bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly controlled nutritional interventions uncover defined immune and microbiome responses in human
Authors: Link Verena M , Hall Kevin , Belkaid Yasmine 
Published: August 2023

Abstract
Previous studies linked diet to numerous physiological functions including the control of the immune system and composition of the microbiome. Here, we report the first human study using a well-controlled cross-over experiment of a vegan, low-fat diet and a ketogenic, low-carbohydrate diet in a clinical setup.
We assess the impact of these dietary interventions via complementary approaches including protein expression via SOMAScan assay, gene expression via RNA-seq, cell population composition via flow cytometry, and metabolomics in the blood, as well as fecal microbiome composition via metagenomics sequencing. Based on functional enrichment analysis of RNA-seq, a vegan diet had a more pronounced impact on the innate immune system than a ketogenic diet as evidenced by enhanced monocyte response, immune activation and upregulation of TNFa, INFa, and INFg responses. On the other hand, a ketogenic diet had a more pronounced impact on B and T cell response. Proteomic analysis uncovers a stronger response to the ketogenic diet in female compared to male participants. Finally, a ketogenic diet alters the microbiome composition significantly more than the vegan diet with enrichment in many microbes including bile-tolerant gut Bacteroides taxa. Pathway analysis in the microbiome and metabolomics data showed changes in amino acid biosynthesis pathways, with many pathways down-regulated in the ketogenic diet. Together this study represents the first comprehensive multidimensional exploration of how diet can impact the immune system and microbiome in human.
Bio-active lipids protect against immune-related adverse events due to immune checkpoint blockade therapy
Authors: Saminathan Priyanka , Mathews Ian T , Henglin Mir , Liu Mingyue , Mercader Kysha , Chee Serena J D W , Campbell Allison , Tiwari Saumya , Watrous Jeramie , Dicker Martina , Dao Khoi , Najhawan Mahan , Quach Lily , Nguyen Thien-Tu Catherine , Nadig Namratha , Fang Camille , Vijayanand Pandurangan , Joosten Leo A B , Decker Roy , Patel Abijit , Netea Mihai , Long Tao , Zheng Pan , Kronenburg Mitchell , Patel Sandip Pravin , Ottensmeier Christian , Kaech Susan M , Cheng Susan , Jain Mohit , Sharma Sonia 
Published: August 2023

Abstract

Introduction
Immune checkpoint blockade (ICB) therapy has been revolutionary in its ability to treat advanced malignancies. Yet many patients receiving ICB develop Immune related adverse events (IRAEs), a leading cause for patients to discontinue treatment. Analyzing patients who develop IRAEs can help advance our knowledge of the molecular drivers of these poorly understood off target toxicities.

Methods
Our recent study of plasma from patients undergoing ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD1) therapy for melanoma, lung cancer or other solid tumors was assessed using high-resolution liquid chromatography-tandem mass spectrometry.

Results
We uncovered a novel protective mechanism related to a class of circulating bio-active lipids that suppress ICB-related IRAEs. Significant reduction of bio-active lipids in circulation was associated with increased ICB-mediated IRAEs. Mouse-models (both DSS-colitis and humanized models) were used to show that supplementation with these lipids ameliorated colonic inflammation without impacting ICB-driven tumor regression. We also uncovered a significant correlation between increasing neutrophil counts and decreased bioactive lipids in circulation.

Conclusion
These results uncover a previously unidentified regulatory mechanism whereby the identified lipids in circulation specifically suppress deleterious inflammation during ICB therapy, while preserving anti-tumor immunity, suggesting that supplementation of bio-active lipids can be developed as a new therapeutic strategy to improve clinical outcomes in cancer immunotherapy.

Supported by grants from NIH (R01CA256133-02)
Impaired local VD3 metabolism contributes to tissue neutrophilic inflammation in chronic rhinosinusitis with nasal polyps
Authors: Xiao Qiao 
Published: August 2023

Abstract

Objective
Vitamin D (VD) possesses immunomodulatory properties, but its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains poorly studied. Herein, we aim to explore the regulation of VD3 function and its effect on local inflammation in CRSwNP.

Methods
25-hydroxyvitamin D3 (25VD3) levels in serum and tissue lysates were detected by ELISA. The expression of VD receptor (VDR), cytochrome P450 family 27 subfamily B member 1 (CYP27B1), the enzymes converting 25VD3 to the active 1,25VD3, and their expression regulation in human nasal epithelial cells (HNECs) were studied by RT-PCR, western blotting, immunofluorescence. HNECs and polyp tissue explants were treated with 1,25VD3. Tissue ECP+ eosinophils and MPO+ neutrophils were stained and quantified by immunofluorescence.

