bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of differentiation of hematopoietic cells by the vaccine adjuvants (75.10)
Authors: Yang Ya-Wun , Chang Chih-Feng 
Published: January 2023

Abstract
Vaccine adjuvants have been used to enhance the immune responses against the co-administered antigens. The mechanisms of action by the adjuvants however remain poorly understood. We attempt to investigate in this study the effect of vaccine adjuvants on differentiation of the hematopoietic system. C57BL/6J mice were vaccinated with ovalbumin (OVA) in L121-adjuvant, an emulsion adjuvant consists of Pluronic L121 that previously shown to stimulate cytotoxic lymphocyte (CTL) effect. Cells were isolated from bone marrow and thymus after vaccination, followed by flow cytometric analysis. Our data showed that treatment of animals with L121-adjuvant skewed the differentiation of hematopoietic cells, resulting in a significant increase of the CD11b+ population at the expense of lineage (lin)+ cells, attributing mainly to a dramatic reduction of the B220+ population. A considerable increase of Lin-/Sca1+/c-Kit+ (LSK) hematopoietic stem/progenitor cells was observed in the bone marrow of immunized mice, suggesting an induction of enhanced cell expansion by the vaccine adjuvant. Treatment of animals with L121-adjuvant also affects the differentiation of cells in the thymus with a decrease of the CD4+/CD8+ double-positive (DP) cells, and a concurrent increase of the CD4+ and CD8+ single positive (SP) populations. These experimental results suggested the differentiation effect of vaccine adjuvants on the hematopoietic system, accounting for the enhanced immunity after immunization.
Human recombinant lactoferrin as a new adjuvant in specific DNA vaccination against ErbB2 (75.2)
Authors: Spadaro Michela , Casule Gabriele , Montone Monica , Merighi Irene , Pericle Federica , Cavallo Federica 
Published: January 2023

Abstract
Lactoferrin triggers several innate immunity mechanisms. Repeated oral administrations of a recombinant human lactoferrin (Talactoferrin, TLF, Agennix, Houston, TX) hamper the growth of both transplantable tumors and autochthonous mammary carcinomas arising in BALB/c mice transgenic for the rat ErbB2 oncogene (BALB-neuT mice). To evaluate the mechanisms that delay the tumor growth and enhance the immune response elicited by a DNA vaccine against rat ErbB2 oncogene, BALB-neuT mice received by gavage PBS or TLF (1 g/kg) once daily, 5 days per week, 3 weeks on and 1 week rest for seven cycles. Following oral TLF we observed: decrease of serum IL4 and IL5; increase of serum IL12 and IFNγ; decrease of immature myeloid cells in tumor draining lymph nodes. When BALB-neuT mice receiving oral TLF were vaccinated with 50 µg of DNA plasmid coding for the extracellular and transmembrane domain of rat ErbB2 we found: extended tumor-free survivals; increased overall survivals; decrease in the number of tumors/mouse; higher titers of vaccine-induced anti-ErbB2 antibodies; similar cytotoxicity activities against ErbB2+ tumors. These findings suggest that TLF is an interesting new adjuvant in DNA vaccination against ErbB2.
Exosomes loaded with α-galactosylceramide amplify antitumor immunity via iNKT cells (75.5)
Authors: Gabrielsson Susanne , Gehrmann Ulf , Hiltbrunner Stefanie , Karlsson Mikael , Näslund Tanja 
Published: January 2023

