bluuebunny/crossref_metadata_2025_split huggingface dataset:
The link between Complement System and Anemia in Gaucher disease
Authors: Pandey Manoj K , Magnusen Albert Frank , McKay Mary Ashley , Hatton Shelby Loraine , Magnusen Daniel Nii Aryee , Rapien Jillian , Nyamajenjere Tsitsi Carol , Dipasquale Betsy Ann , Woods Christopher 
Published: February 2023

Abstract
Gaucher disease (GD) is the classical example of lysosomal storage disease, which happens due to mutations in GBA1 as well as the resultant deficiency of glucocerebrosidase (GCase) and the excess tissue accumulation of glucosylceramide (GC). GD patients have shown high risk for developing anemia, which is characterized by Red blood cells (RBCs) and the hemoglobin (Hb) abnormalities. The exact mechanism by which such blood aberrations progress in GD is not clear. We have described immune complexes of GC-specific IgG autoantibodies in GD, which induced massive complement activation and the resulting complement 5a (C5a) and its cognate receptor 1 (C5aR1)-mediated immune inflammation and tissue disruption in GD. Complement activation had been linked to RBCs and/or Hb abnormalities in several diseases, (e.g., atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, malaria, and β-thalassemia). Hence, we hypothesized that the C5a-C5aR1 activation is critical for anemia development in GD. To indorse this theory, blood from C5aR1 deficient (C5aR1−/−) and sufficient (C5aR1+/+) experimental mouse model of GD as well as the background matched control WT and C5aR1−/− mice were measured for RBCs and Hb with uses of automated system and the FACS staining methods. Our data illustrate that C5aR1+/+ mouse model of GD causes increased shortage of RBCs and Hb when compared to control WT or C5aR1−/− strains. Strikingly, C5aR1−/− mouse model of GD were protected from the loss of RBCs and Hb. These findings suggest that C5a-C5aR1 axis is a critical driver of disease processing of anemia in GD. Targeting C5a-C5aR1 axis may stop or slow down anemia development in GD.
Production of antigen-specific IgE requires the properly timed help from TFH cells in a food allergy model
Authors: Chen Qiang , Dent Alexander 
Published: February 2023

Abstract
Food allergy is characterized by food antigen (Ag)-specific IgE-mediated hypersensitivity. Follicular helper T cells (TFH) have been shown to control IgE production. However, the mechanisms for how TFH cells regulate IgE is not well understood. Utilizing a food allergy model in which mice are sensitized using peanut extract and cholera toxin through oral gavage, we found that peanut-specific IgE but not non-specific IgE requires two intragastric gavage (ig) Ag primings given 7 days apart. QPCR for germline expression of IgE showed that class-switching to IgE mainly occurs after second priming, which is different from IgG1. When NP-OVA and NP-KLH are used as Ags, we found that NP-specific IgE is still produced and thus maintaining the Ag specificity of TFH cells at both primings is not necessary. The expression of several IgE-promoting cytokines including IL-4 and IL-13 were upregulated in TFH cells upon the second priming. The requirement of IL-4 in antigen-specific IgE is validated using antibody blocking and Il4-heterzygote mice. Furthermore, we found that Ag-specific IgE is not produced when the timing between first and second timing is too short (2 days) or too long (2 weeks). TFH cells from these different timing showed different gene profile, indicating a possible role for the regulatory factors Fgl2 and CD39. These suppressive genes have not been associated with TFH function in food allergic IgE before. In conclusion, the production of Ag-specific IgE in gut priming requires a secondary priming and TFH cells play a crucial role through cytokines and other factors.
Effect of non-tuberculous mycobacteria on the protective efficacy of BCG vaccine via modulation of mucosal immunity
Authors: Dutt Taru S , Fox Amy , Karger Burton Richard , Rampacci Elisa , Dhadhwal Rhythm , Youssef Nathan , Obregon-Henao Andres , Henao-Tamayo Marcela 
Published: February 2023

