bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vacuolar ATPase a2-subunit is a multifocal regulator of T cell development
Authors: Peterson Theodore V , Reynolds Joseph M 
Published: January 2023

Abstract
T cells are required for nearly all aspects of the adaptive immune response, and as such, their development into functional maturity is a complex and tightly controlled process. Developing thymocytes must coordinate a host of transcriptional, metabolic, and proliferative changes as they mature, and disturbances in this process underlie a number of diseases and syndromes, including cancers, immunodeficiencies, and autoimmunity. Interestingly, our recent work has identified an essential role for the a2-subunit isoform of the vacuolar ATPase (a2V) – a highly conserved intracellular proton pump – in orchestrating critical changes at multiple points of murine αβ T cell development. Cre-recombinase mediated deletion of a2V restricted to the hematopoietic compartment or immature thymocytes leads to a profound peripheral lymphopenia specifically confined to CD4+ and CD8+ αβ T cells, a condition originating from several deficiencies in intrathymic T cell development. Thymuses of a2V-deficient mice are reduced in size and cellularity, observations temporally correlated with the timing of a2V deletion. These deficiencies are in part tied to perturbations within the Notch1 signaling pathway, and obstructions at the β-selection checkpoint and a near complete failure of positive selection suggest further deficiencies in proliferative and TCR-mediated pathways, and therefore a broad and multifaceted role for a2V during early T cell development. Importantly, these data support a recent focus on V-ATPase as a chemotherapeutic target, and furthermore suggest that a2V may be a specific and efficacious target for combating proliferative potential of autoreactive or malignant T cells.
Single cell RNAseq analysis reveals profound abnormalities in the distribution and diversity of thymic epithelial cells in Rag1 mutant mice
Authors: Pala Francesca , Martins Andrew , Oguz Cihan , Lack Justin , Tsang John , Notarangelo Luigi D , Bosticardo Marita 
Published: January 2023

Abstract
The thymus contains a heterogeneous population of stromal cells which orchestrate T cell development and selection. Recent works highlighted the complexity of thymic stromal cells, and medullary thymic epithelial cells (mTECs) in particular. However, the developmental origin, hierarchy, and function of these subpopulations remain ill-defined. Moreover, the characterization of cortical TECs (cTECs) has been largely restricted to the adult thymus. Here, we compared TEC distribution and gene expression in wild-type (WT) and in mice carrying Rag1 hypomorphic mutations observed in patients with immune deficiency and immune dysregulation.
Single cell RNA-seq analysis of TECs isolated from adult Rag1 mutant mice revealed an excess of cTECs, which segregated in different clusters. The mTEC compartment, albeit reduced, showed a similar distribution of previously described subsets (mTEC I–IV), suggesting perturbation of mTEC development rather than mTEC differentiation into functional subsets. To address whether such abnormalities of cTEC and mTEC abundance and subset distribution in Rag1 mutant mice may reflect defects in TEC development, we extended scRNA-seq analysis to TECs from WT mice of neonatal age. A similar pattern was observed in TECs of adult Rag1 mutant mice and WT mice of neonatal age, indicating altered TEC development when Rag1 activity is perturbed. This defect correlates with a decreased number of double-positive thymocytes, suggesting that impaired lymphostromal cross-talk in the thymus of Rag1 mutant mice (and patients with similar defects) is associated with abnormalities of TEC composition which may contribute to altered immune tolerance that is often observed in these conditions.
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Authors: Bolte Ashley C , Hurt Mariah E , Smirnov Igor , Dutta Arun B , Kovacs Michael A , McKee Celia A , Natale Nick , Ennerfelt Hannah E , Nguyen Bao H , Frost Elizabeth L , Lammert Catherine E , Kipnis Jonathan , Lukens John R 
Published: January 2023

Abstract
Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.
Characterization of the microglia in three non-overlapping lysosomal storage diseases
Authors: cougnoux antony , Drummond Rebecca , Fellmeth Mason , Navid Fatemeh , Collar Amanda , Iben James , Cawley Niamh , Wassif Christopher , Pickel James , Kulkarni Ashok , Lionakis Michail , Porter Forbes 
Published: January 2023

