bluuebunny/crossref_metadata_2025_split huggingface dataset:
The oligoadenylate synthetase-like protein enhances cellular antiviral activity through RIG-I pathway (68.3)
Authors: Sarkar Saumendra , Zhang Yugen , Zhu Jianzhong , Forero Adriana , Ganapathiraju Madhavi , Hartmann Rune , Coyne Carolyn 
Published: January 2023

Abstract
Oligoadenylate Synthetases (OAS) are interferon (IFN) inducible enzymes, which contribute to the host anti-viral activity by inducing RNA degradation via classical OAS-RNaseL pathway. However, the OAS-like protein (OASL), which is strongly induced following virus infection, does not have enzymatic activity to synthesize 2’-5’ oligoadenylates. Therefore, the mechanism of the anti-viral activity of OASL has remained elusive. Here we describe the basis of anti-viral activity of OASL via its ability to modulate type I IFN induction through RIG-I pathway. OASL expressing cells show a strong anti-viral activity against a number of RNA and DNA virus infections in a RIG-I dependent manner. Expression of OASL enhances RIG-I mediated IFN induction. We show that OASL interacts with cytoplasmic viral RNA sensor RIG-I and enhance its activity through its C-terminal ubiquitin like domain. Poly ubiquitin binding to RIG-I is necessary and essential for RIG-I mediated induction of IFN. We demonstrate that following induction of OASL protein it provides the necessary poly Ub binding function of RIG-I. Furthermore, inactive RIG-I mutants, which are defective in ubiquitination and poly Ub binding can be rescued in presence of OASL. We show that OASL specifically enhances RIG-I mediated IFN induction without affecting MDA5, STING activation. Our findings suggest a novel mechanism by which OASL contributes to host anti-viral response.
Characterization of Effector Memory CD8+ T cells in the Synovial fluid of Rheumatoid Arthritis (69.1)
Authors: Kim Hang-Rae , Cho Bon-A , Sim Ji Hyun , Kim Hye Won , Yoo Wan-Hee , Kang Insoo , Lee Eung Bong 
Published: January 2023

Abstract
Little is known about the cellular characteristics of CD8+ T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8+ T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD45RA- effector memory (EM) CD8+ T cells were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. This was accompanied by increased levels of IL-15. The synovial EM CD8+ T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas+ cells were prone to apoptosis. In addition, EM CD8+ T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4+CD8+ T cells and IL-4-producing CD8+ T cells were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8+ suppressor cells increased significantly in the SF of RA patients. Especially, CD8+ T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8+ T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.
Proliferative dysfunction in chronically activated T lymphocytes from chagasic patients (70.1)
Authors: Giraldo Nicolas , Bolaños Natalia , Cuellar Adriana , Roa Nubia , Cucunubá Zulma , Velasco Victor , Rosas Fernando , Puerta Concepción , González John 
Published: January 2023

Abstract
Background: Trypanosoma cruzi persistence has been associated with cardiac and gastrointestinal tissue damage in nearly 30% of the infected individuals; however, the pathogenic mechanisms are yet unknown. This study’s goal was to compare the activation status and proliferative capacity of T lymphocytes among chronic chagasic patients and uninfected controls. Methodology: Twenty-seven chronic chagasic patients, 20 healthy individuals and 28 non-chagasic cardiomyopathy donors were analyzed. Peripheral blood cells were stained with CD3, CD4, CD8, CD28, HLA-DR and CD38. PBMCs were labeled with CFSE and co-cultivated with PHA or T. cruzi lysate; at the fifth day post-stimulation cells were stained for CD3, CD4 and CD8. Results: Chagasic patients displayed higher frequencies of CD4+ (P=0.0001) and CD8+ (P=0.0002) T cells co-expressing HLA-DR and CD38 in comparison with healthy and non-chagasic cardiomyopathy donors. Also, the former group exhibited lower percentages of CD8+/CD28+ T lymphocytes (P=0.0005). After 5 days of stimulation, the proliferation index was lower in both CD4+ (P=0.01) and CD8+ (P=0.04) PHA-stimulated T cells from chagasic donors when compared with both control groups. Conclusions: Despite their increased activation status, the T lymphocytes from chagasic donors displayed reduced proliferative capacity after mitogenic stimulation, corroborating a dysfunctional cellular immune response in the chronic stages of the disease.
The impact of Staphylococcus aureus infection on human B cell responses (70.5)
Authors: Pauli Noel , DeDent Andrea , Huang Min , Henry Dunand Carole , Kim Hwan , Zheng Naiying , Andrews Sarah , Frank Karen , Schneewind Olaf , Wilson Patrick 
Published: January 2023

