bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the role of mouse Ly-6A as immune checkpoint inhibitor
Authors: Capozzoli Benjamin Daniel , Mallon Francine , Bamezai Anil K 
Published: January 2023

Abstract
Discovering new immune checkpoint inhibitors is critical for extending the current strategy of cancer immunotherapy to more cancer patients where blocking a single immune checkpoint inhibitor is insuffcient. We hypothesized that the Ly-6A protein is an immune checkpoint inhibitor. Ly-6A, a member of the Ly-6 supergene family, is a cell surface receptor on CD4+T cells with cell-cell adhesion and cell signaling properties. Naïve CD4+T cells show low expression of Ly-6A protein, while the expression of this protein is highly upregulated in activated and clonally expanding CD4+T cells. While overexpression of Ly-6A on CD4+T cells results in their inhibited antigen-specific clonal expansion of CD4+T cells, consistent with that is CD4+T cells from Ly-6A−/− mice show moderate hyper-responsiveness. To examine the immune inhibitory and potentially immune checkpoint inhibitory role of Ly-6A protein we have transplanted B16 melanoma tumors into Ly-6A−/− mice. We have observed that Ly-6A−/− mice often have smaller tumor volumes or absence of a tumor within the same time frame that C57Bl/6 mice develop consistently large tumors. FACS analysis has also revealed that Ly-6A−/− mice also have more activated TILs compared with the C57Bl/6 mice as well as more active T cell populations in the non-draining and draining lymph nodes. These early results suggest that Ly-6A may behave as an immune checkpoint inhibitor. Additional experiments with B16 cell line, another tumor line (MC38 adenocarcinoma), and antibody blockade of Ly-6A are underway.
Multidimensional single T cell analysis reveals altered T cell biology upon treatment of murine tumor with checkpoint blockade immunotherapy
Authors: Rao Samhita , Kornberg Adam , Lin Sijie , Gharib Karim , Koganti Lahari , Garcia Javier Alejandro Garcia-Vilas , Masuda Kazuya , Han Arnold 
Published: January 2023

Abstract
Checkpoint blockade immunotherapy has shown great success in certain types of cancers, but are ineffective in most cancers. We do not understand why these therapies fail.
Here, we seek to better understand functional changes in T cells in responsive tumors through single cell TCR sequencing and high dimensional phenotypic analysis within single tumor-infiltrating T cells. Through surgical biopsy, we analyze the same tumor longitudinally before and after treatment, enabling us to track the fate of individual T cell clones.
Our data show that the CD4/CD8 ratio decreases upon treatment. T cells expressing inhibitory markers such as PD1, CTLA4, diminish post treatment. We see distinct clusters of effector CD4 and CD8 T cells in treated tumors, including effector CD4 populations with Tfh, Th1 and Th2 phenotypes. CD4 Tregs are greatly diminished upon successful treatment, and diminish through clonal contraction. Furthermore, TCR acts as a unique marker for T cell ancestry, which links T cell function to T cell specificity. Based on TCR clonality, we observe that expanded T cell clones before treatment do not share the same TCRs with expanded T cell clones after treatment. This implies new CD8 T cell clones are recruited into the tumor upon treatment.
From our data, we will be able to identify T cell clones that are phenotypically distinct and expanded in responsive tumors which is critical in understanding what makes for a successful T cell response after immunotherapy.
Monitoring PD-1 Signaling in Tumor Infiltrating Lymphocytes
Authors: Bu Xia , Juneja Vikram R. , Mahoney Katheleen M. , Renolds Carol G. , Mcguire Kathleen A. , Maleri Seth , Hua Ping , Zhu Baogong , Klein Sarah R , Greenfield Edward , Armand Philippe , Ritz Jerome , Sharpe Arlene , Freeman Gordon J 
Published: January 2023

