bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interrogating BDCA3+ dendritic cells in human tumor-draining lymph nodes (127.43)
Authors: van de Ven Rieneke , Haley Daniel , Walker Edwin , Fountain Christopher , Douglas Jeremy , Wood William , Yu Kelvin , Aliabadi Shaghayegh , Fox Bernard , Hu Hong Ming , de Gruijl Tanja , Urba Walter 
Published: January 2023

Abstract
Human blood dendritic cells (DCs) expressing BDCA3 (CD141) have been characterized and described by several groups to represent the human counterpart of the mouse cross-presenting CD8α+ DC. Fully functional cross-presenting DCs are of utmost importance for the induction of tumor-antigen specific CD8 T-cell responses. In the current study, we set out to interrogate BDCA3+ DC within human tumor-draining lymph nodes (LNs) from melanoma and breast cancer patients. For this purpose a 12-color polychromatic flow panel for human DC was developed. CD11c+BDCA3+ cells were found to be of immature phenotype (low in CD80, CD86 and CD83) upon isolation. When comparing a group of 9 tumor-negative LNs with 4 tumor-positive LNs of BrCa patients, the percentage of CD11c+BDCA3+ cells was significantly higher (p&lt;0.03) in the specimen containing tumor metastasis. Moreover, when comparing the activation status of BDCA3+ cells in LNs from advanced melanoma patients that did or did not grossly display evidence of metastatic disease, we observed lower expression of the DC maturation marker CD83 in the grossly positive LNs, suggesting that this population of DC might be affected by active tumor-induced suppression. In ongoing studies we are sorting these BDCA3+ DC to determine their cross-presenting abilities and to determine whether a (tumor-induced) immature phenotype is also reflected in the functional capabilities of these cells.
A critical role of dendritic cells in CD8 T cell IL-10 expression during inflammatory response triggered by CD40-activated B cells (159.16)
Authors: Shimoda Michiko , Bolduc Anna , Powell Domonica , Ametani Yutetsu , Takezaki Mayuko , Nutt Stephen , Kamanaka Masahito , Flavell Richard , Mellor Andrew , Tsubata Takeshi , Koni Pandelakis 
Published: January 2023

Abstract
CD40LBTg mice, expressing a CD40 ligand (CD40L) transgene on B cells, represent a model for human diseases where B cells aberrantly express CD40L or receive excess CD40/CD40L signaling under inflammatory conditions. Here, we show that B cells expressing transgenic CD40L are capable of priming CD8 T cells and generate strong antigen-specific cytotoxicity. Adoptively transferred SIINFEKL peptide-loaded B cells from CD40LBTg but not wild type mice were able to activate self-reactive OT-I CD8 T cells upon immunization with OVA plus alum and trigger diabetes in RIP-OVA mice by enhancing the help of endogenous self-reactive CD4 T cells. CD40L expressing B cells also trigger spontaneous activation of splenic CD8 T cells, which rapidly up-regulate PD-1, Blimp-1 and LAG-3 and lose cytotoxicity along with IL-10 expression via interaction with PDL-1hi CD11c+ dendritic cells in T cell zones. Thus, CD11c+ dendritic cells from CD40LBTg mice exhibit regulatory phenotype, which block granzyme B expression and preferentially induce IL-10 expression in activated CD8 T cells. These results demonstrate that constitutive CD40 signaling on B cells under inflammation increases the risk of breaking peripheral CD8 T cell tolerance. However, the presence of CD40-activated B cells results in PDL-1hi CD11c+ dendritic cells, which exhibit a regulatory role to dampen harmful self-reactive cytotoxicity by promoting IL-10 expression in CD8 T cells.
Diagnostic utility of anti-cyclic citrullinated peptide antibodies in patients with early rheumatoid arthritis in the north of the country in Mexico. (159.18)
Authors: de la Cruz-Galicia Guadalupe , Malacara Mariana , Almanza Rolando , Silva-Belmares Sonia , Rosas-Taraco Adrián 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which primarily causes a symmetric polyarthritis, which can progress into long-term disability. The diagnosis of RA combines the patient history of joint pain and stiffness, laboratory tests including biomarkers that can provide useful information to confirm the diagnosis of RA. To compare the diagnostic utility of biomarkers to confirm the diagnosis of RA, anticyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were tested in patients with early diagnosis RA. We work with 49 patients with RA all fulfilling the revised criteria of the ACR, and healthy volunteers. A commercial ELISA assay kit was used to test for anti-CCP antibodies; RF and CRP were measured by turbidimetric immunoassays; ESR was performed by Wintrobe assay. The levels of anti-CCP antibody titers, and FR were significantly higher in patients with early RA (54 % and 35% respectively) than in healthy controls (p &lt;0.0001), however the 27% of patients were only positive to CCP test. No significant statistical correlation between anti-CCP antibody titers with inflammatory markers such as CRP or ESR was found. A positive predictive value was higher for anti-CCP antibodies in comparison to other markers.
A role for macrophage-derived AIM in humoral immune response and obesity-associated autoimmunity (159.2)
Authors: Arai Satoko , Miyazaki Toru 
Published: January 2023

