bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial metabolite Urolithin A induces expansion of Regulatory T Cells in aryl hydrocarbon receptor (AhR)-dependent manner
Authors: Ghosh Sweta , Haribabu Bodduluri , Jala Venkatakrishna R 
Published: February 2023

Abstract
Intestinal inflammation and loss of gut barrier integrity contribute to severity of inflammatory bowel diseases (IBD). Gut microbiota and their metabolites play an important role in maintenance of immunological balance within the gut. Previously, our group demonstrated that treatment with Urolithin A enhanced gut barrier function by inducing junctional proteins and blocked LPS-induced inflammation. Moreover, treatment with this microbial metabolite mitigated colitis in pre-clinical models. In the current study, we identified novel function for Urolithin A, where treatment with Urolithin A significantly expanded FoxP3+ T regulatory cells (Tregs) both ex vivo and in vivo models. Urolithin A failed to induce Treg expansion in AhR−/− mice suggesting Urolithin A mediates its activities through AhR. Moreover, treatment with Urolithin A mitigated murine model of dextran sulfate sodium (DSS)-colitis and enhanced Treg cell population compared to vehicle treatment. These results suggest that Urolithin A offers multi-pronged beneficial activities on gut epithelial layer (enhanced barrier function), macrophages (down regulation of inflammatory cytokines) and expansion of Treg cells to protect against colitis.
T-bet+ B cells promote adipose tissue inflammation and metabolic disorder during obesity.
Authors: Vanz Carlo , Hagglof Thomas , Dudley Elizabeth , Leadbetter Elizabeth 
Published: February 2023

Abstract
Obesity is a public health crisis affecting a large and ever-growing portion of the global population. Obesity is associated with an increased risk of death and comorbidities, resulting in lower quality of life for obese patients and increased economic costs on healthcare systems. Obesity is linked with a low-grade and chronic inflammation in the adipose tissue, which further exacerbates metabolic dysfunctions. Understanding the mechanisms and immune cell types promoting this inflammation would allow for the development of new therapies to restore immune regulation in obese patients. Our lab has identified a subset of B lymphocytes which is expanded in the adipose tissue of humans and mice during obesity. This subset is characterized by the co-expression of T-bet and CD11c, production of IgG2c, and its expansion is dependent on the presence of iNKT cells. In vivo studies with mice fed a high fat diet reveal that these Tbet+ B cells promote inflammation. Serum transfer experiments and flow cytometry analysis revealed that this effect is mediated through the production of CXCL10 and antibodies. The absence of T-bet+ B cells does not appear to affect adipose CD4+ T cells or NK cells, but it reduces macrophage polarization towards a more proinflammatory phenotype. Transgenic mice engineered to lack T-bet+ B cells not only have reduced adipose tissue inflammation, but present improved metabolic function as well, gaining less weight on a high-fat diet than littermate controls and presenting improved glucose tolerance. Based on these results, T-bet+ B cells represent an interesting potential target to reduce inflammation in obese patients and improve their metabolic functions.
Milk-derived osteopontin shapes the development of the intestinal microbiota
Authors: McClanahan Kathleen , Greer Michael , Olivares-Villagómez Danyvid 
Published: February 2023

Abstract
Breast-feeding is important for the growth and development of infants, delivering nutritional support as well as a wealth of immunological factors that provide protection while the infant immune system matures. Formula-fed infants have an increased risk of negative health outcomes, including obesity, autoimmunity, and infections, and display dysbiosis of the intestinal microbiota compared to breast-fed infants. Of the many components of milk, bioactive proteins provide a potential mechanism by which breast milk can impact the infant microbiota. One protein of interest is osteopontin (OPN), a highly glycosylated phosphoprotein involved in a range of physiological processes including bone mineralization, inflammation, wound healing, and homeostasis of lymphoid cells in the intestinal epithelium. Osteopontin constitutes about 2% of the protein component of milk; however, the impacts of milk-derived osteopontin on the development of the infant microbiota are not yet well understood. We propose that milk-derived osteopontin plays a critical role in the development of the neonatal gut microbiota, and that lack of osteopontin intake during the post-natal period leads to gut dysbiosis.
Peroxisome proliferator-activated receptor gamma activation reverses adipose tissue regulatory T cell dysfunction.
Authors: Smith Alan J , Shantaram Dharti , Liu Joey , Wright Valerie P. , Bradley David , Hsueh Willa A. 
Published: February 2023

