bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive transfers reveal dual roles in the protection against arthritis induction in the DACP rat (P4096)
Authors: Norin Ulrika , Rintisch Carola , Tuncel Jonatan , Bäckdahl Liselotte , Ekman Diana , Holmdahl Rikard 
Published: January 2023

Abstract
The DA rat is a commonly used inbred rat strain in inflammation research due to its susceptibility to numerous experimentally induced models of autoimmunity. We have isolated a spontaneous mutation that abrogates induction of a panel of inflammatory disorders in the DA rat and mapped it to a 2,5Mb region on chromosome 9. This new subset of the DA rat was called DA completely protected, DACP. To elucidate if the protection seen in the DACP rat is conveyed during the induction or the effector phase we utilized the Pristane-induced arthritis transfer model in a reciprocal fashion. Our results showed that cells from the DACP rat did not transfer arthritis to susceptible DA rats whereas cells from the susceptible DA rat caused a mild arthritis in DACP recipients. Looking at the cytokine profile of these cells we saw that cells from the DACP rat produced twice the amount of IL-10 compared to cells from the DA rat and that the production of RANTES was lower in the DACP rat. Differences in levels of IL-10 and RANTES could be one possible explanation for the protection seen in the DACP rat however this remains to be shown. In summary, the DACP rat was unable to develop disease upon arthritis induction but could develop a mild arthritis when receiving arthritogenic cells from the DA rat. Our findings suggest a possible dual role of the spontaneous mutation in the induction phase and the effector phase of arthritis in the DACP rat.
MicroRNA-mediated modulations in hyperactive plasmacytoid dendritic cells in systemic lupus erythematosus (P4072)
Authors: Yan Sheng , Tam Rachel CY , Chan Vera SF , Lau Chak Sing 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) patients are typically presented by their increased serum type I interferon (IFN) activities. Plasmacytoid dendritic cells (pDCs), the most potent type I IFN-producing cells, are found to be hyperactive in SLE. Using the New Zealand Black/White F1 lupus mouse model, we sought for the regulatory mechanism of IFN production by pDCs in SLE. Mice with lupus symptoms such as high titers of serum anti-nuclear antibodies and persistent proteinuria were compared with the pre-symptomatic ones. Upon toll-like receptor (TLR) 7 and TLR9 stimulations, the up-regulations of co-stimulatory markers CD40, CD86 and MHC class II were significantly heightened in bone-marrow-derived pDCs from the symptomatic mice. Furthermore, the expression profiles of over 700 microRNA (miRNAs) in pDCs upon TLR7 activation were analyzed by low-density arrays. Among those, miRNA-155 was the most highly induced and its induction was consistently higher in pDCs from the symptomatic mice. It was previously found in human studies that miRNA-155 regulates type I IFN production by pDCs and itself inversely regulated by the autocrine/paracrine IFN dynamics. Current investigations pursue on the correlation between up-regulated miRNA-155 induction and aberrant pDC functions in SLE using miRNA mimics and inhibitors. Together, our study should reveal miRNA-mediated modulations in pDC abnormalities in SLE.
Immune and ribosomal gene expression associate with relapse in ADAMTS13-deficient thrombotic thrombocytopenic purpura (P4086)
Authors: Edgar Contessa , Terrell Deirdra , Vesely Sara , Dozmorov Igor , Wren Jonathoan , Frank Mark , Merrill Joan , Kremer Hovinga Johanna , James Judith , George James , Farris Amy 
Published: January 2023

Abstract
40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe ADAMTS13 deficiency will relapse. Risk factors for relapse other than severe ADAMTS13 deficiency are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This study asked whether ADAMTS13-deficient TTP patients in remission have peripheral blood transcriptional markers that associate with relapse history. Peripheral blood from 38 patients with acquired autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies, type I interferon activity and global gene expression. A subset of patients (1.4-26.6 year follow-up; median 7.6 years) displayed a peripheral blood type I interferon gene signature that associated with elevated serum type I interferon activity and autoantibodies to RNA-binding proteins but not relapse. A second subset of patients (4.1-26.4 year follow-up; median 11.2 years) exhibited a peripheral blood gene signature composed of ribosomal transcripts that associated with relapse history. Patients who had relapsed also expressed higher natural killer cell, T lymphocyte and HLA transcript levels. The immune transcripts positively correlated with episode number but not with time since last episode. These data link a ribosomal/immune gene signature with relapse in acquired, ADAMTS13-deficient TTP.
Multiple domains of the MBD2 protein are required for transcriptional repression in B cells. (P4382)
Authors: Dege Carissa , Ramirez Julita , Hagman James 
Published: January 2023

