bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of T cell response by Japanese encephalitis virus: a mechanism of immune evasion (VIR5P.1019)
Authors: Cui Min , Yuan Jiaolong , Wang Chong , Zhang Nan , Wang Ke , Wang Kunlun , Hu Pingdong , Lin Xianwu , Yang Hong , Fu Zhenfang 
Published: January 2023

Abstract
Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus, which can escape from the peripheral immune response resulting in serious neuroinflammation. However, the mechanism of JEV immune evasion still remains unclear. In our study, it was found that co-inhibitory molecules CD279 (PD-1) and CD272 (BTLA) were upregulated on T cells in JEV infected mouse. The increase of CD279 on CD8+ T cells was more obvious than on CD4+ T cells in the early stage of infection. The expression of CD274 (PD-1 ligand 1) was also upregulated on dendritic cells and macrophages accordingly. As a consequence, both CD4+ and CD8+ T cell population dramatically decreased in the early stage of infection. Moreover, the CD4+CD25+FoxP3+ regulatory T cells (Tregs) increased in the peripheral immune organs after JEV infection. Splenic Foxp3+ Treg cells kept expanding during the disease pregression; instead, in the blood, Tregs only increased in the early stage. IL-10, which indicating the immunosuppression, also dramatically increased in the same location. Collectively, our data suggest that there are four strategies involved in the JEV mediated immune evasion: upregulating the co-inhibitory molecules on T cells and APCs, inducing T cell apoptosis, expanding the Treg cells, and producing inhibitory cytokines. As a consequence, JEV escapes the immune surveillance and causes fatal CNS infection.
Distinct roles of IFNβ and IFNγ in the production of proinflammatory and antiinflammatory cytokines in bone marrow-derived dendritic cells (BA12P.109)
Authors: Yen Jui-Hung , Kong Weimin , Hooper Kirsten , Kuo Ping-Chang , Ganea Doina 
Published: January 2023

Abstract
IFNβ and IFNγ play distinct roles in MS/EAE. IFNγ exacerbates whereas IFNβ ameliorates the disease of EAE. Dendritic cells (DC) paly a sentinel role in the immune system, and are recruited to the CNS to restimulate encephalitogenic T cells during the course of EAE. We investigate how DC are regulated differently by IFNβ and IFNγ on the production of proinflammatory cytokines IL-12 and IL-23 and of antiinflammatory cytokine IL-10. Moreover, the molecular mechanisms of IFNβ and IFNγ-mediated regulatory effects are also investigated. Our results show IFNβ inhibited the production of IL-12 and IL-23, whereas enhanced the production of IL-10 in activated DC. Although both IFNβ and IFNγ inhibited IL-23 production, IFNγ enhanced IL-12 but suppressed IL-10 production. IFNγ-induced STAT-1/IRF-1 activation is required for IL-12 upregulation and IL-23 downregulation. Although STAT-1 activation is responsible for IFNγ-mediated IL-10 downregulation, IRF-1 activation is not involved in STAT-1-mediated IL-10 downregulation. Similar to IFNγ, IFNβ induced STAT-1 activation to suppress IL-23 production, however, the effect is independent of IRF-1 activation. IFNβ-induced Akt activation and GSK3β inactivation might be responsible for IL-12 downregulation and IL-10 upregulation as GSK3β activation is linked to inflammatory responses. In conclusion, our results provide the molecular mechanisms by which IFNβ and IFNγ utilize distinct signaling pathways to regulate the cytokine productions in DCs.
Differential expression of the transcription factor ARID3a in lupus patient hematopoietic progenitors may affect function (BA12P.101)
Authors: Ratliff Michelle , Ward Julie , James Judith , Webb Carol 
Published: January 2023