Abstract
Adipose tissue (AT) regulatory T Cells (Tregs) play an essential role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs and a corresponding increase in tissue inflammation and systemic insulin resistance in both humans and mice. In human samples, we have found Tregs isolated from visceral AT (VAT) display a dysfunctional phenotype characterized by decreased viability, decreased effector function, and increased expression of inhibitory co-receptors (PD-1 and OX40). VAT Tregs cultured with peripheral blood mononuclear cells (PBMCs) display reduced ability to suppress proliferation, while peripheral blood Tregs suppress proliferation normally. As peroxisome proliferator-activated receptor (PPAR)-gamma has been shown to be a regulator of AT Tregs, we hypothesize that the Treg dysfunction can be reversed by addition of the PPAR-gamma agonist Pioglitazone. We isolated Tregs from VAT and peripheral blood and added cells to CFSE-labelled PBMCs in the presence and absence of Pioglitazone. After 4 days culture, Pioglitazone was found to significantly improve the ability of VAT Tregs to suppress proliferation. This effect was specific to AT Treg populations as Pioglitazone alone did not affect PBMC proliferation. These data suggest that Treg dysfunction contributes to AT inflammation and activation of PPAR-gamma promotes VAT-specific Treg activity providing therapeutic implications for PPAR-gamma agonists. (Partially supported by the OSU Cancer Center Support Grant P30CA016058).
The impact of type I interferon driven cytokines on the plasmablast response to viral pathogens
Authors: Steffen Tara L , Hassert Mariah , Brien James D 
Published: February 2023

Abstract
The plasmablast B cell (PB) response to viruses provides the first wave of functional virus specific antibodies. PBs may undergo immunoglobulin class switch recombination (CSR), giving these antibodies a diverse array of properties and functions that contribute to their mechanisms of viral clearance. Dendritic cells (DCs) can prime a PB response through native antigen production, cell surface interactions, and soluble mediators including cytokines. Additionally, we know that type I interferon (IFN) has dynamic regulatory functions by inducing expression of interferon stimulated genes (ISGs) in addition to having potent anti-proliferative and anti-viral effects. We hypothesize that signaling of type I IFN inhibits the PB response induced by virial infection by impacting the cytokine milieu, magnitude and diversity of the PB response, and mechanisms of antibody mediated protection. As DCs are potent producers of type I IFN and mediate direct interactions with B cells, we employed a DC specific knockout of Ifnar1 from the type I IFN receptor, CD11c Cre X Ifnarfl/fl, to challenge our hypothesis. Overall, we show that ablation of type I IFN signaling followed by infection with Zika virus (ZIKV) results in an increase in PB frequency in lymphoid tissue, increase in CSR, and potent increase in the neutralization capacity of polyclonal sera. The results of these studies can be leveraged to increase immunogenicity of mRNA and attenuated vaccines while targeting for a quicker antibody response.
Characterizing infection of B lymphocytes with vaccine and wild-type strains of measles virus
Authors: Melot Logan , Coughlin Melissa , Rota Paul A , Bankamp Bettina 
Published: February 2023

Abstract
Wild-type (w.t.) measles virus (MeV) infection can result in immunosuppression that does not occur following vaccination. A rhesus macaque model indicated that B cells are a target of infection. The role of B cell infection in MeV-induced immune suppression is not fully understood. We characterize the differences in viral replication in human B cells infected with vaccine (Edmonston Zagreb [EZ]) or w.t. virus.
B cells from healthy donor blood were infected (MOI 1.0) with a GFP-expressing EZ virus or a w.t. virus to evaluate viral replication after 24 and 48 hours. The number of GFP+ cells (EZ infected) or hemagglutinin (H)+ cells (w.t. infected) was measured via flow cytometry. Transcription of the viral nucleoprotein (N) gene was measured by mRNA-specific cDNA generation and N gene specific qPCR. Production of infectious viral particles was measured via endpoint dilution.
In B cells infected with EZ, 30% of cells expressed GFP at 24 hours and 45% of cells expressed GFP at 48 hours. There was a 4.4-fold increase in N gene transcription from 0 to 48 hours. There was no detectable increase in viral titer over input after 48 hours. In B cells infected with w.t. virus, 10% of cells expressed viral H at 24 hours with no increase in H expression at 48 hours. The w.t. virus had a 2.4-fold increase in viral transcription from 0 to 48 hours. There was no detectable increase in viral titer over input after 48 hours.
MeV-infected B cells show viral protein production and N gene transcription at 24 and 48 hours. However, w.t. virus replication may be less efficient as shown by lower percentages of H+ cells at 24 and 48 hours and lower levels of N gene transcription at 48 hours. There is no evidence of infectious virus production by either strain of MeV despite evidence of replication.
Type I Interferon Shapes Humoral Immunity to SARS-CoV-2
Authors: Goldman-Israelow Benjamin , Mao Tianyang , Song Eric , Lu Peiwen , Wong Patrick , Lucas Carolina , Klein Jon , Iwasaki Akiko 
Published: February 2023