Abstract
Exosomes are nanosized membrane vesicles with endosomal origin that can be isolated from a variety of cell types and serve as means of communication between cells. Dendritic cell (DC) derived exosomes can induce adaptive, as well as innate immune responses and have been tested as therapeutic agents in cancer. Here, we investigated whether exosomes can be loaded with the iNKT cell activating ligand α-galactosylceramide (αGC) and whether exosomes loaded with both αGC and the protein antigen ovalbumin (OVA) could amplify both innate and adaptive immune responses. We show that DC-derived exosomes express CD1d and that αGC-loaded exosomes (Exo-αGC) activate iNKT cells in vitro in a CD1d-dependent manner. In vivo, αGC- and OVA-loaded exosomes (Exo(αGC-OVA)) induced NK cell and γδ T cell responses secondary to iNKT cell activation and increased anti-OVA T and B cell responses. Moreover, treatment of tumor-bearing mice with Exo(αGC-OVA) slowed down tumor growth and led to immune cell infiltration into tumor tissue in a OVA-expressing mouse melanoma model. Our results show that activation of iNKT cells by exosomes amplifies both innate and adaptive immune responses in a way that might be beneficial for cancer immunotherapy.
Scavenger Receptor, SRECI activates dsRNA-mediated TLR3 innate immune responses (76.1)
Authors: Murshid Ayesha , Gong Jianlin , Calderwood Stuart 
Published: January 2023

Abstract
SRECI is a scavenger receptor expressed by immune cells and has a role in CD8+ T cell immunity. SRECI can also modulate the function of Toll like receptors which have essential roles in innate immunity. Here we show that SRECI enhances double stranded RNA (dsRNA)-mediated Toll like receptor-3 (TLR3) activation. Viral double stranded RNA (dsRNA) is a pathogen associated molecular pattern (PAMP) indicating viral infection. We found that human monocyte/macrophage THP1 cells as well as bone marrow derived macrophages from mice exhibited increased responses to polyinosine-polycytidylic acid (PolyI:C) and enhanced production of inflammatory cytokines with overexpressed SRECI. Our data also show that intracellular/endocytic TLR3 can directly interact with SRECI in the presence of Poly I:C. Internalized ligand along with TLR3 co-localize in the endosomes of macrophages and TLR3-expressing Hek293 cells. In the absence of Poly I:C there was no such co-localization between these two receptors. We also found that SRECI can stimulate dsRNA mediated TLR3 activation of downstream signaling via NFkB, MAPK and IRF3 molecules which lead to the activation of inflammatory cytokines. We also hypothesize that SRECI is a cell surface receptor capable of internalizing Poly I:C as well as activating TLR3 mediated downstream cytokine production in macrophages.
B cells in primitive vertebrate act as pivotal antigen presenting cells in priming adaptive immunity (P5035)
Authors: Zhu Lv-yun , Nie Li , Shao Tong , Dong Wei-ren , Xiang Li-xin , Shao Jian-zhong 
Published: January 2023

Abstract
The long-held paradigm that B cells are unable to phagocyte large particles has been broken by a new discovery that teleost B cells have potent phagocytic and microbicidal abilities. This finding provides preliminary clues that B cells in primitive vertebrates might act as pivotal antigen presenting cells (APCs) in priming adaptive immunity. In this study, we provide evidence for this suggestion in zebrafish model. By in vitro antigen presentation and in vivo adoptive transfer assays, we found that zebrafish B cells have potent capacity to present both soluble and particulate antigens to prime naive CD4+ T cells. The CD86 and CD83 co-stimulatory molecules were identified to be essential for this process. Besides, IL-4 was found to be able to dramatically promote the B cell-mediated CD4+ T cell priming by up-regulating the expression of CD86, CD83 and MHC II molecules on B cells. Our results suggest that B cells in primitive vertebrates were important professional APCs for the initiation of adaptive immunity, whose functional characterization resembles the dendritic cells (DCs). The CD86 and CD83 were two ancient co-stimulatory molecules originating from teleost fish, whose regulatory functions were conserved from fish to mammals throughout vertebrate evolution. These results benefit to the better understanding of the evolutionary history of B subsets such as the origin of B1 cells, as well as the origin of immune-regulatory signaling networks in adaptive immunity.
Enhancement of antigen presenting ability in the leukemic plasmacytoid dendritic cell line (PMDC05) by lentiviral vector-mediated transduction of CD80 gene (P5059)
Authors: Takahashi Masuhiro , Yamahira Akie , Iwabuchi Minami , Satoh Naoya , Uchiyama Takayoshi , Hashimoto Shigeo , Bogan Brooke , Faure Emmanuelle , Kasahara Noriyuki , Narita Miwako 
Published: January 2023

