bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific recruitment of gammadelta regulatory T cells by tumor cells in human breast cancer (127.38)
Authors: Ye Jian , Ma Chunling , Peng Guangyong 
Published: January 2023

Abstract
Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TILs) in the tumor immunosuppressive microenvironment is essential to cancer treatment and elimination. We recently discovered that enriched gammadelta1 T cell populations in breast cancer TILs can suppress naïve and effector T cell responses and block the maturation and activities of dendritic cells. However, the mechanism(s) governing the gammadelta regulatory T (Treg) cell increase in breast cancer patients remains elusive. In this study, we showed that IP-10 secreted by breast cancer cells significantly attracted the migration of gammadelta Treg cells. Using the loss-of-function assay with neutralizing antibodies against the chemokines secreted by breast cancer cells, we demonstrated that IP-10 was the only functional chemokine that attracts the migration of gammadelta Treg cells by breast cancer cells. We further demonstrated that human breast tumor cells also can attract gammadelta Treg cells in vivo in NOD-SCID mice using live cell imaging systems. In addition, neutralization of IP-10 and CXCR3 significantly inhibited the migration and trafficking of gammadelta Treg cells to the breast tumor sites in vivo. These studies identify the mechanism responsible for the accumulation of gammadelta Treg cells in breast cancer patients and provide novel immunologic approaches capable of preventing the trafficking and generation of gammadelta Treg cells in breast tumor suppressive microenvironments.
Natural cytotoxic anti-tumor antibodies against NeuGcGM3 in healthy donors (127.4)
Authors: Hernandez Ana , Rodríguez Nely , Martínez Darel , Rondón Teresa , Griñán Tania 
Published: January 2023

Abstract
N-glycolylated (NeuGc) gangliosides are not naturally expressed in normal human tissues but are overexpressed in several tumors and have immunosuppressive capacity, contributing to cancer progression. The present work shows the existence of a natural antibody response against NeuGcGM3 in healthy donors. 64 of the 100 donors tested had antibodies that specifically recognized NeuGcGM3 and killed tumor cells expressing the antigen by a complement mediated mechanism. Interestingly, even after complement inactivation 17% of the positive sera showed a direct cytotoxic effect on the tumor cells. This cytotoxicity was dependent on the presence of the antigen on the tumor cells and resembles an oncotic necrosis kind of cell death. The levels of anti-NeuGcGM3 antibodies in the sera of healthy donors and the percentage of donors with this natural immunity decreases with age. Furthermore we could only detect this reactivity in the sera of 5 from 51 lung cancer patients that matched in sex and age the assessed healthy donors. Non-small cell lung cancer patients vaccinated with an idiotypic antibody that mimics NeuGcGM3 elicited specific anti-tumor cytotoxic antibodies and showed longer survival times than non-responder patients. These results suggest the existence of natural antibodies against NeuGcGM3, with anti-tumor immune surveillance functions, that can be boosted in cancer patients, reinforcing the importance of N-glycolylated ganglioside as anti-tumor targets.
Ovarian cancer progression is controlled by phenotypic changes in dendritic cells (127.7)
Authors: Conejo-Garcia Jose , Scarlett Uciane , Rutkowski Melanie , Baird Jason , Fiering Stephen 
Published: January 2023

Abstract
We have characterized the initiation and evolution of the immune response against a new p53-dependent model of aggressive ovarian carcinoma. In these previously healthy tumor-bearing hosts, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors become noticeable and aggressively progress to terminal disease in a comparatively much shorter time. Notably, tumor cells remain immunogenic at advanced stages, but the responsiveness of anti-tumor T cells decreases during tumor progression. Most importantly, their residual protective immunity is abrogated by functionally different microenvironmental DCs massively recruited to advanced tumors. Correspondingly, depleting DCs early in the disease course accelerates tumor initiation, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that aggressive ovarian cancer progression after a comparatively much longer latency period is primarily driven by both the activity of immunosuppressive microenvironmental DCs and intrinsic T cell paralysis, rather than loss of immunogenicity.
Autoantibody profiling from ANA positive population to identify individual at increased risk for systemic lupus erythematosus (159.1)
Authors: Wang Ling , Raj Prithvi , Karp David , Wakeland Ward , Olsen Nancy , Li Quanzhen 
Published: January 2023