Abstract
The role of type I interferon (IFN-I) in SARS-CoV-2 infection has remained controversial. Elevated IFN-I levels are associated with increased COVID-19 morbidity and mortality; however, impaired IFN-I signaling, either genetic or via autoantibodies, is also associated with worse outcomes. While these studies have focused on the role of IFN-I in COVID-19 pathogenesis, its role in modulating adaptive immunity to SARS-CoV-2 remains unknown. Here we investigate the role of IFN-I in shaping the humoral immune response to SARS-CoV-2 infection in both COVID-19 patients and mouse models of SARS-CoV-2 infection. We find that patients with COVID-19 who have higher levels of plasma IFN-I develop lower anti-spike (S1) and anti-receptor binding domain (RBD) IgG levels. Similarly, we find that mice lacking the interferon-α/β receptor (IFNAR) or treated with IFNAR blocking antibodies develop higher levels of anti-SARS-CoV-2 S1 and RBD IgG, as well as higher levels of anti-S1 IgA, IgG1, and IgG2. Furthermore, we find that IFNAR deficiency promotes the development of follicular helper T cells, germinal center B cells, and antibody-secreting cells in the draining lymph node. Accordingly, patients with higher serum IFN-I levels have reduced circulating follicular helper T cells. Despite higher levels of anti-SARS-CoV-2 IgG, sera from IFN-I sufficient or deficient mice harbored comparable neutralizing activities, suggesting reduced antibody potency (IC50/IgG) in IFNAR-deficient mice. Similarly, patients with higher serum IFN-I levels produced higher-potency anti-SARS-CoV-2 antibodies. These findings highlight a beneficial role for IFN-I in modulating cellular responses critical for promoting a potent antibody response to SARS-CoV-2.
Live attenuated viral vectors based on the rubella vaccine strain RA27/3
Authors: Berkower Ira , Zhou Wenshuo , Perry-Anderson Jasper , Felber Barbara , Virnik Konstantin 
Published: February 2023

Abstract
We have developed a series of live viral vectors based on the live attenuated rubella vaccine strain RA27/3. These vectors can express a variety of heterologous vaccine antigens without interfering with vector growth or stable antigen expression. The vaccine inserts were expressed for at least 5 to 10 passages in Vero cells. Proteins as large as the ectodomain of HIV gp140 could be expressed (90 kDa), and they retained the native conformation. Recently expressed vaccine inserts include: P27 Gag protein of SIV, the NANP repeat sequence of malaria circumsporozoite protein, and the receptor binding domain of Sars CoV-2 S1 spike protein.
We have studied these vectors for immunogenicity in a rhesus macaque model. The rubella vectors are based on the rubella vaccine strain, for which one or two doses can elicit lifelong immunity. The vectors are a little different: The best immune response was observed when the macaques were primed with a DNA vaccine, followed by rubella vectors, or when they were primed with rubella vector and then boosted with the native protein. In both cases, an immunization strategy with only one exposure to rubella antigens was better than giving it twice.
This could occur if the secondary response to rubella antigens inhibited the response to the vaccine insert. Alternatively, the strong anamnestic response to a boost of protein antigens suggests that the level of protein expression by the vector was the limiting factor. In future studies, we will test whether vectors with better growth characteristics and stronger antigen expression levels can improve antibody titers, elicit neutralizing antibodies, and protect against a viral challenge.
A CD8 T cell signature in ALS4.
Authors: Campisi Laura , Gromova Anastasia , Arnold Frederick , Mei Xueyan , Beharry Cindy , Fstkchyan Yesai , La Spada Albert , Marazzi Ivan 
Published: February 2023

