bluuebunny/crossref_metadata_2025_split huggingface dataset:
p85a recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression (BA4P.222)
Authors: Tian Linjie , Choi Seung-Chul , Murakami Yousuke , Allen Joselyn , Morse Herbert , Qi Chen-Feng , Krzewski Konrad , Coligan John 
Published: January 2023

Abstract
The rapid and efficient removal of apoptotic cells (AC) prevents the release of the potentially toxic or immunogenic components from dying cells, thereby reducing inflammatory and autoimmune responses. Phagocytosis is the major means of clearing AC, which is dependent on the interaction between “eat-me” signals on AC and receptors on phagocytes. The externalized phosphatidylserine (PS) on AC is the best-known “eat-me” signal. We demonstrate that mouse CD300f (CLM-1) recognizes outer membrane-exposed PS and regulates AC phagocytosis. CD300f accumulates in phagocytic cups at AC contact sites. Phosphorylation within CD300f cytoplasmic tail tyrosine-based motifs initiates signals that positively or negatively regulate AC phagocytosis. Y276 phosphorylation is necessary for enhanced CD300f-mediated phagocytosis through the recruitment of the p85a regulatory subunit of phosphatidylinositol-3-kinase (PI3K). CD300f-PI3K association leads to activation of downstream Rac/Cdc42 GTPase and mediates changes of F-actin that drive AC engulfment. Importantly, primary macrophages from CD300f-deficient mice have impaired phagocytosis of ACs. The biological consequence of CD300f deficiency is predisposition to autoimmune disease development, as FcgRIIB-deficient mice develop a systemic lupus erythematosus-like disease at a markedly accelerated rate if CD300f is absent. This is the first report identifying the mechanism and role of CD300f in AC phagocytosis and maintenance of immune homeostasis.
Ultraviolet B irradiation accelerates the development of lupus-like autoimmunity in wild-type mice induced by topical treatment with TLR7 agonist (BA4P.212)
Authors: Sano Shigetoshi , Kataoka Sayo , Kamijima Reiko , Fujimoto Chisa , Ohko Kentaro , Takaishi Mikiro , Nakajima Kimiko 
Published: January 2023

Abstract
SLE is an autoimmune disease characterized by the production of autoantibodies and inflammatory pathologies such as glomerulonephritis. A number of studies have demonstrated that altered Toll-like receptor 7 (TLR7) signaling contributes to the initiation of SLE in humans and in murine models. Indeed, introduction of Tlr7 null mutation in lupus-prone mice resulted in amelioration of lupus nephritis and reduction of autoantibodies, clearly indicating the contribution of TLR7 to lupus phenotype. We have recently demonstrated that epicutaneous application of TLR7 agonists, imiquimod (IMQ) or R848, leads to systemic autoimmunity in wild-type mice. They developed lupus-like systemic autoimmunity from 4 weeks of topical treatment, but not by peritoneal injection of IMQ, showing elevated autoantibodies to double-stranded DNA and glomerulonephritis, hepatitis, carditis and photosensitivity, indicating that the skin as the primary organ that allows TLR agonists to initiate lupus. Since ultraviolet (UV) irradiation is a worsening factor in SLE, we examined the effect of UVB on the initiation of TLR agonist-induced lupus. Strikingly, UVB irradiation of Balb/c mice facilitated the emergence and increase in the titers of autoantibodies including anti-double stranded DNA induced by topical treatment with R848 from 2 weeks, which was much earlier than R848 alone, strongly suggesting that UV accelerated the TLR7-mediated systemic autoimmunity.
Anti-scavenger receptor immune complexes disrupted marginal zone macrophage integrity via bruton's tyrosine kinase (BA4P.213)
Authors: Li Hao , Wu Qi , Li Jun , Yang PingAr , Luo Bao , Edberg Jeffrey , Hsu Hui-Chen , Mountz John 
Published: January 2023

