bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protease allergens induce attenuated T follicular helper responses compared to aeroallergens resulting in low-affinity IgE production
Authors: Tharakan Anuj , Martin Rebecca 
Published: January 2023

Abstract
Anaphylaxis is a type of severe allergic reaction that is initiated by cross-linking of high-affinity IgE on mast cells leading to mast cell degranulation. Recent evidence demonstrates that T follicular helper cells (Tfh) producing both IL-4 and IL-13, termed Tfh13s, are necessary for the generation of anaphylactic IgE. The mechanisms regulating the polarization of these T cells, however, remain unclear. Parasite infection, which induces strong IgE responses, fails to induce Tfh13 polarization. We therefore hypothesized that papain, a cysteine protease that resembles parasitic CA family peptidases, would similarly fail to induce Tfh13 polarization compared to the aeroallergen Alternaria due to differential action on dendritic cells (DCs). We found that intranasal immunization with LPS+OVA and Alternaria+OVA induced a 2-fold Tfh expansion in the draining lymph node compared to papain+OVA. Additionally, Alternaria stimulated Tfh13 polarization and high-affinity IgE production while papain only induced Th2 responses and non-specific IgE. Analysis of DC migration by immunization with fluorescently tagged OVA alongside these adjuvants revealed markedly different migration kinetics following each stimulus. However, numbers of Ag+ DCs, amount of antigen uptake, and proportions of Ag+ migratory vs. resident DCs in the mediastinal lymph nodes were similar between all groups. Thus, we demonstrate that papain, in contrast to Alternaria, is unable to induce Tfh13 polarization and anaphylactic IgE. We propose that the differential effects of these adjuvants are likely mediated by alternative mechanisms of DC licensing and distinct DC transcriptional profiles.
A novel bovine beta-lactoglobulin-induced passive systemic anaphylaxis model using humanized NOG hIL-3/GM-CSF Tg mice
Authors: Ito Ryoji , Katano Ikumi , Otsuka Iyo , Takahashi Takehi , Ito Mamoru , Simons Peter 
Published: January 2023

Abstract

Background
Food allergy is a common disease that is caused by intake of allergen-containing foods such as milk, eggs, peanuts, and wheat. Systemic anaphylaxis is a severe hypersensitive allergic reaction resulting from degranulation of mast cells or basophils after crosslinking of their surface high affinity IgE receptors (Fce-RI) by allergen-specific IgE and allergens. In this study, we developed a novel human mast cell/basophil-engrafted mouse model that recapitulates systemic anaphylaxis by milk’s major allergen beta-lactoglobulin (BLG).

Method
Human CD34+ hematopoietic stem cells were transferred into NOG (nonTg) or NOG hIL-3/GM-CSF Tg mice. After 14–16 weeks, mature human basophils and mast cells increased in Tg mice, and bovine BLG specific human IgE was intravenously injected in these humanized mice, followed by either intravenous or oral bovine BLG protein exposure, 1 day later. Subsequently, allergic reactions were monitored by measuring body temperature, serum histamine level, and anaphylaxis scoring. Furthermore, the adrenaline agent, ‘epinephrine’ was used to investigate whether the allergic symptoms could be suppressed.

Results
After bovine BLG exposure, body temperature in Tg mice, but not in nonTg mice, gradually decreased within 10 minutes and 80 % of Tg mice died within 60 minutes. Serum histamine levels and anaphylaxis scores in Tg mice were markedly increased compared to nonTg mice after 30 minutes BLG challenge. These allergic symptoms were significantly inhibited by epinephrine treatment in Tg mice.

Discussion
The current hIL-3/GM-CSF Tg mouse model could possibly be used to develop novel anaphylaxis drugs in food allergy.
Selective Serotonin Reuptake Inhibitors Suppress IL-33-Mediated Mast Cell Function
Authors: Kee Sydney Ann , Haque Tamara , Ryan John J 
Published: January 2023

Abstract
Interleukin-33 (IL-33) is an inflammatory cytokine that promotes allergic disease by activating ILC2, Th2 cells, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. Therefore, clinical interventions targeting IL-33 may be beneficial for allergic disease. We have sought ways of re-purposing FDA-approved drugs for use in allergic inflammation. Because drugs in the selective serotonin reuptake inhibitor class (SSRIs) have documented anti-inflammatory effects, we tested the hypothesis that SSRIs can attenuate mast cell function. We show that the SSRI fluoxetine inhibits IL-33-mediated cytokine production in mouse bone marrow derived mast cells in vitro and reduces IL-33-induced peritonitis in vivo. These data indicate that fluoxetine may be an effective therapeutic for IL-33- and mast cell-associated diseases.
Evidence for sexual dimorphism in mast cell-mediated innate immune response against Group B Streptococcus
Authors: Piliponsky Adrian Martin , Gendrin Claire , Quach Phoenicia , Guga Eric , Bhise Gauri , Saha Siddhartha , Brokaw Alyssa , Moeser Adam , Rajagopal Lakshmi 
Published: January 2023