Abstract
Motor neuron disorders (MND) cause disability and death globally. Despite an increasing knowledge of the genetic defects of MND, a clear understanding of the mechanisms of disease initiation and progression is lacking. Recent advance in the field has highlighted that several genes linked to MND are essential for maintaining immune homeostasis, suggesting that dysfunctions in the immune system could influence the development of the disease or aggravate its pathology.
Amyotrophic Lateral Sclerosis 4 (ALS4) is a rare, juvenile form of MND. It is caused by mutations in the gene SENATAXIN (SETX), which encodes for a nuclear helicase ubiquitously expressed. Our group identified SETX as a transcriptional regulator of inflammatory responses.
Since SETX is involved in both MND and the control of the immune response, we hypothesized that underlying defects in the immune system could be associated to ALS4 progression.
We took advantage of the Setx-L389S+/− knock-in (KI) mouse carrying the most common causative variant of ALS4 in humans. Surprisingly, we found that SetxL389S needs to be expressed in both neuronal and immune cells to trigger disease. In parallel, we discovered a pathologic signature consisting of high frequencies of activated CD8 T cells in the central nervous system (CNS) and blood of KI animals. Further analyses showed clonal expansion of aberrant activated CD8 T cells. Dysfunctions in the CD8 T cell compartment have been confirmed in the peripheral blood of ALS4 patients, as compared to age-matched controls.
Collectively, our results suggest that ALS4 is characterized by aberrant CD8 T cell responses of possible autoimmune origin. Our findings have the potential to pave the way for immune-based diagnosis and therapy for patients.
Artemisinin selectively induces ferroptosis and reverses the immunosuppressive state of MDSCs in T cell lymphoma
Authors: Yan De Hong , Zhang Mengqi , Wan Xiaochun 
Published: February 2023

Abstract
The malaria drug artemisinin has previously been identified as a potent anti-lymphoma drug to treat B-cell lymphoma and myeloid leukemia, but treatment of T lymphoma is rarely reported. In this study, we found that artemisinin can not only cause ferroptosis by up-regulating ROS levels and increasing misfolded protein in T cell lymphoma via down-regulating ERK pathway, but also reduce the accumulation of MDSCs, relieve the immunosuppressive effect of MDSCs on effector T cells, induce anti-tumor immune reactivation, and inhibit tumor growth in tumor bearing mice.
This work was supported by the National Key R&D Program of China (2019YFA0906100), National Natural Science Foundation of China (Grants 82071772, 81501356 and 81373112), Key-Area Research and Development Program of Guangdong Province (2019B020201014), the Shenzhen Basic Science Research Project(Grants JCYJ20190807161419228, JCYJ20170818155135838, JCYJ20170818164619194, and JCYJ201 70413153158716), China Postdoctoral Science Foundation (2019M660220), Basic and Applied Basic Research Foundation of Guangdong Province (2019A1515110359), Nanshan pilot team project (LHTD20160004), Start-up funding (CYZZ20180307154657923).
Effects of (+)-naloxone blocking Toll-like Receptor 4 in depression and cognition
Authors: Medina-Rodriguez Eva Maria , Rice Kenner C , Beurel Eleonore , Jope Richard S 
Published: February 2023

Abstract
The immune system has been shown to affect the brain, and consequently behaviors. In particular, increasing evidence indicates that inflammation contributes to susceptibility to depression, which is a leading cause of disability, and for which current treatments are often inadequate. We hypothesized that targeting Toll-like receptor 4 (TLR4), one of the main signaling pathways for triggering an inflammatory response, would lessen stress-induced depression-like behaviors in mice. TLR4 inhibition with the CNS-penetrating drug (+)-naloxone that is a TLR4 antagonist but is inactive at opiate receptors, reversed chronic restraint stress-induced impairments of various depression-like behaviors, as well as cognitive tests in male mice but had no effect in female mice. These effects might be mediated by interferon-β (IFNβ) pathway in microglial cells. Altogether, our results confirmed the critical role of TLR4 in mediating depressive-like behaviors and cognitive impairments and demonstrated that (+)-naloxone might be a promising therapeutic strategy for depression.
Visualization of leukemic B cell clonal dynamics during therapy using tSNE.
Authors: Welch Baustin M 
Published: February 2023