Abstract
AIM (apoptosis inhibitor of macrophage), a member of scavenger receptor cysteine-rich super family (SRCR-SF), is a secreted protein solely produced by tissue macrophages with a direct regulation by a nuclear receptor liver X receptor/ retinoid X receptor (LXR/RXR) heterodimers. AIM circulates in blood at the concentration of 10-100 μg/mL in human. We have reported that AIM is involved in the metabolic syndromes such as atherosclerosis and insulin resistance, mediated by its functions: inhibition of apoptosis in macrophages and induction of lipolysis in adipocytes, respectively. It has been well-known that AIM binds to IgM in blood. However, its physiological significance has not been yet elucidated. In this study, we found that AIM-IgM complex intensely reinforces the stability of AIM protein in blood, and in the meantime, AIM supports the function of IgM. The AIM-IgM interaction enables the maturation of immunity, transition from innate-like immunity mediated by IgM, to adaptive immunity brought about by IgG. These new observations suggest that the modern life style, such as a continuous high-fat diet, may result in an excessive increase of AIM in blood, and appears to affect not only innate-like but also adaptive immunity by supporting the function of IgM. This may cause various disorders based on chronic inflammation including metabolic and autoimmune diseases.
IgM anti-DNA antibody and C1q Immune complexes regulate the production of Interferon-α in plasmacytoid dendritic cells (159.26)
Authors: Son Myoungsun , Diamond Betty 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to autoantigens, and to DNA in particular. Although Immune complexes (ICs) of IgG anti-DNA antibodies are pathogenic, IgM anti-DNA antibodies in SLE are protective. The mechanism responsible for the protective effect of IgM anti-DNA antibody is unclear. We found that a monoclonal IgM anti-DNA antibody cooperated with C1q to suppress interferon (IFN)-α production by plasmacytoid DCs (pDCs). We tested the effects of the antibody on bone marrow-derived pDCs from wild type (WT) and C1q knockout (KO) mice. Interestingly, the absence of C1q significantly enhanced the production of IFN-α induced by IgM anti-DNA antibody. The inhibitory effect of C1q was confirmed using in vivo generated pDCs or in vitro generated pDCs under serum-free conditions. Exogenous C1q suppressed IFN-α transcription in both WT and C1q KO pDCs. Moreover, we identified leukocyte-associated inhibitory receptor (LAIR)-1 as a potential receptor for C1q. Fluorescence labeled C1q strongly bound to pDCs which were highly expressing LAIR-1. LAIR-1 is a collagen receptor containing two ITIMs; its cross-linking with antibody inhibits IFN-a production by pDCs stimulated with DNA containing ICs. In summary, protective IgM anti-DNA antibody/C1q complexes inhibit unwanted IFN-α production through binding to LAIR-1.
The structure of rainbow trout IgM influences antibody-mediated phagocytosis of bacteria (160.16)
Authors: Bromage Erin , Kataria Priti , Ramirez-Gomez Fraancisco 
Published: January 2023