Abstract
We demonstrated previously that the mb-1 (Igα; Cd79a) promoter is demethylated progressively during its activation in early B cell development. Demethylation of promoter CpGs is initiated by binding of the transcription factor, Early B cell Factor 1 (EBF1). EBF1 increases local accessibility and demethylation of mb-1 promoter DNA, which allows for binding by Pax5 prior to transcription. This process is inhibited by Mi-2/NuRD chromatin remodeling complexes. This was evidenced by knockdown of the ATPase subunit of Mi-2/NuRD, Mi-2β (CHD4). Recent work in the laboratory has focused on other components of the Mi-2/NuRD complex to assess their importance for association of Mi-2/NuRD with methylated DNA. A subset of Mi-2/NuRD complexes contains Methyl Binding Domain protein 2 (MBD2). MBD2 binds methylated, but not hydroxymethylated or unmethylated cytosines. We have demonstrated that knockdown of MBD2 using shRNA potentiated mb-1 transcriptional activation only in the presence of EBF1 and Pax5. MBD2 is important for recruiting Mi-2/NuRD complexes to gene targets and for maintenance of heterochromatin. MBD2 comprises arginine-glycine (RG)-rich, Methyl CpG binding (MBD) and C-terminal (CTD) domains. Through mutational analysis, we have demonstrated that multiple domains of MBD2 are important for transcriptional attenuation of the mb-1 gene in B cells. We are now investigating how MBD2 binding is inhibited to de-repress the B cell program in early B cell progenitors.
CTLA4-mediated inhibitory effect on osteoclastogenesis by Tregs in oral cancer (P2047)
Authors: Tomihara Kei , Arai Naoya , Noguchi Makoto 
Published: January 2023

Abstract
Purpose: Despite regulatory T cells (Tregs) have been demonstrated to inhibit inflammatory bone destruction through suppressing osteoclast formation in the bone microenvironment of inflammatory diseases, very little work has been done to characterize Tregs in the microenvironment of cancer bone invasion. In the present study, we investigated the mechanism of interaction between Tregs and osteoclasts in a murine model of oral cancer to elucidate the role of Tregs in the bone invasion of oral cancer. Materials and Methods: SCCVII mouse oral squamous cell carcinoma cells were administered into the right masseter region of a C3H/HeN mouse. After 14 days of tumor inoculation, mice were sacrificed and Tregs were purified from the tumors. Tregs were then cocultured with bone marrow CD11b positive cells in the absence or presence of RANKL and M-CSF for 4 days. Secreted tartrate-resistant acid phosphatase (TRACP) 5b was determined as a marker of osteoclast number. Results: Attenuation of osteoclast-derived TRACP5b was observed in the coculture of tumor derived Tregs and bone marrow CD11b positive cells, and this attenuation of TRACP5b was ameliorated by neutralization of cytotoxic T-lymphocyte-associated antigens-4 (CTLA4). Conclusion: These results indicate that Tregs may play a protective role in bone invasion of oral cancer via suppression of osteoclastogenesis, and CTLA4 may be a key regulator for the suppression of osteoclasts by Tregs in oral cancer.
Myd88 may contribute in several ways to progression of murine mammary carcinoma (P2077)
Authors: Kurt Robert , Carey Maureen , Eidelman Alec , Liberti Maria , Ricca Jacob , Tucker Kyle 
Published: January 2023

