bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decline of influenza-specific T cell repertoire in healthy geriatric donors (85.2)
Authors: Lee Jessica , Oelke Mathias , Ramachandra Lakshmi , Canaday David , Schneck Jonathan 
Published: January 2023

Abstract
While the goal of influenza vaccination is to develop antibodies to protect against a primary infection, clearance of the infection is primarily mediated through CD8+ T cells. The study of the CD8+ T cell response to influenza epitopes is crucial in understanding the disease and associated morbidity and mortality. The age-associated decline of the immune system is believed to be responsible for the increased risk of influenza infection in the geriatric population. Since the CTL response is important for the clearance of influenza infection, we compared the CTL response to immunodominant and subdominant influenza epitopes in HLA-A2+ control adult donors, aged 21-42, to the response in healthy geriatric donors, aged 65 and older. This was done using an artificial Antigen Presenting Cell (aAPC) based stimulation assay which revealed responses that could not be detected by ELISpot. Control donors showed a broad, multi-specific response to the subdominant epitopes, and each donor’s subdominant influenza-specific response was unique. When comparing the control donors’ CTL response to the geriatric donors’, the immunodominant M1 responses were preserved, however, the geriatric donors lacked the broad multi-specific response to influenza-specific subdominant epitopes seen in the control donors. These data indicate that aging leads to a decrease in the subdominant influenza-specific CTL responses which may contribute to the increased morbidity and mortality in older individuals.
Regulation of mast cell signaling by SHP-1 as a phosphatase and an adaptor (86.1)
Authors: Mizuno Kazuya , Nakata Kazuko , Yakura Hidetaka 
Published: January 2023

Abstract
To clarify how SHP-1 regulates mast cell signaling, we generated BMMC from motheaten (me), viable motheaten (mev), and control (WT) mice and examined signaling events and final outputs following FcϵRI and IL-3 stimulation. FcϵRI-induced tyrosine phosphorylation of SLP-76 and LAT, MAPK activation, and cytokine production were increased in me-/mev-BMMC. In addition, phosphorylation of SHP-1 was increased in mev. Since the activity of Lyn and Syk was comparable in all BMMC, these molecules are substrates of SHP-1. me-BMMC showed impaired PLCγ phosphorylation, calcium mobilization, and degranulation, which could not be observed in mev-BMMC. This result suggests that the expression of SHP-1 is sufficient for the positive regulation of these pathways. The absence of SHP-1 expression disrupted the association between SLP-76 and PLCγ. Next, we examined IL-3-dependent cell proliferation and cell death. When BMMC were stimulated with IL-3, ERK activation was increased and sustained in me-/mev. In accordance with increased ERK activation, apoptosis was decreased in me-/mev-BMMC. In contrast to the predicted role of ERK as a pro-survival molecule, IL-3-induced cell proliferation was much lower in me-/mev-BMMC than WT-BMMC. Addition of PD98059 resulted in the suppression of decreased apoptosis and cell proliferation in me-/mev-BMMC. These results suggest that SHP-1 positively regulates IL-3-dependent mast cell proliferation and apoptosis by inhibiting ERK activity.
Anti-IgE monoclonal antibodies that bind to IgE bound by CD23 but not to IgE bound by IgE Fc receptors on basophils (86.10)
Authors: Shiung Yu-Yu , Chiang Chen-Yi , Chen Jiun-Bo , Wu Pheidias , Hung Alfur , Chang Tse Wen 
Published: January 2023

Abstract
IgE is a central mediator responsible for immediate-type hypersensitivity reactions. The anti-IgE monoclonal antibody (mAb), omalizumab, has been shown in numerous clinical trials to be efficacious in the treatment of severe allergic asthma and other allergic diseases. Omalizumab was designed to bind to free IgE in blood and membrane-bound IgE (mIgE) on B cells, but not to IgE bound by the high-affinity IgE Fc receptors (FcϵRI) on basophils and mast cells and by the low-affinity IgE Fc receptors (CD23) on B cells and many other cell types. Additionally, omalizumab can bind to IgE and prevent it from binding to both FcϵRI and CD23. Studies by other groups have also shown that CD23 is involved in the synthesis of IgE and that interfering CD23 function, such as by cross-linking CD23 on B cell surface, can cause the down-regulation of IgE production. We have developed anti-IgE mAbs that mimic omalizumab in various aspects except their ability to bind to IgE on CD23. These newly developed mAbs bind to linear epitopes on IgE. They do not induce the degranulation of IgE-pulsed rat basophilic leukemic cells (RBL SX-38), which had been transfected with the genes of human FcϵRI. The ability of the mAbs to cross-link IgE-occupied CD23 on the cell surface of B cell lines is being tested. The results suggest that these anti-IgE mAbs may render a set of pharmacological mechanisms, which are somewhat different from that of omalizumab, for controlling IgE in patients with allergic diseases.
Adenosine receptor A3AR is responsible for augmenting FcϵRI-induced degranulation of human lung mast cells by extracellular adenosine. (86.17)
Authors: Gomez Gregorio , Schwartz Lawrence 
Published: January 2023

