconds followed by a rapid release. This technique was performed on the rats for 1 minute 3X/day over 7 consecutive days following the onset of measurable inflammation on day 14 post adjuvant injection. Ankle caliper measurements, articular index scoring, popliteal lymph nodes, peripheral blood, and spleens were collected. The LPT-treated rats fell into two groups. LPT responders and non-responders. LPT responders had significantly reduced inflammation (as determined by both in ankle circumference and index scoring). These therapeutically treated animals also had significantly decreased IL-17 expression in their draining popliteal lymph nodes. These results along with our previous findings indicate that LPT can reduce arthritis, alter lymphocyte trafficking and differentiation in secondary lymphoid organs during inflammation. These data suggest that induced lymphatic circulation using osteopathic manipulation may serve as a therapy for chronic inflammation in autoimmune disorders and may also be an enhancement to current treatments.
Androgens may mediate protection through an effect on immunoregulation in lupus-prone mice
Authors: Ma Jing , Harder James W , Alard Pascale , Kosiewicz Michele M 
Published: January 2023

Abstract
Lupus is much more prevalent in females. Depleting androgens via castration increases disease and mortality in male NZBxNZWF1 (BWF1) mice, suggesting androgens are protective. We have found that treatment of male BWF1 mice with CD103-neutralizing antibody induces disease and increases mortality suggesting CD103+ cells are important for disease protection in males. Mesenteric lymph node (MLN) CD103+ dendritic cells (CD103DC) from castrated male mice exhibit decreased ability to induce conversion of CD4+Foxp3+ cells (Tregs) in vitro and decreased expression of RALDH2, an enzyme involved in retinoic acid synthesis (hallmark of CD103DC function) vs control mice. Also, castrated BWF1 male mice have significantly decreased circulating and peripheral LN Tregs vs control mice, suggesting androgens may affect Tregs via an effect on CD103DC. We have found CD103DC express androgen receptor (AR) mRNA levels that are lower than splenic macrophages (positive controls), but higher than splenic myeloid DC (negative controls) suggesting that androgens could have a direct effect on CD103DC. To determine whether signaling through the AR is required for androgen-mediated protection and CD103DC function, male BWF1 mice were treated with flutamide (AR inhibitor). Male mice treated with flutamide exhibited increased disease incidence and severity, and decreased CD103DC function including a decreased ability to induce conversion of Tregs in vitro and decreased expression of RALDH2 mRNA. Taken together, these data suggest that androgens may influence immunoregulation via a direct effect on CD103DC function and may, at least in part, mediate protection from lupus through this mechanism.
LPS elevates ceramide levels through regulating ORMDL3 expression in macrophages and acute respiratory distress syndrome model
Authors: Ma Jason , Ting Nai-Chun , Kuo Ming-Ling 
Published: January 2023

Abstract
Acute respiratory distress syndrome (ARDS) is a respiratory system failure defined by the acute onset of noncardiogenic pulmonary edema and hypoxemia. After triggered by diverse pulmonary toxicants, macrophages accumulate in lung and generate cytotoxic and proinflammatory mediators that induce pathogenic responses, including cytokines, chemokines, proteases and bioactive lipids. Ceramide is a lipid lies within cell membrane bilayer and functions as a signaling molecule, causing production of inflammatory cytokines and cell apoptosis. The generation of ceramide is controlled by serine palmitoyltransferase (SPT), which forms complex with orosomucoid-like protein 3 (ORMDL3) to regulate ceramide levels. Since the level of ceramide is highly associated with lung injury, we aim to investigate how LPS induces ceramide level. PMA-differentiated THP-1 cells were activated by LPS and the ceramide levels were analyzed by using UPLC-TOF-MS system. Proteins regulating ceramide synthesis and relative transcription factors were further determined. We found that ORMDL expressions were down-regulated and ceramides were increased in THP-1 cells upon LPS activation. ORMDL3 transcription factors, p300 and STAT6, were down-regulated but not Ets-1, CREB nor ubiquitin ligase Cbl-b. We established a LPS-induced B6 model for ARDS and analyzed BALF cells, cytokine and chemokine levels, and ceramide composition. ORMDL3 is also down-regulated in ARDS model, which may result in the increase of ceramide levels. Taken together, LPS may increase ceramide levels by regulating ORMDL3 expression through p300-STAT6 axis. These results may provide new therapeutic strategies for ARDS patients by targeting ORMDL3 to control ceramide levels.
Macrophage-restricted tyrosine phosphatase SHP2 is a novel anti-atherosclerotic regulator
Authors: wu chenxia , Xu Chen , Ma Lan , Mao Wei , Cheng Hongqiang , Ke Yuehai 
Published: January 2023

