bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic potential of macrophage TNF production regulates immune mediated diseases (136.5)
Authors: Gillett Alan M , Marta Monica , Olsson Tomas , Harris Robert , Jagodic Maja 
Published: January 2023

Abstract
Tumor necrosis factor (TNF) is produced by several immune cell types in response to injury or infection. A region on rat chromosome 4 regulates several inflammatory diseases including experimental autoimmune encephalomyelitis (EAE), experimental arthritis and experimental autoimmune neuritis. We hypothesized that central inflammatory processes may be controlled by genetic determinants in this region and therefore mapped TNF production using linkage analysis in an advanced intercross line between DA and PVG.AV1 rats. We identified a single TNF regulating quantitative trait locus with a LOD score of 6.16 and confirmed the biological effect in a congenic rat strain. Congenic strain macrophages produced less TNF upon lipopolysaccharide administration and subsequently had a reduced pro-inflammatory phenotype. The reduced TNF potential associated with reduced disease. Congenic rats had reduced EAE compared to control DA rats. We have identified genetically determined regulation of TNF, a central pro-inflammatory cytokine in many diseases. Determination of genes and mechanisms involved in this regulation will be valuable in pathological understanding and treatment development.
Differential regulation of maturation genes in human dendritic cells stimulated with respiratory syncytial virus and TLR agonists (136.8)
Authors: Kallal Lara E , Lukacs Nicholas W 
Published: January 2023

Abstract
Dendritic cells (DCs) undergo rapid phenotypic change upon stimulation of surface and intracellular Toll Like Receptors (TLRs), including upregulation of the lymph node homing receptor, CCR7, and production of cytokines such as IL-10, IL-12 and Type I interferon (IFN). Pathogens are known to interfere with these signatures of DC maturation, and respiratory syncytial virus (RSV) in particular has been shown to antagonize TLR-mediated IFNβ production in dendritic cells. We thus sought to investigate the regulation of CCR7 and IFNβ in human DCs after activation by RSV and TLR agonists. We found that DCs stimulated with polyI:C and LPS, TLR3 and TLR4 agonists, respectively, significantly upregulated CCR7 after 6 and 24 hours. PolyI:C was the most potent upregulator of IFNβ at both 6 and 24 hours, with LPS upregulating this cytokine only at 6 hrs. Though other RSV-induced genes were activated, DCs stimulated with RSV failed to upregulate CCR7 or IFNβ. Analysis of activating (H3K4) and silencing (H3K27) histone modifications at the promoters of CCR7 and IFNβ showed, compared to unstimulated DCs, high H3K4 methylation of CCR7 and IFNβ upon PolyI:C stimulation, whereas LPS showed high H3K4 at CCR7, but high H3K27 at IFNβ. Methylation marks after RSV stimulation did not differ markedly from unstimulated DCs, suggesting that RSV may interfere with cellular machinery that controls gene expression, potentially delaying DC maturation.
This work is supported by NIH R01 AI073876
Non-lymphoid expression of B7-H1 regulates severity of proteoglycan-induced arthritis (137.24)
Authors: Hamel Keith M , Doodes Paul , Cao Yanxia , Wang Yumei , Rodeghero Rachel L , Chen Lieping , Finnegan Alison 
Published: January 2023

Abstract
The immune system has several mechanisms to prevent autoreative T cell activation in rheumatoid arthritis (RA) including the co-inhibitory signal delivered to T-cells by PD-1 ligation of B7-H1/PD-L1 on antigen presenting cells (APCs) and on non-lymphoid tissue. B-cells express B7-H1 and are an important APC population as highlighted by the efficacy of B cell depletion therapy in RA patients. Here we tested B7-H1 expression on B cells in a murine model of RA, proteoglycan-induced arthritis (PGIA). Wildtype (WT) and B7-H1-/- female BALB/c (≥3 months of age) were immunized intraperitoneally with 150 μg human PG in adjuvant [dimethy dioctadecy ammonium bromide (DDA)] 3 times at 3-week intervals. Exacerbation of PGIA was observed in B7-H1-/- mice along with increased titers of autoantibodies and CD4+ T cell proliferation. SCID mice reconstituted with B7-H1-/- B-cells or both B7-H1-/- B and T cells developed a similar intensity of PGIA as mice reconstituted with WT cells. Our results indicate that B7-H1 regulates the onset and severity of PGIA and that non-lymphoid B7-H1 expression is sufficient to control the more aggressive arthritis observed in the complete B7-H1-/- mice. Funding was provided by NIAMS NIH grant AR47657.
Constitutive expression of Foxp3 in conventional T cells reduces cellular proliferation and alleviates autoimmune arthritis (137.25)
Authors: Guo Linjie , Zheng Biao , Han Shuhua 
Published: January 2023