Abstract
Inhaled adenosine induces a bronchoconstrictive response in asthmatics that is attributed to enhanced activation of mast cells in the airways. In this study, we demonstrate that extracellular adenosine augments FcϵRI-mediated degranulation of human mast cells from lung via the adenosine A3 receptor (A3AR). We found that low concentrations (10-7 - 10-6 M) of adenosine and its stable analog NECA enhanced degranulation of mast cells from lung, but not skin. Quantitative real time PCR analysis revealed that lung and skin mast cells expressed equal amounts of A2aAR and A2bAR (A1AR was not detectable), but that lung mast cells expressed a 5-fold greater amount of A3AR mRNA transcripts compared with skin mast cells. This suggested that A3AR was responsible for augmenting degranulation of lung mast cells. Indeed, targeted stimulation with the A3AR-specific agonist HEMADO significantly enhanced mediator release from lung mast cells following FcϵRI crosslinking with an anti-FcϵRIα MAb, but had little effect on skin mast cells. In addition, the enhancing effect of adenosine on lung mast cells could be completely inhibited by inactivating Gi-coupled A3ARs by ADP ribosylation with pertussis toxin. These data provide direct evidence that extracellular adenosine enhances IgE-induced degranulation of human lung mast cells through an A3AR-mediated mechanism; thus supporting a role for A3AR in the bronchoconstrictive response to inhaled adenosine in asthmatics.
Tyrosines in the carboxy-terminal region regulate Syk function (86.18)
Authors: Castro Rodrigo , Zhang Juan , Jamur Maria , Oliver Constance , Siraganian Reuben 
Published: January 2023

Abstract
The Syk tyrosine kinase family has an essential role in immunoreceptor tyrosine-based activation motif (ITAM) signaling. The binding of Syk to tyrosine phosphorylated ITAMs in the subunits of FcϵRI results in a conformational change, with an increase in the enzymatic activity of Syk. This conformational change exposes the COOH terminal region of Syk which has three conserved Tyr residues (Y623, Y624, Y625 of rat Syk). To understand the role of these residues in signaling, wild-type and mutant Syk with these three Tyr mutated to Phe were expressed in Syk-deficient mast cells. There was decreased FcϵRI induced degranulation, together with reduced phosphorylation of MAP kinases p38 and p42/44 ERK. There was a parallel decrease in NFAT and NFκB activation with the mutated Syk. In non-stimulated cells, there was increased tyrosine phosphorylation of the mutated Syk, however, this still increased after FcϵRI activation. In vitro mutated Syk had decreased ITAM-binding and reduced kinase activity. In testing Syk mutated singly at each one of the tyrosines, Y623F had minimal effect while Y624F but specially Y625F had the most reduction in these assays. Also, tyrosines Y624 and Y625 controlled Syk capacity for autophosphorylation. Therefore these tyrosines in the tail region of Syk regulate its kinase activity and their phosphorylation is important for Syk function in mast cell FcϵRI-mediated signaling.
Potent inhibition of calcium mobilization and mast cell activation by the pyrazole derivative BTP2 (86.9)
Authors: Law Mankit , Mottram Laurie , Morales Jose , Peterson Blake , August Avery 
Published: January 2023