Abstract
[Aim] PMDC05, a leukemic plasmacytoid dendritic cell (pDC) line which was established from CD4+CD56+ leukemia cells in our laboratory, showed a capacity of generating antigen-specific cytotoxic T lymphocytes (CTLs). In order to enhance an antigen presenting ability of PMDC05, PMDC05 was transduced with CD80 gene by lentiviral vector, which was named as PMDC11. We investigated whether PMDC11 could enhance allogeneic T cell response. [Materials and Methods] Surface antigen presentation-associated molecules and antigen presenting ability were analyzed in PMDC05 and PMDC11 with or without stimulation by phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore (CI) by flow cytometry or mixed leukocyte culture (MLC). [Results] CD80 gene transduction induced a definite up-regulation of CD1a and HLA-DR in addition to CD80. In original PMDC05 cells, which had antigen presenting ability without any stimulation, PMA/CI could enhance the ability significantly. PMDC11 cells without stimulation had an antigen presenting ability equivalent to PMA/CI-stimulated PMDC05. Measurement of IFN-γ in supernatant of MLC demonstrated that PMDC11 stimulated allogeneic lymphocyte to produce much more IFN-γ compared with PMDC05. [Conclusion] Our data suggested PMDC11 cells, which were established by transducing CD80 gene into PMDC05 cells, could be efficiently applied as antigen presenting cells in adoptive cellular immunotherapy for tumors and severe infections.
Metformin reduces gene expression of adipogenesis and inflammatory cytokines through the modulation of T cell priming in obese-induced Type II diabetic mice (P5063)
Authors: Shin Seulmee , Hyun Bobae , Lee Aeri , Lee Sungwon , Kong Hyunseok , Han Shinha , Song Youngcheon , Kim Kyungjae 
Published: January 2023

Abstract
Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals where obese adipose tissue shows features characteristic of active local inflammation. Metformin is a biguanide derivative used in the treatment of T2D and one of the world's most widely prescribed drugs and have been suggested that metformin has anti-inflammatory properties. Here we show that metformin efficiently attenuates the metabolic disorder in DIO mice and suppresses MHC-restricted antigen presentation in dendritic cells. This study was to investigate the therapeutic effect of metformin on diabetic symptoms in DIO mice. Metformin decreased aipogenesis related gene, FAS, SCD-1, GPAT, SREBP1a, but also suppressed gene expression of innate cytokines than control mice. Metformin decreased both class I- and class II-restricted presentation of exogenous OVA in dendritic cells. Metformin also decreased expression of the co-stimulatory molecules, ICAM-1 and B7-1/-2, and MHC class I and II molecules but not phagocytic activity of DCs. Metformin decreased MHC class II-restricted exogenous antigen presentation in peritoneal macrophages in vivo. These results show that metformin attenuates immune responses followed by decreases MHC-restricted presentation of exogenous antigen in DCs via intracellular processing events. Theses finding suggest that modulation of the antigen presentation pathway could provide a novel means for regulating T cell responses in metabolic diseases.
Analysis of HLA-DQ protein and peptide interaction in association to auto-immune mechanism of narcolepsy. (P5069)
Authors: Sophia Hsuan-Jung Chen , Hiroko Miyadera , Katsushi Tokunaga 
Published: January 2023