Abstract
Autologous hematopoietic stem cell (HSC) transplants have been used for severe cases of autoimmune disease, but success rates for systemic lupus erythrematosus (SLE) patients are less than for other autoimmune diseases. We recently found &gt;40% of SLE patients had increased numbers of peripheral B lymphocytes that express the DNA-binding protein ARID3a, and that numbers of ARID3a+ B cells were associated with increased disease activity. Because ARID3a is also expressed in HSCs, we queried if SLE CD34+ cells abnormally express ARID3a. Indeed, nearly 40% of SLE patients had increased numbers of CD34+ cells with higher expression of ARID3a compared to healthy controls. Progenitors with increased ARID3a expression showed enhanced proliferation in vitro relative to other SLE cultures, and those progenitors generated increased numbers of cells that retained CD34 expression. We hypothesize that variation in ARID3a expression in hematopoietic progenitors contributes to variability in engraftment and are testing that hypothesis using humanized mice. Together, these data suggest new functions for ARID3a in HSCs and autoimmunity.
The autoantibody-inducing CD4 T cell (aiCD4 T cell) causing to systemic lupus erythematosus (SLE) belongs to PD-1+CD45RBlo122lo CD4 subpopulation (BA13P.121)
Authors: Miyazaki Yumi , Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We have shown that repeated immunization of mice with antigen reproducibly led to development of SLE, in which a novel T cell type which we term an autoantibody-inducing CD4 T (aiCD4 T) cell was generated via TCR revision at periphery. The aiCD4 T cell induces varieties of autoantibodies and also helps full maturation of CTL to induce lupus tissue injuries. We further showed that aiCD4 T cell seemed to belong to CD45RBlo122lo CD4 T subpopulation. We are trying to assign CD number on this aiCD4 T cell in more detail. Methods: BALB/c mice were repeatedly immunized with OVA. To investigate gene expression profiles of aiCD4 T cell, we performed microarray analysis of CD45RBlo122lo CD4 T cell after immunization 12x with OVA. CD45RBlo122lo CD4 T cells were isolated referring to programmed cell death 1 (PD-1) expression, and these fractionated cells were adoptively transferred into naïve recipients. Autoantibodies in sera of recipient mice were measured 2 weeks after cell transfer. Results: Under microarray analysis, we found that gene expression of PD-1 was increased x2 in the CD45RBlo122lo CD4 subset. Simultaneously, surface expression of PD-1 protein was also significantly increased in this subset. Adoptive cell transfer of PD-1+CD45RBlo122lo CD4 T cells from 12x immunized mice significantly increased both RF and anti-dsDNA antibody in the naïve recipients. Conclusion: The aiCD4 T cell that induces SLE belongs to PD-1+CD45RBlo122lo CD4 subpopulation.
Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells (BA13P.122)
Authors: Huang Wenting , Kachapati Kritika , Adams David , Wu Yuehong , Leung Patrick , Yang Guo-Xiang , Zhang Weici , Ansari Aftab , Flavell Richard , Gershwin Merrill , Ridgway William 
Published: January 2023

Abstract
Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. Early immunological events in PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells alone transfer biliary disease. Herein we report significantly increased numbers of hepatic terminally differentiated (KLRG1+) CD8 T cells in dnTGFβRII compared to B6; these cells are the major cytotoxic CD8 subset. Unexpectedly, the disease is not simply CD8 T cell intrinsic since mixed bone marrow chimeric mice were protected from biliary disease. Adoptive transfer studies showed that co-transfer of B6 but not dnTGFβRII Tregs prevented dnTGFβRII CD8 T cell mediated cholangitis; the protection was associated with decreased numbers of hepatic KLRG1+ CD8 T cells and with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. DnTGFβRII Treg cells were inferior in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In conclusion, these results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, which has important implications for understanding the early pathogenesis of human PBC.
MAPK/ERK-dependent TCR signaling induces ADAM17-mediated processing of TNFR2 by CD8+ T cells (CCR5P.249)
Authors: DeBerge Matthew , Ely Kenneth , Enelow Richard 
Published: January 2023

Abstract
Elevated levels of soluble TNF receptor 2 (sTNFR2) are observed in a variety of human pathophysiological conditions. Following influenza infection in mice, we found that sTNFR2 levels were elevated in both the serum and airways. As the levels of sTNFR2 in the airways correlated with the CD8+ T-cell response, we were interested in the cellular mechanisms by which CD8+ T cells regulate TNFR2 processing. We found that effector CD8+ T cells express TNFR2 on the cell surface and constitutively release sTNFR2. Activation of the cells by TCR stimulation resulted in a temporary increase in processing of TNFR2. This activation-induced increase required both actin remodeling and lipid raft formation and was dependent on MAPK/ERK signaling. Furthermore, we identified ADAM17 as the protease responsible for TNFR2 processing by CD8+ T cells. Inhibition of ADAM17 resulted in an interaction of both membrane-bound TNF-α and TNFR2 on the CD8+ T-cell surface. Moreover, we observed similar activation thresholds for both TNF-α and TNFR2 processing suggesting that sTNFR2 is important for regulation of sTNF-α levels. Furthermore, genetic deletion or in vivo antibody blockade of TNFR2 during influenza infection in mice enhanced the levels of sTNF-α supporting this hypothesis. Taken together, this study elucidates some of the cellular mechanisms regulating TNFR2 processing and demonstrates that TNFR2 plays an important role in regulating TNF-α levels during infection.
Identification of Fli-1 as a novel regulator of the inflammatory chemokine CCL5/RANTES (CCR5P.253)
Authors: Lennard Richard Mara , Sato Shuzo , Suzuki Eiji , Williams Sarah , Nowling Tamara , Zhang Xian 
Published: January 2023