Abstract
The forkhead family transicrption factor Foxp3 is critically important for the development and function of regulatory T cells (Tregs). Lack of Foxp3 leads to the development of fatal autoimmune lymphoproliferative diseases. Previously studies have shown that ectopic Foxp3 expression can phenotypically convert effector T cells to regulatory T cells. However, we have recently generated Foxp3 transgenic mice under the control of lck distal promoter. The transgene (Tg) Foxp3 is expressed in the majority of CD4+ and CD8+ T cells but at modulate levels. The ectopic expression of Foxp3 renders T cells hyporesponsive but conferred neither Treg phenotype nor suppressive function. In addition, we found that Foxp3 transgenic mice exhibit reduced susceptibility to collagen-induced arthritis (CIA). Foxp3 Tg mice had delayed disease onset and developed milder arthritis compare to wild type controls. The serum autoantibody levels were reduced in Foxp3 Tg mice. Both cytokine production and antigen-specific proliferation were decreased in T cells from draining lymph nodes of Foxp3 Tg mice. It has been shown that in human Foxp3 expression is not only confined to CD4+CD25+ Tregs but also in a high percentage of activated T cells that do not have suppressive capabilities. Thus, our results indicate that Foxp3 may play an important role in regulating immune responses and inflammation by attenuating proliferative responses and cytokine production of antigen-specific T cells.
Mouse Models of Autoimmunity at The Jackson Laboratory (137.40)
Authors: Merriam Jen J , Donahue Leah R. , Lutz Cathleen M , Rockwood Stephen F , Sasner Michael 
Published: January 2023

Abstract
The Jackson Laboratory Repository was established to serve as a centralized resource for the archiving and distribution of genetically engineered mice of high health status. Nearly 400 strains are added to the collection each year. New strains for Systemic Lupus Erythematosus work include NOD Faslgld mice (8223) which develop autoimmunity at ~8 weeks of age. BcN/LmoJ inbreds (7228) develop fatal autoimmune glomerulonephritis. Nba2 congenics (7716) enable genetic study of an NZB-derived QTL. For Type I Diabetes researchers: NOD Itgax-DTR/EGFP (Cd11c-DTR) transgenics (8549) are transiently depleted of dendritic cells upon DT treatment. NOD Foxp3-EGFP/cre mice (8694) enable GFP expression in FoxP3+ cells when crossed with a floxed allele strain (useful for studies of regulatory T cell involvement). Of general interest, we have undertaken a project to comprehensively characterize Cre transgenic strains. A public searchable database presenting embryonic and adult expression patterns and images using terms from the Mouse Anatomical Dictionary is now under construction. Researchers wishing to have strains considered for inclusion in the Repository may submit their strains at: http://www.jax.org/grc/.
The effects of tumor necrosis factor-alpha on in vitro differentiation of natural killer cells (138.13)
Authors: Lee Jiwon , Lee Suk Hyung , Jeong Mira , Choi Inpyo 
Published: January 2023

Abstract
Natural killer (NK) cells are differentiated from hematopoietic stem cells (HSCs) in bone marrow. The differentiation of NK cells is regulated by various factors including soluble growth factors and transcription factors. Here, we demonstrated that tumor necrosis factor-α (TNF-α) is a positive regulator of NK cell differentiation. HSC-derived precursor NK (pNK) cells were further differentiated into mature NK (mNK) cells in the presence of IL-15 in vitro. The potential role of TNF-α on NK cell maturation was evaluated in the presence or absence of IL-15. TNF-α itself induced the expression of NK1.1 and CD122 of mature NK cells and its effects were significantly augmented in the presence of IL-15. IFN-γ production was maximal when NK cells were matured in the combination of IL-15 and TNF-α. Moreover mRNA expression of several transcription factors including T-bet and GATA-3 was increased during TNF-α -mediated in vitro NK cell differentiation. Overall, these data indicate that TNF-α regulates NK differentiation by increasing transcription factors which are crucial for NK maturation.
Severe block in hematopoiesis in the absence of NKAP (138.2)
Authors: Pajerowski Anthony G , Shapiro MIchael J , Shapiro Virginia S 
Published: January 2023

