bluuebunny/crossref_metadata_2025_split huggingface dataset:
Farnesol reduces T cell infiltration in murine CNS inflammatory demyelination
Authors: Ramelow Christina C , Sell Lacey B. , Strawn Kevin D. , Hevrin Theresa , Kirby Trevor O. , Gibson K. Michael , Roullet Jean-Baptiste , Ochoa-Repáraz Javier 
Published: January 2023

Abstract
Farnesol (FOL) is a naturally-produced 15-carbon organic acyclic sesquiterpene alcohol (isoprenol) that acts as a potent blocker of neuronal voltage-gated Ca2+ channels (L- and N-type) and is found in the human brain. FOL has potent anti-oxidant and anti-inflammatory effects in vitro and is neuroprotective in a murine model of neurotoxicity. Because inflammation and neurodegeneration are mechanisms associated with CNS demyelinating diseases, we sought to determine whether FOL treatment would result in protection against experimental autoimmune encephalomyelitis (EAE). We compared the progression of EAE in MOG35–55 immunized female C57BL/6 mice treated orally with FOL (100 mg/kg/daily) emulsified in corn oil, versus vehicle-treated and untreated EAE mice. FOL significantly reduced the average clinical scores of EAE mice when compared to untreated mice and vehicle-treated mice. The protective effect was associated with a significant reduction of CD4+ T cell spinal cord infiltration in FOL-treated mice as assessed by flow cytometry. Although FOL’s mechanism of action remains to be known, we propose that FOL promotes protection against CNS inflammatory demyelination by promoting an anti-inflammatory effect. We compared pro-inflammatory and anti-inflammatory cytokine transcriptional levels in brain tissues of EAE mice and histological analysis of CD4+ T cell CNS infiltration and demyelination. The potential benefit of FOL nanoencapsulation in neuroprotection was explored. We demonstrate that there is a correlation between the reduced neuroinflammation and EAE severity observed in the context of FOL protection. Understanding the neuroprotective effects of FOL may provide insight to novel therapeutic approaches for MS.
Immunotherapy in Probable autoimmune encephalitis without detected autoantibody
Authors: Lee Woo-Jin , Lee Soon-Tae , Hong Sang Bin , Son Hyoshin , Jang Yoonhyuk , Sunwoo Jun-Sang , Park Kyung-Il , Chu Kon , Lee Sang Kun 
Published: January 2023

Abstract
Along with the rapidly expanding spectrum of autoimmune encephalitis (AE), probable AE with no detected autoantibody (AE-NoDab) has become a major category of AE. However, its clinical features, treatment, and prognosis were not demonstrated. In our institutional cohort of all consecutive patients with possible AE in 2012 – 2018, patients diagnosed with AE-NoDab were included in this study. AE-NoDab was subcategorized into limbic encephalitis (LE), acute disseminated encephalomyelitis (ADEM), and antibody negative probable AE (pAE). Patients’ clinical severity was assessed at every week for the first 12 weeks, at every month for the next 9 months, and then at every three months, using the modified Rankin scale (mRS) and the Clinical Assessment Scales in Autoimmune Encephalitis (CASE, score range 0–27) scores. Combination immunotherapy regimens used at each time point were categorized as steroid+immunoglobulin (SI), SI+Rituximab (anti CD-20 mAb, SIR), and SIR+ Tocilizumab (anti IL-6 mAb, SIRT). 136 patients (LE 52[38.2%], ADEM 14[10.3%], and pAE 70 [51.5%]) were followed-up for 39.0±19.6 (range 10–80) months. At last follow-up, 76 (55.9%) patients had favorable mRS outcomes (scores 0–2). Compared to 55 anti-NMDA receptor encephalitis patients, baseline severity was higher, use of immunotherapy was lower, and outcome was poorer in AE-NoDab. There was no difference in clinical characteristics, treatment, and outcomes among subcategories of AE-NoDab. In a linear mixed model analysis, using the SIRT regimen was more effective than conventional regimens such as SIR or SI in lowering CASE scores (both, P=0.001). Early diagnosis and use of combined immunotherapy consisting of SIRT is warranted to improve the poor outcomes of AE-NoDab.
Deficiency in B Cell Maturation Antigen reveals sex differences in Experimental Autoimmune Encephalomyelitis
Authors: Kumar Gaurav , Ko Rose M. , Axtell Robert C. 
Published: January 2023