Abstract
Tuberculosis (TB) continues to increase worldwide despite vigorous attempts to control it. Bacillus Calmette-Guerin (BCG) is the only licensed vaccine currently available for protection against TB, however, its efficacy is highly variable between countries. It has been hypothesized that BCG’s variable protection is due, amongst others, to immunological interference by environmental, non-tuberculous mycobacteria (NTM). However, a definitive mechanism has not been identified so far. Considering the foregoing, we developed a murine model closely resembling the natural history of human exposure to different mycobacterial species, including: 1) BCG vaccination at an early age; 2) exposure to viable NTMs (Mycobacterium avium subsp. avium) via the oral route and 3) maintaining continuous NTM exposure even after TB infection, as occurs in endemic places. Surprisingly, we found that a low dose of NTM via the oral route enhanced BCG-mediated protection 30 days post infection, as determined by decreased TB burden in lungs and spleens of infected mice. We hypothesized that upon oral intake, NTMs would interact with intestinal Peyer’s Patches (PPs) and activate mucosal immune responses. Therefore, we evaluated immune cell populations present in PPs and lungs using flow cytometry. Fifteen days after initiating NTM feeding, higher influx of B220hiMHC-IIhi B cells was observed in PPs of NTM exposed mice, regardless of BCG vaccination status. Similarly, NTM exposure augmented pulmonary CD62LintMHC-IIhiCD19hiB and CD4+ T cells. These results suggest that NTM exposure via the oral route elicit humoral mucosal immunity against TB, and this will be further dissected to leverage mucosal NTMs as a strategy to boost BCG.
A single center, double blind, randomized, placebo controlled trial of anakinra in adult patients with features of Cytokine Storm Syndrome in COVID-19
Authors: Cron Randy Q , Jackson Lesley E , Khullar Nitasha , Chapleau Christopher A , Chatham W Winn 
Published: February 2023

Abstract

Methods:
(ClinicalTrials.gov, NCT04362111) Adult inpatients were recruited with PCR confirmed SARS-CoV-2 infection, radiographic confirmation of COVID-19 pneumonia, new or increasing oxygen requirement, ferritin ≥700 ng/mL, and any 3 of the following: D-dimer ≥500 ng/mL, platelet count &lt;130,000/mm3, white blood cell count &lt;3500/mm3 or lymphocyte count &lt;1000/mm3, AST or ALT &gt;2X the upper limit of normal (ULN), LDH &gt;2X the ULN, C-reactive protein &gt;100 mg/L. Eligible patients were randomly assigned (1:1) to standard of care (SoC) plus anakinra (100 mg subcutaneous every 6 hours for 10 days) or SoC plus placebo. Primary outcome was survival and discharge from the hospital without need for intubation/mechanical ventilation at day 10. Analyses were done on a modified intention-to-treat basis.

Results:
Between August 2020 and January 2021, 32 patients (235 screened) were recruited: 15 assigned to anakinra group and 17 to placebo group. 2 patients in the placebo group withdrew in the initial 48 hours and were excluded from analysis. Median age was 63 years (IQR 56 – 70.3), 20 (66.7%) were men, and 20 (66.7%) Caucasian. At day 10, 1 (6.7%) patient in the anakinra group had died and 2 (13.3%) in the placebo group had died (p=0.54). At hospital discharge, 4 (26.7%) patients in the anakinra group and 4 (26.7%) in the SoC group had died. Confirmed infections occurred in 4 (anakinra) and 2 (placebo), respectively (p=0.36).

Conclusion:
Anakinra added to SoC with dexamethasone did not significantly impact outcomes in study patients with clinical lab features of early cytokine storm syndrome and mild-to-moderate COVID-19 pneumonia. Additional studies are needed to assess efficacy and optimal dosing duration of anakinra in patients with more severe COVID-19.
Bromodomain protein BRD4 directs CD8 T cell differentiation during infection and cancer
Authors: Milner Justin , Toma Clara , Quon Sara , Omilusik Kyla , Scharping Nicole E , Dey Anup , Reina-Campus Miguel , Nguyen Hongtuyet , Getzler Adam J , Diao Huitian , Yu Bingfei , Delpoux Arnaud , Yoshida Tomomi M , Li Deyao , Qi Jun , Vincek Adam , Hedrick Stephen M , Egawa Takeshi , Zhou Ming-Ming , Crotty Shane , Ozato Keiko , Pipkin Matthew E , Goldrath Ananda W 
Published: February 2023