Abstract
Programmed death (PD)-1 pathway blockade is a successful strategy for cancer immunotherapy. However, only a limited number of patients respond. There is great need to identify predictors of therapeutic response to PD-1 immunotherapy. One challenge is that PD-1 expression can mark activated T cells, which are susceptible to PD-1-mediated inhibition, but does not indicate whether a PD-1-mediated immunoinhibitory signal is being delivered. Currently there are no methods to detect active PD-1 signaling and, in turn, successful PD-1 inhibition. Here, we describe a novel antibody that detects PD-1 signaling. This antibody detects phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of both human and mouse PD-1 (phospho-PD-1). Using this anti-phospho-PD-1 mAb, we show that PD-1+ tumor infiltrating lymphocytes (TILs) in MC38 murine colorectal tumors have high levels of phosphorylated PD-1, particularly in PD-1+TIM-3+TILs. Upon PD-1 blockade, PD-1 phosphorylation is markedly decreased in TIM-3+CD8+ TILs prior to tumor clearance. We also observed decreased phospho PD-1 levels in T cells from peripheral blood of human lymphoma patients following treatment with PD-1 and LAG-3 mAb. These data demonstrate that phosphorylation of the ITSM of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Analysis of phospho-PD-1 may serve as a potential biomarker for effective PD-1 immunotherapy.
Interferon alpha promotes extrinsic apoptosis of keratinocytes following exposure to ultraviolet B radiation
Authors: Estadt Shannon N , Moore Tyson , Kahlenberg J. Michelle 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by sensitivity to ultraviolet radiation (UVR). UVR can trigger cutaneous and systemic disease flares, yet mechanisms driving this are not well characterized. Type I interferons (IFNs) are expressed at higher levels at baseline in non-lesional skin of SLE patients and promote increased death of SLE keratinocytes (KCs) after UVR. The manner in which they regulate cell death after UVR is currently unknown. This study explores cell death pathways activated in KCs by type I IFNs and UVR. We treated immortalized human KCs (N/TERTs) overnight with IFNα prior to UVB exposure. Four hours post UVB, Annexin V (AV) and propidium iodide (PI) and cleaved-caspase-3 (CC3) staining were used to measure cell death via flow cytometry. IFNα significantly increased the percentage of CC3+ and AV+PI− cells compared to treatment with UVB alone. Further, IFNα treatment promoted apoptosis at a lower dose of UVB (20 mJ/cm2). Pre-treatment with RIPK1, RIPK3, or caspase-1 inhibitors had no effect on death suggesting this enhanced death does not involve necroptosis or pyroptosis. Use of a pan-caspase inhibitor or a caspase-8 inhibitor significantly reduced AV+PI− cells following IFNα and UVB treatment while treatment with a caspase-9 inhibitor did not, suggesting enhanced activation of the extrinsic apoptosis pathway. These data suggest that photosensitive responses exhibited by SLE patients are likely due to type I IFN priming of keratinocytes that sensitizes cells to undergo increased extrinsic apoptosis after minimal exposures to UVB. Continued investigation into mechanisms by which this occurs will be crucial for developing novel preventative strategies for photosensitivity.
Dysregulation of type I IFN and IL-4R signaling regulates the development of BCR VH and VL repertoire encoding anti-Sm autoantibodies in SLE
Authors: Mountz John D. , Gao Min , Liu Shanrun , Chong Zechen , Wu Qi , Yang PingAr , Chatham W. Winn , Hsu Hui-Chen 
Published: January 2023