Results
25VD3 levels in serum and nasal tissue lysates were decreased in CRSwNP patients compared to control subjects. The expression of VDR and CYP27B1 were reduced in CRSwNP. VDR and CYP27B1 expression in HNECs were downregulated by IFN-γ and poly (I:C). 1,25VD3 suppressed neutrophilic inflammation in HNECs and polyp tissues. Tissue 25VD3 levels negatively correlated with neutrophilic inflammation in CRSwNP.

Conclusion
Reduced 25VD3 level and decreased CYP27B1 and VDR expression may impair local VD signaling activation, and thus exaggerate neutrophilic inflammation in CRSwNP.
CD4 cells and primary immune cells as a veritable factor on reproductive hormones and fertility
Authors: Amadi Emmanuel Chike , Akanno Faith Chisom 
Published: August 2023

Abstract
Immune system contributes to infertility, where Regulatory T cells play major role. Paucity of research in this crucial area, deems pertinent refocusing attentions on it. So, immune cells as veritable factors on fertility & reproductive hormones [Follicles stimulating hormone (FSH); Luteinizing hormone (LH); Prolactin (PRL); Estradiol (EZ); Progesterone (PROG); Testosterone (TESTO)] were investigated at a Teaching Hospital in Enugu, Nigeria between February – October 2022 on a pilot scale. Patients on doctor’s provisional diagnosis of infertility were examined for their hormones’ levels, CD4 & primary immune cells (PIC) counts. So far, seven patients were investigated. Results were analyzed using Paired Students t-test at 5% (0.05) alpha level; & p value of test statistics used for confirmation. All the patients have low CD4 counts (Range: 157–490). Our hypotheses were largely rejected: (i.e. Yes) that CD4 cells & PIC have impact on the hormones; p values confirmed negative correlative association between CD4 & the six hormones; all the PIC have impact on PRL; except on EZ, neutrophil (N) has very significant impact on all the hormones; except on FSH, lymphocytes (L) has very significant impact on all the hormones; only on PRL that all the PIC have impact; except on PRL & TESTO, WBC (T) has no significant impact on the hormones; only N & L have significant impact on the PROG; only WBC (T), N & L have impact on TESTO; except L none of the PIC has significant impact on the EZ. Monocyte, Eosinophil & Basophils has impact only on FSH, LH & PLT. So, under no hormonal abnormality, (except PRL in one patient), the work strongly suggests that the inability to conceive resides on the low CD4 cells, plus impacts of it & PIC on hormones; hence, they are veritable factors.
None
Genome engineering of HMC-1.2 cells renders a human mast cell line with a single KIT mutation: an improved preclinical model for mastocytosis research
Authors: Falduto Guido H , Bandara Geethani , Luker Andrea , Bai Yun , Pfeiffer Annika , Lack Justin , Metcalfe Dean , Olivera Ana 
Published: August 2023

Abstract
The HMC-1.2 human mast cell (huMC) line is often employed in the study of attributes of neoplastic huMCs as found in patients with mastocytosis and their sensitivity to interventional drugs in vitro and in vivo. HMC-1.2 cells express constitutively active KIT, an essential growth factor receptor for huMC survival and function, due to the presence of two oncogenic mutations (D816V and V560G). However, systemic mastocytosis is commonly associated with a single D816V-KIT mutation. The functional consequences of the coexisting KIT mutations in HMC-1.2 cells are unknown. We used CRISPR/Cas9 engineering to reverse the V560G mutation in HMC-1.2 cells, resulting in a subline (HMC-1.3) with a single monoallelic D816V-KIT variant. Transcriptome analyses predicted reduced activity in pathways involved in survival, cell-to-cell adhesion, and neoplasia in HMC-1.3 compared to HMC-1.2 cells. Consistently, subcutaneous inoculation of HMC-1.3 into mice produced significantly smaller tumors than HMC-1.2 cells, and in colony assays, HMC-1.3 formed less numerous and smaller colonies than HMC-1.2 cells. However, in liquid culture conditions, the growth of HMC-1.2 and HMC-1.3 cells was comparable. Phosphorylation levels of ERK1/2, AKT and STAT5 were also similar between HMC-1.2 and HMC-1.3 cells. However, HMC-1.3 cells were more susceptible to KIT, JAK2, and BCL2 inhibitors than HMC-1.2. Our study reveals that the additional V560G-KIT oncogenic variant modifies transcriptional programs induced by D816V-KIT, confers a survival advantage, alters sensitivity to interventional drugs, and increases neoplasia, suggesting that huMCs with a single D816V-KIT (HMC-1.3) variant may represent an improved preclinical model for mastocytosis.
This work was supported by the Division of Intramural Research of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID).
Potential role for a Nematode Pan Allergen (NPA) in Tropical Pulmonary Eosinophilia (TPE)
Authors: Katru Samuel Christopher , Balakrishnan Anand Setty , Hadadianpour Azadeh , Smith Scott Alan , Kalyanasundaram Ramaswamy 
Published: August 2023

