bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilization of Myristica fragrans Houtt. reduces serum sialic acid in type II diabetes mellitus (P3103)
Authors: Mollik Md. Ariful Haque 
Published: January 2023

Abstract
Scientists are searching for new leads from the natural sources to combat different diseases. The studies were undertaken to discover new drugs from the natural sources. The beneficial effects of Myristica fragrans Houtt. are not limited to hypoglycemia only, but it also ameliorates diet induced obesity, insulin resistance, and exhibit cardioprotective effects. The studies attempt to investigate the effect of Myristica fragrans Houtt. fruit juice on a newly investigated risk factor, sialic acid in type II diabetes mellitus. A total of 48 type II diabetes mellitus patients, divided into group A (n=24), and group B (n=24) were investigated during the studies. The patients of group A were following Myristica fragrans Houtt. fruit juice treatment along with diet control, whereas the patients of group B were on diet control only. Serum sialic acid decreased in group A from 66.21±2.30 mg/dl to 63.59±2.10 mg/dl (&lt;0.11) but, increased in group B from 66.55±1.70 mg/dl to 68.24±2.50 mg/dl (&lt;0.12), compared to baseline. Post-treatment between group comparison revealed a significant difference (&lt;0.05). The beneficial effects on fasting plasma glucose and glycohemoglobin were also greater in group A compared to group B as was the case with blood lipids, weight, and blood pressure. The studies provide another mechanism for the cardioprotective effect of Myristica fragrans Houtt. and further strengthen its value in the management of type II diabetes mellitus.
Obesity associated inflammation as a risk factor to cancer development: clinical implications (P3113)
Authors: Nehete Pramod , Hanley Patrick , Nehete Bharti , Buchl Stephanie 
Published: January 2023

Abstract
During the last two decades, the percentage of obese adults and children has been steadily increasing. In addition to increasing the risk of coronary heart disease, stroke, hypertension, and diabetes, obesity increases the risk of a variety of cancers such as breast (postmenopausal), endometrial, colon, kidney, esophagus, gallbladder, and pancreas. This elevated risk of cancer appears to be highly correlated with a low-grade systemic inflammation due to the obesity itself. Chimpanzees are our closest genetic relative and share a multitude of human diseases including obesity and cancer. We investigated the inflammatory mediators involved with obesity in a diet controlled animal model to elucidate possible explanations for obesity related cancers. We observed that the obese group has significantly higher plasma levels of pro-inflammatory cytokines (e.g. IL-6, interferon- γ and tumor necrosis factor-α) and also higher amount of adipocytokines (e.g. Leptin, Glucagoan, GLP-1, Amylin (total), C-peptide and Insulin). We further expect that the serum from the obese group to present a unique signature profile that stimulates healthy PBMC’s to induce specific pro-inflammatory cytokines and gene-transcriptional factors. These findings will support that this bioassay may not only have utility as an early mechanistically informative inflammatory biomarker for obesity and cancer but may also prove useful in monitoring changes in the inflammatory state during therapeutic interventions.
c-kit signaling pathways regulate EAE susceptibility in male SJL mice (P3119)
Authors: Short Abigail , Walker-Caulfield Margaret , Brown Melissa 
Published: January 2023

Abstract
Females are more susceptible to autoimmune diseases, including multiple sclerosis (MS), a demyelinating disease of the central nervous system. While genetic, hormonal, and immune differences have been implicated, the mechanism for this female bias remains unclear. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), recapitulates many of the features of the human disease; including the significant sex dimorphism. We previously reported that wild type (WT) female SJL mice exhibit more severe disease than their c-kit mutant counterparts and that this phenotype is mast cell dependent. In contrast, male SJL-Kit-W/W-v mice develop significantly more severe EAE than their WT littermates. This c-kit dependent difference in male disease corresponds to a more robust peripheral CD4+ T cell response at day 10 post disease induction. Male SJL-Kit-W/W-v mice demonstrate a higher percentage and number of encephalitogenic GM-CSF producing PLP(139-151)-specific CD4+ T cells when compared to their WT controls. These data indicate that c-kit signaling exerts its protective effects in the periphery by regulating the magnitude and quality of the autoreactive T cell response. This effect is male specific given that the peripheral T cell GM-CSF responses in WT and Kit-W/W-v females are equivalent. Further studies are ongoing to define the cell type that is the target of c-kit signals and the mechanism by which c-kit exerts its disparate effects in male and female SJL mice.
Neuroprotective effects of bee venom phospholipase 2 by suppression of neuroinflammatory responses in mouse model of Parkinson’s disease: role of CD4+CD25+Foxp3+ regulatory T cells (P3125)
Authors: Chung Eun Sook , Bae Hyunsu 
Published: January 2023