Abstract
Antinuclear antibodies (ANA) are positive in over 90% systemic lupus erythematosus (SLE) patients but are also present in about 20% normal population. In order to delineate the correlation between ANA expression and the risk for lupus, we investigated the autoantibody profiles that are best associated with ANA in a cohort of 106 samples with different ANA titers from SLE, incomplete lupus (ILE) and normal controls (NC), using a slide-based autoantigen array bearing 80 specificities. The antibodies which showed best correlation with ANA were the IgG AutoAbs against RNA-associated antigens (Ro, La, Sm, snRNP) and histones (H3, H1, H2A, H4). There are only 3 autoAbs (H1, H2B, Scl-70) showed significant increase in ANA+ NC group compared with ANA- NC (p&lt;0.05), while more than a dozen IgG AutoAbs, including Ro, La, Sm/RNP, H1, H2B, H4, dsDNA, chromatin, collagen VI, CENP, were significantly increased in SLE compared with ANA+ NC (p&lt;0.05). ILE patients have similar autoAb profiles to SLE with the exception of anti-chromatin and anti-U1snRNP. More IgM autoAbs were expressed in ILE than SLE but none of them were correlated with ANA. This data suggested that ANA+ individuals are usually accompanied by an increased number of IgG autoAbs. When more than 5 AutoAbs appeared, especially the transition from anti-histone to anti-RNA and anti-DNA antibodies may indicate an increased risk for SLE. Monitoring the autoAbs in ANA+ population may be beneficial for early diagnosis of lupus.
Anti-U1C autoantibody interferes with the U1C-mediated splicing of both Ang1 and Tie2 genes in human pulmonary artery smooth muscle cells (159.10)
Authors: Komai Koichiro , Okuyama Tatsuki , Sasaki Yohei , Hashiramoto Akira , Shiozawa Kazuko , Shiozawa Shunichi 
Published: January 2023

Abstract
Purpose: We previously showed that the frequency of the splicing variant of Angiopoietin-1 gene with nt805GGT insertion (Ang1/ins) was significantly increased in the Japanese patients with MCTD and those with PH (Shiozawa K et al., Arth. Rheum. 52: S283, ‘05). Because anti-U1RNP Ab is highly associated with the patients with MCTD, we investigated the correlation between anti-U1RNP Ab and the splicing of Ang1. Although we found that anti-U1C Ab specifically affects the splicing of Ang1 (Komai K et al., J. Immunol. 186: 44.3 (Abstr) '11), other genes also might be affected because U1RNP is the general splicing factor. We have now studied the contribution of anti-U1C Ab to the splicing of endothelial tyrosine kinase receptor Tie2 gene which codes the receptor of Ang1. Methods: Anti-U1C Abs were introduced into human pulmonary artery smooth muscle cells using PULS-in (Polyplus) with recombinant proteins of U1A, U1C or U1-70k respectively. After 24hrs, Tie2 mRNAs were obtained by RT-PCR. Results: Several Tie2 variants were induced with anti-U1C Ab only in the case with the introduction of U1C recombinant protein. Major products were 1100, 900, 600, 550, 450 and 400bp fragments. The 550 bp fragment was the Tie2-468 variant which was identified previously (Jin P et al., Arth. Res. & Ther. 10: R73, '08). Conclusions: Our results suggest that anti-U1C Ab interferes with the splicing of both Ang1 and Tie2 genes and induced variants may affect the pathogenesis of MCTD or those with PH.
Anti-dengue virus nonstructural protein 1 antibodies cause endothelial cell damage via ceramide-regulated GSK-3 and NF-kappaB activation (159.19)
Authors: Chen Chia-Ling , Lin Chiou-Feng , Wan Shu-Wen , Wei Li-Shiung , Lin Yee-Shin 
Published: January 2023

