bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut IgA abundance in adult life can protect from DSS colitis even if maternal IgA received in early life is inadequate
Authors: Gupta Suman , Basu Srijani , Bal Vineeta , Rath Satyajit , George Anna 
Published: January 2023

Abstract
Susceptibility to DSS induced colitis has been shown to depend on various host and microbial factors, the caveat being that most of these studies have used gene-deficient or gnotobiotic mouse models. In order to study specific factors contributing to colitis susceptibility under more physiological conditions we used inbred mouse strains that differ in their IgA responses but are otherwise healthy. We found that the IgA high strain CBA/CaJ (CBA) is resistant to DSS-colitis unlike the IgA low strain C57BL/6 (B6) strain and resistance correlated with extensive IgA-coating of fecal bacteria and lower fecal bacterial loads. Additionally, we found a more robust intestinal barrier in CBA mouse, along with lower intestinal inflammation and bacterial translocation during colitis induction. Through homologous fecal microbial transplants we found that the IgA-uncoated fraction of B6 flora was relatively more colitogenic. Further, experiments with F1 and F1xParent ‘backcrossed’ progeny generated separately with CBA and B6 dams indicated that pups born to IgA high proximal dams were resistant to colitis. These results indicate a role of passive maternal IgA and active IgA in colitis resistance. In order to understand whether early exposure to passive IgA alone can confer resistance to colitis, we foster-nursed B6 pups on CBA dams and vice-versa but it did not have an effect on DSS susceptibility. Interestingly, oral administration of immunoglobulins to B6 adults did decrease DSS associated disease. Collectively, our data indicate that higher gut IgA in adult life plays a more important role as compared to maternal IgA received during early life in conferring resistance to DSS colitis.
JAML-CAR – A Mechanism of T Cell Antitumor Immunity
Authors: McGraw Joseph Michael , Witherden Deborah , Havran Wendy L 
Published: January 2023

Abstract
The junctional adhesion molecule-like protein (JAML) is expressed by a variety of immune cell subsets and binds the Coxsackie and adenovirus receptor (CAR), an adhesion molecule expressed in epithelial tissues. Previous work from our lab demonstrated that JAML-CAR interactions are a unique costimulatory mechanism that controls activation of tissue-resident γδ T cells. High expression of JAML within tumors is associated with improved patient survival in a variety of epithelial cancers, yet the role of JAML-CAR interactions in antitumor immunity has not been characterized. Based on this evidence and the fact that CAR is expressed in epithelial tissues where many tumors arise, we hypothesized that JAML-CAR interactions are critical for antitumor immunity. Initial results utilizing the B16F10 melanoma model show that JAML−/− mice are more susceptible to tumor growth and have fewer γδ and CD8 T cells within tumors compared to WT mice. In WT mice, JAML is upregulated on γδ and CD8 T cells following activation, and a large fraction of γδ and CD8 tumor-infiltrating lymphocytes express JAML. Expression of CAR in mouse B16F10 melanoma is detectable within tumor margins but not within the tumor interior, and in human melanoma, CAR expression decreases with increased malignancy. This data suggests that tumors can downregulate CAR to escape immune responses. In support of this hypothesis, overexpression of CAR on B16F10 melanoma results in slower tumor formation and growth in WT mice but not RAG−/− or JAML−/− mice, which indicates that expression of CAR sensitives tumors to immune detection. These results show that JAML-CAR interactions are critical for T cell antitumor immunity and may be a novel therapeutic target to treat epithelial cancers.
Deep characterization of tumor microenvironments using single cell multi-omics analysis
Authors: Montesclaros Luz , Boutet Stephane C , Taylor Sarah E B , Stubbington Michael J T , Giangarra Valeria , Lau Julia K , Sapida Jerald , Ziraldo Solongo , Pfeiffer Katherine A. , Zheng Grace , Barrio Alvaro Martinez , Lee Josephine Y , Marrs Samuel , Wu Kevin , Mikkelsen Tarjei S 
Published: January 2023