Abstract
Previously we reported that Myd88 contributed to growth, metastasis, and expression of CCL2 and CCL5 by mammary carcinoma implying that constitutive signaling through Myd88 contributes to tumor progression. To begin to decipher downstream effects of Myd88 signaling in the tumor cells we used RNA interference and a Myd88 inhibitory peptide and then screened for expression of genes involved in signaling and the cell cycle. Some of the alterations that were found included TLR signaling components such as Tirap, Tollip, Irak1 and Irak2 suggesting a potential feedback mechanism for Myd88 in TLR signaling in the tumor cells. Many of the genes that were modulated upon Myd88 inhibition may contribute to multiple downstream effects such as inflammation, migration and growth. For instance, genes utilized for the NFKb and MAPK pathways including NF-KB1, IKB-beta, MEK, JNK and p38 exhibited reduced expression upon Myd88 inhibition. Genes encoding proteins that could regulate the cell cycle such as p53, cyclins B, D, and F were also modulated, and a role for Myd88 in cell cycle progression was confirmed by cell cycle analysis which showed that Myd88 was important for progression to the G2 phase of the cell cycle. Collectively, these data imply that Myd88 may contribute to tumor progression by regulating several pathways (apoptosis, proliferation, migration and/or inflammation), and underscores the importance of delineating the role of Myd88 in murine mammary carcinoma.
T cells from DNAM-1 deficient mice display immunological synapse defects that impair anti-tumour immunity (P2009)
Authors: Oliaro Jane , Rambsbottom Kelly , Russell Sarah , Smyth Mark 
Published: January 2023

Abstract
DNAX accessory molecule 1 (DNAM-1/CD226) is an adhesion molecule expressed on all CD8+ cytotoxic T cells (CTLs) that acts as an accessory molecule to promote CTL functions such as activation, differentiation, migration and effector function. DNAM-1 interacts with LFA-1, a critical molecule for immunological synapse formation between T cells and antigen presenting cells, and for cytotoxic killing of target/tumour cells. Indeed, mice lacking DNAM-1 display abnormal T cell responses and anti-tumour activity; however, the mechanism involved is not well understood. Here, we investigate the immunological synapse between OT1 DNAM-1 deficient T cells and antigen presenting cells, and show that DNAM-1 deficiency results in reduced proliferation and expansion of T cells in response to antigen presentation, which correlates with a decrease in cytokine production. Furthermore, we demonstrate that activated OT1 DNAM-1 deficient T cells show reduced stable conjugations with tumour cells and decreased recruitment of LFA-1 and lipid rafts to the immunological synapse, which correlates with reduced killing in vitro. This polarity defect may explain why DNAM-1 deficient mice cannot clear tumours in vivo and highlights the importance of the immunological synapse in T cell mediated anti-tumour immunity.
Generation of cellular responses following FcR targeting in the mucosa in a Francisella tularensis model. (P4288)
Authors: Bitsaktsis Constantine , Gosselin Edmund 
Published: January 2023

Abstract
Numerous studies have demonstrated that targeting antigens to FcγR can increase their immunogenicity and generate protective immune responses in various infection models. Previously, we have shown that targeting fixed Francisella tularensis bacteria to FcγRI and III in mice, via intranasal immunization with immune complexes, enhances specific immune responses that are protective against this pathogen. In this study we have utilized our F. tularensis model to dissect the "in vivo" cellular immune responses generated following FcγR targeting. Our results demonstrate for the first time that targeting fixed Francisella tularensis to FcγR: 1. increases the recruitment and activation of dendritic cells in the lungs of immunized mice, 2. increases the frequency and number of effector memory CD4+ T cells during F. tularensis infection in an IL-12-dependent manner, and 3. increases the frequency and number of IFN-γ producing effector memory T cells upon "in vitro" re-stimulation. These data, collectively, confirm the effectiveness of FcγR targeting as a vaccine strategy against infections with mucosal pathogens, and for the first time demonstrate the "in vivo" immunological mode of action involved in the observed protection.
Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in a non-human primate model (P3021)
Authors: Jin Cong , Liang Mifang , Han Ying , Jiang Hong , Li Chuan , Zhu Hua , Wei Qiang , Qin Chuan , Li Dexin 
Published: January 2023