Abstract
Immunopathogenesis of dengue virus (DV) infection is involved in hemorrhagic syndrome resulted from coagulopathy and vasculopathy. We have proposed a mechanism of molecular mimicry in which antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-react with human endothelial cells and cause NF-κB-regulated inflammation and NO-regulated apoptosis. However, the involvement of membrane sphingolipid signaling following the binding of anti-DV NS1 Abs to endothelial cells is unresolved. We found that anti-DV NS1 caused the formation of lipid raft-like structure and that disrupting the lipid raft formation by methyl-β-cyclodextrin decreased NO production and apoptosis. Treatment with anti-DV NS1 Abs elevated ceramide generation in lipid rafts. Pharmacologically inhibiting acid sphingomyelinase (ASMase) decreased anti-DV NS1-mediated ceramide and NO production as well as apoptosis. Exogenous ceramide treatment caused biogenesis of inducible NO synthase (iNOS)/NO and apoptosis through a NF-κB-regulated manner. Furthermore, activation of glycogen synthase kinase (GSK)-3 was required for ceramide-induced NF-κB activation and iNOS expression. Notably, anti-DV NS1 Abs caused GSK-3-activated NF-κB and iNOS expression which was regulated by ASMase. These results suggest that anti-DV NS1 Abs bind to endothelial cell membrane and cause inflammation and apoptosis via a mechanism involving the ASMase/ceramide/GSK-3/NF-κB/iNOS/NO signaling pathway.
B lineage-specific deletion of Bim leads to lymphoproliferative and autoimmune disease (159.23)
Authors: Wright Jacqueline , Clark Emily , Takeuchi Osamu , Zinkel Sandra , Satterthwaite Anne , Khan Wasif 
Published: January 2023

Abstract
Autoreactive B cells are known to contribute to the onset and progression of a variety of autoimmune diseases including systemic lupus erythematosus (SLE). To prevent this, the B cell receptor (BCR) exerts specificity-based quality control and B cell activating factor receptor (BAFF-R) maintains homeostasis primarily through controlling apoptosis. An appropriate balance in the levels of the pro- and anti-apoptotic members of the Bcl-2 family is central to this process. Using mice with B lineage-specific deletion of the pro-apoptotic gene Bim (B-bim-/-), we showed that B cell autonomous dysregulation of apoptosis is sufficient to cause systemic autoimmune disease with lymphoproliferation. B-bim-/- mice display progressive splenomegally and lymphoadenopathy with a significant increase in B cells as well as an overall increase in innate and T cells which display markers of activation. B-bim-/- mice had higher serum levels of autoantibodies and proinflammatory cytokines. These mice also displayed increased lymphocyte proliferation and infiltration of the salivary gland, lung and liver. Furthermore, accumulation of lymphocytes in the B-bim-/- mice results in the formation of tertiary lymphoid structures. These results suggest that apoptosis resistant B-bim-/- B cells can acquire an activated phenotype and become pathogenic, culminating in the activation of T cells and the generation of a pro-inflammatory microenvironment leading to systemic autoimmunity. In addition, massive lymphoproliferation and inflammation may predispose B-bim-/- mice to B cell and other hematopoietic malignancies.
Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)-bisphosphate regulates B cell activation and autoantibody production (159.5)
Authors: Jayachandran Nipun , Landego Ivan , Gibson Ian , Miller Angela , Wullschleger Stephan , Alessi Dario , Marshall Aaron 
Published: January 2023

Abstract
Activation of PI3-kinase enzymes through the BCR is essential for B cell development and function. Active PI3Ks generate D3 phosphoinositide PI(3,4)P2 that bind to signaling molecules such as TAPP (Tandem PH domain containing protein) adaptor via their C terminal PH domain. This interaction leads to translocation of TAPPs to the plasma membrane. However, the role of TAPP adaptors in regulating PI3K signaling in B cell is not completely understood. We have performed studies on TAPP mutant mice, where a mutation was introduced to the C terminal domain of both TAPP1 and TAPP2 to determine the effect of uncoupling TAPPs from PI(3,4)P2. The studies showed an enhanced B cell activation and elevated serum antibody levels in these mice, suggesting an inhibitory role associated with TAPPs in B cells. To test whether the aberrant responses observed in B cells leads to autoimmunity in these animals, we analyzed their serum and observed a progressive increase in anti-dsDNA antibodies in the aging cohort. This along with other observed characteristics such as the presence of anti-nuclear antibodies within the serum, progressive development of lymphopenia and glomerulonephritis in aged mice is reminiscent of lupus. We are currently working to define the cellular interactions involved in this autoimmune phenotype and the signaling mechanism associated with the inhibitory role of TAPPs.
Lipoteichoic acid induces B cell activation in female MRL/lpr (fas) mice: implications for lupus cerebritis (159.6)
Authors: Dasgupta Subhajit , Molano Ivan , Bandyopadhyay Mausumi , Kindy Mark 
Published: January 2023

