bluuebunny/crossref_metadata_2025_split huggingface dataset:
Full Activation of Autoreactive B Cells Requires Helper Signals from Plasmacytoid Dendritic Cells (99.32)
Authors: ding chuanlin , Yan Jun 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is characterized by dysregulated autoreactive B cell activation. Previous studies demonstrate that plasmacytoid dendritic cells (pDCs) play a pivotal role in the pathogenesis of SLE. This study was undertaken to investigate the mechanisms of interactions between pDCs and autoreactive B cells. After co-culture of anti-small nuclear ribonucleoprotein particle (snRNP) B cells with activated pDCs via toll-like receptor (TLR)-7 or -9 agonist, we found that pDCs could significantly enhance autoreactive B cell proliferation and autoantibody production. In addition, autoreactive B cell activation via BCR engagement was also augmented by activated pDCs. This in vitro enhancement effect was further demonstrated by an in vivo B cell adoptive transfer experiment, demonstrating that autoreactive B cell proliferation was significantly decreased in MyD-88-deficient mice compared to that in wildtype mice. Neutralization of IFN-α and IL-6 could abrogate partially enhanced B cell activation via pDCs. Transwell studies demonstrated that pDCs could provide activation signal to B cells in a cell-to-cell contact manner. The involvement of the ICAM-LFA-1 pathway, but not the CD40L-CD40 pathway, was discovered to mainly contribute to this effect. These data suggest that pDCs regulate autoreactive B cell activation by soluble factors as well as cell-to-cell direct interactions. (This work was supported by an Arthritis Foundation Postdoctoral Fellowship)
Effects of expression Fli1 transcription factor on lupus disease development in NZM2410 mice (99.35)
Authors: Zhang Xian , Mathenia Jeremy , Reyes-Cortes Emmanuel , Molano Ivan , Gilkeson Gary 
Published: January 2023

Abstract
The Fli1 gene is a member of the ets family of transcription factors that is expressed in hematopoietic cells. Two-fold overexpression of Fli1 protein in transgenic mice results in the development of a lupus-like disease. Expression of Fli1 in systemic lupus erythematosus (SLE) patients and animal models of lupus is higher compared to normal controls. Here we examined the effects of reduced Fli1 expression on disease development in NZM2410 mice, an animal model of SLE.
We generated Fli1 knockout heterozygous mice (Fli1+/-; Fli-1 homozygous knockout is embryonic lethal). Compared to wild-type (Fli1+/+) mice, we found that expression of Fli1 protein in Fli1+/- mice was reduced by half. Autoantibodies, Urinary albumin excretion and serum immunoglobulin concentrations were measured by ELISA.
Fli1+/- NZM2410 mice survived significantly longer than Fli1+/+ NZM2410 mice. At the age of 52 weeks, 81% Fli1+/- NZM 2410 mice survived, whereas only 35% of Fli1+/+ mice survived. There were significant low urinary albumin excretions in Fli1+/- NZM2410 mice compared to Fli1+/+ NZM2410 mice at the age of 34 weeks. Compared with Fli1+/+ NZM2410 mice, Fli1+/- NZM2410 mice have significantly decreased levels of IgG anti-dsDNA and glomerular antigen (GA) antibodies at the age of 34 weeks.
Our results suggest that the expression of Fli1 plays an important role in disease development in NZM2410 mice.
Src-like adaptor protein (SLAP) deficiency leads to decreased autoantibody production (99.37)
Authors: Peterson Lisa K , Shaw Laura A , Dragone Leonard L 
Published: January 2023

Abstract
Background: Intrinsic defects in lymphocyte signaling have been implicated in the pathogenesis of autoimmunity. SLAP has been shown to influence BCR levels and signaling in developing B cells. We hypothesize that SLAP deficiency will enhance the negative selection of autoreactive B cells leading to decreased autoantibody production.
Methods: To test this hypothesis we immunized SLAP-deficient and wild-type BALB/c mice with a peptide mimitope for dsDNA that leads to the development of dsDNA antibodies and a systemic lupus erythematosus-like autoimmune disease. In addition, we used a second model where we generated SLAP-deficient mice expressing an autoreactive BCR heavy chain 3H9H/E56R (56R) that binds dsDNA to determine how SLAP deficiency impacts BCR repertoire selection and autoantibody production.
Results: SLAP-deficiency led to decreased serum levels of dsDNA antibodies in both experimental systems with a 6-fold reduction in the mimitope treated mice and a 3-fold reduction in dsDNA antibodies in the SLAP-deficient 56R mice. Flow cytometric analysis of bone marrow B cell subsets in SLAP-deficient 56R mice revealed a 27% reduction in fraction D, 37% in E and a 2-fold reduction in F, with a 19% increase in lambda usage compared to controls.
Conclusions: These data support the hypothesis that SLAP deficiency enhances negative selection of autoreactive B cells leading to decreased autoantibody production.
IL-17 activates the classical NF-κB signaling pathway to upregulate chemokine signal inhibitor molecules RGS16 and RGS13 in autoimmune B cells of BXD2 mice (99.49)
Authors: Xie Shutao , Hsu Hui-Chen , Wang John , Wu Qi , Li Jun , Li Hao , Mountz John D. 
Published: January 2023