Abstract
Atherosclerosis is a main pathological basis for cardiovascular diseases. Macrophages, featured in phenotypic and functional plasticity, play critical roles in initiation, progression, and regression of atherosclerosis. Our previously studies have shown that protein tyrosine phosphatase SHP2 regulates macrophage polarization, the immune homeostasis mediated by the interactions between macrophages and epithelial cells in mouse lung and intestine, and a tumor-favorable immune microenvironment. However, a potential role of SHP2 in atherosclerotic macrophages remains unknown. The expression of SHP2 is increased in macrophages within human atherosclerotic plaques. SHP2 allosteric inhibitor and macrophage-specific SHP2 deletion worsened atherosclerosis in ApoE null mice. Total cholesterol and low-density lipoprotein were increased in SHP2 inefficient mice. SHP2 inefficiency promoted inflammatory M1 polarization and inhibited anti-inflammatory M2 polarization, which was ApoE-null-dependent. Less cholesterol accumulation was observed in SHP2 inefficient macrophages and cholesterol transporter CD 36 was downregulated. To further explore the underlying mechanism, RNA sequencing was performed using SHP2 deleted macrophages with or without oxLDL treatment. Taken together, our studies using SHP2 knockout mice and specific inhibitor suggest that SHP2 is a novel anti-atherosclerotic regulator in promoting inflammatory macrophage phenotype.
The effect of N-butyl benzyl phthalate, a common plasticizer, on endometriosis development
Authors: Lee Joyu , Sharma Pooja , Suen Jau-Ling 
Published: January 2023

Abstract
Endometriosis is an estrogen-dependent and chronic inflammatory disease, which retrograded menstrual endometrial cells enter the pelvis and abnormally grow outside the uterine cavity. Severe symptoms such as infertility and chronic pelvic pain are typically observed in 6%–10% of reproductive-aged women. Previous study demonstrates that phthalates are capable to disrupt the endocrine system, especially by mimicking estrogen functions. Among them, n-butyl benzyl phthalate (BBP), a plasticizer for vinyl foams and artificial leather, is able to work as a selective agonist through the binding of ERα, and subsequently interrupt the endocrine regulation. This study aimed to explore the effect of BBP on endometriosis. We established a surgery-induced murine model and exposed the mice at physiologically relevant dose of BBP mimicking human exposure. The result showed that chronic exposure to BBP did not promote the growth of endometrial lesions, however, the lesion survival rate in BBP-treated mice was significantly increased compared to vehicle-treated mice. Our data showed that BBP exposure promoted the infiltration of monocytes (Ly6c+CD11b+F4/80-) and plasmacytoid dendritic cells (pDCs; CD11c+/lowPDCA-1+) in the lesions. In addition, the percentages of CD44+ cells in the infiltrated monocytes and pDCs in the BBP-treated group were significantly higher than those in the control. Also, BBP exposure promoted ICAM-1 expression in CD45− endometriotic lesion cells. The results suggest that BBP exposure may enhance endometrial cell adhesion through altering innate cell subset migration. The detail mechanism of BBP effect on endometriosis development awaits further investigation.
NFkB mediated sustained inflammation promotes hepatobiliary injury in Sickle Cell Disease
Authors: Pradhan-Sundd Tirthadipa , Vats Ravi , Sundd Prithu 
Published: January 2023

Abstract
Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock-in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD-associated hepatopathophysiology applying our recently developed quantitative liver intravital imaging, RNA sequence analysis, and biochemical approaches. SCD mice manifested sinusoidal ischemia, progressive hepatomegaly, progressive inflammation, hyperbilirubinemia, and increased ductular reaction under basal condition. NFkB activation in the SCD mice liver inhibited FXR signaling and its downstream targets, leading to loss of canallicular bile transport, sustained inflammation and altered bile acid pool. Intravital imaging revealed impaired bile secretion into the bile canaliculi, which was secondary to loss of canallicular bile transport and bile acid metabolism, leading to intrahepatic bile accumulation in SCD mice liver. These findings are the first to identify that NFkB-FXR dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury and liver inflammation in SCD. Improved understanding of these processes could potentially benefit the development of new therapies to treat sickle cell hepatic crisis.