Abstract
Activation of B cells, production of autoantibodies and formation of immune complex with complements are hallmark immune aberrations in lupus. The female MRL/MpJ (Faslpr/ Faslpr) mice develop spontaneous lupus-like symptoms and distinct brain specific neuronal dysfunction. These mice are recognized to study mechanism of immune responses in lupus and cerebritis. We found, elevated mRNA expression of TLR2, IL6 and IL17F in spleen tissues from 22 weeks old MRL mice with progression of disease. The flow cytometry analysis demonstrated an expansion of activated CD19+CD86+ B cells in LTA injected MRL/lpr mice. The expanded B cell pool was found less IgM+B220+ cells in 22 weeks old MRL/lpr-LTA mice than the age matched untreated mice. The IgM-IgG+B220+ cells were found higher in LTA treated mice. The LTA injection also induced an expansion of CD21+CD23+ B cells in 22 weeks old MRL/lpr mice. Studies are underway to determine mechanism of TLR2 and IL17F mediated signals on auto reactive B cell activation and switch in balance from tolerance to antigen specific effector immune responses during onset of lupus as well as in distinct brain specific cerebritis.
CD45RBlo 122lo autoantibody-inducing CD4 T cell (aiCD4 T cell) causes systemic lupus erytematosus (SLE) (159.7)
Authors: Miyazaki Yumi , Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We have repeatedly immunized non-autoimmune-prone mice with the antigen to show that a novel T cell type which we termed an autoantibody-inducing CD4 T (aiCD4 T) cell was generated via TCR revision, and this aiCD4 T cells induced autoimmunity, i.e., SLE. We show here that the aiCD4 T cell, required for the generation of not only varieties of autoantibodies but also CTL and tissue injuries, belongs to CD45RBlo 122lo CD4 subpopulation. Methods: BALB/c mice were immunized 12x with OVA, and were depleted of CD4 T cells by anti-CD4 antibodies. The aiCD4 T cell of the mice immunized 12x with KLH was transferred into the mice immunized 8x with OVA to prove aiCD4 T cell-help. Proteinuria and IFNγ-producing CD8 T cell in spleen were examined. To assign CD number on aiCD4 T cell, surface markers were examined after 12x immunization with OVA. Results: In the BALB/c mice, CTL remained immature after immunization 8x with OVA. However, the transfer of CD4 T cells of the mice immunized 12x with KLH matured CTL and induced lupus nephritis. This was due to the aiCD4 T cells generated after repeated immunization capable of inducing autoantibodies. We then adoptively transferred subfractions of CD4 T cells into naïve recipients to identify the CD marker of aiCD4 T cell. We found that the aiCD4 T cells capable of inducing RF and anti-dsDNA antibody existed in CD45RBlo 122lo subfraction. Conclusion: The aiCD4 T cell that causes SLE belongs to CD45RBlo 122lo CD4 T subpopulation.
Thymocyte- and B-cell derived vesicles, incorporated into IgG2a-bound complexes, activate autoreactive B cells through a BCR/TLR-dependent mechanism (159.8)
Authors: McCahan John , Bossaller Lukas , Marshak-Rothstein Ann 
Published: January 2023

Abstract
B-cells from AM14 transgenic mice are a model of self reactive B-cells. They express an antigen receptor specific for IgG2a and make a class of autoantibody known as rheumatoid factor (RF). We had previously reported that immune complexes (ICs) composed of IgG2a-chromatin or IgG2a-RNA can stimulate AM14 B-cells by the synergistic engagement of the antigen receptor and a member of the Toll-like receptor (TLR) family. The source of the antigen in this system is derived from the co-culture itself but it is unclear in what form the auto-antigen exists. Using biotinylated syngeneic cells and an IgG2a anti-biotin monoclonal antibody (mAb) we found that the mAb together with remarkably low numbers of biotinylated B-cells or biotinylated-thymocytes induced substantial AM14 B-cell activation and proliferation. This effect was mostly dependent on the synergistic engagement of the BCR and TLR9, and to a lesser extent on TLR7. Interestingly, we saw even stronger proliferative responses with the cell free portion of the biotinylated-B-cell or biotinylated-thymocyte culture supernatants in this system. Confocal microscopy showed, that vesicles released from biotinylated cells are delivered via anti-biotin IgG2a antibodies to AM14 B- cells. Our findings suggest that self-reactive B-cells can be stimulated by auto-antigen in association with cell-derived vesicles through a TLR 7/9 mediated process.
Dual infections with Mycobacterium avium ss. paratuberculosis and bovine leukemia virus alter regulatory T cell prevalence and activity in cattle. (160.12)
Authors: Coussens Paul , Roussey Jonathon , Murphy Brooke 
Published: January 2023