Abstract
During hematopoiesis, proper differentiation of the long-term, multi-potent, self-renewing hematopoietic stem cell (HSC) results in the cellular components of blood. The lineage fate decisions that occur during hematopoiesis result from the coordinated regulation of transcriptional activators, repressors, and chromatin modifiers. We have identified NKAP as a novel regulator of hematopoiesis, that functions at least in part as a transcriptional repressor. In this study we employ a combination of conditional and inducible mouse models of NKAP deletion to explore the role of NKAP in hematopoietic development starting at the HSC stage. Our models allow for both the pan-deletion of NKAP starting in the HSC stage by using a vav-cre transgenic, as well as temporally regulated deletion of NKAP in the hematopietic compartment through the use of the interferon-inducible mx1-cre model system. These complimentary approaches allow us to conclude that NKAP functions in a cell intrinsic manner, as a member of a unique group of transcriptional regulators, and is necessary in the earliest stage of definitive hematopoiesis.
Notch target gene deregulation and leukemogenesis occur independently of RBPJ in Ikaros null thymocytes. (138.23)
Authors: Chari Sheila , Winandy Susan 
Published: January 2023

Abstract
Both Ikaros and Notch are transcriptional regulators that are essential for normal T cell development. Cooperative mutations causing a reduction in Ikaros activity and an increase in Notch activation have been hypothesized to promote T cell leukemia. However, it is not known whether Notch deregulation plays a preferential or obligatory role in the leukemias that arise in Ikaros null (Ik-/-) mice with 100% penetrance. In order to answer this question, we abrogated Notch target gene activation in Ik-/- thymocytes using conditional inactivation of the DNA-binding Notch-target gene activator RBP-J. Through analyses of these mice we have made two important discoveries.
First, thymocytes that lack either Ikaros alone or both Ikaros and RBP-J exhibit high level derepression of Notch target genes. However, this derepression is not observed in thymocytes lacking RBP-J alone, which suggests that Ikaros, but not RBP-J, is required for Notch target gene repression in DP thymocytes. This data represents a major shift in our understanding of regulatory factors involved in Notch target gene repression. Secondly, Ik-/- mice develop clonal T cell populations, a hallmark of leukemia, with similar kinetics in the presence or absence of RBP-J. The appearance of clonal populations in the thymus and spleen of Ik-/- mice lacking RBP-J indicates that T cell transformation in the absence of Ikaros does not require deregulated Notch signaling.
Coordinate Regulation of TCR signaling, Notch, and Gata3 in T Cell Development (138.27)
Authors: Agyemang Amanda , Zhang Xianyu , Laky Karen , Fowlkes B.J. 
Published: January 2023

Abstract
The transcription factors, Notch and Gata3, are both involved in the intrathymic development of CD4 lineage T cells. It has been proposed that Gata3 is critical in CD4 T cell maturation after lineage commitment. To the contrary, we find that disruption of the Gata3 gene re-directs a fraction of MHC II-restricted thymocytes to the CD8 lineage. Moreover, Gata3 binds regulatory regions of the ThPOK (Zbtb7b) gene in vivo and is required for the ThPOK expression that enforces CD4 lineage commitment (Nature Immunol. 9:1122). Collectively, these findings place Gata3 developmentally upstream of the CD4/CD8 lineage decision and raise the question of how Gata3 itself is regulated. Our data and that of others suggest that Gata3 expression is regulated by TCR signaling, but Gata3 can also promote TCR signaling/expression. Therefore, Gata3 may operate in a self-reinforcing feedback loop during positive selection to achieve the levels of TCR signaling required for ThPOK induction and CD4 lineage commitment. In the differentiation of peripheral Th2 cells, Gata3 transcription can be regulated by Notch. We find that Notch and Gata3 promote TCR signal transduction prior to positive selection, as well as the selection/maturation of CD4/CD8 T lineages. Thus, we have designed genetic and expression studies to investigate whether Notch regulates Gata3 in thymocytes.
Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Characterization of a novel cell surface protein CSP82 on bone marrow cells that induce DP58 (138.32)
Authors: Al-Shaibi Nisreen , Ghosh Swapan K 
Published: January 2023