Abstract
Staphylococcus aureus, S. aureus, is a growing concern in medicine due to the rise of antibiotic resistant strains, such as Methicillin Resistant Staphylococcus aureus (MRSA). Infection and clearance of this bacterium does not lead to immunity to future infections in humans. S. aureus utilizes a variety of virulence factors in order to evade and actively suppress an effective immune response; one of particular importance to humoral immunity is Staphylococcus Protein A (SpA). SpA has the ability to act as a B cell superantigen and anti-opsonin. We address the effects of S. aureus infection on human B cell populations and how the bacterium is able to prevent long lasting, protective immunity; analyzing the effect of infection in humans at the resolution of individual B cells. Focusing on human subjects that have experienced infections, we report on our initial efforts to characterize the kinetics and magnitude of B cell activation by flow cytometry and ELISPOT analysis. Further, we show the ability to derive S. aureus specific monoclonal antibodies (mAbs) from individually sorted B cells in the context of human infection; analyzing the responding B cell BCR repertoire to better understand the human response to this pathogen and how it prevents the generation of useful immunity. It is hoped that specific human monoclonal antibodies to S. aureus virulence factors could be used for therapeutic and prophylactic purposes, or identify epitopes to direct vaccine design.
Deficiency of Id3 (inhibitor of DNA binding 3) results in Inflammation in salivary glands and gamma-delta (gd) T cell lymphoma (71.11)
Authors: Kasagi Shimpei , Maruyama Takashi , Li Jun , Chen Wanjun 
Published: January 2023

Abstract
Id3-/- mice have been shown to develop a T cell-dependent autoimmune-like sjogren’s syndrome(SS). The dysregulated differentiation between Foxp3+ Tregs and Th17+ T cells in Id3-/- CD4+ T cells promoted us to study whether the autoimmune-like SS in Id3-/- mice was associated with the abnormal expression of Th17 cells in the target organs. We focused on the salivary glands and lachrymal glands, as they are main target tissues involving in SS. 50% of Id3-/- started to show proinflammatory CD4+ infiltrating cells in the salivary glands. Significantly higher frequency of Th1 and Th17 cells were observed in Id3-/- salivary glands, and higher frequency of Th17 and lower frequency of Tregs were observed in Id3-/- spleen. Notably, 26% mice Id3-/- mice developed gd T cell lymphoma. The gd T lymphoma cells were characterized by dysregulated IL-17 production and high expression of an oncogene, c-myc. Adoptive transfer of Id3-/- gd T lymphoma cells to Rag1-/- mice resulted in gd T lymphoma, suggesting that Id3 may regulates gd T cell tumor development.
Crosstalk between colonic epithelial cells and macrophages (71.7)
Authors: Kristek Maja , Rahman Arman , Loscher Christine 
Published: January 2023

Abstract
Macrophages are the most abundant mononuclear phagocytes in the intestine. Unlike other macrophage populations, intestinal macrophages seem to be in a state of partial activation showing no response to inflammatory stimuli, no production of pro-inflammatory cytokines and low expression levels of innate response receptors. Intestinal macrophages are thought to derive from circulating blood monocytes, which are fully responsive to inflammatory stimuli. Therefore it is probable that the intestinal environment itself is responsible for altering the phenotype of these macrophages upon arrival in the gut. In order to explore whether the intestinal environment can influence macrophage phenotype and function J774A.1 macrophages were conditioned with supernatants from the murine colonic epithelial cell line, CMT-93. Conditioning of J774 cells with CMT-93 media altered the expression levels of innate response receptors and cytokine production. Furthermore, conditioning with CMT-93 media modulated the macrophage response to Toll-like receptor stimuli. They acquired more of a regulatory phenotype with the down-regulation of CD80, CD40 and MHC class II expression and IL-12p40 production, along with increased production of TNF-α. This data implicates intestinal epithelial cells as one of the factors that can change and shape macrophage response, therefore it is important to investigate this crosstalk further in order to understand its role in the maintenance of intestinal homeostasis.
The Microbiota Limit CX3CR1+ Cell-Dependent Trafficking of a Pathogenic Bacterium to the Mesenteric Lymph Nodes. (71.9)
Authors: Diehl Gretchen , Longman Randy , Zhang Jing-Xin , Breart Beatrice , Schwab Susan , Littman Dan 
Published: January 2023