Abstract
Macrophage receptor with collagenous structure (MARCO) and scavenger receptor A (SR-A) are marginal zone macrophage (MZM) restricted scavenger receptors that play important roles in apoptotic cell (AC) clearance in the spleens. We identified that in SLE patients, higher serologic levels of anti-scavenger antibodies at early stage were associated with the late development of end-stage-renal disease. In lupus prone BXD2 mice, elevated anti-MARCO/anti-SR-A antibodies in the sera correlated with the loss of MZMs in the spleens. To determine the molecular connection between anti-MARCO/anti-SR-A and MZM loss, immune complexes (ICs) generated from a mixture of AC-Ags and autoantibodies (autoAbs) produced from BXD2 mouse were administrated to B6 mice. Interestingly, disruption of MZMs was observed in mice administered ICs generated from AC-Ags plus polyreactive autoAbs that exhibit high reactivity to both MARCO and SR-A. Confocal imaging analysis showed that, in these mice, there were high levels of bruton's tyrosine kinase (Btk) phosphorylation (pBtk) in the MZMs. Increased pBtk was also observed in MZMs of BXD2. Delivery of Ibrutinib, a Btk inhibitor. systemically or Ibrutinib-liposome as MZM targeted, prevented MZM loss and attenuated autoantibodies and IC-mediated glomerulonephritis in BXD2 mice. As we also identified the loss of MARCO+ MZMs in SLE patient spleens, the present study suggests the potential in development of anti-Btk in MZMs as a novel therapy for lupus.
Aryl hydrocarbon receptor attenuation of sub-chronic cigarette smoke-induced pulmonary neutrophilia is associated with retention of nuclear RelB and suppression of intercellular adhesion molecule-1 (CAM1P.233)
Authors: Rico de Souza Angela , Zago Michela , Eidelman David , Hamid Qutayba , Baglole Carolyn 
Published: January 2023

Abstract
Cigarette smoke exposure is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia. As there is currently no information on the AhR prevention of lung inflammation due to varied and prolonged exposure regimes, we exposed control and AhR-/- mice to cigarette smoke for 2 weeks (sub-chronic exposure) utilizing low and high exposure protocols and evaluated pulmonary inflammation. Sub-chronic cigarette smoke exposure increased pulmonary neutrophilia dose-dependently in AhR-/- mice. There was no difference between smoke-exposed AhR+/- and AhR-/- mice in the expression of cytokines associated with neutrophil recruitment. However, expression of pulmonary intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule involved in neutrophil migration and retention, was higher in AhR-/- mice. Nuclear RelB, an anti-inflammatory NFkB transcription factor, was significantly lower in sub-chronically exposed AhR-/- mice. These data support that absence of the AhR contributes to heightened pulmonary neutrophilia in response to on-going cigarette smoke exposure. Inter-individual variations in AhR expression may enhance the susceptibility to cigarette smoke induced diseases.
Aryl hydrocarbon receptor negatively regulates type I interferon production and the development of murine lupus (CCR1P.245)
Authors: Lee Soyoung , Ripley Barry , Chinen Ichino , Millrine David , Kishimoto Tadamitsu 
Published: January 2023

Abstract
Systemic lupus erythematosus is a highly heterogenous multi-organ autoimmune disease characterized by the production of diverse autoantibodies and a broad spectrum of clinical manifestations. The etiology and pathogenesis of lupus remain unclear. Our current understanding highlights an important role for autoantibodies and numerous studies in both animals and humans now suggest an important role for type I interferon (IFN) in the pathogenesis of lupus. Type I IFN signaling and subsequent feedback induction of type I IFN production, are critically dependent on the STAT1 transcription factor. How type I IFN activity is regulated through inhibition of STAT1 function is poorly understood. Here, we show that type I IFN production and signaling both in cultured plasmatoid dendritic cells, and in vivo, is significantly higher in Aryl hydrocarbon receptor (AHR) knockout mice compared to wild-type mice, following stimulation with TLR7/9 agonists. We demonstrate that through TLR7/9 signaling or by IFN-α, expression of AHR is induced, which in-turn forms an inhibitory interaction with STAT1. This interaction attenuates both type I IFN signaling and in-turn, positive-feedback induction of type I IFN. Furthermore, in pristane-induced murine lupus, we found that production of type I IFN and expression of IFN-stimulated genes in AHR knockout mice is higher than in wild-type mice. In conclusion, AHR negatively regulates type I IFN signaling and production and the development of murine lupus.
Design of a bioinformatics practicum aimed at integrating concepts in immunology, virology, and pharmaceutical sciences in pharmacy curricula (EDU1P.253)
Authors: O'Donnell Lauren , Andrick Benjamin , Meng Wilson 
Published: January 2023