Abstract
The Fli-1 transcription factor is implicated in the pathogenesis of systemic lupus erythematosus (SLE) in both human patients and murine models of lupus. Lupus-prone mice with reduced Fli-1 expression have significantly less nephritis, prolonged survival and significantly decreased infiltrating inflammatory cells into the kidney. The chemokine, CCL5, attracts inflammatory cells and expression is increased in patients with SLE. In this study, decreased expression of CCL5 mRNA was observed in kidneys of NZM2410 mice with reduced Fli-1 expression. CCL5 protein expression was significantly impaired in endothelial cells treated with Fli-1 specific siRNA compared to controls. Fli-1 binds to Ets binding sites in the CCL5 promoter and transfection assays show that Fli-1 drives transcription in a dose-dependent manner. Mutation of the Fli-1 DNA binding domain demonstrates that activation of the CCL5 promoter is through direct binding by Fli-1. Ets1 also drives transcription from the CCL5 promoter, although Fli-1 driven transactivation is significantly stronger. The Ets1 transcription factor acts as a dominant negative to Fli-1, indicating that the genes may share a DNA binding site. Fli-1 is a novel regulator of CCL5 gene transcription. Combined with previous results, demonstrating that Fli-1 regulates MCP-1, we conclude that Fli-1 is a critical regulator of proinflammatory chemokines and affects disease pathogenesis by regulating factors involved inflammatory cell recruitment.
Essential role of IL-17 in renal damage associated with autoimmune glomerulonephritis (CCR6P.279)
Authors: Ramani Kritika , Pawaria Sudesh , Maers Kelly , Biswas Partha 
Published: January 2023

Abstract
Autoimmune Glomerulonephritis results in significant mortality and morbidity in numerous auto-inflammatory kidney diseases. The chronic inflammatory state is considered to be a driving force for AGN. In recent years the IL-23/Th17 axis appears to contribute to the pathogenesis of human and experimental AGN. However, the role of IL-17 receptor signaling in renal pathology associated with AGN is poorly defined. Here, using a murine model of accelerated experimental autoimmune glomerulonephritis, we showed that IL-17RA signaling is critical for the development of renal pathology and inflammatory changes in the kidney. Consequently, mice deficient in IL-17RA signaling exhibited diminished renal inflammation and infiltration of the innate effector cells in the kidney, correlating with the reduced expression of IL-17 responsive genes. IL-17 enhanced the production of proinflammatory cytokines and chemokines from tubular epithelial cells, which are implicated in the recruitment of innate effector cells in the kidney. Finally, neutralization of IL-17A ameliorated renal pathology in wild type mice following aEAGN induction. These results clearly demonstrated that IL-17RA signaling significantly contributes to renal tissue injury in AGN and suggest that blocking IL-17RA may be a promising therapeutic strategy for the treatment of proliferative and crescentic glomerulonephritis.
Heat shock protein 90 involves IL-17-mediated skin inflammation under thermal stimuli (CCR6P.280)
Authors: Woo So-Youn , Kim Bo Kyung , Park Minhwa , Kim Ji-Yon , Cho Kyung-Ah , Lee Kyung Ho 
Published: January 2023