Abstract
Understanding the complexity of cell interactions in the tumor microenvironment (TME) requires the ability to distinguish each cell type, and is a prerequisite of personalized cancer treatments. Here, we use a fully integrated system for single cell RNA sequencing, to simultaneously profile the transcriptome, cell surface proteins and immune repertoire of cells from primary colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Each tumor varied in type and proportion of its cellular components, and in particular in the proportion of immune cells. The CRC tumor consisted of T (3% CD4+, 3% CD8+), B lymphocytes (5% CD79A+) and plasma B cells (11% IGH high). Repertoire sequencing identified a clonal expansion (&gt;4% of B cell clonotypes) suggesting a strong B cell response in this tumor. The NSCLC tumor displayed a marked immune cell infiltration containing predominantly B cells (30% CD79A+ and 8% IGH high plasma B) with a very limited clonal expansion. The MALT lymphoma consisted of only T and B lymphocytes (31% CD4+, 8% CD8+, 57% CD79A+). In addition to the activated CD4+ and CD8+ T cells, Tfh and Treg cells were clearly identified as well as two distinct large B cell populations showing plasmacytic differentiation. Analysis of the B cell repertoire revealed a large expanded clone bearing an IGHV segment associated with parotid MALT lymphoma. These findings emphasize the importance of combining repertoire and gene expression sequencing data to determine the nature and clonality of an immune response. This method enables full characterization of tumor heterogeneity and the adaptive immune response to the TME and will be key in the development of successful immunotherapies.
Irreversible electroporation stimulates a pro-inflammatory tumor microenvironment in pancreatic cancer
Authors: Brock Rebecca Michaela , White Natalie B , Ringel-Scaia Veronica Marie , Coutermarsh-Ott Sheryl L , Eden Kristin , Coutri Jenna , Manuchehrabadi Navid , Davalos Rafael V , Allen Irving C 
Published: January 2023

Abstract
Pancreatic cancer is a major cancer with a survival rate of only 6% due to late diagnosis and the aggressiveness of the malignancy. There is also a severe lack of viable treatment options due to the localization of the primary tumor near major blood vessels and bile ducts as well as the highly immunosuppressive nature and metastatic potential of pancreatic cancer. New ablative techniques for pancreatic tumors are being developed; however most are thermal and can cause damage to the delicate surrounding structures. Non-thermal irreversible electroporation (IRE) uses short, high frequency electrical pulses to permeabilize cancer cell membranes and illicit cell death. IRE has shown promising results in clinical trials of late-stage, locally advanced cases. Here we utilize several models of pancreatic cancer in vitro, ex vivo, and in vivo to determine the effect of IRE on cell death pathways, cancer pathways, and immune signaling. IRE elicits pro-inflammatory cell death via necrosis and pyroptosis in immunocompetent murine and human patient-derived xenograft models. This pro-inflammatory environment can stimulate immune cell infiltration to the tumor site, halting tumor progression. Moreover, a non-thermal ablative approach also preserves cancer cell antigens that can lead to better immunosurveillance against reoccurrence and metastatic lesions. With the advent of these new techniques, the impact of such technologies to the tumor microenvironment and immune system need to be assessed to determine their clinical application. IRE is proving to be a safe and effective treatment for pancreatic cancer as it not only ablates the primary tumor site but also stimulates the immune system to recognize and combat the tumor throughout the body.
Inhibition of PI3K promotes anti-tumor immune responses to Mantle Cell Lymphoma
Authors: Shissler Susannah Claire , Webb Tonya J 
Published: January 2023