Abstract
The organization of the intestine makes regulating inflammation a unique challenge. The lumen of the intestine contains not only partially digested food, but also an enormous load of beneficial bacteria (up to 10^12 organisms/gram of contents). As commensal and pathogenic bacteria contain the same immunostimulatory molecules, it is unclear how the intestinal immune system can distinguish between the two. We hypothesized that recognition of commensals modulates intestinal immune responses to limit inflammation. To this end, we examined immune responses against non-invasive Salmonella Typhimurium in MyD88-deficient mice or wildtype mice treated with antibiotics to reduce their microbiota. We found that, in the presence of commensals, non-invasive Salmonella, a pathogen whose entry is limited, is unable to reach the mesenteric lymph nodes (MLN). However, in animals where the load of commensals has been reduced with antibiotics or in animals deficient for MyD88, non-invasive Salmonella trafficks to the MLN in a CCR7-dependent manner. This trafficking to the MLN results in the induction of IgA. Additionally, we found that CX3CR1+ mononuclear phagocytes, an intestinal cell population previously thought to be non-migratory, are responsible for this trafficking of non-invasive Salmonella. These findings indicate that recognition of commensals limits the amount of antigen reaching the MLN. This in turn limits induction of immune responses and serves to reduce intestinal inflammation.
Catenarin, an anthraquinone compound, inhibits CXCR4 and CCR5 pathways to protect against type 1 diabetes in NOD mice (72.1)
Authors: Yang Wen-Chin , Shen Ming-Yi , Jang Yu-Song , Chen Zeng-Weng , Chang Cicero 
Published: January 2023

Abstract
Inflammation contributes to leukocyte migration, termed insulitis, and β cell loss in type 1 diabetes (T1D). Naturally occurring anthraquinones are claimed as anti-inflammatory compounds; however, their actions are not clear. This study aimed to investigate the effect and mechanism of catenarin on the inflammatory disease, T1D. Catenarin and/or its anthraquinone analogs dose-dependently suppressed C-X-C chemokine receptor type 4 (CXCR4)- and C-C chemokine receptor type 5 (CCR5)-implicated chemotaxis in leukocytes. Catenarin, the most potent anthraquinone tested in the study, prevented T1D in non-obese diabetic mice. Mechanistic study showed that catenarin did not act on the expression of CCR5 and CXCR4. On the contrary, catenarin inhibited CCR5- and CXCR4-mediated chemotaxis via the reduction of the phosphorylation of mitogen-activated protein kinases (p38 and JNK) and their upstream kinases (MKK6 and MKK7) and calcium mobilization. Overall, this study demonstrates the preventive effect and molecular mechanism of action of catenarin on T1D, suggesting its novel use as a prophylactic agent in T1D.
CM3457, a potent and selective oral CRAC channel inhibitor, suppresses T and mast cell function and is efficacious in rat models of arthritis and asthma (72.3)
Authors: Ramos Stephanie , Grigoryev Sergey , Rogers Evan , Roos Jack , Whitten Jeffrey , Stauderman Kenneth , Velicelebi Gonul 
Published: January 2023