Abstract
Tropical Pulmonary Eosinophilia (TPE) is an asthma-like hyper-responsive syndrome characterized by accumulation of a high number of eosinophils in the lungs leading to severe respiratory morbidity in patients infected with lymphatic filariasis (LF), a helminth parasitic infection that affects 51 million people in 47 different countries worldwide. Subjects showing TPE also have circulating microfilariae (larval stages of LF) and a high titer of parasite-specific IgE in their blood. IgE and eosinophils are thought to play a major role in TPE pathology. However, specific antigens that are released from microfilariae responsible for generating the IgE antibodies in TPE are not known. Therefore, in this study, we screened a phage displayed cDNA expression library of Wuchereria bancrofti microfilaria with human monoclonal IgE antibodies generated from B cells isolated from TPE patients. The iterative screening identified WbNPA (Nematode Pan Allergen) and WbTCTP (Translationally Controlled Tumor Protein) as IgE antibody binding antigens. Subsequent analysis showed that rWbNPA and rWbTCTP can result in the release of histamine from mast cells in an IgE-dependent and independent manner. rWbNPA can induce accumulation of eosinophils in the peritoneal cavity of mice and can trigger the secretion of IL-2 and TNF-α from alveolar macrophages. These results suggest that WbNPA and WbTCTP have a potential role in the pathology of TPE in LF infections.
Sex-dependent influence of LMAN1 on lung function and allergen-induced airway hyperresponsiveness
Authors: Sauber Faith , Swaby Lindsay , Tigno-Aranjuez Justine , Miller Madelyn H , Zhang Bin 
Published: August 2023

Abstract
We recently reported LMAN1 as a regulatory receptor capable of downregulating NF-kB signaling in response to house dust mite (HDM) in vitro. In this follow up work, we have subjected WT and LMAN1 KO mice to a HDM model of allergic airway inflammation and assessed lung function and airway hyperreactivity (AHR). Given our previous in vitro findings, we had expected worsened disease in the absence of LMAN1. Interestingly, when mice were stratified by sex, we observed that while female, HDM-treated LMAN1 KO mice exhibited signs of enhanced airway narrowing and closure and enhanced AHR compared to their WT counterparts, male, HDM-treated LMAN1 KO mice showed the opposite trend. These sex-dependent effects appeared to be localized to the peripheral airways. We additionally characterized the type and extent of immune cell infiltration into the airway and highlight those features which might account for the gender-biased effects of LMAN1 on lung function in the setting of allergic asthma.
IFNγ, IL-4, and IL-13 upregulate IL-31 receptor alpha in airway smooth muscle cells to induce airway hyperresponsiveness in asthma
Authors: Akkenapally Santhoshi Vani , Yombo Dan J K , Geereddy Bhanuprakash Reddy , Madala Satish K 
Published: August 2023

Abstract
Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and goblet cell hyperplasia. AHR is a major cause of hospitalization, morbidity, and mortality in allergic asthma. Both Th1 and Th2 cytokines, including IFN-γ, IL-4, and IL-13 have been shown to induce AHR; however, the underlying mechanisms remain unclear. We observed a significant increase in the expression of IL-31RA, but not its cognate ligand IL-31 during house dust mite- and Schistosoma mansoni soluble egg antigen-induced allergic asthma. In support of this, IFN-γ and Th2 cytokines, IL-4 and IL-13, upregulated IL-31RA but not IL-31 in airway smooth muscle cells (ASMC). Importantly, the deficiency of IL-31RA was sufficient to attenuate contractility of ASMC and allergen-induced AHR but had no effect on inflammation and goblet cell hyperplasia. Similarly, the loss of IL31RA attenuated both IFNγ and IL13-induced AHR with limited changes in inflammation and goblet cell hyperplasia. Importantly, suggesting a mechanism for direct regulation of ASMC contractility, IL-31RA increased muscarinic acetylcholine receptor 3 (CHRM3) expression and calcium signaling. Together, these results suggest an important role for IL-31RA in the regulation of ASMC contractility and AHR distinct from airway inflammation and goblet cell hyperplasia in asthma.
This research was supported by NIH NHLBI grants 1R01HL157176 and 5R01HL134801
IL-17A deficiency alleviates PM-induced allergic asthma by suppressing Th17 cell secretion cytokines and mucus overproduction
Authors: Jee Youngheun , Yang Jiwon , Kim Hyo Jin , Dinh Duong Thi Thuy , Udayanganie Olupathage Indrachapa , Ko Mi-Ok 
Published: August 2023