Abstract
The pathogenesis of inflammatory skin disease involves an interaction between immune cells and keratinocytes and Th17-mediated immune response is one of them. Several chemokines (CXCL1, CXCL5, and CXCL8) and antimicrobial peptides (β-defensin [BD1], LL37, S100A8 and S100A9) were transcriptionally upregulated in keratinocyte cell line (HaCaT) upon stimulation with IL-17. IL-17 binds to a heterodimeric receptor consisting of IL-17RA and IL-17RC, and adaptor protein Act1 binds to IL-17RA and mediates IL-17-induced signaling pathways. Because heat shock protein 90 (Hsp90) activity is required for IL-17 signalling via Act-1, we have evaluate the effect of Hsp90 inhibition on keratinocytes on IL-17-mediated cytokine and antimicrobial peptides. HaCaT cells were treated with 100 ng/ml of IL-17 or IL-22 for 24 hrs followed by 1 uM of 17-allylaminogeldanamycin (17-AAG) and collected for the analysis. We found that Hsp90 inhibition by 17-AAG under IL-17 stimulation led to decrease of CXCL1 but increase of CXCL5. In contrast to IL-17 and 17-AAG stimulation of HaCaT cells at 37°C, expression of Act1 and Act1 binding Hsp90 were increased after heat stimulation at 42°C for 30 min. These observation demonstrate the possible immune modulatory effect of the heat on keratinocytes during progression of inflammatory skin disease
Prostaglandin E2 inhibits IL-27 production by bone marrow-derived dendritic cells (CCR6P.281)
Authors: Hooper Kirsten , Yen Jui-Hung , Ganea Doina 
Published: January 2023

Abstract
Interleukin-27 (p28/EBI3) is expressed by activated antigen presenting cells and has been shown to have immunosuppressive functions including the inhibition of Th17 cell development and the induction of type 1 regulatory T cells (Tr1). In vivo studies demonstrated the anti-inflammatory effects of IL-27 in murine models of collagen-induced arthritis (CIA), inflammatory bowel disease (IBD), and experimental autoimmune encephalomyelitis. We showed previously that PGE2 has proinflammatory effects in models of CIA and IBD through the stimulation of IL-23 production and subsequent development of Th17 cells. Here we report on a novel proinflammatory function through the inhibition of IL-27 production by LPS-stimulated murine BMDC. A similar effect was observed in the dendritic, macrophage and microglia cell lines DC2.4, RAW264.7 and BV2. We determined that the effect of PGE2 was mediated through EP2/EP4 receptors and induction of cAMP. Studies targeting various downstream signaling pathways are in progress. These studies further elucidate the mechanisms involved in the inflammatory role of PGE2, and might identify additional therapeutic targets for the treatment of inflammatory autoimmune diseases.
Multiple TRIM proteins are targets of autoimmune response in lupus and Sjogren's syndrome. (HUM7P.308)
Authors: Rybakowska Paulina , Wolska Nina , Klopocki Arkadiusz , Sivils Kathy , James Judith , Bagavant Harini , Deshmukh Umesh 
Published: January 2023

Abstract
TRIM21 belongs to the large family of tripartite motif containing proteins, and is often targeted by autoantibodies in lupus and Sjogren’s syndrome. Considering the significant protein domain homology between different TRIM proteins, we hypothesized that additional TRIM proteins are targets of autoimmunity. Based on the literature, in this study we investigated autoantibody responses to TRIM38. While 9% of lupus patients (n=149) had anti-TRIM38 antibodies, the incidence in Sjogren’s syndrome patients (n=150) was 12%, and in controls (n=50) it was 4%. With respect to TRIM21, the incidence was 62%, 68%, and 4% respectively. In Sjogren’s syndrome patients, the presence of anti-TRIM38 antibodies was closely associated with the increased severity of dry eye parameters. Epitope mapping studies showed that anti-TRIM21 antibodies reacted with the RING, Coiled coil and PRY-SPRY domains of TRIM21, whereas anti-TRIM38 antibodies reacted only with the Coiled coil and PRY-SPRY domains of TRIM38. All anti-TRIM38 positive patients also had anti-TRIM21 antibodies. Affinity purified anti-TRIM21 antibodies from lupus patients did not immunoprecipitate TRIM38, indicating lack of cross-reactivity at B cell level. However, we observed T cell cross-reactivity between TRIM21298-312 and TRIM38302-316. Our study suggests that immune responses to TRIM proteins can evolve through epitope spreading and contribute towards exacerbating the pathogenesis in autoimmune disorders.
Soluble Fas ligand activates the CX3CL1-CX3CR1 axis by enhancing proteinase activity during arthritis in Fas-independent manner (HUM7P.312)
Authors: Kim Donghyun , Jeong Dongjin , Kim Hye Sung , Kim Hye Young , Lee Seung Hyo , Shin Eui-Cheol , Lee Eun Bong , Chung Doo Hyun 
Published: January 2023