Abstract
We have previously reported that IL-17 upregulated the expression of rgs13 and rgs16 to attest the migration response of B cell to CXCL12. This specific effect of IL-17 on B cells is associated with the development of spontaneous germinal center in the spleens of autoimmune BXD2 mice. This study is to determine if NF-κB signaling is involved in IL-17 mediated upregulation of RGS proteins in B cells. Western blotting and confocal imaging analyses both showed that IL-17 stimulation of B cells from BXD2 mice resulted in rapid (5 min) activation of the classical NF-κB pathway which can be characterized by phosphorylation of p65 (P-p65) and translocation of P-p65 to the nuclei. Significantly higher level of activated P-p65 was found in BXD2 B cells than in B6 and BXD2-Il17r-/- B cells (&gt;4.0-fold, p&lt;0.01). Expression of the endogenous p50 subunit of NF-κB in BXD2 B cells was also higher than in B6 B cells (5.0-fold, p&lt;0.01) but was surprisingly lower than in BXD2-Il17r-/- B cells (2.5-fold, p&lt;0.01). The activated NF-κB pathway by IL-17 in B cells correlated with the upregulation of RGS16 and RGS13 in both protein and mRNA levels. Inhibition of P-p65 significantly down-regulated the expression of rgs genes (6.0-fold), and released the B cell migration arrest induced by IL-17 stimulation. These data suggest that IL-17 directly upregulates the expression of RGS through activating the classical NF-κB pathway in autoreactive BXD2 B cells.
Taenia crassiceps infection and its antigens abrogate Experimental Autoimmune Encephalomyelitis, a role for alternatively activated macrophages (AAMφ) (99.51)
Authors: Reyes Jose L , Espinoza Arlett F , Terrazas Luis I 
Published: January 2023

Abstract
Helminth infections induce strong immunoregulation and may modulate subsequent pathogenic challenges. Taenia crassiceps causes chronic infections, induces Th2-biased responses and recruits AAMΦ with suppressive ability. To test the influence of this cestode on autoimmunity, we infected C57BL/6 mice with 40 T. crassiceps metacestodes, 8 weeks later Experimental Autoimmune Encephalomyelitis (EAE) was induced with MOG35-55 on infected and uninfected mice. It was found that T. crassiceps-infected mice delayed the onset of EAE; only 50% of them displayed symptoms and those were significantly less severe than uninfected mice. They also had decreased MOG-specific spleen cell proliferation, low IL-17 production and low leukocyte infiltration in the spinal cord. Levels of TNFα in sera and transcripts for TNFα and iNOS in CNS were lower in previously infected mice. AAMΦ markers Ym1, Relm-α and Arg1 were over-expressed in CNS of EAE T. crassiceps-bearing mice, whereas T-bet was expressed in EAE mice. Injection of 50μg of soluble T. crassiceps Ag at the onset of EAE abrogated the symptoms. Infection and Ag induced AAMΦ expressing PDL1 & PDL2 which suppressed anti-MOG specific cell proliferation; such effects were inhibited in mice receiving chlodronate-loaded liposomes. Thus, T. crassiceps' immune-regulation decreases EAE severity by dampening T cell proliferation and migration to CNS with a key role for AAMΦ.
Tim-1 expressed on dendritic cells enhances effector T cell responses and inhibits development and function of regulatory T cells (99.9)
Authors: Xiao Sheng , Kuchroo Vijay K 
Published: January 2023