Abstract
The tetrameric IgM molecule is the dominant immunoglobulin found in the serum of fish. In contrast to the fully polymerized mammalian IgM, teleost IgM is variably disulfide cross-linked resulting in considerable structural diversity. Recently, it was revealed that following vaccination, rainbow trout alter the assembly of their antigen-specific IgM. It was hypothesized that these different IgM forms may allow this molecule to switch effector functions. To investigate whether there was a link between structure and function, we used serum with differing IgM structural profiles and evaluated their ability to mediate phagocytosis. We discovered that when IgM was fully disulfide cross-linked it increased phagocytosis of the antibody-opsonized bacteria. Conversely, when a larger percentage of the IgM was held together by electrostatic forces, phagocytosis was diminished. Control experiments proved that differences in antibody coating were not responsible for the differences in phagocytic potential of the antibody pools. Thus, rainbow trout IgM that is more heavily disulfide polymerized facilitates antibody-mediated phagocytosis more effectively. To our knowledge, this is the first time that IgM structural diversity has been demonstrated to affect a biological function critical for the protection against infectious disease.
Differential gene expression changes associated with sub-clinical Mycobacterium avium subsp. paratuberculosis infection in cattle: a transcriptomic study (160.2)
Authors: Purdie Auriol , Begg Douglas , de Silva Kumidika , Plain Karren , Whittington Richard 
Published: January 2023

Abstract
Paratuberculosis or Johne's disease is characterised by a lengthy sub-clinical phase that may persist for years prior to development of clinical disease. Mechanisms leading up to clinical disease are poorly understood although the early sub-clinical phase is reportedly characterised by a pro-inflammatory response largely driven by Th1 cytokines. The objectives of this study were to evaluate early gene expression changes in calves exposed to the causative agent, Mycobacterium avium subsp. paratuberculosis (MAP). Blood samples were drawn at three early time points, from a Johne’s field trial consisting of a mixed population of Holstein and Holstein Red cattle. Four MAP exposed and four unexposed control cattle were sampled at each time point and processed to Affymetrix GeneChip Bovine Arrays. Ontological analysis revealed a number of differences in gene expression between the two populations at the individual time points. In addition a subset of genes associated with the MHC were consistently altered across all MAP-exposed samples in comparison to the unexposed controls, suggesting significant changes to the antigen processing and presentation pathways in MAP-exposed animals. This differential regulation in response to MAP is a significant finding in the understanding of the mechanisms of pathogenesis and may lead to an aid to test for susceptibility.
Induction of pro-inflammatory cytokines by traditional and nano formulations of anti-cancer drug Paclitaxel (161.11)
Authors: Ilinskaya Anna , Dobrovolskaia Marina , McNeil Scott 
Published: January 2023

Abstract
Paclitaxel is a natural product with known anti-cancer activity. Paclitaxel is insoluble in water and requires the use of delivery vehicle. Historically two formulations of this drug were introduced into clinic: traditional, known as Taxol®, and more recently, nanotechnology-based, named Abraxane®. Several studies have reported that in murine macrophages Paclitaxel mimics endotoxin in induction of expression of several proinflammatory genes, and have suggested that Paclitaxel and endotoxin share the same receptor (TLR4) to initiate inflammatory signalling. These earlier studies utilized traditional formulation Taxol®. Nanotechnology offers many benefits to drug delivery such as reduction of drug toxicity, change in its biodistribution and controlled drug release. Clinical use of Abraxane® demonstrated decreased toxicity of this formulation as compared to that of Taxol®, however no study comparing cytokine induction profile of Paclitaxel in nano and traditional formulations has been reported so far. We have revisited this question and conducted an in vitro study evaluating induction of proinflammatory cytokines by traditional and nano formulations of Paclitaxel. Taxol®, but not Abraxane® resulted in induction of proinflammatory cytokines. This data was consistent between three cell culture models - whole blood, PBMC and MonoMac6 cell line. The mechanisms of cytokine induction by Taxol® will be discussed.
AP-1 and NF-κB regulate osteopontin gene expression in anti-CD40 treated B cells (161.16)
Authors: Dsilva Sehba , Hiroaki Kaku , Rothstein Thomas 
Published: January 2023

