bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1 regulates affinity maturation of allergen-specific antibodies and severity of peanut allergy in mice
Authors: Lama Jyoti K , Iijima Koji , Kobayashi Takao , Kita Hirohito 
Published: February 2023

Abstract
Programmed cell death-1 (PD-1), a member of the CD28 family, is critical for regulation of immune cell activation and maintenance of peripheral tolerance. Blocking antibodies against PD-1 have been used to sustain activation of T cells in cancer immunotherapy. T follicular helper (Tfh) cells play important role in the differentiation and maturation of antigen-specific B cells. Tfh cells highly and constitutively express PD-1; however, our knowledge is limited regarding the role of PD-1 in Tfh cell function and antibody response. We addressed this question by using a Tfh-dependent mouse model of peanut allergy. When naïve BALB/c mice were exposed to peanut flour by inhalation for 4 weeks, they developed peanut allergy as demonstrated by increased plasma levels of peanut-specific IgE and IgG antibodies and manifestation of acute anaphylaxis upon challenge with peanut extract. To examine the roles of PD-1, we administered a PD-1 blocking antibody to the animals during their exposure to peanut flour. Mice administered anti-PD-1 did not develop anaphylaxis even when they were challenged with peanut extract. Anti-PD1 treatment increased the number of Tfh cells and germinal center B cells in draining lymph nodes, and it increased plasma levels of peanut-specific IgG antibodies. Importantly, PD-1 blockade promoted the accumulation of low-affinity antibodies while it maintained the levels of high-affinity antibodies. These findings suggest that quality of allergen-specific antibodies affects the severity of allergic immune responses. Understanding the mechanisms that explain how PD-1 regulates the Tfh-B interaction and affinity maturation of antibodies likely leads to a better understanding of pathophysiology of allergic diseases.
Functions of an Environmental Allergen in Induction of Food Allergy.
Authors: Buelow Lauren M , Tat Kiet , Schroeder-Carter Lindsay , Carroll Daniela , Hoji Aki , Cook-Mills Joan M 
Published: February 2023

Abstract
Food allergy can be induced in neonatal mice with heterozygous skin barrier mutations and skin co-exposure to detergent, food allergen and a ubiquitous environmental allergen Alternaria Alternata (Alt) at doses in dust. In this study it was determined whether cytokines are induced by Alt in development of allergy to peanut extract (PNE). In preliminary RNAseq data, Alt induced expression of IL33, oncostatin M (OSM) and amphiregulin (Areg) in the skin of neonatal flakey tail (FT+/−) mice with heterozygous skin barrier mutations. In FT+/−, but not WT neonates, qPCR analyses revealed skin expression of IL33 and OSM following Alt or Alt+PNE exposure compared to neonates with saline skin exposure, while IL33 and OSM were not induced by skin exposure to PNE alone. The expression of Areg was induced by Alt, PNE or Alt+PNE in FT+/− neonates. It was determined whether intradermal injection of recombinant IL33 (rIL33), rAreg or rOSM could substitute for Alt during skin sensitization to PNE. PNE skin sensitization with intradermal rIL33 was sufficient for oral PNE induced anaphylaxis, whereas skin sensitization with intradermal rAreg or rOSM during skin exposure to PNE was not. Injection of neutralizing antibodies for Areg and OSM blocked anaphylaxis in Alt+PNE exposed neonates, indicating that Areg and OSM are required for PNE-induced anaphylaxis prior to skin sensitization. Analysis of skin IL33, Areg and OSM gene expression and plasma protein for IL33, Areg and OSM defined a pathway for IL33, Areg and OSM in Alt+PNE skin. Thus, Alt stimulated expression of IL33 and a pathway of OSM and Areg in concert with PNE to induce food allergy in FT+/− pups. These data have important implications for studies of detection of risks for sensitization to food allergens.
Dysregulated TGF-β Signaling Leads to Cell-Intrinsic Changes in T cell Development that Promote Allergic Inflammation
Authors: Haque Tamara , Weissler Kate , Schmiechen Zoe , Leak Lashawna , Laky Karen , Frischmeyer-Guerrerio Pamela A 
Published: February 2023