Abstract
The most specific predictor for systemic lupus erythematosus (SLE) and lupus nephritis (LN) is the presence of anti-Smith (Sm) autoAb. Mechanisms leading to selection bias for anti-Sm development is unclear. We found that anti-Sm levels in SLE correlated with increased endogenous IFN-β and interferon-stimulated genes (ISGs) in combination with low (IL-4R) network genes. Using flow cytometry analysis of 47 SLE patients, we found that anti-Sm+ patients exhibited an increased ratio of IFN-β+ activated naive (aNAV) B cells and a decrease in IL-4R+ resting naive (rNAV) B cells. Using a combined 10X single-cell transcriptomics and BCR usage analysis, anti-Sm+LN+ISGhiIL4Rlopatients (Sm+) were compared with anti-Sm−LN− ISGloIL4Rhi patients (Sm−). BCR heavy chain analysis showed that while B cells from Sm+ patients exhibit greater usage of IGHV1-2, IGHV4-34, and IGHV4-39 genes, Sm− SLE patients exhibit greater usage of IGHV3-30, IGHV3-33, and IGHV4-31 genes. Preferential Ig light chain usage for ISGhi B cells was IGLV1-51, IGLV3-21, IGLV6-57, IGKV1-5, IGKV3-15 and IGKV 6-21. Dominant heavy-light chain pair usages for the Sm+ patients were IGHV4/IGKV1 and IGHV4/IGKV3. IGHV4-34, which is intrinsically autoreactive and the target of the 9G4 anti-idiotype Ab, was found to be expressed by the ISGhiIL4Rlo B cells derived from the same Sm+ patients. The results indicated that increased levels of ISGs and decreased levels of IL-4R pathway genes are the two dominant signatures and the underlying mechanisms leading to selection and activation of anti-Sm+ B cells. Verification that the B-cell IFN-β and IL-4R phenotypes are associated with race (AA vs. EA), repertoire (anti-Sm+) and disease (LN+) would lay the basis for targeted rational therapies.
AIM2 deficient mice develop severe Systemic Lupus Erythematosus pathogenesis due to elevated type I interferon signaling
Authors: Meng Guangxun , LU Ailing , WU Shuxian 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) often involves kidney damage, and the inflammasome-caspase-1 cascade had been demonstrated promoting renal pathogenesis. However, our present work found that deficiency of Aim2 led to enhanced nephritis in pristane-induced experimental lupus model. We further found that increased type I interferon (IFN-I) signal in the Aim2−/− mice was in tandem with exaggerated SLE. Moreover, adaptive immune cells were also involved in the interstitial nephritis in the glomeruli of Aim2−/− mice. Of note, even without pristine challenge, Plasmacytoid dendritic cells in the kidney of Aim2−/− mice were significantly more abundant compared with control animals. A transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of IFN-I-induced genes in the kidney at different developmental stages. Taken together, our study demonstrates a critical role for AIM2 in suppressing IFN-I production and development of SLE.
Type 1 interferons promote allo-antibody responses to RBC transfusion in a lupus mouse model
Authors: Gibb David R , Madany Emaan , Kadi Najwa El , Pandya Sumaarg , Ng Kessandra , Jefferies Caroline Anne 
Published: January 2023

Abstract
Red blood cell (RBC) transfusion exposes recipients to hundreds of unmatched minor RBC antigens. This exposure can lead to production of alloantibodies that can cause potentially fatal hemolytic events. Prior studies have reported that inflammatory states, including autoimmune disease, in the transfusion recipient can promote alloimmunization. Recent studies reported that pro-inflammatory type 1 interferons (IFNα/β) regulated RBC alloimmunization in multiple mouse transfusion models. Interestingly, patients with systemic lupus erythematosus (SLE) have an increased frequency of alloimmunization and express an IFNα/β gene signature. Thus, we tested the hypothesis that IFNα/β activation in lupus promotes RBC alloimmunization by utilizing the pristane-induced lupus mouse model. Pristane significantly induced serum IFNα and expression of multiple interferon-stimulated genes (ISG) in peritoneal fluid cells, including inflammatory macrophages. Following transfusion with allogeneic RBCs expressing the KEL antigen, pristane-treated WT mice produced significantly elevated levels of anti-KEL IgM and anti-KEL IgG, compared to untreated mice. Pristane-treated mice lacking the IFNα/β receptor (IFNAR1−/−) or IFNα/β-inducing transcription factors (IRF3/7−/−) mice failed to produce ISGs and produced significantly lower levels of anti-KEL IgG compared to WT mice. In conclusion, pristane induction of a lupus-like phenotype promoted alloimmunization to the KEL RBC antigen in an IFNα/β-dependent manner. These results warrant further investigation of the role of IFNα/β in alloimmunization to other RBC antigens and the contribution of IFNα/β responses to the increased frequency of alloimmunization in patients with SLE.
Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis
Authors: Wu Xunyao 
Published: January 2023

Abstract
Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1β and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
Organic compound farnesol as possible inhibitor of inflammasome complex, in murine macrophages and mouse model of multiple sclerosis
Authors: Sell Lacey B , Ramelow Christina C. , Strawn Kevin D. , Hevrin Theresa , Kirby Trevor O. , Gibson K. Michael , Roullet Jean-Baptiste , Ochoa-Repáraz Javier 
Published: January 2023