Abstract
Osteopontin (OPN) is a glycoprotein that is implicated in many physiological and pathological processes. Elevated levels of OPN are linked to autoimmunity and cancer and correlate with disease progression. In the immune system, macrophages, dendritic cells, T and B cells express OPN. The regulatory elements involved in B cell OPN expression are poorly understood. Our objective is to determine the regulatory elements critical for OPN expression in B cells. B cells express OPN when stimulated with anti-Ig post treatment with IL-4 or CD40L. To determine the regulatory elements, we made four overlapping OPN promoter-luciferase constructs extending from -2000bp to +80bp. We then transfected 1C10 (anti-CD40 antibody) treated and anti-Ig stimulated primary murine B cells with the OPN promoter constructs. We saw an increase in luciferase activity in the promoter construct containing binding sites for AP-1, Ets and Runx2. Significantly, mutagenesis of the AP-1 site abrogated this increase in luciferase activity. To investigate the role of NF-κB in OPN expression, we used an NF-κB inhibitor to evaluate OPN expression in B cells stimulated with anti-Ig post treatment with1C10. NF-κB inhibition reduced OPN transcript expression in these cells. In conclusion, preliminary data indicate that AP-1 and NF-κB play a role in OPN expression in anti-CD40 treated B cells.
Under Bcl-2 surveillance, cytokines, autophagy-dependently, induce p53-independent CD54 expression (161.4)
Authors: Wang Chi-Yun , Chiang Tzu-Hui , Chien Shun-Yi , Tseng Po-Chun , Yang Tsan-Tzu , Chuang Ji-Jui , Chen Chia-Ling , Lin Chiou-Feng 
Published: January 2023

Abstract
p53 is required for stress-induced CD54 expression; until now, its role has less investigated for IFN-γ- and TNF-α-induced such effects. However, IFN-γ caused CD54 expression in human non-small cell lung cancer A549 cells even with p53 silence, but controversially had no effects on H1299 and AS2 cells carried p53 mutation. To investigate the unexpected IFN-γ resistance, there was not as much of change on IFN-γ receptor expression among these cells; however, IFN-γ-activated Jak2/STAT1/IFN regulatory factor (IRF) 1 was decreased. Aberrant activation of Src homology domain-containing phosphatase (SHP) 2, but neither suppressor of cytokine signaling (SOCS) 1 nor SOCS3, was essential for IFN-γ resistance to decrease CD54. Notably, autophagy deficiency was shown in resistant cells and determined IFN-γ resistance accompanied by increasing mitochondria and reactive oxygen species. TNF-α also acted accordingly by autophagy to induce IκB degradation, NF-κB activation, and CD54 expression independent of p53. These results demonstrate that under Bcl-2 surveillance, IFN-γ and TNF-α induce p53-independent but autophagy-regulated CD54 expression.
Immunogenic Peptides Derived from the Transcription Factor ERG as a Vaccine for Prostate Cancer (162.17)
Authors: Kissick Haydn , Dunn Laura , Lu Bin , Sanda Martin , Arredouani M. Simo 
Published: January 2023

Abstract
The suitability of immunotherapy as a treatment for prostate cancer (PCa) has recently been demonstrated in a number of clinical trials. While these studies have provided a strong proof of principle, there is considerable room for improvement. One potential strategy is to identify new targets specific to PCa that could be immunized against and with this in mind, we have implemented an in silico-in vitro-in vivo¬ procedure for designing and assessing the suitability of MHC-I-restricted peptides as anti-PCa vaccines. In this study, we investigated peptides designed from ERG, a transcription factor expressed in around 50% of human PCa cases. We used in silico protein cleavage and peptide-binding algorithms to design HLA-A2.1 restricted peptides from the Erg protein. The binding of the in silico designed Erg peptides was then assessed in vitro and shown to bind HLA-A2.1 effectively. Additionally, when peptides were tested in vivo, they generated a strong immune response in humanized HLA-A2.1+ mice and overcame peripheral tolerance in prostate specific Erg expressing TRAMP-HLA-A2.1-ERG+ mice. Finally, it was found that a greater CD8+ T-cell recall response against human ERG+ PCa cell lines occurred in ERG immunized HLA-A2.1+ mice compared to controls. Together these data support the validity of our peptide design method and indicate that peptides derived from the overexpressed gene Erg could be used in an anti-PCa vaccine.
Breaking immune tolerance to prostate-associated tumor antigens through Tim-1 receptor (162.20)
Authors: Arredouani M. Simo , Kissick Haydn , Dunn Laura , Strom Terry , Sanda Martin 
Published: January 2023