Abstract
Particulate matter (PM) aggravates airway and lung inflammatory response in allergic asthma by directly inducing Th17 cells to secrete Th17 cell-associated inflammatory factors and chemokines. IL-17A is a key Th17 cell secretion pro-inflammatory cytokine. In this study, we investigated the role of IL-17A in PM-induced allergic asthma in mice. 7–8 weeks old wild type (WT) mice, and similarly IL-17A knockout (KO) mice, were divided into four experimental groups (healthy control, PM only, OVA only, OVA+PM treatment groups) and treated accordingly. Inflammatory cell and eosinophil infiltration were increased in the PM-induced WT mice compared to WT healthy control, but were decreased in KO mice compared to PM-induced WT mice. Among toll-like receptors (TLRs) that play an important role in innate immune response, TLR2/4/7 expression was significantly increased in PM-induced WT mice, but was reduced in KO mice. Furthermore, we observed decrease in mRNA expression of IL-13, IL-17A, IL-22, and TGF-β among cytokines of Th2 and Th17 cells in KO mice. PM-induced WT mice facilitated the overt histopathological symptoms of allergic asthma such as mucus overproduction and goblet cell hyperplasia while KO mice showed mitigated such responses compared to PM-induced allergic asthma WT mice. These results prove that IL-17A plays a key role in pathogenesis of PM-induced allergic asthma.
This research was funded by the Ministry of Education.
Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of Th9 cells to promote allergic inflammation
Authors: Schwartz Daniella M , Son Aran , Meylan Francoise , Gomez-Rodriguez Julio , Kaul Zenia , Sylvester McKella , Kitakule Moses , Falduto Guido H , Wang Chujun , Manthiram Kalpana , Qi Chen-Feng , Gurram Rama , Zhu Jinfang (Jeff) , Schwartzberg Pamela , Milner Joshua , Guererrio Pamela 
Published: August 2023

Abstract
Allergic diseases are a major global health issue, causing significant morbidity and mortality. Interleukin-9 (IL-9) producing T helper 9 (Th9) cells promote allergic inflammation, yet Th9 effector functions are incompletely understood because the heterogeneity and instability of Th9 cells makes them challenging to study. Although the significance and mechanisms of Th9 instability are unknown, T cell receptor (TCR) activation is hypothesized to play a key role. Conversely to this paradigm, we found that resting Th9 cells did not require TCR restimulation for IL-9 production, which was induced by STAT5- and STAT6-dependent paracrine cytokines. This mechanism was seen in circulating T cells from allergic patients and was restricted to recently activated cells. Analysis of IL-9+ T cells from allergic subjects revealed a transcriptional program that was enriched for activation pathways and unstable over time, with IL9 amongst the least stable genes. Prolonged resting of cells decreased the accessibility of STAT5-dependent IL9 enhancers, inactivating the locus. In vivo, Th9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, Th9 expansion was associated with STAT activation and responsiveness to JAK inhibitors. These findings suggest that Th9 instability is a negative checkpoint on TCR-independent inflammation that breaks down in allergic disease, and that JAK inhibitors should be considered for allergic patients with a Th9 signature.
Supported by the NIAID intramural research program (2018-2022), University of Pittsburgh start-up funds (2022-current), and the National Psoriasis Foundation (Robertson Fellowship, 2018-2021; Translational Grant, 2022-current)
Defining complex T-cell signatures linked to rhinovirus infection in the lower airways of children with severe asthma
Authors: Bryant Naomi , Muehling Lyndsey M , Teague W Gerald , Woodfolk Judith A 
Published: August 2023