Abstract
Cytosolic Ca2+ changes in mast cells are central for driving their activation. Thus, pharmacological tools that inhibit this process represent unique strategies for inhibiting mast cell function. We find that the pyrazole compound BTP2 inhibited FcϵRI-triggered sustained Ca2+ influx in a mast cell-like cell line RBL-2H3 with little effect on the tyrosine phosphorylation of cellular proteins. It also did not affect FcϵRI-induced phosphorylation of mitogen-activated protein kinases Erk1/2, JNK, and p38 nor downstream c-fos expression. This suggests that BTP2 inhibits Ca2+ mobilization without affecting the FcϵRI signal transduction cascade. BTP2 inhibited degranulation and β-hexosaminidase release in RBL-2H3 cells. Consistent with this effect, BTP2 inhibited antigen-induced histamine release in vivo. BTP2 also inhibited cytokine secretion of IL-2, IL-3, IL-4, IL-13, and TNF-α by BMMCs. Analysis of structure-function relationships between the BTP2 parent compound and its derivatives implicate a role for the trifluoromethyl group at both carbon positions 3 and 5 of pyrazole in the inhibition of degranulation of RBL-2H3 cells, with a more dominant effect evoked by the trifluoromethyl group at C3. In conclusion, our studies indicate that pyrazole compounds can provide the molecular framework for the design of specific inhibitors of Ca2+ entry mechanisms and further BTP2 as a medicinal candidate for the treatment of allergic reactions and other mast cell-mediated diseases.
EGCG Inhibits Inflammation Independently of AMPK (87.10)
Authors: Reilly Christopher , Regna Nicole , Peairs Abigail 
Published: January 2023

Abstract
Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects in immune cells. EGCG has been shown to activate the metabolic regulator, AMP-activated protein kinase (AMPK). Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine if EGCG would inhibit inflammation in AMPK deficient mesangial cells. Cultured mesangial cells from MRL/lpr mice were treated with siRNA for mouse Prkaa2-Design A, specific for AMP-activated protein kinase-alpha (AMPK-α) or siRNA negative control for mouse. After 48 hours, the cells were serum-starved for 2 hours, treated with 50 μM epigallocatechin-gallate (EGCG) for one hour, and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-γ for 30 minutes. The addition of siRNA inhibited AMPK expression in mesangial cells. LPS/IFN-γ induced inflammatory mediator production (iNOS expression, supernatant NO, and interleukin-6) as expected. Interestingly, EGCG blocked inflammatory mediator production in the AMPK deficient cells suggesting EGCG inhibits inflammatory pathways independently of AMPK to decrease inflammatory mediatory production. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells independent of AMPK.
Bio-distribution and in vivo antioxidant properties of cerium oxide nanoparticles (87.26)
Authors: Hirst Suzanne , Karakoti Ajay , Tyler Rom , Sriranganathan Nammalwar , Seal Sudipta , Reilly Christopher 
Published: January 2023

Abstract
Cerium oxide nanoparticles have oxygen defects in their lattice structure that enable them to scavenge oxygen radicals. Recent reports have shown nanoceria to act a regenerative free radical scavenger in a physiological environment. The goal of our study was to perform a comprehensive analysis of the biological distribution and in vivo antioxidant capabilities of nanoceria. We examined three peroral (PO), intravenous (IV), and intraperitoneal (IP) administration routes along with deposition, clearance, histology and WBC counts in nanoceria administered mice. We also examined if nanoceria would decrease ROS production in mice treated with carbon tetrachloride (CCl4). As determined by inductively coupled plasma-mass spectrometry (ICP-MS), nanoceria organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria distribution was confirmed with IVIS in vivo imaging, and deposition was confirmed with transmission electron microscopy (TEM). Nanoceria administration did not induce histopathology, however it did raise WBC counts. Nanoceria administration to mice with induced liver toxicity reduced liver 8-isoprostane, urine 8-OHdG, and plasma MDA levels markers of oxidative stress. Our studies show that nanoceria remains deposited in tissues and decreases ROS, suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress.
Obesity increases the production of pro-inflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin-resistance (87.32)
Authors: Youm Yun-Hee , Yang Hyunwon , Badanmagsar Bolormaa , Gimble Jeffrey , Greenway Frank , Mynatt Randall 
Published: January 2023