Abstract
Mast cell response to stimuli was recently described to be sexually dimorphic with female mast cells exhibiting increased ability to produce and release mediators upon activation. This suggests that female mast cells may have evolutionary advantages and an important role in innate immunity. In fact, sexual dimorphism of mast cell innate immune function may be particularly relevant to our understanding of mast cell contribution to host immunity against Group B Streptococcus, a bacterial pathogen associated with pre-term birth. This hypothesis is supported by our published studies, which indicate that mast cells contribute to host defense against systemic GBS infection and our observations that female mice are more efficient in their ability to limit systemic GBS infection than male mice. The contribution of individual sexually dimorphic factors to the immune response against GBS is unknown.
Here, we show that female mice produce higher amounts of pre-formed coagulation factor XIIIA (FXIIIA) when compared to corresponding male mice, and that female bone marrow-derived cultured mast cells contain higher amounts of FXIIIA than male mast cells. We used FXIII-deficient mice to show that FXIIIA decreases the severity of systemic GBS infections. Moreover, our studies indicate that FXIIIA limits GBS dissemination by enhancing bacteria entrapment within fibrin clots.
Together, these studies have the potential to provide novel mechanistic understanding into how female mast cells contribute towards defense against GBS infection and promote successful pregnancies via the release of FXIIIA.
Blocking of mast cell-mediated passive anaphylaxis to peanut using covalent heterobivalent inhibitor in a humanized mouse model
Authors: Alakhras Nada Salem , Shin Jaeho , Smith Scott S. , Bilgicer Basar , Kaplan Mark H. 
Published: January 2023

Abstract
Anaphylaxis to peanut allergen is a severe hypersensitive allergic reaction characterized by life-threatening symptoms. Anaphylaxis is mediated by IgE-dependent mast cell activation that leads to the release of inflammatory mediators. In a previous report, we described the design of a covalent heterobivalent inhibitor (cHBI) that selectively forms covalent bonds with allergen specific-IgE (sIgE) on mast cells and abates allergic reactions in ex-vivo peanut challenges. Here, we utilized a humanized mouse model to recapitulate key features of anaphylaxis to peanut in humans, and we examined the efficacy of cHBI in blocking the anaphylactic reaction in this model. NSGS (NOD-scid Il2rgnull IL-3/GM-CSF/SCF) mice engrafted with human hematopoietic stem cells were treated with an allergen-specific human IgE monoclonal antibody and then challenged with a peanut allergen. We found that the peanut-challenged humanized mice can develop rapid anaphylaxis and mast cell degranulation following challenge. The anaphylactic reaction was characterized by a substantial decline of core body temperatures and upregulation of human mast cell degranulation markers. Additionally, we found that the severity of the anaphylactic reaction is hIgE dose-dependent. Most importantly, cHBI protected the mice from developing an anaphylactic reaction demonstrating the ability of cHBI to block IgE-mediated allergic reactions in the humanized mice. Overall, our results show that the humanized mouse model is a novel model to study human mast cell IgE-mediated allergic reactions and demonstrate that cHBI is an effective potential therapeutic inhibitor for food allergy.
IFNγ-induced mechanisms restrict intracellular replication of the lysosome-adapted bacterial pathogen, Coxiella burnetii
Authors: Ganesan Sandhya , Andrews Jenna M. , Alvarez Natalie N. , Baskerville Maia J. , Roy Craig R. 
Published: January 2023

Abstract
Coxiella burnetii is an intracellular bacterial pathogen that causes flu-like illness called Q-fever. C. burnetii extensively subverts host-cell vesicle traffic to create an acidic, lysosome-derived vacuole to support its intracellular replication. This is a unique evolutionary adaptation since lysosomal environment is hostile to most microbes. IFNγ signaling is essential for host protection against C. burnetii, but the underlying immune defense strategies are not well-defined. Using siRNAs to deplete IFNγ-induced genes, we identified that restriction of intracellular C. burnetii requires atleast two host factors, Indoleamine Dioxygenase 1 (IDO1) and Syntaxin 11 (STX11). IDO1 activity depletes tryptophan availability by catabolizing cellular tryptophan. This mechanism renders C. burnetii metabolically inactive since it is a tryptophan auxotroph, but is not sufficient to clear the infection. STX11 is a SNARE protein (Soluble NSF Attachment Protein Receptor) that promotes fusion of lysosome-derived organelles with target membranes. Bacterial replication as well as size of the C. burnetii-containing vacuole (CCV) are significantly increased in STX11-deficient cells. These cells also exhibited increased extracellular release of lysosomal proteins. STX11 over-expression reverses these phenotypes. Furthermore, STX11 accumulated in the CCV during infection. We hypothesize that STX11 regulates CCV-associated cargo-sorting and vesicle fusion events, leading to a sub-optimal vacuolar environment for C. burnetii. These findings demonstrate that, IFNγ-induced nutrient deprivation and altered intracellular niche can synergistically and effectively restrict lysosome-adapted pathogens.
Preoperative exercise protects the liver from surgical stress by altering the immune environment
Authors: Zhang Hongji , Xia Yujia , Onuma Amblessed , He Jiayi , Tsung Allan , Huang Hai 
Published: January 2023