Abstract
Rhinovirus (RV) infection is a risk factor for the development of asthma and acute wheezing episodes. RV-specific Th1 cells are expanded in the blood of adults with asthma, even in the absence of infection. Such cells are further amplified during acute infection and resemble those CCR5+ T cells found in the lower airways of children with severe asthma. We posit that in early childhood, pathogenic T cells induced by repeated RV exposures are sustained by cues in the inflamed airways and serve to drive chronic inflammation. Little is known about the complexity and function of T cells in the lower airways of children with severe asthma, or their relation to RV, due to challenges in obtaining lung specimens and low T-cell numbers in the airway lumen. We leveraged high-dimensional single-cell phenotyping, marker enrichment modeling for designation of complex molecular signatures, and the novel machine learning algorithm, T-REX, to discriminate rare pathogenic T cells in the airways that are linked to RV infection in children aged 1–15 years who had severe asthma (RV PCR+, n=3; RV PCR-, n=8). Our novel workflow identified activated (CD38+), proliferating (Ki-67+) and tissue-resident (CD69+) CCR5+CD4+ T cells (CD45RO+ICOS+CD95+CD27+PD-1+TCF-1+) in the lower airways of all children; however, this cell population was markedly expanded in RV+ children (median of 10% vs 1% of total T cells) and was over 9-fold enriched in the airways compared with blood. Notably, these cells were inversely correlated with inhaled corticosteroid dose. Our findings suggest that the expansion and persistence of RV-induced lung-resident T cells contribute to chronic airway inflammation in children with severe asthma.
Supported by grants from NIH/NIAID (RO1 AI077653, R21 AI160334)
Prophylactic and therapeutic use of synthetically glycosylated antigens to limit allergic airway disease
Authors: Medellin Jorge E Gomez , Ung Trevor Wai-Ming , Kurtanich Trevin Robert , Reda Joseph William , Wang Thomas , Chang Kevin , Cao Shijie , Swartz Melody A , Hubbell Jeffrey 
Published: August 2023

Abstract
Asthma is a disease involving chronic airway inflammation affecting more than 300 million people worldwide. There is currently no cure for asthma. While effective, corticosteroids cause broad immune suppression and long-term debilitating disease. Novel immune modulatory therapeutics leave patients vulnerable to infections. Therefore, there is a current need for new therapeutics that target the underlying causes of the disease without triggering detrimental side effects.
Through synthetic glycosylation, our platform targets hepatic antigen presenting cells and leverages the liver’s tolerance-inducing mechanisms to limit inflammatory T cell responses, while promoting regulatory T cell (Treg) responses, thus preventing broad immunosuppression. In a model of experimental allergic airway inflammation, prophylactic treatment with synthetically mannosylated OVA (pManOVA) ameliorated the allergic response to inhaled OVA. Our treatment reduced lung and airway eosinophilia, systemic levels of IgE and OVA-specific IgG1, and airway mucus. Furthermore, pManOVA treatment reduced OVA specific lung TH2 cells, and exhibited reduced production of IL-4, IL-5 and IL-13 upon antigen specific restimulation. Treatment with pManOVA was accompanied by induction of OVA-specific Tregs, which negatively correlated with features of allergic airway disease. In previously sensitized mice, therapeutic intervention with pManOVA reduced airway and lung eosinophilia, B cell and CD4+ T cell inflammation. Altogether, these data suggest a potential role for prophylactic and therapeutic intervention with synthetically glycosylated allergens in ameliorating disease severity in a model of allergic airway inflammation.
CD3ζ ITAM Diversity Determines Chimeric Antigen Receptor Signaling and Function
Authors: Majumdar Shubhabrata , Echelibe Hilda , Bettini Matthew L 
Published: August 2023

Abstract
One of the major challenges facing CD28-based CAR-T immunotherapy is a lack of long-term T-cell persistence in patients. CD28 CARs exhibit strong signaling patterns that result in an acute tumor-killing response. However, based on studies with the conventional TCR, strong signaling favors terminal differentiation of T-cells that get exhausted faster while weaker CAR signaling favors more stem-like memory T-cell states with longer persistence. Hence attenuation of CAR signaling strength is a viable strategy for long term survival of CD28-CAR T-cells. Previous work has suggested that reducing CD3 ITAM diversity to single ITAM sequences while keeping the number of ITAMs same, attenuates TCR signaling strength to different extents. Based on this, we have designed modified ITAM diversity restricted CD28 based anti-CD19 CARs with the goals of optimizing CAR signaling and studying the non-redundant signaling properties of the individual ITAMs in the context of CARs. Our approach is different from reducing ITAM multiplicity as there is evidence suggesting that ITAM numbers might be important for CAR sensitivity. We hypothesize that the individual ITAM non-redundancy and the reduction in ITAM diversity will allow for optimization of CAR T cell signaling and improve T-cell persistence while maintaining sensitivity to low ligand densities. We have observed that our modified CARs can kill CD19+ leukemia cells in vitro. We observe functional differences in terms of cytokine production, proliferation, AICD and exhaustion. We have also observed differences in signal strength based on ITAM usage. These observations support the non-redundancy of ITAM signaling and open the possibility of optimizing CAR persistence and function in patients.