Abstract
Variants in genes in the Transforming Growth Factor Beta (TGFβ) signaling pathway are associated with allergic diseases suggesting that this cytokine may be a central player in the allergic diathesis. The role of TGFβ in preserving T cell mediated self-tolerance is well appreciated but how disruption in this pathway promotes allergic inflammation is unclear. We previously demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in TGFBR1 and TGFBR2, are highly predisposed to allergic disease. LDS patients and mice harboring a knock in allele (Tgfbr1mut) of an LDS mutation known to cause severe disease in humans exhibit higher levels of total and food specific IgE. These serologic changes were associated with higher frequencies of T follicular helper (Tfh) cells and lower T follicular regulatory (Tfr) cells. Using a mixed bone marrow and fetal liver chimera model, we showed that these alterations in T cell development are cell intrinsic. Chimera models also demonstrated that the TGFβ mutation drives higher IgE production despite the presence of wildtype Tregs. Furthermore OVA specific Tgfbr1mutOTII cells were more likely to accumulate in the peyers patch and differentiate into Tfh cells in response to orally ingested OVA. These findings correlated with increased AKT/pS6 signaling downstream of TCR in Tgfbr1mut T cells, and mTOR inhibition decreased Tgfbr1mut OTII Tfh cells in response to fed ova. Additionally, RNA sequence analysis of murine Tgfbr1mut Tfh cells revealed enhanced PI3K/AKT pathway activity. These findings suggest that TGFβ signaling plays an important role in T cell development and function via the PI3K/AKT pathway that when disrupted promotes allergic inflammation.
The role of the stress-activated transcription factor Nrf2 in OVA-induced food allergy
Authors: Jin Yining , Boss Allison P. , Bursley Jenna K. , Gangur Venugopal , Rockwell Cheryl Elizabeth 
Published: February 2023

Abstract
Food allergies are rising at a striking rate, but the underlying cause is unclear. The purpose of the studies was to determine the effect of the food preservative tert-butylhydroquinone (tBHQ) in a mouse model of food allergy. Our preliminary studies show that skin-sensitization with OVA induced an elevated OVA-IgE level in mice on a tBHQ diet. Likewise, in response to oral challenge, a greater decrease in body temperature during anaphylaxis was observed in the tBHQ group. Previously published in vitro studies suggest that tBHQ promotes Th2 polarization through activation of the stress-activated transcription factor, Nrf2. Therefore, we proposed the hypothesis that tBHQ exacerbates allergic response in OVA sensitized mice through activation of Nrf2. We implemented adoptive transfers of CD4 T cells from wild-type or Nrf2-null mice into immunodeficient mice (all mice received wild-type B cells). The study revealed marked genotype differences. Notably, dietary tBHQ had little effect on food allergy in recipients of Nrf2-deficient CD4 T cells. These mice showed attenuated sensitization as compared to wild-type CD4 T cells recipients. Strikingly, mice receiving Nrf2-deficient T cells did not become anaphylactic following challenge. In contrast, tBHQ caused an increase in OVA-IgE levels and a greater drop in body temperature in mice receiving wild-type CD4 T cells, suggesting these effects are Nrf2 dependent. In addition, recipients of Nrf2-deficient CD4 T cells showed an attenuated percentage of Th2 cells and mast cell degranulation response, following challenge. Taken together, these data suggest a critical role for Nrf2 during food allergy and demonstrate that tBHQ exacerbates food allergy in a CD4 T cell-Nrf2 dependent manner.
Mixed species live biotherapeutic product improves immunological tolerance in food allergy
Authors: Qayum Amina Abdul , Valladares Ricardo , Gehrig Jeanette 
Published: February 2023