Abstract
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma that is characterized by a chromosomal translocation resulting in overexpression of Cyclin D1, dysregulation of the cell cycle, and constitutive activation of phosphatidylinositol 3 kinase (PI3K). MCL patients also have decreased natural killer T (NKT) cells – an innate-like lymphocyte population involved in initiating the anti-tumor immune response. We hypothesize that constitutive activation of PI3K in MCL alters CD1d-mediated antigen processing and presentation, ultimately resulting in decreased anti-tumor NKT cell responses. To investigate the role of PI3K on MCL survival and immunogenicity in vitro and in vivo, we utilized a panel of PI3K inhibitors (PI3Ki). Pretreatment of human MCL cell lines with micromolar concentrations of PI3Ki resulted in increased apoptosis and enhanced immunogenicity. While dual PI3K/mTOR inhibitor Dactolisib (BEZ-235), completely abrogates NKT/T cell responses of in vitro, stimulated peripheral blood mononuclear cells, PI3K-specific inhibition allows immune cells to function. In a murine model of MCL, PI3Ki-treated animals had decreased tumor burden and increased NKT/T cell responses to ex vivo stimulation with the most significant effect seen in the Buparlisib (BKM-120)-treated group. To elucidate the mechanism, MCL cells were treated in vitro with BKM-120 and flow cytometric analysis indicated increased CD1d expression, but decreased MHC class I expression. These results suggest that selectively targeting PI3K can reduce toxicity, as well as have a significant impact on tumor burden and immune function.
Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes
Authors: Lu Chunwan , Klement John D. , Ibrahim Mohammed L. , Redd Priscilla S. , Zhou Gang , Liu Kebin 
Published: January 2023

Abstract

Background
Type I interferons (IFN-I) have recently emerged as key regulators of tumor response to chemotherapy and immunotherapy. However, IFN-I function in immune cells in the tumor microenvironment is largely unknown.

Methods
IFNAR1 knock out and mixed chimera mice, and mice with IFNAR1 deficiency only in T cells were used to determine IFN-I function in immune cell tumor infiltration and tumor development. IFN-I-regulated genes in CTLs were identified and functionally analyzed by genome-wide gene expression profiling and molecular approaches.

Results
IFNα13 and IFNβ are selectively expressed in colon carcinoma tissues in vivo. Although IFNAR1 KO mice exhibited increased susceptibility to carcinogen and inflammation-induced sarcoma and colon tumorigenesis, IFNAR1-sufficient tumors grow significantly faster in IFNAR1 KO mice and in mice with IFNAR1 deficiency only in T cells, suggesting that IFN-I functions in T cells to enhance host cancer immunosurveillance. Surprisingly, unlike in an anti-viral immune response, IFNAR1-deficient T cells exhibit no deficiency in generation of antigen-specific CTLs and IFNAR1-deficient CTLs infiltration level is similar as compared to that of WT CTLs in colon tumor-bearing mice. Gene expression profiling identified Gzmb as an IFN-I target gene in tumor-infiltrating CTLs and in antigen-specific CTLs in vivo. Mechanistically, we determined that IFN-I activates STAT3 that binds to the Gzmb promoter to activate Gzmb transcription in CTLs. IFN-I also regulates GZMB expression in human T cells, but IFNAR1 is not only significantly down-regulated in human colon carcinomas but also down-regulated in CTLs of human colon cancer patients as compared to normal colon and CTLs from healthy donors.
GITR agonism triggers antitumor immune responses through IL-21–expressing follicular helper T cells
Authors: Koh Choong-Hyun , Kim Il-Kyu , Kang Tae-Seung , Shin Kwang-Soo , Jeon Insu , Song Boyeong , Lee Jeong-Mi , Im Jiyoung , Kang Yejin , Kang Chang-Yuil 
Published: January 2023

Abstract
Treatment with glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) elicits potent antitumor immune responses in various tumor models. In this study, we demonstrate the crucial role of interleukin (IL)-21–producing follicular helper T (Tfh) cells in DTA-1-induced tumor inhibition. Administration of DTA-1 increased IL-21 expression from CD4 T cells, which is mainly made up of Tfh cells, in an antigen specific manner. Furthermore, mice treated with a neutralizing antibody to IL-21 receptor and Bcl6fl/flCD4cre mice exhibited abrogated antitumor activity induced by DTA-1. Mechanistically, IL-4 plays critical roles for the induction of IL-21–expressing Th cells by GITR co-stimulation, which is mediated by Bcl6 and c-Maf. Thus, our findings identify GITR co-stimulation as an inducer of IL-21–expressing Tfh cells and provide a novel mechanism for its antitumor activity.
CD73-dependent tumor resistance to agonistic anti-4-1BB therapy through TGF-β
Authors: Chen Siqi , Fan Jie , Zhang Minghui , Qin Lei , Dominguez Donye , Long Alan , Zhang Bin 
Published: January 2023