Abstract
Lysosomal storage diseases (LSDs) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme or transporter deficiencies. Depending on the affected metabolic pathway, these diseases manifest with somatic or central nervous system signs and symptoms. Neuroinflammation is a hallmark feature of LSDs with neurologic involvement such as mucolipidosis type IV (Mcoln1) or Niemann-Pick disease, type C1 (Npc1), but not Fabry disease (Gla). We investigated the properties of microglia from these three disorders using mouse models and a combination of flow cytometric, RNA sequencing, biochemical and immunofluorescence analyses. Stored material is present in the microglia of the different mice however only in Niemann-Pick disease, type C1 did we observe that neuroinflammation increases with disease progression. Fabry disease mice do not have neurological manifestation, and this is reflected by the minor changes in microglial properties. Lastly, mucolipidosis type IV mice have an early gliosis which decreases with disease progression. Comparison among microglia transcriptome profiles form these 3 diseases, and other disorders where transcriptome data is available, showed similarities with other neurodegenerative diseases.
The phenotypic similarities between microglia from rare monogenic disorders, where the primary metabolic disturbance is known, and common neuroinflammatory diseases may provide novel insights for therapeutic intervention.
The role of myeloid cell-specific ten eleven translocase 2 (TET2) in regulation of neuroinflammation
Authors: Munie Ashley N , Segal Benjamin 
Published: January 2023

Abstract
Multiple Sclerosis (MS), is an inflammatory demyelinating disease of the central nervous system (CNS) believed to be autoimmune in etiology. Analysis of legions from MS patients, as well as studies in Experimental Autoimmune Encephalomyelitis (EAE), a murine model of MS, have indicated that myeloid cells play a critical role in the pathogenesis of CNS autoimmunity. Recently, Ten-Eleven Translocation 2 (TET2) was identified as a susceptibility locus for MS. TET2 is a Fe(III), α-ketoglutarate dependent enzyme that catalyzes the oxidation of methylated cytosine to 5′-hydroxymethyl cytosine (5hmC), a stable epigenetic mark. There is growing evidence that TET2 acts as a negative regulator of myeloid cell activation. Further, TET2 and 5hmC are reduced in peripheral blood mononuclear cells of MS patients compared with healthy volunteers. The objective of the current study is to investigate the hypothesis that reductions of TET2 expression and activity in myeloid cells is a critical step in the development of pro-inflammatory myeloid cells during CNS autoimmunity. Our laboratory has found that Tet2 transcripts levels and 5hmC content are reduced in CNS-infiltrating myeloid cells at the peak of EAE compared with the onset or late stages. Adoptive transfer of encephalitogenic CD4+ Th17 cells into Tet2−/+ mice lead to an exacerbated clinical course compared with their Tet2+/+ counterparts. Our data suggests that TET2 expression and activity is dysregulated in myeloid cells and limits neuroinflammation and chronic neurological disability. Interventions that promote Tet2 expression in myeloid cells may ameliorate EAE and, by extension, MS.
Age-Dependent Synthesis of Diverse Autoantibodies in the 3xTg-AD Model of Alzheimer’s Disease
Authors: Ma Donglai , Song Wei , Kapadia Minesh , Fahnestock Margaret , Sakic Boris 
Published: January 2023

Abstract
Elevated levels of serum autoantibodies are a well-documented phenomenon in patients with Alzheimer’s disease (AD), but the nature of the autoimmunity is unclear. Triple-transgenic (3xTg-AD) mice are a well-established model that develops AD-like pathology. We observed that recent cohorts of male 3xTg-AD mice exhibit autoimmune manifestations, yet lack plaque/tangle pathology. In the current study, we identified the time course and type of autoantibodies produced during the progression and attenuation of systemic autoimmunity. Tissue samples were collected from 3xTg-AD and wild type (WT) males and females at 2, 6 and 12 months of age. Serum autoantibodies were measured by both indirect immunofluorescence and 16-antigen line immunoassay. To assess immunosuppression, serum samples from a separate cohort of mice chronically exposed to cyclophosphamide were also assessed. Several autoantibody types increased in frequency and concentration in aging 3xTg-AD mice, particularly in adult males. The most prevalent were anti-nuclear autoantibodies, particularly those targeting the nucleosomes. Among the panel of autoantibodies measured, reactivity to a single antigen (nucleosomes) was observed in the majority of samples. A few mice showed reactivity to other autoantigens, such as histones, dsDNA, RNP/Sm, AMA-M2 and rib. P. Reactivity to all autoantigens was abolished in mice exposed to the immunosuppressant cyclophosphamide. The emergence of circulating autoantibodies similar to classical autoimmune diseases (such as lupus) suggests an important, yet unreported aspect of pathology in this AD model. Future studies are aimed to elucidate the origin and role of the autoantibodies in the context of phenotype loss in 3xTg-AD males.
Linking environmental exposures to molecular regulation of inflammation via epigenetic histone signatures in an exacerbation prone pediatric asthma cohort
Authors: Knapp Jennifer R , Harmacek Laura D , Crooks James , Tu Ting-Hui Clair , Magallon Roman E , Leach Sonia M , Danhorn Thomas , Schiltz Allison , Voelker Dennis R , Siebold Max A , Thornburg Jonathan W , Fingerlin Tasha E. , Liu Andrew W , O’Connor Brian P. 
Published: January 2023