Abstract
The human gut microbiota is central to early-life immune system education, including the establishment of immune tolerance, and thus represents an important target for the development of preventative interventions against food allergy (FA).
The composition of the gut microbiota, and specific bacterial members within the microbiota, have been shown to impact allergic disease development in animal models by limiting basophil hematopoiesis, influencing macrophage polarization, and enhancing regulatory T cell activity. With a growing body of evidence showing the gut microbiota is an important environmental factor contributing to FA development comes an opportunity to translate this knowledge into novel approaches for treating and preventing FA.
Using a proprietary human gut microbiota consortium, we have developed a mixed species live biotherapeutic product (LBP) to alleviate FA development and severity. We show that this LBP can directly interact with human immune cell populations modulating immune signaling pathways including TGF-beta, FFARs, chemotaxis, and NFkB inhibition. We also demonstrate that supplementation with this LBP can reduce OVA induced oral anaphylactic severity in mice with humanized gut microbiota. This protective effect may be attributed to increased fecal antigen-specific IgA levels and enhanced intestinal TGFb levels. These data describe immunological mechanism of a mixed species LBP that is protective in mouse FA model.
Dendritic cell metabolism regulates allergic sensitization in asthma
Authors: Tharakan Anuj , Martin Rebecca 
Published: February 2023

Abstract
Allergic asthma is a respiratory disease characterized by airway inflammation driven by T-helper 2 (Th2) cytokines and antigen-specific IgE (Ag-specific IgE). Ag-specific IgE production requires T follicular helper 13 cells (Tfh13s), which are a population of IL-4/13+ Tfh cells. Tfh13 polarization is induced by type 2 conventional dendritic cells (cDC2s), however, the mechanisms by which cDC2s regulate Tfh13 polarization are unclear. We hypothesized that cDC2s would exhibit distinct transcriptional responses following in vivo exposure to the Tfh13 inducing stimuli, Alternaria, compared to non-Tfh13 polarizing stimuli, such as LPS or the protease papain. Thus, we treated mice intranasally with LPS, papain, or Alternaria plus fluorescently tagged OVA and sorted OVA+ migratory cDCs from the mediastinal lymph node (mLN) for RNA-seq analysis. Principal component analysis revealed that these stimuli induced unique transcriptional signatures in migratory cDCs. Gene set enrichment analysis demonstrated significant downregulation of oxidative phosphorylation (OXPHOS) genes in Alternaria stimulated cDCs compared to LPS or papain. We therefore hypothesized that Alternaria induces metabolic perturbations in cDC2s, whereby they upregulate glycolytic metabolism and decrease OXPHOS, and this metabolic profile was involved in Tfh13 polarization. To test this hypothesis, mice were either fed ad libitum or fasted for 12 hours prior to Alternaria exposure. Fasted mice exhibited a significant reduction in mLN Tfh13s and Th2 cells. Thus, we demonstrate that glucose metabolism may regulate allergic sensitization in asthma. Future experiments will aim to elucidate the role of cDC2-intrinsic metabolism in Tfh13 polarization.
Resolvin D2 Promotes the Resolution of Lung Inflammation in Allergen-Induced Asthma
Authors: Peh Hong Yong , Bruggemann Thayse R , Wong WS Fred , Levy Bruce D 
Published: February 2023

Abstract

Background:
Asthma is a chronic inflammatory disease without complete resolution. The production of specialized pro-resolving mediators (SPMs) is defective in asthma, so they represent a potential therapeutic opportunity. We hypothesize that docosahexaenoic acid derived resolvin D2 (RvD2) can promote the resolution of asthma.

Methods:
BALB/c mice were challenged intra-tracheally with house dust mite (HDM). Bronchoalveolar lavage (BAL) fluid was collected at predefined protocol endpoints for peak inflammation and during resolution. To determine impact on resolution, some mice were given RvD2 (100 ng, intra-nasally) for 2 days after the last HDM challenge, and the resolution index for eosinophils and other markers were calculated.