Abstract
Yun-Hee Youm, Hyunwon Yang, Bolormaa Vandanmagsar, Jeffrey M. Gimble, Frank Greenway, Randall Mynatt and Vishwa Deep Dixit Emerging evidence suggests that increase in activated T cell populations in adipose tissue may contribute towards obesity-associated inflammation and insulin-resistance. Here we asked whether, 1)the adipose-resident T cells(ARTs) produce cytokines in response to T cell receptor(TCR) ligation. 2)If the extralymphoid ARTs possess unique TCR repertoire compared to lymphoid-resident T cells and if obesity alters the TCR diversity in specific adipose depots. 3)Can specific elimination of T cells regulate inflammation and insulin-action in obesity? We found that obesity reduced the frequency of naïve ART cells in subcutaneous fat and increased the effector-memory cells in visceral fat. The purified ARTs from obese mice had higher frequency of IFNγ+, Granzyme B+ cells and upon TCR ligation, produced pro-inflammatory cytokines and chemokines. Importantly extralymphoid ARTs exhibited markedly restricted TCR diversity and obesity further compromised the TCR repertoire in adipose depots. Collectively, these data establish that ARTs have restricted TCR-Vβ repertoire and T lymphocytes contribute towards the complex proinflammatory microenvironment of adipose tissue in obesity. However,specific depletion of extralymphoid T cells in visceral fat alone is insufficient to reverse obesity associated feed-forward cascade of inflammation and insulin-resistance.
Exosomes mediate pregnancy-associated suppression of central nervous system inflammation in a murine model of multiple sclerosis (87.7)
Authors: Williams Jessica , Smith Kristen , Cox Gina , Shawler Todd , Whitacre Caroline 
Published: January 2023

Abstract
Multiple sclerosis (MS) is thought to be a cell-mediated autoimmune disease that ultimately leads to demyelination and severing of nerve axons within the CNS. It is known that pregnancy suppresses MS relapses, particularly during the third trimester. We have recapitulated this observation in murine experimental autoimmune encephalomyelitis (EAE). A serum factor is implicated as responsible for EAE suppression during pregnancy. We observed that serum exosomes, nano-sized facilitators of intercellular communication, are significantly more concentrated during late pregnancy in mice. To determine which proteins are expressed in pregnancy versus control-derived exosomes, we performed differential gel electrophoresis followed by mass spectrometry. Several identified proteins have important functions in both the immune and CNS compartments. Proteins enriched in pregnancy exosomes facilitate the local action of corticosterone, scavenge oxygen-derived free radicals, inhibit matrix metalloproteases, and provide survival signals to oligodendrocytes, the myelinating cell of the CNS. Thus, we explored the effects of exosomes on EAE and on immune and CNS cells, including analyzing inflammatory cytokine profiles of myelin-specific T cells and the proliferation and maturation of oligodendrocyte precursor cells. Determining the mechanism by which pregnancy exosomes suppress inflammation and examining their neuroprotective properties will aid in the development of novel MS therapies.
Non-Coding RNA regulation of TNFα (88.10)
Authors: Sullivan Kathleen , Song Li , Bagashev Asen , Fitzgerald Michael 
Published: January 2023

Abstract
Non-coding RNAs have been implicated in the regulation of expression of numerous genes. In many cases, the regulation occurs by miRNAs. Less well understood is the mechanism of transcriptional regulation by long non-coding RNAs. We observed bi-directional long non-coding RNAs upstream of the TNFα gene in a region where a transcriptional repressor, GCF2, is known to bind. We examined the role of these long non-coding RNAs by knocking down each strand. Knockdown of the antisense species led to de-repression of TNFα expression in a cell line not normally competent for expression. Knockdown of the antisense species displaced GCF2 from the promoter and using an RNA immunoprecipitation, we showed that GCF2 bound less of the antisense transcript after knockdown. Conversely, knockdown of the sense transcript led to increased binding of GCF2 at the promoter. To understand how these transcripts might be regulating TNFα expression, we examined the binding characteristics of GCF2 using a biosensor. GCF2 bound more avidly to dsRNA and DNA:RNA hybrids than to dsDNA. To define the target chromatin characteristics, we used ChIP analyses. Histone marks of repression as well as EZH2, Suz12 and argonaute bound to the upstream region of the TNFα gene in repressed cells. These data demonstrate that TNFα is regulated at the level of non-coding RNAs in the upstream promoter region and implicate GCF2 in the non-coding RNA-mediated repression of TNFα.
Th17-specific demethylation and methylation-sensitive STAT3 binding at a DNA element in the IL-17 promoter (88.13)
Authors: Thomas Rajan , Wells Andrew 
Published: January 2023