Abstract
Environmental exposures, such as air pollution, are correlated with asthma susceptibility and airway inflammation. Epigenetic mechanisms can translate these exposures to regulation of molecular pathways that drive asthma pathogenesis. Indeed, specific epigenetic modifications have been linked to regulation of asthma-associated inflammation. Yet, there have been no studies linking environmental exposures to direct regulation of molecular mechanisms driving dysfunction of inflammation in pediatric asthma. Here we examined a cohort of exacerbation prone pediatric asthmatics tracking exposure through multiple air monitoring methods, including personalized vest monitors, stationary monitors, and Colorado DPHE monitors. We performed ChIP-seq examining histone modifications in PBMCs and integrated the epigenetic data with the environmental exposure data from the air pollution monitors. Our results statistically linked specific histone modifications in PBMCs to specific types of environmental exposures within the pediatric asthmatics. Annotation of these histone modifications to proximal genes identified a potential immune program regulating asthma inflammation. Concomitant examination of the PBMC transcriptome enabled functional analysis of epigenetic regulation of these immune genes. The resultant molecular profiles can be used to identify biomarkers for patient stratification and disease course prediction. Moreover, these studies identify a potential link between the molecular programming associated with environmental exposures and regulation of key biological pathways, which alter immune cell activity that ultimately can increase asthma exacerbation in children.
Human and murine eosinophils differ in their ability to synthesize key bioactive lipids involved in asthma
Authors: Archambault Anne-Sophie , Brassard Julyanne , Bernatchez Émilie , Martin Cyril , Di Marzo Vincenzo , Laviolette Michel , Boulet Louis-Philippe , Blanchet Marie-Renée , Flamand Nicolas 
Published: January 2023

Abstract

CONTEXT
High eosinophil (EOS) counts is a key feature of asthma. EOS notably affect the asthmatic response by the mean of their lipidome. Mouse models have been developed in the hope of defining new pharmacological targets to treat asthma. However, many pinpointed targets could not be translated into clinics, underscoring that key differences exist between mice and humans. Herein, we compared the ability of human (h) and mouse (m) EOS to synthesize key bioactive lipids from arachidonic acid (AA) and docosahexaenoic acid (DHA).

RESULTS
In response to AA, hEOS synthesized both LTC4 and LTB4 while mEOS only synthesized LTB4. The synthesis of the 15-lipoxygenase products 15-HETE and 12-HETE also differed, hEOS producing them at a 5:1 ratio while mEOS producing them at a 1:2 ratio. mEOS consistently synthetized more PGE2 than hEOS. As for DHA, mEOS produced ten times the levels of specialized pro-resolving mediators (resolvins, maresins and protectins) than hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-AG and its congener 2-DHG, a biosynthetic pathway that was 10 – 50 times less important in mEOS.