Abstract
Human narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and abnormalities of rapid eye movement (REM). Strong HLA class II association was determined where the narcoleptic individuals of diverse ethnic backgrounds share a specific HLA class II haplotype, DQA1*01:02-DQB1*06:02. It has been also reported that hypocretin in the CSF of narcoleptic patients are significantly decreased and that hypocretin producing cells are disrupted in patients’ brain. We hypothesized that hypocretin or other proteins specifically expressed in hypocretin producing cells in the hypothalamus, are presented by HLA-DQA1*01:02-DQB1*06:02, and induce activation of self-reactive T cells. To analyze the peptide-binding reperitore of HLA-DQA1*01:02-DQB1*06:02, we transduced murine fibroblast cells with HLA-DQA1*01:02-DQB1*06:02 (suscceptible), DQA1*01:03-DQB1*06:01 (resistant), DQA1*01:03-DQB1*06:03 (resistant), and DQA1*01:02-DQB1*06:04 (neutral) alleles by retrovirus-vectors and confirmed stable DQ proteins expression. Using these cell lysates we analyzed binding affinity of synthetic peptides designed for hypocretin-A, -B, and other proteins expressed in hypocretin producing cells.
Analysis of HLA-DR protein and peptide interaction in association to type 1 diabetes in Japanese. (P5071)
Authors: Chen Cindy Chia-Jung , Miyadera Hiroko , Tokunaga Katsushi 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disorder that mediates destruction of insulin-producing pancreatic cells. Previous genetic association studies reported HLA II to be the major factor for increased susceptibility to T1D. Yet, knowledge remained limited on disease mechanism in Japanese. The purpose of current study is to elucidate immunological mechanism of risk and protective alleles and to determine the peptide binding repertoire of T1D susceptible DR alleles in the Japanese for Zinc Transporter 8 (ZnT8), one of the established auto-antigenic peptides. We expressed DR9 (DRA*01:01-DRB1*09:01), DR4(DRA*01:01-DRB1*04:05), DR8 (DRA*01:01-DRB1*08:02) contributing to susceptibility to T1D in the Japanese and DR15 (DRA1*01:01-DRB1*15:01) that are associated with protection in mammalian cells. A plate based peptide binding assay system was established using nickel coated microtiter plates to measure the binding of synthetic peptides to recombinant DR proteins. Established DR9 binding motif was searched in ZnT8 sequences. Binding characteristics of risk and protective DR allele products including DR9 are examined in utilization of a 20mer ZnT8 peptide library.
Lysosomal transporter SLC15A4 regulates Toll like receptor 7/9-mediated antibody production (P4195)
Authors: Kobayashi Toshihiko , Toyama-Sorimachi Noriko 
Published: January 2023

Abstract
Solute Carrier family (SLC) 15A4 is known to be a proton-coupled transporter expressed by the immune and nervous systems, specifically carrying free histidine and certain di- or tri-peptides. Previous studies reported that SLC15A4 gene is associated with the autoimmune disorders such as inflammatory bowel diseases and systemic lupus erythematosus. However, the precise mechanism of how this transporter contributes to pathogenesis of these diseases remains unclear. We have investigated the functional involvement of SLC15A4 in the innate immune system, as this transporter is highly expressed in innate immune cells, and is known to reside on the lysosomal membranes. We previously reported that SLC15A4 plays crucial roles in TLR9- and NOD1-mediated cytokine production in dendritic cells (DCs). Here we show that SLC15A4 is also important for TLR7-triggered immune responses not only in DCs but also in B cells. We found that SLC15A4 is also expressed in B cells, and activation of naïve SLC15A4-deficient B cells was attenuated when triggered by TLR7 or TLR9 ligand, showing impaired IFN-beta or IL-6 production. Moreover, SLC15A4-deficient B cells failed to produce IgG2c antibody in vitro and in vivo. Although further investigation is necessary to understand the precise mechanism, our findings suggest that TLR7 or 9 activity, such as antibody production could be regulated in lysosomes by SLC15A4.
Interferon regulatory factor 8 deficiency causes phenotypic and functional changes in myeloid cells inside and outside the CNS (P4145)
Authors: Campbell Iain , Terry Rachael , Xie Rui Dan , Almolda Beatriz , Villacampa Nàdia , Minten Carsten , King Nicholas , Gonzalez Berta , Castellano Bernardo 
Published: January 2023