Abstract
In the present study, we examined whether bee venom phospholipase 2 (bvPLA2) promotes the survival of dopaminergic (DA) neurons in the MPTP-induced mouse model of Parkinson’s disease (PD). Treatment of bvPLA2 prevented degeneration of DA neurons in the substantia nigra (SN). This nueroprotection of bvPLA2 associated with the suppression of microglia and inhibition of infiltration of CD4+ T cells into the SN. Additionally, CD4+CD25+Foxp3+ Tregs were significantly increased in vivo and in vitro after treatment of bvPLA2. The increased proportion of Tregs by bvPLA2 treatement remained highly suppressive ex vivo. To determine whether this neuroprotective effects of bvPLA2 associated with Tregs, we used transgenic DEREG (depletion of regulatory T cells) mice, which express a diphtheria toxin receptor under control of the Foxp3 locus, allowing selective depletion of Foxp3+ Tregs. Interestingly, bvPLA2 treatment did not prevent MPTP neurotoxicity in mice depleted of Tregs by dt treatment. Therefore, our present studies indicate that the neuro-protective effect of bvPLA2 might be associated with its anti-inflammatory properties resulting from modulation of peripheral immune tolerance by Tregs.
Beryllium activates innate pattern recognition receptors, promotes migration and activation of dendritic cells from the lung to draining lymph nodes and drives development of memory CD4 T cells (P3129)
Authors: McKee Amy , Mack Doug , Fontenot Andrew 
Published: January 2023

Abstract
Beryllium exposure results in chronic beryllium disease, a granulomatous lung disorder characterized by the presence of a beryllium-specific adaptive immune response. The impact of beryllium on the innate immune system is poorly understood. The aim of this study was to determine whether beryllium promotes activation of innate pattern recognition receptors that drive the development of pathological CD4 T cell responses. Similar to aluminum hydroxide, a common vaccine adjuvant, beryllium particles induce IL-1β secretion in an Nlrp3-dependent manner and the release of host DNA during inflammation. Unlike aluminum, beryllium-induced IL-1β secretion requires TLR4. A single beryllium exposure in the lungs of mice promotes migration of DCs to the draining lymph nodes and upregulation of DC costimulatory molecules in a MyD88-dependent manner. Beryllium enhances priming and maintenance of memory CD4 T cells to conventional protein antigen and can generate beryllium-specific CD4 T cell responses in HLA-DP2 transgenic mice in the absence of an additional adjuvant. Together, these data suggest that beryllium activates multiple innate immune receptors and promotes pathological immune responses in susceptible individuals by promoting activation of DCs that drive long-lived CD4 T cell responses. Future work is aimed at understanding which innate receptors are required for beryllium to activate DC in vivo and drive CD4 T cell effector and memory function.
Chronic inflammasome activation promotes the development of spontaneous colitis (P3149)
Authors: Zhang Jinyu , Guo Beichu 
Published: January 2023

Abstract
The inflammatory cytokine IL-1β plays a critical role in the pathogenesis of inflammatory bowel disease. IL-1β production is controlled by inflammasomes, a multiple protein complex that has emerged as a critical player in the pathogenesis of inflammatory and autoimmune diseases. However, the role of inflammasomes in intestinal inflammation remains controversial, while clinical studies show elevated levels of IL-1β protein in intestinal tissues and cells of inflammatory bowel disease patients, several recent studies suggest that inflammasome and IL-1β provide protection against chemically induced colitis. In this study, we demonstrate a critical role of chronic inflammasome activation in the development of colitis. Our data showed that chronic intestinal inflammation was associated with increased enhanced inflammasome activities and IL-1β production in colon tissues. Moreover, ATP or Alum-induced IL-1β processing significantly increased in bone marrow-derived macrophages in IL-10 deficient mice compared with wild type mice. We also found that IL-10 could directly inhibit NLRP3 inflammasome activation and IL-1β processing. Furthermore, our results indicate that inhibition of inflammasome activities with IL-1R antagonist or caspase inhibitor could suppress IL-1β and IL-17 production from inflamed colon tissues. Together, our results support a novel mechanism in which chronic inflammasome activation promotes the development of intestinal inflammation.
CD177 participates in a novel mechanism for regulating neutrophil recruitment (P3093)
Authors: Wang Jun-Xia , Nigrovic Peter 
Published: January 2023