Abstract
Tim-1 has been reported to be expressed on CD4+ T cells upon activation and to regulate Th2 responses. Here we report that Tim-1 is constitutively expressed on dendritic cells (DCs), the key instigators of adaptive immune responses. Tim-1 engagement in DCs induces a signaling cascade with NF-kB acivation, and promotes their maturation, resulting in upregulation of costimulatory molecules and production of proinflammatory cytokines. Such DCs enhance effector T cell (especially Th17) responses but inhibit de novo generation of Foxp3+ regulatory T cells (Treg). In vivo when given at the induction of immune response, agonistic anti-Tim-1 antibody enhances immunogenic function of DCs, decreases suppressive function of Foxp3+ Treg, and substantially increases proinflammatory Th17 responses as well as Th1 responses. The anti-Tim-1 treatment induces more severe experimental autoimmune encephalomyelitis (EAE) in susceptible mice, and also breaks tolerance and induces disease in the EAE-resistant strain of mice. These findings indicate that Tim-1 has an important role in the innate immune system in that Tim-1 signaling in DCs decreases immune regulation by Treg and promotes effector T cell responses.
Erythropoietin increases macrophage-mediated suppression in a model of the tumor microenvironment (100.1)
Authors: Riggs James , Orlowski Michelle 
Published: January 2023

Abstract
Erythropoietin (EPO), a glycoprotein that increases RBC production, is used to reverse chemotherapy-induced anemia in cancer patients. Unfortunately some patients have experienced accelerated tumor growth and decreased survival rates. We have been modeling the in vivo tumor microenvironment by culturing murine peritoneal cavity (PerC) cells in vitro. Many tumors have significant leucocyte composition including increased representation of myeloid suppressor cells. When PerC T cells are activated in a macrophage-rich environment such as this their proliferation is suppressed. Interferon-gamma (IFN-g)-triggered inducible nitric oxide synthase (iNOS) expression by macrophages drives T cell suppression via arginine catabolism. Addition of 1-methyl arginine (1-MA), a competitive inhibitor of iNOS, recovers the T cell response. We have studied EPO’s impact upon T cell activation in the PerC macrophage model. Exogenous EPO increased T cell suppression by C57BL/6J (wildtype) macrophages and this effect could be blocked by the addition of 1-MA. EPO’s enhanced suppressive effect was not evident with macrophages from iNOS or IFN-g receptor knockout mice. Studies of BALB/c PerC T cells, which were less susceptible to iNOS-mediated suppression, revealed that EPO had no effect upon T cell activation. These results suggest that exogenous EPO can increase T cell suppression and does so by acting through an IFN-g/iNOS-triggered myeloid cell pathway. Supported by NIH AREA R15-CA136901-01.
Lymphotoxin induces tumor evasion through TGF-beta signaling (100.10)
Authors: Park Chang-Eon , Kang Hyung-Sik 
Published: January 2023

Abstract
While major histocompatibility class I (MHC class I) expression was inhibited in mice administrated with pIRES-LTab plasmid, it was elevated in the spleen and liver of lymphotoxin(LT)a-/- and LTbR-/- mice. Consistent with this, the expression of genes that upregulated MHC class I was downregulated in mice administrated with pIRES-LTab plasmid, but it was upregulated in the spleen and liver of LTa-/- and LTbR-/- mice. In addition, gene expression of Fas and FasL was also regulated by LT in vitro and in vivo. Whereas gene expression of TGF-b receptor was upregulated in the large intestine of LTa-/- and LTbR-/- mice, its expression was increased in mice immunized with pIRES-LTab plasmid as a DNA adjuvant. Administration of pIRES-LTab plasmid prolonged the survival rate of mice challenged with human papillomavirus (HPV)-transformed mouse TC-1 tumor cells, and delayed the growth rate of the TC-1 cells. Gene expression of smad3 and smad4 was increased in colon and small intestine of LTa-/- and LTbR-/- mice. These results collectively suggested that MHC class I expression was regulated by LT-induced upregulation of TGF-b expression, and subsequently tumor evasion might be induced by suppression of MHC class I.
Epidermal expression of oncogenic ras subverts cytotoxic inflammation by skewing infiltrating myeloid cells towards an immunosuppressive phenotype. (100.16)
Authors: Gunderson Andrew , Mohammed Javed , Glick Adam 
Published: January 2023