Abstract
Calcium-release activated calcium (CRAC) channel inhibitors represent a new class of oral immunomodulatory agents with a potential safety profile suitable for chronic dosing to treat autoimmune disorders. Calcium entry through CRAC channels is a critical step in the functional responses of T cells and mast cells. Patients with mutations in CRAC channels are known to have a form of severe combined immunodeficiency, wherein the adaptive immune response is suppressed without major impairment of other organ systems. CalciMedica has discovered several novel small molecules that selectively inhibit CRAC channels, and is currently developing the first of these inhibitors, CM2489, for the treatment of psoriasis. We describe here the properties of CM3457, another selective CRAC channel inhibitor that is structurally distinct from CM2489. CM3457 potently inhibits CRAC channels, Th1, Th2 and Th17-derived cytokine production, T cell proliferation, and mast cell degranulation. Once-daily oral dosing of CM3457 significantly inhibits inflammation and joint histopathology in a rat collagen-induced arthritis model. CM3457 also inhibits lung inflammation and eosinophilia, as well as improves lung function, in a rat OVA-induced asthma model. These data provide evidence that CM3457 may be an effective therapeutic in the treatment of autoimmune disorders and asthma.
Novel insights into the effects of spingosine-1-phosphate receptor modulators on monocytes (72.6)
Authors: Lewis Nuruddeen , Haxhinasto Sokol , Anderson Shawn , Fogal Steve , Stefanopoulos Dimitria , Brown Maryanne , Modis Louise 
Published: January 2023

Abstract
Sphingosine-1-phosphate (S1P) receptors are critical for lymphocyte egress from secondary lymphoid organs and S1P receptor modulators effectively suppress lymphocyte circulation. FTY720, a novel S1P1,3,4,5 modulator, is currently approved for the treatment of multiple sclerosis. Despite the current progress in elucidating the function of S1P receptors on lymphocytes, the role of S1P receptors on innate immune cells are incompletely understood. S1P receptors are widely expressed on cells of the innate immune system and have been demonstrated to modulate cell trafficking, activation, cytokine production, organization in secondary lymphoid tissues, maturation, and antigen presentation. We determined the effects of FTY720 and an S1P1,4,5 modulator on innate immune cells under normal and inflammatory conditions using experimental autoimmune encephalitis in mouse and rat as our model systems. We will present our findings on the impact of these two S1P receptor modulators on monocytes. This data contributes to the current understanding of S1P receptors in rodents and provides novel insight into additional functions of S1P receptor modulators.
Decreasing immunogenicity of ESC derived cardiomyocytes (73.1)
Authors: Karabekian Zara , Idrees Sana , Jamshidi Aria , Sarvazyan Narine 
Published: January 2023

Abstract
One of the major obstacles to repair damaged myocardium with embryonic stem cell derived cardiomyocytes (ESC-CM) is their rejection by non-syngeneic hosts. We aimed to reduce the immunogenicity of these cells by downregulation of MHC class I molecules (MHC-I) on their surface. Cardiomyocytes were derived from mouse ESC in which puromycin resistance gene is driven by a cardiac-specific promoter. They formed beating cardiomyocyte layers and expressed cardiac specific proteins. Interferon gamma treatment was used to mimic the effects of inflammatory stimuli on the expression of MHC-I. Transduction of ESC-CM with beta-2-microglobulin shRNA decreased expression of MHC-I in both interferon gamma-treated and untreated samples. When MHC-I downregulated ESC-CM were used as in vitro targets, activation of cognate T-lymphocytes was significantly reduced. Moreover, in vivo, MHC-I downregulated cells exhibited improved survival when injected i.p. into allogeneic, but not to syngeneic mice. To confirm that this strategy can be used for different cell types, the results were verified using W19 fibroblasts. In the past, ESC-CM have been shown to improve ischemic myocardium in syngeneic or immunocompromised animals. Inhibition of MHC-I via shRNA offers a simple approach to minimize the immunogenicity of these cells for use in allo- or xenogeneic recipients. Extension of this methodology to ESC of larger mammals can provide a source of less immunogenic cardiomyocytes for human heart repair.
Increased anti-melanoma efficacy of hu14.18K322A by combining with αCD40 +CpG (74.1)
Authors: Alderson Kory , Luangrath Mitchell , Elsenheimer Megan , Gillies Stephen , Navid Fariba , Rakhmilevich Alexander , Sondel Paul 
Published: January 2023