Abstract
Fas/Fas ligand (FasL)-mediated apoptotic and non-apoptotic processes have long been known to regulate inflammatory responses. FasL exerts biological functions through two different forms in vivo: a membrane-bound FasL (mFasL) and soluble FasL (sFasL). It is unknown whether sFasL contributes to the pathogenesis of joint inflammation. Here, we found that sFasL triggered soluble CX3CL1 generation from fibroblast-like synovial cells by enhancing proteinase activity, which induced CX3CR1+ joint immune cell migration and chemokine production in an apoptosis-independent manner in mice and humans. Murine and human synovial cells deficient for Fas were minimally affected by sFasL-mediated induction of joint inflammation. Blockade of sFasL or CX3CR1 attenuated antibody-induced arthritis in mice. Therefore, we propose a novel function of sFasL in regulating joint inflammation via the CX3CL1-CX3CR1 axis, a process that occurs independently of Fas ligation. This novel axis may be a useful therapeutic target for arthritis.
Adults with indolent systemic mastocytosis have elevated peripheral blood myeloid-derived suppressor cells compared to chronic urticaria and healthy controls. (HUM7P.320)
Authors: Damle Sheela , Lofti-Emran Sahar , Ward Brant , Saleem Sheinei , Conrad Daniel , Schwartz Lawrence 
Published: January 2023

Abstract
MDSCs are a heterogeneous population of immature myeloid cells shown to be immunomodulatory in many diseases. In humans, they are identified by surface expression of CD33 and CD11b and lack of HLA DR. MDSCs are further divided into monocytic (M-MDSCs, CD14+) and granulocytic (G-MDSCs, CD15+) subsets. Our previous data showed that the prevalence and suppressive activity of murine MDSCs was augmented by the presence of mast cells (MCs). Indolent systemic mastocytosis (ISM) is a human disease caused by the clonal expansion of MCs. We propose that increased MCs and MC mediators frequently associated with mastocytosis produce an increase in peripheral blood MDSCs. Peripheral blood mononuclear cells (PBMCs) were isolated from blood obtained from adults with ISM and from chronic urticaria (CU, drug control), and healthy (H) age-matched controls. PBMCs, labeled with antibodies against HLA-DR, CD33, CD11b, CD15, and CD14, were analyzed by flow cytometry. MDSC concentrations in blood (x 106 cells/mL, mean ± standard error) were calculated. MDSC concentration was elevated (p&lt;0.0001) in ISM (15±7) versus CU (1.4±0.4) and H (2.8±0.4). The G-MDSC subset (9.4±4, 0.6±0.1, 1.5±0.3 for ISM, CU, and H respectively, p&lt;0.001) largely accounted for this elevation. A similar, non-significant trend (p=0.24) is seen in the M-MDSCs (1.6±0.5, 0.4±0.1, 0.7±0.3). Overall, these results demonstrate that MDSCs, particularly G-MDSCs, are elevated in the blood of patients with ISM, warranting further study.
Interleukin-17 Targets Ppp6c for epidermal hyperplasia via NF-kappaB-dependent MicroRNA miR-31 induction (HUM7P.300)
Authors: Wang Honglin , Yan Sha , Zhang Lingyun , Ke Fang , Bai Jing , Liu Zhaoyuan , Xu Zhenyao , Liu Jinliu 
Published: January 2023

Abstract
The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediator in this disease. However, it is unclear how IL-17 induces epidermal basal keratinocyte hyperproliferation in psoriasis. To explore the mechanism of IL-17 in epidermal hyperplasia in psoriasis, we focused on microRNA(s) induced by IL-17 as these small non-coding RNAs play an important role in regulation of cellular proliferation. Among all the microRNAs we screened, microRNA-31 (miR-31) is the only one extremely sensitive towards IL-17 for its induction in keratinocytes. Its expression in both the epidermis of lesional skin of human psoriasis patients and mouse psoriasis models is IL-17 inducible and NF-kappaB dependent. A causal relationship between IL-17-dependent miR-31 induction and basal keratinocyte hyperproliferation has been then established by constructing and analyzing epidermal conditional knockout of miR-31 (miR-31fl/fl/Keratin 5-Cre) engineering animals. A careful genomic analysis led us to realize that miR-31 targets protein phosphatase 6 (ppp6c), a negative regulator restricting G1 to S phase progression. As expected, ppp6c is suppressed by IL-17 through the miR-31 induction and is diminished in human psoriatic epidermis. We thus have uncovered a novel mechanism that helps explain how T helper (Th)-17 cells signal to basal keratinocytes for their hyperproliferation in psoriasis.