Abstract
Multiple sclerosis (MS) is immune mediated demyelinating disease of the central nervous system (CNS) leading to neuronal damage. The disease is heterogeneous with respect to onset and clinical course, being more prevalent in women then in men with a ratio of 3:1. Further sex differences have been observed with males having a more severe and debilitating disease course compared to females. The complex interplay of immune cells, sex hormones or genetic differences could be contributing to these clinical phenomena, which remains to be elucidated. In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, several reports have demonstrated no sex differences in disease onset or severity in C57BL/6 mice. Herein we report that deficiency in B Cell Maturation Antigen (BCMA) in C57BL/6 mice reveals a sex difference in EAE. BCMA plays a prominent role in B cell function, however the role BCMA plays in MS and EAE is unknown. Our initial goal of this project was to determine the impact BCMA deficiency has on EAE. In doing so we confirmed that EAE disease was not different in males and females from BCMA+/+mice. Strikingly in the BCMA−/− mice, there was a significant increase in EAE disease severity in males compared to females. The increased EAE in the BCMA−/− male mice was associated with increased demyelination and infiltration of inflammatory T cells and macrophages into CNS. Also, we observed decreased splenic transitional B cells in male BCMA−/− mice compared to females. Castration of mice significantly reduces EAE in BCMA−/− mice as compared to sham controls. Altogether, our data demonstrate that male hormones exacerbates EAE in BCMA−/− mice by augmenting inflammatory responses compared to females leading to increased neuro-inflammation.
Identification of markers of relapse in EAE using high-resolution quantitative mass spectrometry
Authors: Chase Carol Ann , Trementin Guillaume , Mullens Conor , Haskins William E , Forsthuber Thomas 
Published: January 2023

Abstract
Approximately 85 percent of individuals newly diagnosed with multiple sclerosis have the relapsing-remitting form of the disease characterized by attacks of neurologic symptoms that are unpredictable in occurrence and duration. Currently there are no clinically available biomarkers predictive of relapse. To address this need, we investigated CNS proteome changes over the disease course of relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in SJL mice as a preclinical model of the disease. Using a high-throughput quantitative preparation technique and high-resolution Bruker timsTOF mass spectrometry, we were able to identify thousands of unique proteins at each disease timepoint. Principal component analysis of protein expression confirmed that the remission and relapse phases of disease cluster independently, indicating distinguishable variation in protein expression profiles between the two disease states. Importantly, statistical testing identified proteins with differential expression in the CNS at different stages of disease, several of which are CNS specific. We are seeking to detect corollary changes in these CNS-specific proteins in the serum, pointing to a minimally invasive means of monitoring disease progress and measuring drug efficacy. Our study will validate homologous human biomarkers to guide treatment in individual patients and allow for proactive therapeutic intervention. Furthermore, our results may provide insights into mechanisms that contribute to disease pathology and offer novel therapeutic targets.
Case study: mepolizumab prevents progression of eosinophilic granulomatosis with polyangiitis with involvement of the central nervous system which is refractory to conventional immunotherapy
Authors: Son Hyoshin , Hong Sang Bin , Jang Yoonhyuk , Lee Woo-Jin , Sunwoo Jun-Sang , Jeon Daejong , Lee Soon-Tae , Park Kyung-Il , Lee Sang Kun , Chu Kon 
Published: January 2023

Abstract
Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis involving small-sized vessel. It manifests mainly as asthma or eosinophilia, but the literature reported involvement of the central nervous system (CNS) in 5%, while isolated CNS involvement is very rare. We describe a case of isolated CNS involvement of EGPA which was refractory to conventional immunotherapy and treated with mepolizumab, an anti-interluekin-5 monoclonal antibody. A previously healthy 51-year-old man was referred to the neurology department for memory decline persisting for a month. Magnetic resonance imaging (MRI) showed the multifocal lesion in the periventricular and frontal lobe. Analysis of cerebrospinal fluid revealed an elevated protein concentration and leukocytosis. Considering his age, clinical course, and laboratory findings, steroid and intravenous immunoglobulin was started for autoimmune encephalopathy. Two months after discharge, the patient experienced new symptom – gait disturbance. The follow-up MRI showed increased extent of the previous lesions and the new lesions. To confirm the diagnosis, brain biopsy was done, and the finding was consistent with EGPA. We decided to start mepolizumab as second-line treatment, and observe the stationary course and absence of further progression of the lesion in the follow-up MRI. Mepolizumab for EGPA patients was introduced to achieve protocol-defined remission and clinical benefit compared to the placebo group in the several studies. Our case signifies possibility of mepolizumab to halt further progression of the disease clinically and radiologically, for the patient with isolated CNS involvement of EGPA which is unresponsiveness to conventional immunotherapy.
Cognitive deficit and neuroinflammation were abolished by a single adoptive transfer of Regulatory T cells in 3xTg mouse model of Alzheimer’s disease
Authors: Yang HyeJin , Park Seon-Young , Kim Kyunghwa , Baek Hyungjung , Hong Minwoo , Cha Nari , Bae Hyunsu 
Published: January 2023