Abstract
Many advancements in the understanding of multiple sclerosis (MS) have been made through the use of laboratory models. One commonly used model is experimental autoimmune encephalomyelitis (EAE), a mouse model characterized by central nervous system (CNS) inflammation and demyelination, allowing for symptoms resembling some of the most prominent features of the human disease. Although the exact etiology of MS is still being investigated, experiments with EAE have shown that the NLRP3 inflammasome complex of the innate immune system is critical and necessary for disease development. The inflammasome complex can be assembled in all innate immune cells, including microglia and astrocytes in the CNS. Dysregulation of inflammasome activity can result in uncontrolled inflammation, which underlies many chronic diseases, and metabolic and autoimmune disorders such as MS. Our lab has shown that farnesol a 15-carbon organic sesquiterpene and primary alcohol, reduced EAE disease severity and onset and also decreased T-cell infiltration into the CNS. However, the mechanisms of its action have yet to be fully defined. Therefore, in-vitro work on murine macrophages is being conducted to investigate how farnesol may be potentially affecting the pathway of the inflammasome complex and providing this protection. Furthermore, since farnesol is a quorum-sensing molecule that impacts biofilm formation, other studies of ours are aimed at evaluating how farnesol affects the gut-brain axis and specifically the gut microbiome of EAE mice.
Effects of using nanogel-cross-linked porous gel with cell adhesion factor for cell transplantation
Authors: Sato Yoshiki , Yamamoto Kenta , Takizawa Shigeta , Adachi Keiji , Oseko Fumishige , Amemiya Takeshi , Kishida Tsunao , Yamamoto Toshiro , Mazda Osam , Kanamura Narisato 
Published: January 2023

Abstract

Objective
Transplantation of engineered three-dimensional (3D) tissue may provide therapeutic benefits to patients with various diseases. To achieve this goal, appropriate 3D scaffolds and cells are required. We report a cell transplantation experiment in which a cell adhesion factor is incorporated into a porous crosslinked nanogel to attach cells.

Materials and Methods
RGDC and fibronectin were incorporated to attach cells to the porous cross-linked nanogel. RGD-conjugated, Fibronectin-coated, and non-coated NanoCliP-FD matrices were soaked in the cell suspension, and air bubble was pushed out of the matrices with tweezers to allow infiltration of the cell suspension into the matrices. The adhesion between the porous crosslinked nanogel and the cells was evaluated by staining and WST assay. Thease samples were used for cell transplantation.

Results
When different cell adhesion factors were incorporated into the porous cross-linked nanogel, it became clear that the adhesion modes were different. When cells were transplanted using a complex in which cells and porous crosslinked nanogel were adhered, tissue recovery was observed.

Discussion
By incorporating a cell adhesion factor into the porous crosslinked nanogel, it became possible to use it as a cell transplant material. Cells attached to the porous cross-linked nanogel are considered to be very useful for tissue recovery.
Functional differences in behavior of monocyte/macrophage from HIV+ patients versus healthy subjects
Authors: Lozano Javier , Chow Dominic C , Ndhlovu Lishomwa C , Siriwardhana Chathura , Liu Jocelyn , Irei Jason , Nagamine Lorna , Shikuma Cecilia , Boisvert William A 
Published: January 2023