Abstract
It has been suggested that one factor limiting cancer immunotherapy in clinical trials are immunological checkpoints that impede vaccine-induced anti-tumor responses. We postulate that manipulating lymphocytes and dendritic cells through the Tim-1 receptor, a membrane protein that regulates the vigor and differentiation of these cells, using an agonist monoclonal antibody could enhance cytotoxic lymphocyte (CTL) responses to prostate tumor-associated antigens. We used an approach that combines concomitant immunization against a model prostate tumor-associated antigen (TAA) SV40 Tag and treatment with an agonist anti-Tim1 antibody and assessed Tag-specific CTL responses two weeks later. Ab treatment of TRAMP mice resulted in elevated Tag-specific CTL in both spleen and prostate-draining lymph nodes, indicating that manipulating Tim1 results in circumventing immune tolerance to Tag antigen. We then tested this strategy for human epitopes derived from the prostate cancer-specific antigen ERG and SIM2 by combining anti-Tim1 antibody with an ERG- and SIM2-derived HLA-A2.1-restricted peptide vaccine in HLA-A2.1 transgenic mice and showed that CTL responses to ERG and SIM2 epitopes are elevated in the presence of anti-Tim1 Ab. Further characterization of lymphocyte differentiation post-immunization/anti-Tim1 treatment revealed that major shifts in T cell differentiation occur. Our findings suggest that targeting Tim1 could be successfully combined with prostate cancer vaccines.
Intraperitoneal immunization prevents autologous and non-autologous tumor growth on the omentum (162.22)
Authors: Sedlacek Abigail , Gerber Scott , Lord Edith 
Published: January 2023

Abstract
Tumor cell metastasis to the peritoneal cavity (PC) is a serious concern for many cancers, including ovarian and colon tumors. Upon introduction to the PC, tumor cells bind to the omentum, a tissue comprised of adipose embedded with organized immune aggregates (IA) thought to have regulatory function. Interestingly, it is to these IA that tumor cells initially bind and thrive. This presents a unique situation in which tumor cells are in close proximity to potential effector cells. However, without a stimulus to override their regulatory function, IA fail to control tumor growth. Thus, we attempted to stimulate a response by immunizing mice with a lethally irradiated colon adenocarcinoma cell line: Colon38 (C38). Our data demonstrates that i.p. immunization with C38 is capable of preventing growth of C38 upon live tumor challenge. Although T cells are necessary to generate this response, when CD8 or CD4 T cells were depleted during the effector phase, tumor growth was still controlled; suggesting T cells are not the effector cells. Interestingly, in mice immunized with C38 and challenged with another tumor cell line, E0771, tumor growth was also prevented. This non-specific response is unique to the PC, as mice that were immunized with C38 and challenged with E0771 by an alternate (i.m.) route developed tumors. Together, these data suggest that i.p. immunization results in T cell induction of an innate/non-specific anti-tumor response.
Therapeutic efficacy of a fully human anti-CD27 monoclonal antibody in a murine colon carcinoma model (162.23)
Authors: Forsberg Eric , He Li-Zhen , Borrelli Kathleen , Boyer James , Gergel Lauren , Pilsmaker Catherine , Round Sarah , Naylor Sarah , Hammond Russell , Marsh, Jr. Henry , Keler Tibor , Thomas Lawrence 
Published: January 2023

Abstract
The costimulatory molecule CD27 is constitutively expressed on the majority of mature T cells, memory B cells, and a portion of NK cells. The interaction of CD27 with its ligand CD70 plays an important role in effector capacity and memory in T cells; in clonal B cell expansion and germinal center formation; and in NK cell cytolytic activity. Agonistic anti-mouse CD27 mAbs have been shown to have potent anti-tumor activity. A panel of fully human antibodies recognizing human CD27 was generated and we have previously shown that our lead clone (1F5) can mediate anti-tumor effects using the BCL1 B-lymphoma line in human CD27-transgenic (hCD27-Tg) mice. In order to further investigate the mechanism of this anti-hCD27 monoclonal and its activity in a therapeutic setting we assessed anti-tumor activity using the CT26 murine colon carcinoma line. CT26 cells were delivered s.c. to hCD27-Tg animals and five doses of 1F5 were delivered to mice i.p. beginning on days 3, 5, or 7. In multiple experiments, tumor growth in mice treated with 1F5 was substantially delayed or prevented compared to that of control-treated mice. When 1F5-treated surviving mice were rechallenged with CT26 cells, without additional anti-CD27 antibody treatment, tumors did not grow in most animals. These data support the continued clinical development of this anti-CD27 mAb to enhance immune responses in cancer therapy. Investigations of immune cell subset depletions and combination therapies are ongoing.