Abstract
In response to infection and malignancy, antigen-specific CD8 T cells differentiate into functionally diverse populations that are critical for resolving disease and providing durable immunity. Here, we utilized an in vivo RNAi screening strategy to identify transcriptional and epigenetic regulators controlling CD8 T cell fate. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we revealed an essential role for the chromatin modifier and BET family member BRD4 in supporting T cell differentiation during infection and cancer. BRD4 was found to bind diverse regulatory regions critical to effector T cell differentiation and was essential for transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion or chemical inhibition of BRD4 resulted in impaired maintenance of a terminal effector phenotype. In preclinical models of cancer, BRD4 was also required for formation of a terminally differentiated CD8 T cell state in the tumor microenvironment, which we show holds implications for immunotherapies. Tailored inhibition of BRD4 enhanced immune checkpoint blockade efficacy; however, complete ablation of BRD4 activity blunted T cell effector function and adoptive cell therapy efficacy. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis-regulatory elements to control CD8 T cell fate and stability of lineage identity, and provide insight for understanding the efficacy and full therapeutic potential of BET inhibition and T cell immunotherapies.
Histone deacetylase inhibition can revert induced resistance to immune checkpoint blockade in a mouse model of prostate cancer.
Authors: Rahmy Sharif , Lu Xin 
Published: February 2023

Abstract
Castration resistant prostate cancer (CRPC) is one of the leading causes of death in men in the United States, with a 5-year survival rate of 28%. Immune checkpoint blockade (PD-1 & CTLA4 inhibition, ICB) is a novel therapeutic strategy based on restoring the tumoricidal activity of cytotoxic T-lymphocytes. ICB therapy has produced spectacular results in the treatment of melanoma but shows almost no effect in CRPC.
We have developed a model system of advanced prostate cancer (Pten−/−/Tp53−/−/Smad4−/−) consisting of a parental (ICB sensitive) cell line and an ICB resistant subline (PPS-ICBR). We analyzed the transcriptome and found significant changes associated with ICB resistance. Subsequently we reversed some of those changes with Vorinostat, a histone deacetylase inhibitor. Mice injected subcutaneously with the PPS-ICBR cell line showed no response to Vorinostat or ICB therapy, but when combined 40% of the mice were completely cured, and another 40% showed significant reductions in tumor growth. We dissociated the tumors and used mass cytometry to determine the changes in the tumor immune microenvironment. ICB + Vorinostat therapy causes a significant increase in CD4+ & CD8+ T-cells, and a significant decrease in M2 macrophages. Concurrent with this decrease in M2 macrophages we observed a significant increase of TNFα+/iNOS+ monocyte derived dendritic cells.
Our goal is to study the underlying mechanisms that can transdifferentiate an immuno-suppressive tumor immune microenvironment towards a tumor-suppressive immune microenvironment and improve clinical outcomes.
Analysis of immune biomarkers in cancer patients with solid tumors versus healthy subjects
Authors: Acharya Devansh , Gao Haoran , Jorgensen Rick Dean , Hamdan Muhammad , Al-Ahmad Hussein , Thomas Brittani , Chamarthy Ushasree , Gangur Venugopal , Srkalovic Gordan 
Published: February 2023

Abstract
Cytokines and other immune regulatory molecules are critical players in the immune response against cancer. There is growing interest in testing the potential utility of systemic immune biomarkers to track cancer progression and to use them as predictors of effective responses to cancer therapy. The central hypothesis guiding this project is that specific immune biomarkers will serve as predictors of effective vs. ineffective immunotherapy in patients with malignant diseases. The objective of this study was to establish baseline of immune markers in patients already started treatment with immunotherapy (n=10) (T), patients starting, but not yet treated (S) with immunotherapy (n=10) and subjects without diagnosed malignant disease (W) (n=10). Blood was collected and plasma was isolated and used in the biomarker (100 markers) analysis using a protein microarray method (RayBiotech). The biomarkers in the three groups were analyzed by Principal Component Analysis, heat map with clustering, and differential expression based on p value, and Significance Analysis of Microarrays (SAM). Although 15 biomarkers were significantly different between S vs. W groups, based on SAM, only seven were found differentially expressed. Similarly, although 10 biomarkers were significantly different between T vs. W groups, based on SAM, only one biomarker was found differentially expressed. Furthermore, SAM revealed that responders (n=4) vs. stable (n=5) subgroup of patients within the T group exhibited 22 differentially expressed biomarkers. Future larger studies will be needed to evaluate whether immune markers will be able to predict effective vs. ineffective responses to immunotherapy and whether they may have therapeutic potential.
IgG epitopes processed and presented by IgG+ B cells induce suppression by human thymic-derived regulatory T cells
Authors: Hsieh Li-En , Sidney John , Boyle David L. , Firestein Gary S , Sette Alessandro , Franco Alessandra 
Published: February 2023