Abstract
We identified IRF8 as a constitutive and IFN-γ-stimulated nuclear factor in microglia of the CNS. IRF8 is a transcription factor with a key role in the cellular response to IFN-γ but is also pivotal in myeloid cell differentiation. Here we employed IRF8 KO mice to determine the role of IRF8 in microglial development and function in the healthy CNS and in the microglial response to injury (facial nerve axotomy [FNA]) or infection (West Nile Virus [WNV] encephalitis). Microglia were present in the CNS of IRF8 KO mice but showed altered morphology and significantly reduced surface area and had alterations in a number of key markers including reduced levels of Iba1, CCR2 and CCR5 but increased levels tomato lectin binding. Following FNA the microglial response was markedly delayed and attenuated in IRF8 KO mice and the wrapping of motor neuron cell bodies by microglia involved in synaptic stripping and phagocytosis was incomplete. Finally, IRF8 KO mice had increased susceptibility to WNV accompanied by a marked reduction in both microglial cell activation and leukocyte accumulation in the brain. In the periphery, ly6Cint monocytes were increased in number but exhibited defective trafficking to the infected CNS while ly6Chi monocytes were almost completely absent. In conclusion: (1) IRF8 is a major intrinsic determinant of the microglial phenotype in the healthy and the diseased CNS, and (2) IRF8 has a crucial role in the development and trafficking of inflammatory monocytes.
The regulation of plasma cell function through soluble mediators of the CD28/B7 pathway (P1005)
Authors: Holthausen David , Njau Modesta , Jacob Joshy 
Published: January 2023

Abstract
CD28 is the secondary co-stimulatory molecule that is crucial for optimal activation of naïve T cells and their differentiation into effector T cells. Activation of T cells without co-stimulation, renders the cells anergic. The influence of CD28 is not limited solely to T cells. CD28 as well as its ligand B7.1/2 are found on short- and long-lived plasma cells. We have demonstrated that signaling via CD28 acts as a negative regulator of plasma cell function. The removal of the CD28 signal leads to a hyperactive plasma cell state, with enhanced longevity, and increased antibody production in individual plasma cells. Interestingly, soluble forms of CD28, B7 and CTLA-4, are seen in the sera of patients with chronic human diseases, including autoimmunity, allergic asthma, and chronic hepatitis. We hypothesize that soluble CD28/B7 mediators will transiently block the CD28/B7 interaction on plasma cells and enhance autoantibody production. The research presented will compare the appearance and time course of the soluble mediators in mouse models of chronic and acute disease.
A lamprey monoclonal VLR antibody recognizes a novel plasma cell antigen (P3020)
Authors: Yu Cuiling , Herrin Brantley , Jaye David , Cooper Max , Ehrhardt Götz 
Published: January 2023

Abstract
Variable lymphocyte receptor B (VLRB) antibodies of the jawless sea lamprey are composed of leucine-rich repeat (LRR) units instead of the Ig-based units of conventional mammalian antibodies. Structural analyses of three monoclonal VLRB antibodies paired with their cognate antigens indicate that antigens bind to variable residues in the beta-sheets located on the inner concave surface of the solenoid VLRB protein and to a flexible loop structure protruding from the C-terminal LRR. We recently demonstrated that VLRB antibodies can be used in standard laboratory techniques such as flow immunocytometry, western blotting, immunoprecipitation and mass spectrometry-based protein identification. In an effort to identify novel biomarkers on human plasma cells, we screened a VLRB library generated from lamprey larvae immunized with human bone marrow of multiple myeloma patient and isolated a monoclonal VLRB antibody (MM3) that selectively recognized plasma cells from myeloma patients, normal individuals and two non-human primates, Rhesus macaque and Sooty mangabey monkeys. Surprisingly, screening of a diverse panel of human cell lines indicated expression of the MM3 antigen by two of nine B cell lines, but not by plasmacytoma cell lines. Trypsin and periodate sensitivity of the MM3 epitope suggested the glycoprotein nature of the cell membrane antigen. We conclude that the recombinant VLR MM3 antibody recognizes a novel plasma cell marker.
Polymorphisms of the transforming growth factor-beta 1 gene in relation to idiopathic recurrent miscarriage (P6248)
Authors: Almawi Wassim , Finan Ramzi , Al-Zaman Intissar , Mustafa Fekria 
Published: January 2023