Abstract
Background: Neutrophils are the sine qua non of inflammatory arthritis, and contribute to pain, swelling, and tissue injury, rendering neutrophil migration to the joint a potential therapeutic target. We recently found that the murine neutrophil surface protein Ly6G modulates chemotaxis via interaction with β2 integrins. Whereas CD177 is a neutrophil-specific human protein in the same gene family, we sought to identify the role of CD177 in human neutrophil recruitment. Method: Flow cytometry was used to analyze the levels of cell surface proteins in circulating neutrophils and in neutrophils from inflamed joints. Fluorescence lifetime imaging microscopy/Fluorescence resonance energy transfer assay (FLIM/FRET) was used to quantify CD177-β2 integrin interactions. Result: In patients with rheumatoid arthritis, synovial neutrophils exhibit higher levels of surface CD177 expression comparing with blood neutrophils. Using FLIM/FRET, ~40% CD11a and ~20% CD11b β2 integrins interact with CD177 on surface of resting blood neutrophils. In vitro, a specific CD177 antibody inhibits LTB4-induced conformational activation of CD11b β2 integrin, which is correlated with an impaired neutrophil migration towards LTB4 in anti-CD177 treated cells in a transwell system. Conclusion: CD177 regulates neutrophil chemotaxis and may serve as a potential neutrophil-specific therapeutic target in neutrophilic inflammatory diseases such as arthritis.
Natural autoantibodies protect from autoimmune disease (P4050)
Authors: Chen Qing , Beardall Michael , Mannoor Kaiissar 
Published: January 2023

Abstract
Natural autoantibodies (NAAs) arise naturally without exogenous Ag stimulation. They constitute a substantial proportion of the normal Ab repertoire. They are mainly of the IgM class, unmutated, and typically polyreactive. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic mice expressing a prototypic NAA, named ppc1-5, we found that the expression of NAA in the autoimmune MRL-lpr mice protect from autoimmune manifestations. To demonstrate that the protection is, at least in part, via the secreted NAA per se, we administered purified ppc1-5 IgM to the wt MRL-lpr mice. We observed substantial reduction in proteinuria and kidney IC deposition, and prolonged survival in mice injected with ppc1-5 IgM as compared to those that received either PBS or control IgM. The ppc1-5 IgM injected mice had decreased levels of anti-Hep2 ANA and anti-dsDNA of the IgG3 subclass, although the total IgM and IgG levels did not alter significantly. We demonstrated that the ppc1-5 NAA, but not the control IgM, bound to apoptotic cells with a high capacity. Examination of cytokine production showed that the administration of ppc1-5 NAA significantly reduced the production of IFNgamma and IL-10 by CD4+ T cells. Taken together, our data demonstrate that the low-affinity, self-reactive NAAs can protect from lupus nephritis, and suggest that they may do so by promoting removal of apoptotic cells, and by regulating T-cell function.
The lupus susceptibility locus Sle1 facilitates the peripheral development and selection of anti-DNA B cells through impaired receptor editing (P4054)
Authors: Kim Hang-Rae , Chang Soog-Hee , Kim Tae-Joo , Kim Young-Joo , Liu Yang , Min So-Youn , Park Min-Jung , Park Hyun-Sil , Nam Ki-Hoan , Seong Seung-Young , Kim Ho-Youn , Mohan Chandra 
Published: January 2023

Abstract
Systemic lupus erythematosus is characterized by the spontaneous production of IgG autoantibodies in patients and lupus-prone mice. In this study, we investigated the effect of the Sle1 lupus susceptibility locus on the peripheral development of 56R+ anti-DNA transgenic B cells by tracking 56R+B cells in mice without (B6.56R) or with the Sle1 locus (B6.Sle1.56R). Compared to B6.56R mice, B6.Sle1.56R mice exhibited increased class-switched IgG2a anti-DNA antibodies in their serum, encoded by the transgene. Interestingly, within the spleen, Sle1 facilitated the development of these cells into clusters of IgG2a class-switched B cells juxtaposed to CD4+ T cells within extrafollicular sites. Through sequence analysis of B cell hybridomas, we also found that B cells from B6.Sle1.56R mice are inefficient at immunoglobulin heavy chain and light chain editing. Thus, the immunoglobulin heavy chains in Sle1.56R+ B cells are partnered more often with cationic light chains that facilitate DNA binding. Taken together, these findings indicate that the Sle1 lupus susceptibility locus may facilitate the emergence of anti-DNA B cells by subduing B cell receptor revision, and possibly by shaping extrafollicular development of effector B cells, though the precise molecular mechanisms await further study.
Integrin ITGAM/CD11b negatively regulates BCR signaling to maintain autoreactive B cell tolerance (P4062)
Authors: Ding Chuanlin , Ma Yunfeng , Chen Xingguo , Cai Yihua , Liu Min , Hu Xiaoling , Yan Jun 
Published: January 2023