Abstract
Alzheimer’s disease (AD) is characterized by progressive cognitive and functional loss leading to neurodegeneration. Although the details are unclear, recent substantial literature suggest that neuroinflammation can facilitate or initiate neurodegeneration of AD. We previously reported the therapeutic potential of regulatory T cells (Tregs) modulating neuroinflammation to protect cells against neurodegeneration. This study assessed the impact of regulatory T cells in the context of Alzheimer’s diseases and investigated the therapeutic effects by adoptive cell therapy with Tregs. When regulatory T cells were administered in the 3xTg animal model of AD, cognitive impairment was markedly improved. Microglial activation and reactive astrocyte in AD mice were dramatically abolished after a single injection of adoptive transfer of regulatory T cells. We confirmed these therapeutic potential of adoptive transfer of Tregs in intraventricular amyloid-β-injected mice model. Altogether, our studies suggest that regulatory T cell adoptive transfer may alleviate neurodegeneration of Alzheimer’s disease (AD).
IFNAR signaling augments T cell and plasmacytoid dendritic cell activation during costimulation blockade resistant rejection
Authors: Habib Jakob , Mathews David , Dong Ying , Breeden Cynthia , Adams Andrew 
Published: January 2023

Abstract
Costimulation blockade (CoB) is a promising new transplant immunosuppression strategy offering improved long-term allograft survival without the nephrotoxicity of calcineurin inhibitors. However, increased risks of T cell mediated acute rejection have impeded the widespread adoption of CoB. Type I interferon (IFN) produced predominantly by plasmacytoid dendritic cells (pDCs) in response to innate immune signals, induce systemic inflammation that may prime the adaptive immune system for acute rejection. Here we investigate how signaling through the type I interferon receptor (IFNAR) contributes to CoB-resistant allograft rejection. We performed fully MHC-mismatched skin grafts from Balb/cJ donors to C57BL/6 recipients. Mice were treated with CoB alone (250 μg CTLA4-Ig + 250 μg anti-CD154 given by IP injection day 0, 2, 4, 6) or in conjunction with anti-IFNAR (250 μg given day 0, 2, 4, 6). CoB treatment improved graft survival but resulted in CoB-resistant rejection, while CoB+anti-IFNAR significantly improved graft survival. We found that CoB+anti-IFNAR led to a reduction in the activation and effector function of CD8+ T cells compared to CoB alone, demonstrated by reduced frequencies of CD44+CD8+ T cells and an inhibition of IFN-gamma and TNF-alpha production by CD8+ T cells. In addition, we observed reduced CD80 and MHC I expression on conventional DCs (cDCs) and pDCs treated with CoB+anti-IFNAR compared to treatment with CoB alone. These data suggest that signaling through IFNAR augments cDC and pDC activation and is associated with CD8+ T cell activation and effector functions in order to promote CoB-resistant allograft rejection.
Identification of immunologic factors associated with allograft rejection using NGS T cell receptor repertoire data
Authors: Vetter Julia , Aschauer Constantin , Heinzel Andreas , Reindl-Schweighofer Roman , Jelencsics Kira , Hu Karin , Oberbauer Rainer , Winkler Stephan , Schaller Susanne 
Published: January 2023

Abstract
T and B cells are known to play an important role in transplant rejection. Nevertheless, the factors that lead to rejection are not yet fully understood. We have developed a general bioinformatics pipeline for processing T cell receptor (TCR) and immunoglobulin (IG) repertoire next-generation sequencing (NGS) data for comparing immune repertoire properties between multiple groups of samples. Using such a pipeline can help to identify properties of the immune repertoire increasing the risk of allograft rejection after transplantation.
Our pipeline is implemented in Python 3.7. Various methods for processing, analyzing and comparing multiple immune repertoire NGS samples are provided. The pipeline returns detailed information about the sequencing quality and provides calculations and visualizations in regard of clonality, diversity, clonotype overlap as well as V(D)J gene analysis and similarity analysis of TCR and IG repertoires.
The functionality of the pipeline will be demonstrated on immune repertoire sequencing data from eight kidney transplant patients with sequential samples. For all patients mixed lymphocyte reactions (MLRs) have been performed to identify alloreactive T cells. With our clonotype overlap analysis module we were able to identify alloreactive clonotypes and to subsequently track changes in the alloreactive repertoire after transplantation.
Out-of-the-black-box: Standardisation of the EliSpot Method for immunomonitoring in personalized Immunosupression after solid organ tranplantation
Authors: Ettischer-Schmid Nicole , Strecker Kevin , Stein Maik , Reinke Petra , Preyer Rosemarie 
Published: January 2023