Abstract
Severe Fever with Thrombocytopenia Syndrome (SFTS) emerged as an infectious disease in 2010 in rural China, and its causative agent SFTS virus (SFTSV) is a new member of the family Bunyaviridae, genus phlebovirus, most closely related to the heartland virus recently discovered in Missouri, the US. To develop effective vaccines and therapeutics against this emerging pathogen, animal disease models are urgently needed. Here, we report the first findings of measurable clinical disease in non-human primates infected with SFTSV. In the primate model, the abrupt fever, thrombocytopenia, and leukocytopenia were duplicated. Substantially enhanced aspartate aminotransferase, creatinine, and lactate dehydrogenase in serum was observed, indicating pathological lesions in organs. Viremia peaked around 3 to 5 days after the inoculation of SFTSV. Viral RNA was detected in the spleen, lymph node, liver, kidney, and intestine. Virus-specific IgM and IgG antibody responses were induced, and cytokines IFN-γ and eotaxin were significantly enhanced in the acute phase. Scattered necrosis and degeneration of hepatocytes in liver, as well as glomerular hypercellularity, mesangial thickening, and congestion in Bowman’s space in kidney were observed after 4 weeks of SFTSV infection. Thus, we established a non-human primate model which resembles major clinical features of the human SFTS disease, and further studied virus-specific immune responses and histopathological changes in this primate model.
Antigen-specific immunoglobulin responses correlate with plasma viral load in SIV/SHIV infected controller macaques (P3049)
Authors: Pahar Bapi , Kenway-Lynch Carys , Pan Diganta , Das Arpita , Marx Preston , Wang Xiaolei , Srivastav Sudesh , Veazey Ronald 
Published: January 2023

Abstract
There is increasing evidence suggesting an unexpected potential for non-neutralizing antibodies to prevent HIV infection. Consequently, identification of functional B cell epitopes for HIV is also important for developing preventative and therapeutic strategies. We therefore explored the antigen-specific immune responses following SIV or SHIV infection in rhesus macaques to determine functional B cell epitopes and identify factors that may influence control of plasma viremia. Functional B cell epitopes are a minimum of 10 amino acids in length for SIV and occur in similar regions despite differences in the route of mucosal SIV inoculation. Peptide-specific IgG responses generate primarily against gp41, V1-V3 regions of gp120, and the NC and p6 regions of Gag. Controller macaques showed much greater IgG responses to Nef, Tat, and p15 and p27 regions of Gag protein compared to absent or minimal responses in non-controller macaques. Antigen-specific IgM and IgA responses share similar epitopes to that of IgG, however the responses are much more limited. Moreover, antigen-specific IgA responses did not correlate with plasma viremia. Our study has shown that Env-specific IgG responses are not reliable prognostic indicators, unlike Gag, Nef, and Tat-specific IgG responses for SIV/SHIV controllers. Therefore, generation of early functional Gag, Nef and Tat-specific IgG responses may be important therapeutic strategies for the control or prevention of HIV/AIDS.
Type I IFN suppresses Type II IFN triggered antimicrobial responses in humans (P1277)
Authors: Teles Rosane , Graeber Thomas , Modlin Robert 
Published: January 2023

Abstract
The mechanism by which Type I IFNs contribute to immune suppression in bacterial infections in humans was investigated by studying leprosy as a model. The Type I IFN, IFN-β, as well as an inducible regulatory pathway involving sequential induction of IL-10 were differentially expressed in progressive lepromatous (L-lep) vs. the self-limited tuberculoid (T-lep) lesions. A common IFN-β gene signature was detected in the peripheral blood of active tuberculosis patients and the skin lesions of L-lep patients, with approximately half of the common IFN-β induced genes also induced by IL-10. Contrary to the expression of Type I IFNs and inducible genes, the Type II IFN, IFN-γ, and downstream genes that comprise antimicrobial pathways were differentially expressed in T-lep vs. L-lep lesions. The IFN-γ-induced macrophage antimicrobial response was inhibited by IFN-β and IL-10, by a mechanism involving blocking the generation of bioactive 1,25-dihyroxyvitamin D as well as inhibiting induction of antimicrobial peptides cathelicidin and DEFB4. Together, these data identify the ability of IFN-β to induce IL-10 as a mechanism by which Type I IFNs inhibit Type II IFN induced host defense pathways and thereby contribute to the pathogenesis of bacterial infections in humans.
T cell-suppression during acute Toxoplasma gondii infection does not involve APC and is a consequence of Treg-mediated IL-2 deprivation and death of proliferating T cells (P1279)
Authors: Salinas Nohemí , Olguín Jonadab , Castellanos Carlos , Saavedra Rafael 
Published: January 2023