Abstract
The hallmark of systemic lupus erythematosus (SLE) is loss of immunological tolerance and B cell hyperactivity. Recent studies demonstrated an association between the variant of the integrin-α-M (ITGAM, also called CD11b) gene and SLE susceptibility, severity of disease, and pathogenic anti-dsDNA antibody production. However, the cellular and molecular mechanism by which CD11b regulates disease pathogenesis is not understood. We found that autoreactive B cells defective of CD11b exhibited hyperproliferative responsiveness to B cell receptor (BCR) cross-linking. CD11b deficiency promoted cell cycle progression and B cell survival, which was associated with elevated anti-apoptotic gene and protein levels. In vivo engagement of BCR resulted in increased autoAb production and kidney Ig deposition in CD11b-deficient mice. CD11b-deficient autoreactive B cells had the decreased tyrosine phosphorylation including Lyn and CD22 with decreased SHP-1 recruitment but increased calcium influx. Colocalization analysis revealed that the inhibitory effect of CD11b is due to its cis-interaction with CD22. Interestingly, B cells transfected with wildtype CD11b or rs1143679 (R77H) lupus associated variant of CD11b suggest that this mutation completely impairs CD11b regulatory effect on BCR signaling. Taken together, these results reveal the negative regulatory role for CD11b in maintaining autoreactive B cell tolerance.
Vaccination against DLK-1 and DLK-2 as a cancer therapy (P4306)
Authors: Fabian Kellsye , Sabins Nina , Storkus Walter 
Published: January 2023

Abstract
Previous studies suggest that by improving Notch signaling in the tumor microenvironment (TME), one may rescue tumor infiltrating T lymphocyte function and inhibit tumor growth in vivo. Delta-like homolog 1 (DLK-1) and Delta-like homolog 2 (DLK-2) are homologous transmembrane proteins whose ectodomains may be shed from the cell surface by the action of the tumor necrosis factor alpha converting enzyme. Both the membrane-associated and soluble forms of DLK-1/-2 serve as antagonists of Notch receptor-mediated signaling. We report that DLK-1 is differentially expressed by vascular pericytes of murine renal cell carcinomas (RENCA) and have shown that vaccination of RENCA-bearing BALB/c mice with DLK-1-derived peptides or cDNA results in the activation of specific CD8+ T cells, the recruitment of these T cells into the TME and the normalization of tumor vasculature in vivo. However, DLK-1 and DLK-2 have been reported to counter-modulate each other’s expression. Here we show that DLK-1-based vaccination leads to the T cell-dependent loss of DLK-1 expression in RENCA tumors, but to an apparent compensatory increase in TME expression of DLK-2. We have recently defined H-2d class I-presented peptide epitopes recognized by CD8+ T cells and are currently evaluating the therapeutic benefits of vaccines targeting both DLK-1 and DLK-2 in our RENCA model. We believe that such vaccines will have significant translational value for the treatment of many solid, vascularized forms of cancer.
Infection-mimicking materials to regulate dendritic cell subsets and T cell in situ for cancer vaccination (P4324)
Authors: Ali Omar , Doherty Ed , Dranoff Glenn , Mooney David 
Published: January 2023

Abstract
Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We have designed macroporous polymers mimicking key aspects of bacterial infection that may be used to directly control immune-cell trafficking and activation in the body. These systems have been applied as cancer vaccines in murine models of melanoma and glioma where they mediated tumor-specific responses eradicating large and distant tumors. These vaccines may be modified to present a variety of infectious cues with temporal control to finely tune the magnitude of immune responses to cancer cells. Consequently, this tool allows us to define a local and specific immune signature that correlates with vaccine efficacy. The results motivate clinical translation of immunologically active materials for cancer vaccination.
A role for the GITR pathway in anaphylaxis (P4326)
Authors: Murphy Judith , Merghoub Taha , Houghton Alan , Wolchok Jedd 
Published: January 2023