Abstract
We described a human regulatory T cell (Treg) population activated by IgG+ B cells presenting peptides of the heavy constant region (Fc) via processing of the surface IgG underlying a model for B cell-Treg cooperation in the human immune regulation. Functionally, Treg inhibited the polarization of naive T cells toward a pro-inflammatory phenotype in both a cognate and a non-cognate fashion. Their fine specificities were similar in healthy donors and patients with rheumatoid arthritis (RA), a systemic autoimmune disease. Four immunodominant Fc peptides bound multiple HLA class II alleles and were recognized by most subjects in the two cohorts. The presentation of Fc peptides that stimulate Treg through the processing of IgG by dendritic cells occurred in myeloid dendritic cells cDC1 and cDC2. Different routes of antigen processing of the IgG impacted Treg expansion in RA patients.
Immunological gene signatures in B cell follicle reticular cells are highly conserved across organs and species
Authors: Lütge Mechthild , Onder Lucas , Cheng Hung-Wei , Stanossek Yves , De Martin Angelina , Spannagel Lisa , Soneson Charlotte , Robinson Mark , Pikor Natalia , Ludewig Burkhard 
Published: February 2023

Abstract
Secondary lymphoid organs (SLO) such as the spleen, lymph nodes and Peyer’s patches are strategically positioned to survey bodily surfaces and to support the generation of cellular and humoral immunity. The movement and interaction of antigens, antigen presenting cells, B and T lymphocytes within SLOs is coordinated by specialized fibroblastic reticular cells (FRCs) that form dedicated microenvironments and provide essential niche molecules such as the chemokine CXCL13. High-resolution transcriptomic analysis of Cxcl13-expressing cells in mouse models has previously enabled the molecular characterization of heterogenous B cell-interacting reticular cells (BRC) in lymph nodes. However, it remains unknown to what extent the molecular identity of niche-forming BRCs is conserved across SLOs. Here, we employed single cell RNA-sequencing of Cxcl13-expressing cells from murine lymph node, spleen and Peyer’s patch to compare the molecular identity of BRCs across SLOs. While structural and developmental genes dominated organ-specific gene signatures, we found conserved gene signatures reflecting crucial immunomodulatory functions. The highest conservation was observed in follicular dendritic cells, a BRC subset specialized in the capture and presentation of antigen. Moreover, immunomodulatory gene signatures were preserved in BRCs from human lymph nodes and palatine tonsils highlighting the important role of BRC-defined microenvironments in steering efficient immune responses in SLOs across species.
CD45-dependent regulation of B cell receptor signaling in atherosclerosis
Authors: Ma Shelby , Mussbacher Marion , Moriarty Alina , Keeter W. Coles , Gauronskas Phillip , Waseem Tayab , Galkina Elena 
Published: February 2023

Abstract
Atherosclerosis is an inflammatory disease of the large and medium size arteries that is characterized by deposition of oxidized lipids within the vessel. While specific antigens are not well characterized, data show that the immune response is involved in atherogenesis. The role of B cells in atherosclerosis is B cell specific: FO B cells are proatherogenic, while B1 and MZ B cells serve as protective. B cell development, activation, and differentiation is dependent on B cell receptor signaling while important costimulatory molecules, like CD45, assist in the initial propagation of signal. To date, it is unknown how regulation of BCR signaling by CD45 impacts activation and functions of B cells in atherosclerosis.
We took advantage of transgenic mice that express low levels of CD45 (CD45L/L) and examined the phenotype of CD45L/L B cells. We demonstrate that low expression of CD45 leads to attenuated BCR-induced B cell activation via the reduced Ca2+ flux and phosphorylation of ERK, BTK, and SYK kinase, while favoring MZ and B1 B cell differentiation in homeostatic conditions. To test the effects of B cells expressing low levels of CD45 in atherosclerosis, we performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient atherosclerotic prone mice. After 23–28 wks of western diet feeding, the CD45L/L vs WT B cell recipients had reduced lesion formation accompanied by increased MZ B cells and decreased germinal center formation. This suggests that attenuation of BCR signaling through CD45 affects B cell subset differentiation and activation and highlight a potential role of BCR-related signaling in regulation of immunity in atherosclerosis.
Transcriptional and phenotypic analysis of distinct T-cell subsets may reveal novel pathogenetic and diagnostic signatures of Kawasaki disease
Authors: Cotugno Nicola , Sessa Libera , Pascucci Giuseppe Rubens , Ruggiero Alessandra , Di Cesare Silvia , Amodio Donato , Ferro Giuseppina , Medri Chiara , Buonsenso Danilo , Chinali Marcello , D’Anna Carolina , De Jacobis Isabella Tarissi , Villani Alberto , Rossi Paolo , Marchesi Alessandra , Palma Paolo 
Published: February 2023