Abstract
Foxp3+ Treg (Treg) mediate the suppression of T-cell proliferation observed during the acute Toxoplasma gondii infection in mice. This suppression in T-cell proliferation is related to an IL-2 mechanism. We studied the suppression mechanisms of Treg on T cells in a model of toxoplasmosis using transgenic Foxp3EGFP mice. We analyzed if APC were involved during Treg-suppression of T-cell. Removal of APC from spleen cells from infected mice did not modify suppression and further elimination of Treg led to a complete restored proliferation, demonstrating that APC are not involved in Treg-mediated suppression. Low IL-2 levels were detected in supernatants of APC-free T cells from infected mice. IL-2 levels and T-cell proliferation were restored when Treg and T cells were separated by transwells, indicating that Treg require contact to induce suppression. Although Treg did not inhibit il-2 mRNA levels in T cells, they were able to reduce proliferation of CTLL-2 cells in the IL-2 bioassay, strongly suggesting that Treg act by IL-2 deprivation. Kinetic analysis of T cell proliferation showed that T cells from infected mice die after a few rounds of division in vitro, but addition of rIL-2 or removal of Treg abolished this effect. We conclude that suppression of T-cell proliferation during acute T. gondii infection is mediated by Treg in the absence of APC by IL-2 deprivation, requiring cell contact between T cells and Treg, thus leading to death of proliferating T cells.
Role of histone acetylation, cAMP signaling, and mitogen-activated protein kinase pathways in butyrate-induced host defense peptide gene expression in chicken HD11 macrophage cells. (P1283)
Authors: Sunkara Lakshmi , Jiang Weiyu , Zhang Guolong 
Published: January 2023

Abstract
Host defense peptides (HDPs), critical components of innate immunity of animals, act as direct antimicrobials and immunomodulators. We found that, butyrate, a short-chain fatty acid and histone deacetylase inhibitor, enhances HDP gene expression and reduce Salmonella enteritidis colonization in chickens. However, the molecular mechanisms of butyrate-mediated HDP gene induction remain elusive. Here, we dissected the role of histone acetylation, cAMP signaling, and mitogen-activated protein kinases (MAPKs) in HDP expression in butyrate treated HD11cells. Our real-time PCR results revealed that, in addition to butyrate, several other histone deacetylase inhibitors also enhanced the expression of AvBD9, a chicken beta-defensin gene. In contrast, histone acetyltransferase inhibitors suppressed butyrate-mediated AvBD9 gene induction. Moreover, inhibition of p38 MAP kinase or c-Jun N-terminal kinase, but not extracellular signal regulated kinase, diminished AvBD9 gene expression with butyrate. Interestingly, agonists of the cAMP signaling pathway increased AvBD9 expression either alone or synergistically with butyrate. Collectively, our results showed that histone acetylation, and MAPKs and cAMP pathways play an important role in butyrate-regulated AvBD9 gene expression. A detailed understanding of the transcriptional regulatory mechanisms of HDP expression may facilitate the development of antibiotic-free strategies to disease control and prevention in both animals and humans.
tRNA-derived RNA fragments: A new family of regulatory molecules controlling respiratory syncytial virus replication. (P1401)
Authors: Bao Xiaoyong , Wang Qingrong , Lee Inhan , Ren Junping , Lee Yong Sun 
Published: January 2023

Abstract
The discovery of small non-coding RNAs (sncRNAs) with regulatory functions is a recent breakthrough in biology. Among sncRNAs, microRNA (miRNA), derived from host or virus, has emerged as elements with high importance in control of viral replication and host responses. However, the expression pattern and functional aspects of other types of sncRNAs, following viral infection, are unexplored. In order to define expression patterns of sncRNAs, as well as to discover novel regulatory sncRNAs in response to viral infection, we applied deep sequencing to cells infected with human respiratory syncytial virus (RSV), the most common cause of bronchiolitis and pneumonia in babies. RSV infection leads to abundant production of tRNA-derived RNA fragments (tRFs) that are ~30 nucleotides (nts) and correspond to the 5’-half of mature tRNAs. At least one tRF, which is derived from tRNA-Glu-CTC, represses target mRNA in the cytoplasm and promotes RSV replication. This demonstrates that this tRF is not a random by-product of tRNA degradation but a functional molecule. The biogenesis of this tRF is also specific, as it is mediated by the endonuclease angiogenin, not by other nucleases. In summary, our study presents novel information on the induction of a functional tRF by viral infection.