Abstract
The purpose of this educational design is to develop hands-on experiences to equip pharmacy students with bioinformatics skills through analysis of immunological problems. The instructional template uses bioinformatics tools available in the public domain to predict potential adverse drug events through identification of shared T-cell epitopes between commonly prescribed protein drugs and viral antigens. We developed a module using the web-based tools Immune Epitope and Database and Analysis Resource (http://www.iedb.org) to predict histocompatibility complex (MHC) molecules ligands and the NCBI protein database to select viral and peptide drug sequences for comparison. IEDB contains scanning tools by which sequences retieved from NCBI-PB can be analyzed for shared epitopes. Initially, students analyzed tumor necrosis factor-alpha inhibitors, a class of protein drugs that are often prescribed for chronic inflammatory diseases. Students were tasked to construct matrices representing overlapping MHC-II ligands for each drug-antigen pair. A preliminary analysis identified in the drug infliximab (heavy-chain 52-61: IRSKSINSAT) a molecular mimicry of a known T cell epitope in influenza A hemagglutinin (322-334: PRYVKQNTLKLAT)). The ultimate goal is to develop transportable exercises that can be implemented throughout the curriculum and to provide experience to students in analyzing major classes of biologic drugs and infectious pathogens.
Smurf2 regulates hematopoietic stem cell self-renewal and aging (HEM2P.256)
Authors: Trabucco Sally , Ramkumar Charusheila , Kong Yahui , Zhang Hong , Gerstein Rachel 
Published: January 2023

Abstract
The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence. In this study, we found that mice deficient in Smurf2 had an expanded hematopoietic stem cell (HSC) compartment in bone marrow under normal homeostatic conditions, and this expansion was associated with enhanced proliferation and reduced quiescence of HSCs. Surprisingly, increased cycling and reduced quiescence of HSCs in Smurf2-deficient mice did not lead to premature exhaustion of stem cells. Instead, HSCs in aged Smurf2-deficient mice had a significantly better repopulating capacity than aged wild-type HSCs, suggesting that decline in HSC function with age is Smurf2-dependent. Furthermore, Smurf2-deficient HSCs exhibited elevated long-term self-renewal capacity and diminished exhaustion in serial transplantation. As we found that the expression of Smurf2 was increased with age and in response to regenerative stress during serial transplantation, our findings suggest that Smurf2 plays an important role in regulating HSC self-renewal and aging.
The role of GM-CSF in dendritic cell development in vivo (HEM3P.284)
Authors: Bhattacharya Palash , Haddad Christine , Alharshawi Khaled , Prabhakar Bellur 
Published: January 2023

Abstract
We have earlier demonstrated that CD11b+CD11c+ dendritic cells (DCs) derived ex vivo from bone marrow precursors with GM-CSF (GM-BMDCs) can selectively expand natural Foxp3+ regulatory T-cells (Tregs) in a contact dependent manner through OX40L/Jagged-1 co-signaling. However, an ‘in vivo’ counterpart of these GM-BMDCs is not known. In contrast BMDCs derived ex vivo using FLT3L (FL-BMDCs) are considered to be phenotypical and functional equivalents of physiological steady-state DCs. In addition, mice lacking GM-CSF or its receptor do not show a severe defect in DC development while FLt3L deficiency severely affects the physiological development of all types of DCs. To determine the role of GM-CSF in DC-development in vivo, we treated Flt3L deficient mice with GM-CSF and found no evidence of CD11c+ DC development. In contrast, we saw near complete reconstitution of DCs in these mice with Flt3L treatment. Surprisingly, we could successfully generate CD11c+ GM-BMDCs from bone marrow precursors isolated from these Flt3L deficient mice. Interestingly, these GM-BMDCs also express surface markers associated with precursor cells, macrophages and granulocytes. To address these various contradictions, we propose that G-BMDCs generated ex vivo represent a myeloid precursor population rather than fully differentiated DCs. These ‘precursors’ require other cytokines for their terminal differentiation; thus, Flt3L is critical for their differentiation into steady-state DCs.
An automated data analysis strategy to identify and classify hematologic neoplasms (HEM3P.287)
Authors: Tang Mengxiang , Zhu Jason , Zhang Wenchang , Crespo Oliver 
Published: January 2023