Abstract
Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying immune suppressive mechanisms remain incompletely understood. In our study, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB (anti-CD137) Ab therapy. In particular, anti-4-1BB treatment can downregulate the expression of CD73 on T cells by preferentially driving CD73− effector T cell response and achieve tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. Furthermore, we find the same observation in the combination of anti-CD73 and anti-GITR, another agonist antibody. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB and anti-GITR therapy by sustaining CD73 expression primarily on infiltrating CD8+T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy with increased number and function of T cells. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.
Defining the mechanisms of B cell initiated autoimmune disease
Authors: Bazile Cassandra A , Wright Jacqueline A , Clark Emily S , Carlesso Gianluca , Gao Linlin , Mahmoud Tamer , Boucher Justin , Kleiman Eden , Satterthwaite Anne B , Harhaj Edward , Khan Wasif N 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) afflicts more than 1.5 million individuals in the United States with very limited and debilitating therapeutic options. The etiology of the disease remains unclear. It is hypothesized that in SLE, peripheral B cell tolerance is breached by inappropriate survival of autoreactive cells. Consistently, overexpression of B cell activating factor (BAFF), a key regulator of B cell survival can rescue autoreactive B cells and contribute to autoimmune disease. BAFF counters apoptosis in part through decreasing BH3-only pro-apoptotic protein Bim. Notably, both BAFF and Bim are physiological regulators of B cell tolerance. Therefore, to define the role of B cells and B cell tolerance in the initiation and progression of autoimmune disease we created a mouse model wherein gene encoding Bim is selectively deleted in B cells (B.Bimf/f). Initial analyses of these mice suggest that B cells can initiate an autoimmune pathogenesis phenotypically similar to SLE, with mice exhibiting splenomegaly and increased CD21loCD23lo B cells. Given that persistent activity of NF-kB in B cells can also result in autoimmune diseases, we are now investigating whether the persistent NF-kB and dysregulated apoptosis can synergize in SLE pathogenesis. To that end, we have crossed B.Bimf/f mice with a mouse line that lacks a recently discovered potential negative regulator of NF-kB, ZFAND6 (B.Bimf/f x ZfanD6−/−). Preliminary findings suggest that the compound mutant mice display exacerbated autoimmune symptoms with higher incidence of splenomegaly and kidney pathology. These preliminary results suggest that a breach in tolerance (B.Bimf/f ) and persistent NF-kB activity cooperate in the initiation and severity of SLE pathogenesis.
Multiple tolerance checkpoints suppress low-affinity germline precursor B cells of high affinity anti-dsDNA antibody-producing cells in BCR knock-in mice
Authors: Mohammed Marwa Ali El Hussien , Sakakibara Shuhei , Tsai Chau-Yuan , Kikutani Hitoshi 
Published: January 2023

Abstract
Previously, we revealed that disease-associated dsDNA-reactive high-affinity antibodies evolve from ssDNA-reactive low-affinity germline precursors through clonal expansion and affinity maturation in acute systemic lupus erythematosus (SLE) patients. Our findings raise questions whether low-affinity precursors of anti-dsDNA antibody producing cells are subjected to immune tolerance, and under what conditions they expand and undergo affinity maturation in vivo. To address these questions, we generated G9gl, a site-directed knock-in (KI) mouse line carrying reverse mutated forms of VH-DH-JH and Vk-Jk regions of an acute SLE patient-derived high-affinity anti-dsDNA antibody. G9gl heterozygous mice had reduced numbers of B cells in their periphery, and half of peripheral B cells expressed endogenous IgH from non-KI allele due to receptor editing.
G9gl-expressing B cells exhibited several anergic phenotypes, including reduced surface BCR and shorter life span. Yet, they underwent class-switching and produced antibodies following CD40 and IL-4 in vitro stimulation. G9gl B cells responded to ssDNA, but not dsDNA in vitro, and were selectively excluded from germinal center reaction in several conditions such as Treg depletion and DNA-conjugated mBSA immunization in vivo. However, some of G9gl-expressing B cells differentiated to somatically mutated IgG+ memory B cells when immunized with bacterial DNA-conjugated mBSA.
Therefore, multiple tolerance checkpoints prevent low-affinity anti-DNA precursor B cells from undergoing clonal expansion and affinity maturation in germinal centers. However, G9gl-expressing B cell might undergo class-switching and somatic hypermutation through the extra-follicular pathway.
Distinct chromatin modifications at the Il33 locus in mast cells contribute to sex dimorphic susceptibility to EAE, an autoimmune CNS demyelinating disease
Authors: Brown Melissa Ann , Yang Yuchen 
Published: January 2023