Abstract
CD4+ helper T cells can be instructed by non-antigen-specific signals to differentiate into functionally distinct subsets with exclusive patterns of cytokine production. Activation in the presence of TGFbeta and IL-6 results in the development of Th17 cells that produce IL-17, an inflammatory cytokine that is not expressed by Th1 or Th2 lineage cells. The promoter region of the IL-17A gene contains 12 CpG dinucleotides, leading us to test whether the IL-17 gene is regulated epigenetically by DNA methylation. In Th1 and Th2 cells, all CpG dinucleotides were heavily methylated (80-100%), with the exception of the -33 dinucleotide adjacent to the TATA element, which was 70% methylated in all cell lineages. The Th17 differentiation program was associated with a selective, 4-fold increase in demethylation (from 90% to 60%) at CpG dinucleotides -144 and +13 bp from the transcriptional start site. Interestingly, the -144 CpG is located within a consensus element (CCpGTCA) for STAT3, a transcription factor that is required for IL-17 gene induction and Th17 differentiation. We find that STAT3 from Th17 nuclear extracts binds with high affinity to this CCpGTCA element in vitro, but shows low affinity binding to the methylated CmeCpGTCA element. These results suggest that signals from the TGFbeta and/or IL-6 receptors lead to demethylation of a STAT3 element in the IL17A promoter, and epigenetically program the IL-17 locus for transactivation by STAT3 in the Th17 lineage.
Ikaros silences the ifnγ gene during T cell anergy and T helper polarization (88.14)
Authors: Thomas Rajan , Chunder Neelanjana , Chen Chunxia , Taylor Justin , Pearce Edward , Wells Andrew 
Published: January 2023

Abstract
Ikaros is a zinc finger transcription factor required for lymphocyte development, but recent studies indicate that this factor also regulates peripheral T cell function. Our previous studies showed that Ikaros is a major repressor of il2 gene expression during the induction of T cell anergy, and in the present study, we have examined the role of Ikaros in ifnγ gene expression in CD4+ T cells. We find that Ikaros binds to the endogenous ifnγ and tbx21 loci, an event associated with increased DNA methylation at the ifnγ gene. Loss of Ikaros function in vitro resulted in increased IFNγ production by anergic T cells and Th2 cells, and was reinforced in Th2 cells by dysregulated expression of Tbet. Loss of Ikaros function in vivo led to an inappropriate Th1 response to the Th2 parasite S. mansoni, and also led to increased ifnγ gene expression and fatal intestinal immunopathology in a DSS model of colitis. Our results show that Ikaros is an important transcriptional repressor of Tbet and IFNγ expression, and further establish a role for Ikaros in T cell tolerance and T helper polarization.
Transgenic mice with inducible Kallikrein expression as a tool to study immune-mediated and spontaneous lupus nephritis (88.24)
Authors: Shao Xinli , Yang Ru , Yan Mei , Zhou Jinchun , Ramin Indu , Wakeland Ward , Mohan Chandra , Igarashi Peter , Li Quan-Zhen 
Published: January 2023

Abstract
Kallikreins (klk) play important roles in anti-GBM autoantibody-induced glomerular nephritis (AGN) and potentially lupus nephritis (LN). In this study, we have established a transgenic mice strain with inducible klk expression specifically in kidney tubular cells. The double transgenic mice carry two sets of transgenes, the mklk1 gene located down-stream of a CAG promoter-driven LacZflox-/- and the CreERT2 which is driven by kidney specific promoter (KSP). We have detected the LacZ expression in the kidneys and other tissues of the transgenic mice without induction. After induction by Tamoxifen, the mice expressed high level of klk1 in the kidneys but not in other tissues. The kidney specific expression of transgenic klk1 was confirmed by Q-PCR, Western blotting and immunohistochemistry. The expression of klk1 was co-localized in kidney tubular cells with Cre. Several inflammation cytokines, including IL-12, IP10 and MIP-1, were identified to be increased in the kidney of transgenic mice along with the elevated expression of klk1. The anti-oxidant molecules, Oxr1 and GSTM2, were also increased. In order to evaluate the protective effect of klk against the spontaneous LN, the CreERT2/mKlk1 transgenes were breed onto B6.Sle1.Sle3 lupus mice. We have confirmed the inducible expression of klk1 in the kidneys of the CreERT2/mKlk1/Sle1.Sle3 mice. These mice will be aged to 6-8 months and the effects of klk1 on the development of lupus nephritis will be evaluated.