Abstract
Johne’s disease (paratuberculosis) is a chronic disease of domestic ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP) that currently ranks as one of the most costly diseases in the U.S. Dairy Industry. We proposed that the chronic nature of Johne’s disease would result in development of regulatory T cells (Tregs). Tregs would shift immune responses away from a pro-inflammatory Th1 to an unproductive Th2 response. In the course of studies on Tregs and MAP, we uncovered a confounding effect due to bovine leukemia virus (BLV) infection. Healthy control cattle displayed significant FoxP3 (Tregs) staining in mesenteric lymph nodes, but lymph nodes from BLV infected cattle were devoid of FoxP3 expressing cells. Concurrent infection with MAP partially restores FoxP3 expressing cell populations. BLV infection also reduces TGFβ (2-fold reduction) mRNA abundance in mesenteric lymph nodes, while concurrent infection with MAP partially restores TGFβ mRNA levels. In peripheral blood mononuclear cells, BLV infection reduces abundance of TGFβ, but dramatically enhances abundance of IL-10 mRNA. Taken together, our results suggest that BLV alters immune profiles to favor progression of MAP infection. Recent estimates suggest over 83% of U.S. dairy operations are currently positive for BLV and approximately 68% are positive for MAP. If concurrent infection with these two pathogens increases losses due to MAP, then the economic consequences could be staggering.
Studies on the biological function of virus-like particles of foot and mouth disease (160.13)
Authors: Chang Yu-Ching , Cheng Yung-Chih , Wang Ting-Fang , Liang Shu-Mei 
Published: January 2023

Abstract
Foot and mouth disease (FMD), a severe and highly contagious viral disease of cloven-hoofed animals, is the most economically devastating livestock disease in the world. The development of a cheap and noninfectious virus-like particle (VLP) vaccine has now attracted worldwide interest. In this study, we used SUMO fusion technology to produce a VLP of FMD virus (FMDV). The purified FMD-VLPs morphologically resembled FMD virions and were able to interact with host receptors in a manner similar to FMDV. Immunization of guinea pig or swine with FMD-VLPs resulted in the production of anti-FMDV neutralizing antibodies. RT-PCR analysis of peripheral blood mononuclear cells (PBMC) from the FMD-VLPs-immunized swine revealed that FMD-VLPs enhanced the transcription of Th1-like cytokines (IFN- and IL-2) and Th2-like cytokines (IL-4 and IL-10). Further investigation of the immune mechanisms revealed that FMD-VLPs induced maturation of dendritic cells (DCs) via toll-like receptors 2 (TLR2) to induce CD4+ and CD8+ T proliferation. These results suggest that FMD-VLPs could be used as an effective vaccine candidate against FMDV.
The canine MHC class I allele, DLA-88*50801, presents peptides of varying lengths with three key anchor residues (160.14)
Authors: Ross Peter , Buntzman Adam , Holmes Jennifer , Gojanovich Greg , Miller Keith , Collins Edward , Frelinger Jeffrey , Hess Paul 
Published: January 2023

Abstract
The binding of a peptide to a major histocompatibility (MHC) class I allele depends upon a few key residues within the peptide sequence, which is present only in ~1-2% of peptides in an average protein. Identification of this motif allows one to select candidate epitopes from a protein that may be recognized by cytotoxic T lymphocytes (CTL). While several studies have determined the binding specificities of numerous class I alleles in both humans and mice, no such study has been performed in the domestic dog. The principal aim of this study was to determine the peptide binding motif of a prevalent MHC class I allele, Dog Leukocyte Antigen (DLA) -88*50801. We hypothesized that a conserved binding motif could be identified through sequencing of endogenously presented peptides eluted from DLA-88*50801. To accomplish this goal, a plasmid encoding the DLA-88*50801 gene with an attached flag tag was stably transfected into a canine cell line (DH82). DLA-88*50801 protein was obtained through affinity purification of lysate from ~8 x 109 cells. Bound peptides were eluted from the MHC binding groove utilizing low pH and heat, isolated by size exclusion and affinity purification, and subjected to tandem mass spectrometry analysis to obtain individual peptide sequences. Sequences were manually aligned to determine the binding motif. This study provides essential information to study CTL responses in dogs.