Abstract
Kawasaki disease (KD) is an acute vasculitis occurring in children &lt;5yo that can result in coronary artery lesions. Our study aims to define novel pathogenetic and diagnostic signatures through flow cytometry and gene expression of T cell subsets. Peripheral Blood Mononuclear Cells of twenty-four KD patients at diagnosis (KD), twelve febrile patients (FC) and eighteen age-matched healthy controls (HC) were collected. Frequency of T regulatory cells (Treg), peripheral T follicular helper cells (pTfh) and maturational T cell subsets (Naïve, Central Memory, CM; Effector Memory, EM; terminally differentiated memory, TEMRA) were assessed by FACS (CytoFLEX-Beckman Coulter). Transcriptional levels of 96-genes in sort-purified CM, Treg and EM have been analysed by Fluidgm (Biomark). We found that KD have lower frequency of CM and EM compared to HC (p=0.003 and p=0.005), lower frequency of pTfh cells compared to HC (p=0,008), and in line with previous literature, lower Treg compared to HC (p=0.07). Instead, FC have a higher frequency of EM (p= 0.002; p=0.001) and TEMRA (p=0.004; p=0.006) and lower Naive (p=0.005; p=0.003) compared with both HC and KD. At transcriptional level, a distinct signature was found in EM of FC, with 26 and 16 differentially expressed genes (DEGs) compared to KD and HC. These preliminary data suggest that KD present a distinct phenotypic and transcriptional T cell signature, suggesting additional diagnostic and pathogenic insights able to distinguish KD from FC. Future studies with a similar multi OMIC approach could help identifying prognostic signature in KD.
Pioglitazone improves alcohol-induced alveolar macrophage phagocytic dysfunction via increases in microRNAs-1264 and -107.
Authors: Yeligar Samantha M 
Published: February 2023

Abstract

Objective:
People with a history of alcohol use disorders (AUD) are 2–4 times more likely to develop lung infections, in part due to impaired alveolar macrophage (AM) immune function. Ethanol (EtOH) induces oxidative stress via increases in NAPDH oxidase (Nox)1 and Nox2 and decreases in peroxisome proliferator-activated receptor (PPAR)γ, leading to AM phagocytic dysfunction. Since PPARγ activation with its ligand pioglitazone (PIO) attenuated acute lung injury, we hypothesized that PIO upregulates Nox1-related microRNA (miR)-1264 and Nox2-related miR-107, thereby lowering Nox1 and Nox2 expression and oxidative stress and improving AM phagocytic function.

Methods:
AM were isolated from C57BL/6J mice fed EtOH (20% w/v) in the drinking water for 12 wks ± PIO (10 mg/kg/day by oral gavage during week 12). In parallel, a mouse AM cell line, MH-S cells, were transfected ± 50 nM miR-1264/-107 mimics and treated ± 0.08% EtOH for 3 d ± 10 μM PIO on day 3. miR-1264 and -107 were assessed by qRT-PCR. Nox1 and Nox2 mRNA and protein levels were measured by qRT-PCR and cytoimmunostaining. Oxidative stress was assessed with DCFH-DA and Amplex Red assays. AM phagocytosis was evaluated by S. aureus internalization.

Results:
In vivo and in vitro, EtOH: decreased miR-1264/-107 levels, increased Nox1 and Nox2 expression, enhanced oxidative stress, and impaired phagocytosis. miR-1264/-107 mimics or PIO reversed these EtOH-induced AM derangements.

Conclusions:
PIO rapidly upregulated miRs-1264/-107 and attenuated EtOH-induced AM oxidative stress and phagocytic dysfunction. Our studies suggest PIO as a clinically relevant intervention to mitigate AM immune derangements and may decrease susceptibility of lung infections in people with a history of AUD.