Abstract
We previously described a novel protein, DP58 that occurs constitutively in murine brain nuclei and as a cytosolic phosphoprotein during bone marrow (BM) differentiation into promyeloid dendritic progenitors (Front. Bioscience 12, 2947, 2007;. BBRC, 321, 26, 2004). DP58 protein is not detectable in immature or mature dendritic cells. In this study, we describe a GPI-linked receptor lactoferrin CSP82 on BM that is involved in induction of cytosolic DP58 in dendritic progenitors. Furthermore, to fully characterize CSP82 receptor, we determined whether iron could be its natural ligand playing important roles in facilitating differentiation of BM cells. Previous reports show that iron has a significant role in the differentiation of macrophages and dendritic cells from haematopoietic stem cells. This report shows that iron (ferrioxamine) acting on CSP82 can facilitate induction of DP58 protein. Moreover, the expression of DP58 protein can be inhibited by desferrioxamine; but when these cells are supplemented with ferrioxamine, DP58 induction is restored. Further support comes from the experiment in which CSP82 expression in BM cells is inhibited by antisense oligos, with consequent failure of iron to induce DP58. Our preliminary results suggest that iron-binding CSP82 receptor on BM cells play important roles in early differentiation of promyeloid dendritic progenitors expressing cytosolic phosphoprotein DP58.
Human cord blood, but not adult bone marrow, gives rise to IL-7-independent B cell production (138.5)
Authors: Payne Kimberly J , Baez Ineavely , Milford Terry-Ann , Benitez Abigail , Galloway Nicholas , Rogerio Jaqueline W , Sahakian Eva , Wall Nathan R , Dovat Sinisa , Parrish Yasmin Khan 
Published: January 2023

Abstract
IL-7 is critical for B cell production in adult mice, however its role in human B lymphopoiesis is controversial. Using a novel, human-only culture model we show that IL-7 increases human B cell production by &gt;60-fold from hematopoietic stem cells (HSCs) in both cord blood (CB) and adult bone marrow (BM). IL-7-induced increases are dose-dependent and specific to CD19+ cells. STAT5 phosphorylation and expression of the Ki-67 proliferation antigen indicate that IL-7 acts directly on CD19+ cells to increase proliferation at the CD34+ and CD34- pro-B cell stages, but not among CD19- B lineage precursors. As compared to CB, adult BM shows a reduction of in vitro generative capacity that is progressively more profound in developmentally sequential B cell precursor populations, resulting in a ~50-fold reduction in IL-7-dependent B lineage generative capacity. Without IL-7, HSCs in CB, but not BM, give rise to a small but consistent population of CD19LO B lineage cells that express EBF and PAX-5 and respond to subsequent IL-7 stimulation. Flt3 ligand, but not TSLP, was required for the IL-7-independent production of human B lineage cells. These data provide evidence that human B cell production from adult BM is dependent on IL-7 and suggest that a mechanism in addition to the "developmental switch" observed in the mouse model may be responsible for IL-7 dependency in adult human B lymphopoiesis. Supported by NIH K01 DK066163 (KJP).
ADAM10 regulates B cell development and immunoglobulin production (138.6)
Authors: Gibb David R , El Shikh Mohey , Kang Dae-Joong , El Sayed Rania , Crawford Howard , Tew John G , Conrad Daniel H 
Published: January 2023

Abstract
Members of the disintegrin and metalloprotease (ADAM) family can regulate lymphocyte development and function by cleaving membrane receptors. Previous studies showed that ADAM10 cleaves the B cell receptors, CD23 and Notch2, in vitro. However, in the absence of in vivo models, the physiologic impact of these events has not been examined. Thus, we generated B cell-specific ADAM10 KO and transgenic (Tg) mice to determine the role of ADAM10 in B cell development and function. Notch signaling regulates the differentiation of common lymphoid progenitors (CLPs) by promoting T cell fate. Accordingly, overexpression of ADAM10 in CLPs completely blocked B cell development. Deletion of ADAM10 from B cells in ADAM10fl/fl, CD19-cre+ mice prevented differentiation of marginal zone B cells, which is dependent on Notch2 signaling. In addition, expression of CD23 on ADAM10null B cells was dramatically elevated while levels of soluble CD23 were reduced in serum. As a result, IgE production by ADAM10fl/fl, CD19-cre+ mice was remarkably suppressed upon immunization, mimicking the response of CD23Tg mice. Finally, production of IgG1 and IgG2b was profoundly inhibited, suggesting a novel role for ADAM10 in class-switching to IgG. These results illustrate the physiologic role of ADAM10 in Notch signaling and CD23 cleavage. Moreover, they identify ADAM10 as a critical regulator of B cell development and immunoglobulin production.
AHA 0815066E, NIAID R01AI18697, NIAID U19AI077435
The interplay of CD23 and ADAM10 and its role in IgE synthesis (139.1)
Authors: mathews joel , Chen Bing-Hung , Saha Nayanendu , Conrad Daniel 
Published: January 2023