Abstract
Immune modulation using monoclonal antibodies has a significant impact on the overall survival of patients with metastatic melanoma. Monoclonal antibodies that engage members of the tumor necrosis factor receptor (TNFR) superfamily have shown promising tumor protection in preclinical models. Glucocorticoid-induced TNFR-related protein (GITR) is a particularly potent target for tumor immunotherapy. A single dose of GITR agonist antibody results in 60% protection from established B16 melanoma tumors. Therefore, several doses of anti-GITR may be necessary in order to fully eradicate established tumors. Because GITR is expressed throughout the immune system, we investigated whether multiple doses of anti-GITR result in adverse immune-related events. We observed that three doses of anti-GITR cause anaphylaxis, a side effect that has not been reported using this or other TNFR superfamily agonist antibodies. Anaphylaxis was not observed upon the first or second doses of anti-GITR or in GITR knockout mice. Anti-GITR-induced anaphylaxis is associated with a severe drop in body temperature and elevated serum proinflammatory cytokine levels. We are further investigating the causes of toxicity resulting from repetitive anti-GITR treatment and whether this effect can be reversed or prevented while preserving the antitumor activity of anti-GITR, an important step given the translational potential of this therapy.
SA-4-1BBL and monophosphoryl lipid A as a novel adjuvant system with potent therapeutic efficacy against cancer in the absence of detectable toxicity and autoimmunity (P4334)
Authors: Dinc Gunes , Srivastava Abhishek K , Sharma Rajesh , Yolcu Esma , Zhao Hong , Shirwan Haval 
Published: January 2023

Abstract
Although subunit cancer vaccines based on tumor associated antigens (TAAs) are attractive as treatment modalities, they have limited therapeutic efficacy due to their weak immunogenicity and tumor immune evasion mechanisms. Adjuvants with potent immune stimulatory activities as component of TAA-based vaccines can overcome these limitations. In this study, we used the combination of a novel SA-4-1BBL costimulatory molecule and Toll-like receptor 4 (TLR 4) agonist monophosphoryl lipid A (MPL) with distinct mechanisms of action as a novel adjuvant system and HPV E7 as TAA in a mouse cervical cancer model. A single immunization resulted in eradication of 100% of established E7 expressing TC-1 tumors. The combined adjuvant therapy required CD8+ T cells and IFN-γ responses for efficacy. Importantly, the efficacy of the vaccine was achieved in the absence of detectable toxicity and autoimmunity as assessed by liver enzymes, blood urea nitrogen, alteration in the number of T cells, B cells, NK cells, NKT cells, macrophages, and dendritic cells, histology of major tissues, gross anatomical evidence of organ toxicity, and antibodies against ssDNA as a sign of autoimmunity. Taken together, these data demonstrate the utility of SA-41BBL/MPL as a novel adjuvant system for the development of therapeutic TAA-based subunit cancer vaccines in the absence of detectable toxicity and autoimmunity.
Influence of cytokine auto antibodies on serum IFNα activity in SLE (P6287)
Authors: Kuruganti Srilalitha , Deshpande Ashlesha , Chatham Winn , Walter Mark 
Published: January 2023

Abstract
The type-I interferon (IFN-I) family consists of 12 IFN-α subtypes as well as IFN-β and IFN-ω. IFN-α subtypes are thought to play a pivotal role in the pathogenesis of autoimmune diseases such as lupus by enhancing the production of anti-nuclear autoantibodies and driving end organ damage in patients with lupus nephritis. Despite the putative role of IFN-αs in disease, serum IFN-α activity levels are often low or undetectable in lupus patients. Auto antibodies (AAbs) against a single IFNα subtype (IFNα4) have been detected in lupus patients suggesting they may alter serum IFNα activity and disease severity. To better understand this relationship, we have measured total IFNα and IFNα subtype-specific AAbs levels in lupus patient serum. Our results thus far reveal an excellent correlation between IFNα activity and AAb levels, suggesting AAbs may provide an indirect marker of cytokine activity in some patients. Toward this end, we have determined the AAb profile for eleven cytokines implicated in lupus to understand their relationship to IFNα levels and overall disease severity. The resulting cytokine profile will be presented towards the goal of determining the best targets for anti- cytokine therapy in lupus.