Abstract
Many autoimmune diseases, including multiple sclerosis (MS) exhibit a striking female bias, but the underlying mechanisms remain poorly understood. Using the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which recapitulates this sex dimorphism, we previously demonstrated that preferential IL-33 expression contributes to male protection. IL-33 expression by mast cells in PLP139–151-immunized males activates type 2 innate lymphoid cells, which in turn drives a non-pathogenic Th2 response to myelin peptide. Testosterone directly activates Il33 in male but not female mast cells, but this male-specific response is also maintained with other modes of activation, including FcɛR1-crosslinking, suggesting there are constraints on the chromatin landscape that limit Il33 expression in females. Here we use ChIP and ATAC-seq to show that the dynamics of chromatin modifications at the Il33 locus is sex-dimorphic. At steady state, ChIP assays reveal activating H3K4me3 and H3K9ac histone modifications at the promoter and conserved non-coding sequences within the Il33 gene are most prevalent in male-derived cells, while H3K27me3 repressive marks dominate in females. This pattern is similar in IgE-DNP-activated mast cells. Increased basal Il33 chromatin accessibility assessed by ATAC-seq is evident in males. Together, these results indicate that while testosterone can directly stimulate IL-33 production, it also exerts effects on Il33 during development conferring a higher potential for expression in males.
Effects of mechanical stress on cells derived from human oral mucosa
Authors: Yamamoto Toshiro , Sato Yoshiki , Yamamoto Kenta , Asai Taku , Oseko Fumishige , Kanamura Narisato 
Published: January 2023

Abstract

Objective
When a denture is applied, the oral mucosa is exposed to mechanical stress (MS) including occlusal force via the denture. Clinically, inflammation is occasionally observed in the oral mucosa immediately below the denture despite a proper fit. In this study, we applied MS to cells derived from human oral mucosa and evaluated its effects.

Materials and Methods
Subconfluent human oral mucosal epithelial cells (HO-1-N-1) and human gingival fibroblasts (HGF) were used to seed 1´105 cells/dish and, after 24 hours, subjected to MS (1 and 3 MPa, 60 min) using a hydrostatic pressurizer. Morphological changes of the cells were examined by Giemsa stain, and changes in cell activity were measured by the WST assay. In addition, mRNA was collected from the cells, and I Inflammatory cytokines and growth factors genes were measured by real-time RT-PCR assay and ELISA.

Results
HO-1-N-1 showed no morphological change by Giemsa stain but exhibited a significant decrease in cell activity by WST assay. Next, in HO-1-N-1, the expression of Inflammatory cytokines, and ICAM mRNA was significantly increased after MS at 1 MPa but was attenuated at 3 MPa. In HGF, the expression of IL-6 mRNA was enhanced. In HO-1-N-1 and HGF, the IL-6 and IL-8 protein levels increased significantly after MS. Furthermore, in HGF, the EGF and FGF-2 protein levels increased significantly by stimulation at 3 MPa.

Discussion
MS applied to the oral mucosa immediately below the denture caused a decrease in the activity of oral mucosal epithelial cells and induced enhancement of inflammatory cytokine production. Also, excessive MS was suggested to promote the cure of oral mucosa wounds by promoting the production of growth factors in the oral mucosa.