Abstract
Increased risk of atherosclerotic cardiovascular diseases is common in HIV+ adults on stable antiretroviral treatment (ART). A key step in the development of the atherosclerotic plaque is the transmigration of monocytes to the plaque area and their differentiation into macrophages and eventually foam cells. The objective of this study was to determine if the propensity of monocytes to transmigrate as well as their ability to take up and efflux cholesterol is affected by HIV infection. Monocytes (transmigration) and differentiated macrophages (lipid metabolism) from HIV+ ART treated patients were compared against those from matched controls as a single point cross-sectional study. Monocyte transmigration was assessed by transwell assay using MCP1 as a chemoattractant, whereas lipid uptake was measured by flow cytometry analysis of internalized acetylated LDL and cholesterol efflux by tracking tritiated cholesterol excreted from the cell after exposure to HDL. Interestingly, isolation of monocytes via negative selection with magnetic beads revealed that the yield of monocyte was significantly lower from HIV+ patients compared to controls. While no significant differences were found in cholesterol uptake or efflux parameter, the ability of monocyte to transmigrate was slightly increased in HIV patients compared to controls suggesting that the chemotactic function of monocytes may be partly responsible for the differences in the atherosclerosis risk in patients with HIV.
Human eosinophils and neutrophils biosynthesize novel 15-lipoxygenase metabolites from 1-linoleoyl-glycerol and N-linoleoyl-ethanolamine
Authors: Archambault Anne-Sophie , Tinto Francesco , Martin Cyril , Dumais Elizabeth , Rakotoarivelo Volatiana , Laviolette Michel , Silvestri Cristoforo , Kostrzewa Magdalena , Ligresti Alessia , Boulet Louis-Philippe , Di Marzo Vincenzo , Flamand Nicolas 
Published: January 2023

Abstract

BACKGROUND
The endocannabinoids 2-AG and AEA are lipids regulating many physiological processes, notably inflammation. The endocannabinoidome includes other monoacylglycerols (MAG) and N-acyl-ethanolamines (NAE) such as 1-linoleoyl-glycerol (1-LG) and N-linoleoyl-ethanolamine (LEA). Endocannabinoid hydrolysis inhibitors are now being tested as potential anti-inflammatory agents. By increasing MAG and/or NAE levels, these inhibitors will likely increase the levels of their metabolites. Herein we investigated whether 1-LG and LEA were substrates for the 15-lipoxygenase pathway, which is strongly involved in asthma and its severity. We thus assessed how human eosinophils and neutrophils biosynthesized the 15-lipoxygenase metabolites of 1-LG and LEA. Linoleic acid (LA), a well-documented substrate of 15-lipoxygenases, was used as positive control.

RESULTS
We synthesized the putative 15-lipoxygenase metabolites of 1-LG and LEA using Novozym435 and soybean lipoxygenase. Eosinophils, which express the 15-lipoxygenase-1, metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was almost complete after 5 minutes. Substrate preference of eosinophils was LA&gt;LEA&gt;1-LG. Human neutrophils, which express the 15-lipoxygenase-2, also metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was maximal after 30 seconds. Substrate preference was LA≫1-LG&gt;LEA. Importantly, the new 15-lipoxygenase metabolites we disclose were found in tissues from humans and mice.

CONCLUSIONS
We successfully showed that human eosinophils and neutrophils transforms 1-LG and LEA into novel 15-lipoxygenase metabolites. How these new metabolites modulate the inflammatory cascade is now being explored.
The Use of Moodle Apps and Khan Academy Short Videos to Engage Students to Learn Microbiology/Immunology
Authors: Fazal Nadeem , Fadhil Shams , Edquiban Marianne , Olk Sandra 
Published: January 2023

Abstract
The purpose of this research project was to look at the use of technology in Immunology education. There have been reports that non-conventional ways do not effectively deliver the content matter to the students. We used Moodle and online resources to evaluate ways to enhance student engagement and participation. In the past we have investigated and published innovative methods to accomplish this goal. In the current study we used pre-lectures as a tool to enhance student learning and performance. The intent was to enforce and supplement classroom teaching and not introduce an alternative. During the spring semester a didactic course of Immunology is taught to first year pharmacy students at Chicago State University. Prior to this investigation we surveyed and determined that students are challenged with this course of Immunology. Other than being introduced to Immunology for the first time, they struggle with getting used to workload in a professional school and time management. Since our preliminary survey showed that students do not always have enough time to watch one-hour long lecture videos, we decided to use short and topic-focused videos &lt;10 minutes. Students could listen driving to school, work, or during the 10-minute breaks between classes. For the purpose of this research project we selected reliable online resources that offered information via short lecture videos. Usage data showed that Khan Academy videos were among the top choices among students. We selected Immunology short videos and provided links to via Moodle, which allowed us the pertinent usage data over the entire semester. Our data showed that those students who listened to pre-lectures Immunology videos performed significantly better in exams than those who did not.