Abstract
Cancer development is frequently accompanied by inflammation and immune activation. The nature of this inflammatory response, however, is non-uniform and can consist of cells with opposing functions. To characterize the innate immune response to neoplastic epithelial tissue, we used an epidermally-restricted transgenic mouse model of oncogenic H-Ras expression in which epidermal hyperplasia and premalignant progression induces aberrant myelopoesis and cutaneous hyperinflammation associated with the formation of myeloid resident epithelial microabscesses. Antibody mediated depletion of neutrophils concurrent with transgene activation ablated neutrophil infiltration and microabscesses resulting in increased epidermal thickening relative to isotype controls. Neutrophils isolated from mice expressing ras for 1 week killed keratinocytes in vitro, suggesting that the in vivo myeloid response to oncogenic ras expression is initially a cytotoxic one. Simultaneously, there is cutaneous upregulation of genes implicated in the activation, function and recruitment of myeloid derived suppressor cells (MDSC) such as GMCSF, GCSF, MMP9, VEGF, S100A8/9, CCL2, and IL1β. This coincides with upregulation of IL4Rα on myelocytes, increased percentage of Tregs, and decreased effector T cell responses from 1 to 2 weeks post H-Ras expression. These data suggest that the acute cytotoxic neutrophil response is replaced by a suppressor myeloid phenotype that could enhance neoplastic progression.
Anaplastic plasmacytomas associated with NFATc2 deficiency in aged B6 mice (100.4)
Authors: Modiano Jaime , Highfill Sarah , Matise Ilse , Morse Herbert , Jubala Cristan , Coffey David , O'Sullivan Gerard , Bellgrau Donald 
Published: January 2023

Abstract
NFATc2 is an intrinsic negative regulator of lymphocyte proliferation that promotes T cell anergy, cell cycle arrest, and possibly differentiation to the Fox-P3+ T regulatory phenotype. NFATc2 knockout (KO) mice show systemic peripheral expansion of lymphocytes with reduced thresholds for T cell activation. Unlike NFATc2 KO in mixed (H2b X H2bc) or H2d backgrounds, homozygous NFATc2 B6 KO mice did not develop splenomegaly, but instead developed systemic lymphadenopathy that was most pronounced in mesenteric and submandibular lymph nodes. The mice retained a reduced threshold of activation for both B- and T-cells. When compared to wild type and heterozygous littermates, mice had greater frequency of mixed lymphocytic infiltrates in kidney, liver, and salivary glands. Six of 11 NFATc2 KO mice that were allowed to reach 16 to 20 months of age developed anaplastic plasmacytomas in the mesenteric lymph nodes, a phenotype that was not seen in 17 age matched WT or heterozygous KO littermates. This suggests NFATc2 deficiency facilitates development of plasma cell tumors in the H2b background. We propose this may be driven by chronic antigenic stimulation and is due to poorly restrained intrinsic negative regulation and not due to extrinsic immunologic defects. These mice represent a valuable resource to explore mechanisms that account for progression from inflammation to malignancy. SLH and JFM contributed equally to this work.
Murine Hepatocellular Carcinoma Stem Cells Express Pluripotency-associated Transcription Factors and are Sensitive to Immune Mediated Apoptosis. (101.16)
Authors: de Kluyver Rachel , Stauffer Jim , Brooks Alan , Shanker Anil , Sayers Tom 
Published: January 2023

Abstract
Current evidence supports the view that cancer stem cells (CSCs) constitute the primary pathogenic component of both metastases and minimal residual disease and that elimination of CSCs is required for cure. Cell surface markers have been used to identify CSCs but fail to identify CSC in all tumors from the same tissue or in all patients. Therefore there is a need to define and test more reliable markers of CSCs. Oct-4, Sox-2 and Nanog transcription factors are key regulatory factors in maintenance of pluripotency and have been demonstrated to be robust intracellular biomarkers for tissue and cancer stem cells. A GFP-based reporter driven by a promoter responsive to Nanog or Oct-4 was used to mark pluripotent tumor cells from in vitro cultured, cancer cell lines (breast cancer- 4T1.2), and from autochthonous hepatocellular carcinoma. The molecular profile of primary Akt/β-Cat-induced murine HCC recapitulates that observed in poor prognosis Ep-CAM+/AFP+ human HCC. Ep-CAM and CD133 and Nanog and Oct-4 are independent CSC markers. Directly ex vivo, murine HCC stem cells express abundant CD1d and MHC class II in addition to TNF-R2, lymphotoxin-β receptor (LTβR) and DR5. The functional significance of CD1d, MHC class II, TNF-R2, LTβR and DR5 expression will be assessed in future studies. This study will provide valuable proof-of-principle data to the merits of CSCs as targets for curative anti-cancer therapies.
In vivo analysis of cellular sentinels for extracellular Heat Shock Protein-peptide complexes. (101.2)
Authors: Messmer Michelle , Binder Robert 
Published: January 2023