Abstract
Targeted monoclonal antibodies (mAb) can be used therapeutically for tumors with identifiable antigens such as disialoganglioside GD2, expressed on neuroblastoma and melanoma. αGD2 mAbs have been clinically successful in patients with neuroblastoma. An important mechanism of mAb therapy is Antibody Dependent Cellular Cytotoxicity (ADCC). Combinatorial therapeutic strategies can dramatically increase the anti-tumor response elicited by mAbs. We combined a novel αGD2 mAb, hu14.18K322A, with an immunostimulatory regimen of agonist CD40 mAb and class B CpG-ODN 1826. This combination immunotherapy produced a synergistic anti-tumor response in a syngeneic model of melanoma with minimal tumor burden, resulting in long-term cure of mice. NK depletion in B6 mice showed NK cells were required for the anti-tumor effect. Anti-tumor responses were also observed in tumor-bearing SCID/beige mice; thus NK cell cytotoxicity was not essential. Interrogation of the myeloid population in the peritoneal cavity showed an increase in neutrophils and monocytes with high Fc receptor expression after treatment with αCD40 +CpG. Furthermore, plastic adherent peritoneal cells inhibited tumor cells in vitro in an antibody-dependent manner. These data highlight the importance of myeloid cells as potential effectors in immunotherapy regimens utilizing tumor-specific mAb and suggest further studies are needed to investigate the therapeutic potential of activated myeloid cells.
Immunization with E1A expressing tumor cell line enhances antigen specific tumor immunity (74.5)
Authors: Korrer Michael , Zhang Yuwen , Zhang Jian , Routes John 
Published: January 2023

Abstract
The stable expression of Adenovirus (Ad) E1A in tumor cells reduces tumorigenicity by 1,000 fold, an effect dependent on the elicitation of an NK cell and T cell mediated antitumor response. We generated B6 fibrosarcoma cell lines (MCA tumor cells) that stably expressed ovalbumin (MCA-OVA) or full-length E1A fused to ovalbumin (MCA-E1A-OVA) to test the hypotheses that E1A could function as a molecular adjuvant to induce a robust anti-tumor immune response to other weakly or non-immunogenic tumor antigens. MCA E1A-OVA was more susceptible to killing by NK in vitro and 1000 fold less tumorigenic than MCA or MCA-OVA in vivo. Immunization with 1X10^5 live MCA-OVA or MCA- E1A-OVA tumor cells elicited comparable numbers of IFNγ- and TNFα -producing OVA specific CD8 T cells that had similar cytolytic activity against OVA-expressing target cells in in vivo CTL killing assays. Immunization of MCA-OVA or MCA-E1A-OVA cells also increased the number of MCA-OVA cells required to form tumors by 1,000 fold in an anatomically distant site. However, primary tumors developed at the site of immunization with MCA-OVA but not MCA-E1A-OVA cells. These data demonstrate that immunization of live MCA-E1A or MCA-OVA tumor cells can elicit a robust, systemic anti-tumor immune response. However, primary tumor progression occurs at the site of inoculation following immunization with MCA-OVA cells despite the induction of an anti-tumor immune response.
Granulocytic and monocytic populations of tumor-infiltrating myeloid-derived suppressor cells (MDSC) suppress T cell proliferation through independent mechanisms (74.7)
Authors: Raber Patrick , Wyczechowska Dorota , Rodriguez Paulo 
Published: January 2023

Abstract
Granulocytic and monocytic myeloid-derived suppressor cells (G-MDSC and M-MDSC) are hallmarks of chronic inflammatory environments and major mediators of T cell suppression in cancer. We aimed to determine the mechanisms by which tumor-associated G-MDSC and M-MDSC suppress T cell proliferation. Our results suggest that MDSC isolated from lung carcinoma-bearing mice impaired the proliferation of activated T cells thorough an arrest in the G0-G1 phase of the cell cycle. This effect was not caused by a decreased T cell activation, as an increased expression of the early activation markers CD25 and CD69, and high production of IL-2 were detected in T cells co-cultured with MDSC. The anti-proliferative effect induced by MDSC was prevented after the addition of inhibitors of arginase and inducible nitric oxide synthase (iNOS). Interestingly, arginase I was exclusively expressed in G-MDSC, whereas iNOS was expressed mainly in M-MDSC. Additional results showed that G-MDSC produced higher levels of reactive oxygen species (ROS), whereas M-MDSC produced more peroxynitrites (PNT). Expression of gp91phox in G-MDSC regulated their production of ROS. In addition, M-MDSC-induced suppression was overcome using a PNT scavenger or an inhibitor for S-nitrosylation. These results suggest that sub-populations of MDSC suppress T cell proliferation through independent mechanisms. Targeting of these pathways may enable the design of new therapeutic approaches to reverse T cell tolerance in cancer.