Abstract
Individual Immunotherapy for transplantation patients has been moved more and more into the focus of transplant centers, as individualized therapy approaches enable to minimize long-term side effects and increase the quality of life for the patients.
The Enzyme-Linked ImmunoSpot assay (EliSpot) has become a powerful tool in solid organ and stem cell transplantation. In an European multicenter study, the Bio-DrIM project c, the use of the EliSpot has been extensively evaluated with regard to monitoring of viral (Epstein-Barr Virus, EBV; Human Cytomegalovirus, HCMV and BK Virus, BKV) reactivation during immunosuppressive therapy after kidney transplantation.
The reference institute established SOPs and trained the attending sites. Additionally, EliSpot Reader Systems and EliSpot kits were extensively technical validated to guarantee that all centers reach the same results.
A total of 21 plates with 1983 wells were counted. Linear regression of all 1983 pairs of values lead to a linear regression line with the equation y=1.026*x+0,06888 and a Pearson correlation coefficient R2=9988, demonstrating the high concordance of each reader system.
To further demonstrate the extraordinary high standardization of the procedure, Inter- and Intra-Assay evaluation were performed. In the set of analyzed results the CV % varied under 20 %, which is far below cellular assays specified by the FDA with 25 %.
In conclusion, the combination of the EliSpot method with the EliSpot Reader System is a high-performance tool for diagnostics and monitoring of immunosuppression. Based on the high standardization potential, this state-of the-art technology will play an important role in diagnostic validation of next generation personalized therapy.
Regulation of ultraviolet radiation-induced cutaneous DNA damage by type I interferons
Authors: Sherwani Mohammad Asif , Ahmad Israr , Raman Chander , Elmets Craig , Yusuf Nabiha 
Published: January 2023

Abstract
Type I interferons (IFNs) are cytokines, that are important regulators of immune responses and are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) radiation is a proven environmental carcinogen, and exposure to solar radiation contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in repair and replication of DNA. It is believed that type I IFNs reduce cellular proliferation and allow DNA repair in various diseases. Interferon receptor 1 (IFNAR1) is critical for signaling of type I IFNs. We hypothesized that type I IFNs (IFNα/β) will repair UVB induced DNA damage in mice. To test our hypothesis, shaved mice lacking IFNAR1 and wild type mice on a C57BL/6 background were irradiated with single dose of UVB radiation (100 mJ/cm2). Skin samples were examined for CPD by immunofluorescence and ELISA. We found that mice lacking IFNAR1 had more CPD as evident by ELISA and histology. In order to determine the cell type, which produces type I IFNs in skin after UVB exposure, single cell suspensions were prepared from irradiated skin samples and stained for type I IFNs using flow cytometry. We found that type I IFNs were produced by inflammatory monocytes (CD45+CD11b+Ly6C+). We also found that DNA repair gene XPA was downregulated in the mice lacking IFNAR1. In conclusion, our studies show that mice lacking the IFNAR1 had decreased repair of UVB induced CPD in the skin. Our ongoing studies will elucidate whether type I IFNs regulate development of UVB induced skin tumors.
Autocrine IL6 activates the STAT3-DNMT axis to silence the TNFa-RIP1 necroptosis pathway to sustain myeloid-derived suppressor cell survival and accumulation
Authors: Smith Alyssa D. , Lu Chunwan , Payne Daniela , Paschall Amy V , Klement John David , Redd Priscilla S , Ibrahim Mohammed , Yang Dafeng , Han Qimei , Liu Zhuoqi , Shi Huidong , Hartney Thomas , Nayak-Kapoor Asha , Liu Kebin 
Published: January 2023