Abstract
Transforming growth factor, β1 (TGFB1) plays a significant role in the pregnancy outcome. We investigated the association of TGFB1 exon 1 (rs1800471, rs1800470) and promoter region (rs1800469, rs1800468) polymorphisms with recurrent pregnancy loss (RPL) in 675 Tunisian women: 304 women with a history of three consecutive pregnancy loss of unknown etiology with the same partner, and 371 age-matched multiparous control women. TGFB1 genotyping was done by TaqMan assays. Higher minor allele frequency (MAF) for rs1800471 (i.e. +915G/C or R25P) (P &lt; 0.001), but not for rs1800470, rs1800469, or rs1800468 was found in cases compared to controls. Significant difference in the distribution of rs1800471 genotypes was seen between RPL cases and control women, irrespective of the genetic model used. Increased RPL risk was seen with rs1800471 allele C in both heterozygous and even more so in the homozygous state, thus establishing a dose-dependent effect. Haploview analysis revealed differential linkage disequilibrium between TGFB1 SNPs analyzed. TGFB1 haplotypes analysis identified 8 common haplotypes (rs1800471/rs1800470/rs1800469/rs1800468) with three (GTTG, Pc = 0.014; CCTG, Pc = 0.003, and CTCG, Pc = 0.01) being positively associated with RPL, while one (GCCG, Pc = 0.009) was negatively associated with RPL. This study provides the first evidence that TGFB1 genotype is possibly associated with RPL.
ATF4 is induced by ROS and regulates Th1 and Th17 cells (P6219)
Authors: Yang Xi , Gao Xin , Zhu Yibei , Li Gang , Zhang Xueguang , Xiao Guozhi , Cao Huiling , Chen Xinchun , Yang Qianting , Lu Binfeng 
Published: January 2023

Abstract
Reactive oxygen species (ROS) play a major role in the pathogenesis of chronic inflammatory and autoimmune diseases. It is well established that ROS modulate T cell-mediated immune responses. However, little is known about underlying molecular mechanisms of how ROS regulate T cell immune responses and how T cells adapt to high levels of ROS. We demonstrated that ROS induced ATF4 in activated T cells. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates cellular redox state and amino acid metabolism. We found that, in the high ROS condition, ATF4-/- Th1 cells failed to produce IFN-γ whereas WT Th1 cells still made large amounts of IFN-γ. Inhibition of ROS by addition of antioxidants recovered the IFN-γ production by ATF4-/- Th1 cells, suggesting ATF4 is critically required for the function of Th1 cells in the presence of high levels of ROS. ATF4-/- antigen presenting cells (APC) promoted IL-17 production, suggesting ATF4 plays an important role in APCs in suppressing Th17-driving cytokines. In addition, we demonstrated that experimental allergic encephalomyelitis (EAE) was exacerbated in ATF4 deficient mice compared with wild type (WT) mice. The number of autoreactive Th1 cells was decreased whereas that of autoreactive Th17 cells was elevated in ATF4-/- mice compared with WT mice. Our study establishes that ATF4 promotes Th1 and suppresses Th17 immune responses and likely plays an important role in autoimmunity and cancer immunology.