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+ CD5+ clonal B lymphocytes in the blood, bone marrow, and peripheral lymphoid organs. Many patients with CLL never receive treatment for the leukemia and therapy is typically only initiated upon progression of disease-related clinical complications. Treatment options for progressing patients range from chemoimmunotherapy (CIT) to small molecule inhibitors that target pro-survival signaling pathways in leukemic B cells, such as the BTK inhibitor ibrutinib. Although therapy regimens have improved, there is still no cure for CLL, in part due to clonal evolution of the leukemic B cell. The goal of this study is to document the clonal dynamics of CLL B cells at baseline and at response evaluation(s) for alterations in clonal architecture and expression of cell surface markers associated with therapy resistance using the single cell flow cytometry analysis tool, t-distributed stochastic neighbor embedding (t-SNE). Biobanked peripheral blood mononuclear cells were obtained from patients that underwent frontline CIT or ibrutinib, or secondary ibrutinib therapy. Fourteen parameter flow cytometry was performed and subjected to tSNE analysis to document CLL B cell clonal architecture and evolution in patients undergoing the various therapies. Profound differences in treatment responses and leukemic cell clonal dynamics were observed which may inform the discovery of novel biomarkers associated with therapy resistance.
NLRP7 interacts with EBP1 providing evidence for its role in molar pregnancies and development.
Authors: So Matthew , Lupfer Christopher R 
Published: February 2023

Abstract
Recurrent hydatidiform molar pregnancies are characterized by uncontrolled proliferation of trophoblasts resulting in the failure of the embryo and placenta to develop properly. Previous studies genetically mapped a mutation in NLRP7 as a cause for recurrent molar pregnancies with abnormal methylation patterns. The goal of this study is to identify human proteins that interact with NLRP7, especially those that are involved in DNA acetylation and methylation, which could lead to the development of molar pregnancies. A yeast two-hybrid system using a human cDNA library was used to screen for interacting proteins and protein interactions were verified by co-immunoprecipitation in HEK 239T cells. Additional experiments are being performed to determine the change in global methylation when NLRP7 and EBP1 interact. Yeast screening results indicated several proteins that interact with NLRP7, however further testing will be focused on the interaction with EBP1, a human protein involved in growth regulation. Having potentially identified a protein involved in development through acetylation/deacetylation that interacts with NLRP7, we hope to shed more light on the molecular pathways that lead to the formation of recurrent molar pregnancies.
An Assay to Monitor the Engagement and Modulation of CD6 on T cells as a Clinical Biomarker of Treatment with Itolizumab
Authors: Bisconte Angelina R , Kisselbach Lynn , Ng Cherie , Ampudia Jeanette , Chu Dalena Ngoc , Belkina Natalya , Connelly Stephen , Phippard Deborah 
Published: February 2023

Abstract
Itolizumab is a novel first-in-class monoclonal antibody that selectively targets the co-stimulatory molecule CD6, a receptor that is highly expressed on CD4 and CD8 T cells and plays an important role in activation and migration. Monitoring target engagement and changes in receptor levels is critically important to interpreting clinical data. To evaluate the pharmacodynamic properties of itolizumab treatment on T cells in patients including those with graft versus host disease (GvHD), Precision for Medicine has developed and validated a 10-color flow cytometry assay to assess the engagement and modulation of cell-surface CD6.
The assay was validated using whole blood from healthy donors. Blood was spiked with five concentrations of drug selected based on expected PK in the clinical study. The assay conditions were optimized for sensitivity, signal: noise ratio, detection of free receptor, receptor-bound itolizumab and total surface CD6. Itolizumab was detected using a fluorochrome conjugated α-human IgG1 antibody while total surface CD6 expression was assessed using an antibody to a non-competing site on CD6. For validation, pre-set criteria were used to assess inter-assay, intra-assay, inter-operator precision and post-staining stability. Technical validation was successfully met; and the assay performs within acceptable precision parameters.
Measuring cell-based receptor engagement and fate in patients on immuno-modulatory therapies is very challenging. This assay was designed and validated to be both sensitive and selective in the quantification of CD6 receptor occupancy and modulation to facilitate the determination of an optimal therapeutic dose in autoimmune and inflammatory diseases.