Abstract
Accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. However, the underlying mechanism of MDSC accumulation in the tumor microenvironment (TME) remain incompletely understood. We report that MDSC accumulation is regulated by the TNFα-RIP1-mediated necroptosis. We determined that inhibition of DNMTs with Decitabine (DAC) abolished MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes (CTLs) in tumor-bearing mice. DAC-induced decrease of MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, DAC also abolished MDSC-like cell accumulation in IRF8 KO mice, indicating that DNA methylation does not regulate MDSC lineage differentiation but mediates MDSC accumulation at post differentiation stage. We determined that DAC decreased MDSC accumulation through increasing cell death and identified RIP1-dependent necroptosis as target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter is hypermethylated in tumor-induced MDSCs in vivo. Consequently, DAC dramatically increased TNFα level in MDSCs and neutralizing TNFα significantly decreased MDSC cell death. Furthermore, recombinant TNFα induced MDSC cell death in a does- and RIP1-dependent manner. IL6 which is expressed in MDSCs in tumor-bearing mice and human colorectal cancer patients. Our data shows that the autocrine IL6 activates the STAT3-DNMT axis to epigenetically silence the TNFα-RIP1 necroptosis pathway to sustain MDSC survival and accumulation in cancer. Targeting the TNFα-RIP1 necroptosis is potentially an effective approach to supress MDSCs to activate tumor-reactive CTLs in the TME.
Hedgehog signaling induced metabolic reprogramming is essential for M2 polarization of macrophages in breast cancer
Authors: Hinshaw Dominique C , Hanna Ann , Sherpa Tshering , Samant Rajeev , Shevde Lalita 
Published: January 2023

Abstract
Current treatments for breast cancer offer little relief to patients with metastatic disease. The aberrant activation of Hedgehog (Hh) signaling enables cancer cells to survive, proliferate, and metastasize. Effective metastasis depends upon the surrounding immune microenvironment. Macrophages (MΦ) can be polarized to M1 (inflammatory) or M2 (suppressive), and increased populations of M2 tumor infiltrating MΦs are correlated with worse prognosis. We have discovered that Hh signaling contributes to M2 polarization. M1 and M2 MΦs have inherently different metabolic profiles, so we hypothesize that Hh signaling alters M2 MΦ metabolism to reflect M1 MΦ metabolism, leading to diminished M2 phenotype and function within the tumor microenvironment (TME).
Methodology includes a mouse model of mammary carcinoma, RNA-seq, mass spectrometry-based metabolomics, confocal imaging, and flow cytometry.
We elucidated the impact of Hh signaling blockade on the metabolism of MΦs diminishing their M2 polarization. Inhibition of Hh signaling reduces MΦ O-GlcNAcylation which directly correlates with the diminished suppressive attributes of M2 MΦs through the reduced activity of STAT6. Since STAT6 plays a dual role in governing the M2 phenotype and fatty acid oxidation, this ultimately enacts a metabolic cascade, including lipid utilization, cellular bioenergetics and mitochondrial morphology and function, that metabolically alters M2 MΦs to resemble M1 MΦs.
We have discovered that blockade of Hh signaling initiates a metabolic cascade diminishing the M2 phenotype and function. This knowledge will help us to better understand how to target and diminish the pro-tumorigenic phenotypes of MΦs in the TME and at the metastatic site.
Circular RNA AEBP2 modulates dendritic cells by the hnRNP/pP65 signaling pathway
Authors: Zhou Qinfeng , Wang Bowen , Koropatnick James , Min Weiping , McAlister Vivian , Greasley Adam , Zheng Xiufen 
Published: January 2023

Abstract
Circular RNA (circRNA) has been the focus of research in recent years. However, circRNA is rarely reported in dendritic cells (DCs). In our study, Microarray analysis of circRNA showed that circular RNA AEBP2 (circAEBP2) is significantly up-regulated in mature DCs compared with immature DCs. Knockdown of circAEBP2 in DC with siRNA arrests DCs at immature status with lower expression of MHC class II, CD40, CD80, and CD83, as well as decreasing the expression of Phosphorylation of nuclear factor-kappa B p65. CircAEBP2 -silenced DCs failed to activate allogeneic CD4+ T cells and CD8+ T cells in vitro. RNA immunoprecipitation assays show heterogeneous nuclear ribonucleoproteins (hnRNP) are enriched by circAEBP2 probes which have complementary circAEBP2 sequence, indicating circAEBP2 interacts with hnRNP. The effect of circAEBP2 silenced DCs on induction of anti-tumor immunity is investigated in an ongoing murine melanoma model. In conclusion, our results demonstrate that circAEBP2 regulates the development and function of DCs through interacting the hnRNP/pP65 signaling pathway. CircAEBP2 will be a new potential target for DCs-based immunotherapy.