Abstract
Cell immunophenotyping using flow cytometry has historically been a powerful tool in screening and diagnosing hematologic neoplasms. The capability of flow cytometers to measure multiple markers simultaneously allows detecting and quantifying normal and aberrant immune cell populations in blood samples. However, analysis of multidimensional flow cytometry data remains cumbersome and limited to serial analysis of bivariate plots. The slow and visually-dependent method relies on an expert’s expertise to identify and gate immune cell populations based on the expression and intensity of targeted protein marker staining. This conventional gating method is subjective, time consuming, and hardly takes advantage of all the dimensionalities of the data. An automated data analysis strategy to identify abnormal populations and classify samples in a gating-free manner has been developed. This automated analysis contains algorithms to extract features from high dimensional data, merge features and create profile for each sample, and classify samples based on established profiles. This generalized analysis strategy could be applied to analyze multidimensional data. An application on hematologic neoplasm classification is presented here. More than 100 samples, including health and patient samples, stained with a same eight color antibody cocktail were acquired using a BD FACSCanto II, and was used to show the accuracy of the automated analysis method is higher than 90%.
ERK signals that promote γδ T cell development require ERK interaction with DEF domain-containing targets (HEM3P.276)
Authors: Wiest David , Lee Sang-Yun , Coffey Francis , Fahl Shawn , Peri Suraj , Hedrick Steven , Fehling Hans , Zuniga-Pflucker Juan-Carlos , Kappes Dietmar 
Published: January 2023

Abstract
Differential induction of ERK signals has been implicated in numerous fate decisions; however, the molecular basis by which gradations in ERK signaling specify alternate fates remains poorly understood. We report here that divergence of the αβ and γδ T cell fates is dependent upon differences in the extent of T cell receptor (TCR) induced activation of ERK signaling. Adoption of the γδ fate is linked to greater amplitude and duration of ERK activation, but ERK activation does not promote γδ development by phosphorylation of substrates like Rsk. Instead, ERK promotes adoption of the γδ fate by physically interacting with DEF domain containing targets through its DEF binding pocket (DBP). The DEF domain-containing targets include immediate early genes (IEG) such as the transcription factor early growth response gene 1 (Egr1). Egr1 protein is normally unstable, but is stabilized by DEF-DBP mediated interaction with ERK. Thus, ERK signals promote γδ development by stabilizing IEG proteins, including transcription factors, thereby enabling them to transactivate targets not possible in the absence of this increase in stability.
Neutrophil extracellular traps as a source of high density lipoprotein oxidation in lupus-related cardiovascular disease. (HUM1P.312)
Authors: Smith Carolyne , Vivekanandan-Giri Anuradha , Pennathur Subramaniam , Kaplan Mariana 
Published: January 2023

Abstract
Lupus patients are fifty times more likely to experience a cardiovascular event, such as stroke or myocardial infarction, compared to age- and sex-matched controls. This is not explained by traditional “Framingham” risk factors, such as obesity and smoking, but possibly by the presence of “proinflammatory”, oxidized high density lipoprotein (HDL). Enzymatic sources of HDL oxidation include myeloperoxidase (MPO) and nitric oxide synthase (NOS), two enzymes which our group has found highly present in neutrophil extracellular traps (NETs). NET structures, composed of chromatin and antimicrobial peptides, are produced by granulocytes under pathogen stimulation or spontaneously in lupus patients. It was therefore predicted that NETs, highly active in lupus patients, can transform HDL into an oxidized form which is linked to proinflammatory and proatherosclerotic pathways. We examined the levels of chloro- and nitro-tyrosine oxidation in HDL from lupus patients and control donors via tandem mass spectroscopy. Finally, we digested lupus and control granulocyte NETs and incubated this with unoxidized HDL in the absence or presence of MPO and NOS-specific inhibitors. Lupus patients exhibited higher levels of regiospecific HDL oxidation versus control. Active NOS and MPO from NETs induced HDL oxidation patterns linked with cardiovascular disease (CVD). This represents a completely unexplored cellular source of HDL oxidation for lupus associated CVD.
Kidney resident B cells and plasmacytoid dendritic cells in the urine of systemic lupus erythematosus patients. (HUM1P.313)
Authors: Scott Eric 
Published: January 2023