CONCLUSIONS
Our data show that the lipidomes of hEOS and mEOS differ, notably by their production of leukotrienes, their opposite 15-HETE/12-HETE ratio, their ability to synthesize specialized pro-resolving mediators (mEOS &gt; hEOS), and the inability of mEOS to synthesize anti-inflammatory endocannabinoids. We thus propose that in mouse models of asthma, the impact of LTB4 is likely overrated, the role of specialized pro-resolving mediators amplified, and the role of endocannabinoids underrated, compared to asthmatics.
The leukotriene B4 receptors contributes to neutrophil-dominant asthmatic airway inflammation via IL-1β and IL-17 production
Authors: Kwak DongWook , Park Donghwan , Jang Jae-Hyun , Kim Jae-Hong 
Published: January 2023

Abstract
The leukotriene B4 is one of the chemo-attractant molecule for neutrophils, its receptors, BLT1/2 may contribute to neutrophil-dominant airway inflammation. Therefore, we investigated whether BLT1/2 signaling was associated with neutrophil-dominant severe asthma. The role of BLT1/2 as well as 5-/12-lipoxygenase in neutrophil-dominant airway inflammation was investigated using pharmacological inhibitors in murine model. Blockade of BLT1/2 significantly suppressed airway inflammation including thickness of airway wall, recruitment of immune cells and IL-17 production in neutrophil-dominant airway inflammation. 5-/12-LOX, upstream of LTB4 receptors was also critical for neutrophil-dominant airway inflammation and synthesis of IL-17. Furthermore, inhibition of 5-/12-LOX, BLT1/2, suppressed NF-κB activation, thus attenuating airway inflammation and production of IL-17, suggesting that NF-κB lies downstream of BLT1/2 in neutrophilic airway inflammation. Our results suggest that ‘5-/12-LOX-BLT1/2-NF-κB’ cascade significantly contributes to neutrophil-dominant airway inflammation through IL-17 synthesis. What is interesting is IL-1β also acts important role in the neutrophil-dominant asthmatic condition with IL-17 production. The high-expression level of IL-1β which is mainly produced by NLRP3 inflammasome activation already reported clinically in the sputum of neutrophilic asthma patients. Consequentially, our studies suggest that the cooperative mechanism of IL-1β and IL-17 considerably acts to neutrophil-dominant airway inflammation and the leukotriene B4 receptors have possibilities to control the severity via regulation effect of IL-1β and IL-17.
Asthmatic airway inflammation was alleviated by limiting the level of lung extracellular ATP
Authors: Huang Yung-An , Kuo Ming-Ling 
Published: January 2023

Abstract
Asthma is a chronic respiratory disease characterized by recurrently attacks of breathlessness and wheezing. ATP accumulation in bronchoalveolar lavage fluid (BALF) of asthmatic subjects indicates that extracellular ATP (eATP) and downstream responses are involved. The level of eATP is tightly controlled by its release and degradation in healthy tissues. Pannexin-1 is a channel contributing to ATP release, and CD39 is membrane bound apyrase contributing to ATP degradation. Cellular stress or inflammatory stimulation leads increased release of ATP and accompanied with the reduction of CD39. The recombinant adeno-associated virus (rAAV) vectors have been developed for efficient gene transfer with low toxic and difference tissue tropisms. Thus, we generated rAAV-CD39 and rAAV-s10Panx1 and examined their efficacy in OVA-mediated asthmatic mice model. The mice were sensitized intraperitoneally and challenged intratracheally with OVA and treated with the vectors three days before OVA challenge. At the end of procedure, some asthmatic and inflammatory cardinal features were examined. Elevated ATP level either in stimulated-culture supernatant and BALF of OVA-sensitized mice was determined. These two treatments downregulated the levels of ATP in BALF. Several asthmatic features, such as eosinophilia, Th2 cytokine production and AHR were decreased in the treatment groups. These treatments altered the T cell response by targeting the danger signal eATP and its metabolites. Taken together, these approaches are able to downregulate the asthma symptoms with the reduction of inflammatory responses in the lungs. Based on these results, eATP can be considered as a potential gene therapy target for asthma.
Clinical and immunological evaluation of cat-allergic asthmatics living with or without a cat
Authors: Wambre Erik , Bajzik Veronique , DeVeaux Michelle , Meier Pretty , Ruddy Marcella , DeBerg Hannah , Wang Claire Q , Farrington Mary , Radin Allen 
Published: January 2023

Abstract

Rationale
We aimed to evaluate the impact of daily cat exposure in cat allergic asthmatics by both clinical symptom and immunological measures.