Abstract
Heat shock proteins are expressed in all cells and chaperone protein and peptide cargoes within cells. Based on their abundance and intracellular localization, HSPs in the extracellular environment have been described as indicators of cellular/membrane damage. Thus, the immune system is designed to detect HSPs in the extracellular environment (either released from dying cells or by immunization) by cell surface receptors such as CD91. Our goal is to identify the subset(s) of antigen presenting cells that detect extracellular HSPs and initiate the immune response. By introducing fluorescent labeled HSPs into mice, cells in the draining lymph node that engage extracellular HSP can be tracked. Our data demonstrates that the CD4+CD11c+ dendritic cells are the predominant antigen presenting cell that internalizes the HSP. The ability of these cells to cross-present HSP-chaperoned peptides and provide co-stimulation is under investigation. These studies will be important for understanding how endogenous HSPs act to alert the immune system of cellular damage and for optimizing immunization regimens with HSP-based vaccines.
CD5 knock out mice display a strong antitumor immune response associated with tumor infiltration by hyperactivated tumor-reactive CD8+ T lymphocytes (101.21)
Authors: Mami-Chouaib Fathia , Franciszkiewicz Katarzyna , Raman Chander , Tabbekh Mouna 
Published: January 2023

Abstract
We have previously reported the TCR inhibitory molecule CD5 impairs reactivity of tumor-specific PBL-derived T-cell clones against the cognate target and controls their susceptibility to activation-induced cell death (AICD) triggered by tumor cells. In this report, we compared the antitumor T-cell response developed against the B16F10 melanoma engrafted in CD5-deficient and wild-type (wt) C57BL/6 mice. Our results indicate that CD5 knock out mice elicit a delayed tumor growth as compared to wt mice, which is associated with tumor infiltration by more activated tumor-reactive T lymphocytes. Our data also indicate that tumor suppression in CD5-deficient mice is transient and that tumor flare up correlates with increase in AICD of tumor-infiltrating CD8+ T cells. Our data suggest that tumor T lymphocyte infiltration occurs at early stages of cancer development and that tumor-mediated AICD is most likely involved in the induction of T-cell tolerance to malignant cells.
Host-derived IL-6 utilizes TGF-β of tumor origin to modulate the differentiation of Treg cells and Th17 against cancer cells (101.26)
Authors: Chiang Hsin-Chien , Chu Rea-Min 
Published: January 2023

Abstract
TGF-β is a key inducer of Treg differentiation, and the presence of both TGF-β and IL-6 is vital to Th17 generation, which plays an important role in autoimmunity. Canine transmissible venereal tumor (CTVT) produces TGF-β during the progression (P) and regression (R) phases; however, during the R phase, tumor-infiltrating lymphocytes (TIL) secrete IL-6 to antagonize TGF-β. We have demonstrated that the level of Treg in peripheral blood mononuclear cells (PBMCs) dramatically increased in the P phase and decreased in R phase, and that exogenous IL-6 reduced Treg generation in TGF-β-containing medium but increased Th17-related mRNA expression. Further, upon addition of supernatant from a P-phase culture, the percentage of Treg cells significantly increased in PBMCs; however, the level decreased when R-phase supernatant was added, and the Th17-associated mRNA level increased. Moreover, using Affymetrix microarray analysis, we identified an autoantigen, YKL40, that was highly-expressed in the R phase. Antibodies against YKL40 were found to decrease the number of IFN-γ-producing cells in PBMCs by ELISPOT. These results suggested TIL-derived IL-6 utilizes TGF-β originating from the tumor, resulting in an increase in Th17, which may enhance the host autoimmunity and consequently break the tumor tolerance against YKL40. These complex interactions may explain how the tumor regresses in canine hosts. Further, YKL40 has the potential for use in the development of a treatment for cancer.
Characterization of a tumor-associated antigen on 9L gliosarcoma (101.31)
Authors: Gaffrey Matthew , Redd Joan 
Published: January 2023

Abstract
Cell surface antigens play a distinct role in the process of cell transformation and proliferation. The malignant, transformed counterparts of glial cells are referred to as glioma cells. Tumors or cancers resulting from the proliferation of these glioma cells constitute some of the most lethal types of cancer. We have characterized a tumor-associated antigen (TAA) expressed on the cell membrane of the 9L rat glisoarcoma (9L-Ag). Previous work has identified this antigen as a glycoprotein. In this study, we further characterize expression of 9L-Ag by normal brain cells, 9L cells, and a non-glial tumor cell line (P3X3Ag8.653). Characterization of 9L-Ag may provide a better understanding of the transformation processes from a normal to a malignant cell, and the role that 9L-Ag and similar TAAs may play in these processes.