Abstract
Renal involvement remains the principal cause of morbidity and mortality in SLE. B cells play a prominent role in kidney pathology in mouse models of SLE. In addition to producing autoantibodies, B cells produce cytokines and can present antigen to autoreactive T cells. Recently, we identified a B cell population with high expression of CD19 and CD20 and low expression of CD21 that is expanded in some human SLE patients. The presence of an expanded CD19hi B cell population correlates with poor long-term outcomes of end stage renal disease. High expression of CXCR3 by CD19hi B cells, suggests that they are trafficking to sites of inflammation, such as the kidney. To test this possibility we examined concurrent patient urine and plasma samples for the presence of B cells by flow cytometry. An Interferon alpha assay was used to determine whether levels were elevated in blood and urine.We identified B cells in ~1/3 of patient samples that are likely of kidney origin. Patients fell into two non-overlapping groups based on B cell phenotype.In the first group, urine B cells exhibited a B cell phenotype, among which were CD19hi B cells, present at the frequency equal to the peripheral blood.In the second group, the B cells exhibited a plasmablast phenotype and these cells spontaneously secreted IgG. Moreover, IFNα levels in plasma correlate significantly with the frequency of CD19hi B cells.
Bisphenol A (BPA) exacerbates acute myocarditis in female BALB/c by activating mast cells and the inflammasome (HUM1P.302)
Authors: Stafford Katelyn , Greyner Henry , Molina Frank , Bucek Adriana , Fairweather DeLisa 
Published: January 2023

Abstract
Myocarditis is an inflammatory heart disease that is the leading cause of heart failure in young adults. Sex hormones play a vital role in development of myocarditis with testosterone driving disease in males. Whereas, estrogen, via Estrogen Receptor α (ERα) mediates cardioprotection in females. Since myocarditis is influenced by sex hormones, it is highly probable that endocrine disruptors (EDs); which interfere with natural hormones, will play a part in the progression of the disease. The human population is exposed to Bisphenol A (BPA), a known ED that binds the ER, from plastics, such as water bottles and plastic food containers. BPA has been found to act through ERβ in cardiomyoctes to increase cardiac arrhythmias. Thus, BPA could increase myocarditis through deleterious actions of the ERβ rather than beneficial effects via ERα. To our knowledge no one has examined the role of EDs like BPA on myocarditis. We found that clinically relevant doses (25 µg/L and 250 µg/L) of BPA increased acute myocarditis compared to control water. We found BPA significantly decreased ERα, while ERβ was significantly increased. We found that mast cells (cKit) are largely responsible for the increase in inflammation along with CD4 Thelper cells. IL-1β, IFN-γ, TLR4, Caspase-1, Mmp9, and ST2 were all increased with BPA treatment which all lead to increased inflammation and disease. We believe that BPA is influencing the inflammasome and mast cells leading to exacerbation of disease in females.
Studying the association of plasma S100A12 and noninfectious pulmonary complication in infants and young children following cardiopulmonary bypass (HUM1P.305)
Authors: Shu Qiang , Liu Xiwang , Chen QiXing , Chen Chi , Shi Shanshan , Shi Zhuo , Yu Jiangen , Lin Ru , Tan Linhua 
Published: January 2023

Abstract
Objective To examine the kinetics of plasma S100A12 and sRAGE in infants and young children with CPB, and to investigate whether they could predict the occurrence of noninfectious pulmonary complication (NPC) after cardiac surgery. Methods 20 patients were in NPC group, which included pleural effusion, chylothorax, partial lung collapse, pulmonary hypertensive crisis, airway disorders, pneumothorax, pneumomediastinum, and phrenic nerve palsy, and 40 patients in no-NPC group. Plasma S100A12 and sRAGE were measured at 6 perioperative time points. Results S100A12 and sRAGE increased immediately after CPB (P&lt;0.001). SRAGE dropped to lower than baseline level (P&lt;0.05), while S100A12 was still at high level 24h after operation (P&lt;0.001). S100A12 and sRAGE immediately after CPB in NPC group were significantly higher than no-NPC group (P&lt;0.05). S100A12 were still higher in NPC group than no-NPC at 24h after operation (P&lt;0.01). S100A12 immediately after CPB was a predictor for postoperative NPC (OR=1.042, 95% CI: 1.010-1.076, P=0.011). S100A12 immediately after CPB were positively associated with MV time (r=0.47, P&lt;0.001), duration of surgical Intensive Care Unit (r=0.407, P=0.002) and hospital stay (r=0.421, P=0.001). Conclusions Plasma S100A12 and sRAGE were significantly increased immediately after CPB; The elevated S100A12 immediately after CPB served as an early reliable biomarker of the occurrence and the prognosis of NPC after CPB in infants and young children.