Methods
Twenty adults with history of cat-induced asthma and rhinitis, positive serum cat dander-specific IgE (sIgE&gt;0.35kU/L) and Skin Prick Test (SPT) were enrolled at a 1:1 ratio according to cat ownership. For comparison, cat extract- and Fel d1- specific basophil sensitivity test (BST), serum sIgE, sIgG4 and SPT were measured on Day 1 and 28; ambulatory spirometry and symptom measures were obtained daily. Feld1 and 4-reactive CD4+ T cells were profiled using a CD154 upregulation assay.

Results
Cat owners had higher clinical symptom scores & medication use and a trend toward lower FEV1 vs. those not living with cats. Significantly higher levels of cat dander sIgG4 were observed among cat owners, but no significant difference was observed for cat-dander sIgE or SPT. All subjects tested positive on BST to Fel d1 and cat dander. Cat-ownership was associated with reduced basophil sensitivity to Fel d1, but had positive BST to Fel d4 and 7. T-cell response to Fel d1 and 4 were differentially polarized, with Fel d1 responses strongly polarized toward Th2 in both groups. No significant correlation was observed between basophil and T cell responses against cat allergen components.

Conclusions
Cat allergic subjects living with a cat demonstrated reduced pulmonary function and greater clinical symptom severity, despite higher medication use and sIgG4. An immunological difference between cat-owners vs. non cat-owners was detected by basophil assay but not by T-cell response.
Development of allergic airway immunity depends on MARCH1-mediated ubiquitination of MHCII and CD86 in dendritic cells
Authors: Castellanos Carlos A , Ren Xin , Liang Hong-Erh , Laidlaw Brian J , Barczak Andrea , Rudolph Joshua , Eckalbar Walter L , Huang Xiaozhu , Cyster Jason G , Locksley Richard M , Erle David J , Ishido Satoshi , Shin Jeoung-Sook 
Published: January 2023

Abstract
Dendritic cells (DCs) play an essential role in the development of type 2 allergic immunity by presenting allergens to cognate naïve T cells inducing production of IL-4 thus priming type 2 T helper (Th2) cells. However, the molecular mechanisms underlying this function are poorly understood. We found that mice deficient in the expression of MARCH1 ubiquitin ligase in DCs were completely resistant to developing Th2 cell inflammation and eosinophilia upon airway exposure to house dust mite allergens. These mice exhibited normal expansion of allergen-specific CD4+ T cells and normal production of IFN-γ from the T cells but demonstrated a significant defect in the production of IL-4, suggesting a specific role of MARCH1 in DC priming of Th2 cells. Remarkably, mice lacking the ubiquitin acceptor amino acids of the MARCH1 substrates, MHCII and CD86, phenocopied MARCH1-deficient mice, indicating that MARCH1 promotes Th2 cell priming by mediating ubiquitination of MHCII and CD86. Ubiquitination of MHCII was important for CD11b+ DCs to transport respiratory allergens to the mediastinal lymph node whereas ubiquitination of CD86 as well as MHCII was involved in transcriptional reprograming of these DCs. In conclusion, dendritic cells depend on ubiquitination of MHCII and CD86 to condition themselves to effectively migrate to the draining lymph node and induce production of IL-4 from allergen-specific naïve CD4+ T cells.
Maternal Alpha-tocopherol Inhibits Development of Food Allergy Early in Life
Authors: Cook-Mills Joan M , Schroeder-Carter Lindsay M , Ramos-Solís Nicole 
Published: January 2023

Abstract
Food allergy can be life-threatening and has had a marked recent increase in prevalence. Interventions are critical to limit the development of food allergy early in life. We demonstrate that maternal dietary supplementation with α-tocopherol blocks development of food allergy. Briefly, female mice received diet supplemented with α-tocopherol or control chow starting at mating with males with skin barrier gene mutations. The pups, that are heterozygous for skin barrier mutations, received six cutaneous co-exposures to a food allergen and an environmental allergen. Oral challenge with food allergen induced anaphylaxis and increased inflammatory mediators in pups from mothers with control chow. Offspring anaphylaxis and expression of inflammatory mediators were blocked by maternal supplementation with α-tocopherol. In conclusion, maternal supplementation with α-tocopherol reduced neonate development of food allergy. These results have implications for supplementation of allergic mothers with α-tocopherol.