Results:
Airway HDM challenge led to marked increases in BAL eosinophils and BAL fluid pro-inflammatory cytokine and chemokine levels. Histology demonstrated changes in airway inflammation and mucous cell metaplasia in HDM-challenged lungs. NF-κB expression was increased in the lungs of HDM allergic mice. Compared to vehicle, treatment with RvD2 significantly decreased BAL inflammatory macrophage and eosinophil counts, and accelerated the resolution of HDM-evoked inflammation with a marked decrease in the resolution index for BAL eosinophils from 5 days to 1 day. Interestingly, RvD2 attenuation of eosinophils specifically targeted a specific eosinophil population, but not the “resident” eosinophils. The impact of RvD2 on NF-kB activity and its GPR18 receptor-mediated actions is under current investigation to determine mechanisms for RvD2’s pro-resolving actions.

Conclusion:
RvD2 promotes resolution of allergen-induced inflammation in a murine model of allergic asthma.
G-protein coupled receptor kinase 2 (GRK2) regulates T cell response in a murine model of house dust mite-induced asthma
Authors: Subramanian Hariharan , Kammala Ananth Kumar , Yang Canchai , Panettieri Reynold A , Das Rupali 
Published: February 2023

Abstract
G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCRs) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/− mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte count, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.
Impact of oral probiotic treatment in murine model of atopic dermatitis
Authors: Jung Ariee , Swartzendruber Julie A , Incrocci Ryan , Toro Rosalind Del 
Published: February 2023

Abstract
The number of people with allergies has been on the rise over the last half-century; and the most common allergen afflicting humans, dogs and cats is the house dust mite (HDM). The rise in allergic disease correlates with an increasingly sterile living environment and reduced exposure to bacteria. We predict that exposure to non-pathogenic bacteria helps educate our immune system to become tolerant to innocuous material, such as allergens. Our previous studies have found that Bacillus subtilis, a gram-positive spore forming bacterium, can reduce the symptoms of HDM-induced allergic lung disease. Our current work is aimed at determining if B. subtilis can also provide protection in a murine model of atopic dermatitis. To test this, we administer B. subtilis by oral gavage 3 days before allergen exposure and weekly-post allergen exposure (total of 9 applications), while HDM extract in PBS is applied topically, after shaving the mouse back, 3 times a week for 8 weeks (total of 24 applications). After 8 weeks the serum is assessed for HDM-specific antibodies by ELISA. Additionally, we monitor symptoms of atopic dermatitis: reduced scratching, skin lesions and histological thickening of the skin. Our results, have identified HDM-specific IgM, IgG1 and IgE levels are unaffected by oral gavage of B. subtilis. This suggests orally administered probiotics are not sufficient to protect from topical allergen sensitization
ADAMTS4 promotes chronic airway inflammation and hyperresponsiveness in HDM-based mouse model of asthma: A potential therapeutic target for asthma traits
Authors: Ghonim Mohamed A. , Boyd David F. , Van de Velde Lee-Ann , Souquette Aisha , Vogel Peter , Thomas Paul G. 
Published: February 2023

Abstract
Asthma is a chronic airway inflammation characterized by combination of immune responses and structural remodeling that involves both large and small airways. The global prevalence of asthma is on the rise with a sizable portion of asthmatics not responding to existing medication, thus posing a substantial health and economic burden. Matrix proteases including A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) contribute to lung damage and repair responses. Our lab has recently reported a critical role for ADAMTS4 in the immunopathology of IAV infection-induced acute lung inflammation through exuberant activity of lung fibroblasts and remodeling of the extracellular matrix. Given the divergent nature of immune responses in chronic airway inflammation compared to infection, we sought to investigate the sustaining role of ADAMTS4 upon persistent exposure to aeroallergen. Using HDM-based asthma model, ADAMTS4 knockout mice exhibited a robust reduction in lung eosinophils, mucus production, and airway resistance compared to their wildtype counterparts. This was associated with a marked decrease in IL-4, IL-5, and IL-13 cytokine production and IgE secretion. Interestingly, ADAMTS4 gene deletion differentially blocked the myeloid cell recruitment to the lungs without affecting their development. Such effects were also associated with significant reduction in alveolar macrophages and peribranchial inflammation. These results suggest that the modulating immune responses by ADAMTS-4 is sustainable beyond the acute phase of inflammation and may be extensively contributing to the immunopathology of chronic airway inflammation, thus harboring a therapeutic potential for the treatment of asthma traits.
Exosomes of MSCs target M2-type Macrophages to promote TGF-β-Dependent Microvascular Stabilization and Functional Recovery in Spinal Cord Injury
Authors: Askenase Philip W 
Published: February 2023