Abstract
CD23, the low affinity IgE receptor, is a type II transmembrane protein expressed on hematopoietic cells and contains two important extracellular domains, the IgE binding lectin head, and the coil-coiled stalk, responsible for CD23's trimeric structure. Mouse models have shown that trimetric membrane bound CD23 regulates IgE synthesis, which ability is lost when CD23 is shed. Recently it was shown that the CD23 sheddase is ADAM10, and shedding is controlled by the trimer stability. In this study, we examined the interactions of CD23 and ADAM10. We found that the binding of ADAM10, using either cell lysates containing ADAM10 or rADAM10 (Janes et al. 2005. Cell 123:291-304.), to CD23 is unlike any other protein that interacts with CD23, in that it binds the stalk region, between amino acids 139-157 in a protease independent manner. When CD23 is destabilized, with the anti-stalk antibody, 19G5, ADAM10 binding increased. Stabilizing CD23 with IgE had the opposite affect. These studies will be further examined with surface plasmon resonance.
Autocrine production of cysteinyl leukotrienes activates human mast cells (139.13)
Authors: Kulka Marianna , Catalli Adriana 
Published: January 2023

Abstract
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability, increased mucus secretion, decreased mucociliary clearance, eosinophil migration, and increased eosinophil survival. We now report that peripheral blood CD34+ progenitor-derived human mast cells and the human mast cell line (LAD2) express both CysLT receptors (CysLT1R and CysLT2R), the G protein-coupled receptors that bind CysLTs. LTC4, LTD4 and LTE4 activated LAD2 to produce MIP-1β and MCP-1 and production of these chemokines was inhibited by the CysLT1R inhibitor, monelukast. LAD2 activated by IgE/anti-IgE produced CysLT (980 + 55 pg/million cells) but LAD2 activated by substance P, a neuropeptide that also binds a G protein-coupled receptor, did not produce CysLT. Montelukast had no effect on SP-mediated LAD2 degranulation. CysLT did not induce human mast cell degranulation but montelukast inhibited FcεRI-mediated human mast cell degranulation by approximately 20% suggesting that autocrine production of CysLT potentiated FcεRI-dependent degranulation. IL-4 (10 ng/mL) in the presence of stem cell factor (SCF; 100 ng/mL) significantly upregulated expression of both CysLT1R and CysLT2R (16% and 32% respectively) and potentiated mast cell responses to LTE4 by up to 25%. Overall, these results show that human mast cell activation and degranulation is subject to autocrine CysLT-induced signaling which can be blocked by CysLT1R inhibitors such as montelukast.
Funded by the Investigator Initiated Studies Program (IISP) from Merck and Company, Inc.
Differential uptake of serum IgE in skin and serosal mast cells(139.14)
Authors: Cheng Laurence E , Wang Zhien , Locksley Richard M 
Published: January 2023

Abstract
Background: Mast cells (MC) are key effector cells in helminth infection and the clinical manifestations of allergic disease. In mice, a subset of MC (Connective Tissue MC) resides at epithelial barriers, such as the skin, or at serosal surfaces, including the peritoneal cavity. These MC exert much of their effector function by virtue of IgE binding to the high affinity Fc epsilon receptor (FcεRI ).
Objective: Although acquisition of serum immunoglobulin E (IgE) by skin MC is central to MC effector function, the mechanisms that govern loading of IgE on skin MC are poorly defined. We hypothesize that different anatomic compartments may exhibit differential serum IgE uptake.
Methods: We used the mouse ear as a source of skin MC. To control the dose and timing of serum IgE, we used a passive, intravenous IgE transfer model with flow cytometric analysis of MC IgE uptake at time points between 1 and 96 hours after infusion. As controls, we examined serum IgE uptake by spleen basophils and peritoneal mast cells (PEC-MC).
Results: We observed differences in IgE uptake by basophils and PEC-MC compared to skin MC. Basophils and PEC-MC displayed uniform loading of IgE that started within 1 hour of IgE exposure. By contrast, skin MC IgE uptake was heterogeneous with only 30% of MC showing significant acquisition of IgE. The timing of uptake was slightly delayed, and the amount of IgE on these cells was also diminished compared to basophils and PEC-MC.
Conclusion and Future Directions: Our data suggest that skin and serosal MC demonstrate distinct patterns of IgE uptake and that a select population of skin MC acquires serum IgE upon exposure. Further work will focus on direct in vivo imaging of MC IgE loading within ear tissue to better understand the underlying reason for decreased skin MC uptake of serum IgE.