Abstract
Intravenous (IV) infusion of mesenchymal stromal cells (MSC) stabilizes the blood-spinal cord barrier and improves functional neurological recovery after spinal cord injury (SCI). However, the MSCs do not traffic to the injury site, but rather lodge primarily in the lungs for a few days. Here, groups of 8 young Sprague Dawley rats received 2 x 10&gt;6 MSCs, their derived exosomes (MSC-exos, 2 x 10&gt;10). in single dose or dividing that dose over 3 days starting on the 10th day following severe contusive SCI, or vehicle control. Locomotion, cell targeting, expression of TGF-β, TGF-β-R, vascular proteins and permeability were determined at 3, 7 and 14 days after treatments. We report that MSC-exos are released in vivo by infused MSCs, distribute systemically, and at the injury site specifically associate with M2-type macrophages. While a single MSC infusion resulted in significant improvement in locomotor recovery, fractionated dosing of MSC-exos over three days was required to achieve similar extent of therapeutic effects as infusion of the MSCs. Both MSCs and fractionated doses of MSC-exos increased numbers and differentiation of M2-type macs expressing TGF-β, with increased accompanying expression of TGF-β receptors and tight junction proteins in the neighboring microvascular, resulting in reduction in blood spinal cord barrier vascular permeability.
SUMMARY: In SCI, IV infused MSCs release MSC-exos in vivo over time that target lesional M2-macs to increase their TGF-β production and further induce TGF-β signaling pathways in the local vasculature to mediate therapeutic effects, likely by release of locally active secondary exosomes transferring miRNAs that induce TGF-β pathways in the neighboring micro vasculature to promote healing.
Lymphangiogenesis near the cribriform plate after cerebral ischemia
Authors: Choi Yun Hwa , Hsu Martin , Laaker Collin , Sandor Matyas , Fabry Zsuzsanna 
Published: February 2023

Abstract
The central nervous system (CNS) has been described as “immune privileged”, but it has been recently hypothesized that antigens, antigen-presenting cells (APCs), and cerebrospinal fluid (CSF) may drain from the CNS into lymphatics in order to provide antigen drainage and fluid homeostasis. This re-discovery of lymphatics ignited an intense debate about the mechanisms of how antigens or immune cells drain from the CNS parenchyma in both steady state and neuroinflammation. Here, we study how lymphangiogenesis near the cribriform plate contributes to recovery of brain tissues following transient ischemic stroke. We employed the 60-minute transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke in mice. We showed that lymphangiogenesis occurs near the cribriform plate, which peaked at day 7 and decreases after 14 days following tMCAO. The lymphangiogenesis occurred through interaction of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C which are produced by CD11b+, CD11c+ dendritic cells. These lymphangiogenic vessels could transport CSF and immune cells which were confirmed by injection of Evans Blue dye through cisterna magna and flow cytometry, respectively. Flow cytometry analysis showed robust leukocyte accumulation, which include macrophages (CD45hi, CD11b+, CD11clow), dendritic cells (CD45hi, CD11b+, CD11chi), CD8 T cells (CD45hi, CD11b−, CD11c−, CD8+), and CD4 T cells (CD45hi, CD11b−, CD11c−, CD4+) near the cribriform plate after 7 days of tMCAO, which also correlated with lymphangiogenesis (CD45−, Podoplanin+, CD31+). Understanding the biology and mechanisms of CNS lymphatic drainages may lead to novel therapeutics for neuroinflammatory diseases.