Abstract

Introduction
Inflammation after liver surgery can lead to post-operative liver dysfunction, significant morbidity and mortality. Preoperative exercise has been associated with reduced postoperative complications. However, the mechanisms behind remain to be elucidated. We hypothesize that preoperative exercise can alter the hepatic immune microenvironment(HIM) to allow protection from liver injury.

Methods
8-week-old mice were randomly divided into exercise and sedentary groups. The exercise group ran on a motorized treadmill at a speed of 12.5 m/min for 60 min/day, 5 days/week for 4 weeks whereas sedentary mice were exposed to the same treadmill but held motionless. Both groups were then subjected to surgical stress as modeled by 70% partial liver ischemia/reperfusion (I/R). Single-cell(SC)RNA sequencing was performed on hepatic CD45+ cells isolated from both groups.

Results
The exercise group had significantly lower serum alanine transaminase compared to sedentary mice after liver I/R. SC-RNA analysis of the hepatic immune cells revealed distinct macrophage subpopulations that correlated with cells derived from both groups. Among these macrophages, the expression of genes related to anti-inflammatory cytokines were significantly higher in exercised mice compared to sedentary mice, whereas pro-inflammatory cytokines and chemokines were significantly lower suggesting that exercise modulates the transcriptomic change in macrophages towards an anti-inflammatory phenotype.

Conclusion
Our study showed that preoperative exercise alters the HIM which offers a rationale for preoperative exercise therapy for patients undergoing liver surgery thereby decreasing post-operative inflammation and morbidity.
Distinct contributions of Type I and Type III IFNs in innate fungal immunity
Authors: Espinosa Vanessa , Dutta Orchi , Mc Elrath Constance , Du Peicheng , Chang Yun-Juan , Cicciarelli Bryan , Pitler Amy , Whitehead Ian , Obar Joshua J , Durbin Joan , Kotenko Sergei , Rivera Amariliz 
Published: January 2023

Abstract
Type I (IFN-α/β) and Type III (IFN-λ) interferons are important mediators of antiviral immunity but whether they are required for antifungal defense is unclear. We report that mice defective in Type I and/or Type III IFN receptor expression are highly susceptible to infection with the opportunistic human fungal pathogen Aspergillus fumigatus (Af). Type I IFN (IFNAR) and Type III (IFNLR1) receptor expression on hematopoietic cells was required for antifungal defense while their expression on non-hematopoietic was dispensable. Consistently, mice with gene-specific deletion of IFNLR1 or STAT-1 on granulocytes were highly susceptible to Af. These data demonstrate a requisite and non-redundant role for Type I and Type III IFNs for the activation of antifungal immunity. In addition, we found that Type III IFNs act as important activators of reactive oxygen species generation in antifungal neutrophils, and require early expression of Type I IFN for optimal induction. Importantly, CCR2+ monocytes act as an important source of Type I IFN, and are required for the optimal expression of Type III IFN and fully functional neutrophil antifungal activity. Dysfunctional neutrophil responses in CCR2-depleted mice were rescued by adoptive transfer of pulmonary CCR2+ monocytes or by exogenous administration of IFN-a and IFN-l. Altogether, our data identified Type III IFNs as major regulators of neutrophil activation, and Type I IFNs as early activators of IFN-λ expression and response. Innate antifungal defense is thus coordinated by the actions of Type I and Type III IFNs, a finding that suggests a broader therapeutic potential for these cytokines as activators of antifungal immunity.
CD3 downregulation on T-cells is concomitant with arginase upregulation on myeloid cells in the synovial fluid of patients with juvenile idopathic arthritis
Authors: Giacalone Vincent D , Cammarata-Mouchtouris Alexandre , Moncada Diego , Shenoy Sreekala , Ponder Lori , Gergely Talia , Vega-Fernandez Patricia , Manos Cynthia , Flanagan Elaine , Prahalad Sampath , Tirouvanziam Rabindra 
Published: January 2023

Abstract

Rationale
Juvenile idiopathic arthritis (JIA) is an inflammatory autoimmune disorder driven by dysfunction of the joint tissue and abnormal immune responses. As deep phenotyping of synovial fluid (SF) might yield new targetable mechanisms of inflammation in JIA patients, we initiated the Emory Multi Omics JIA Immunology (EMOJI) project.

Methods
Patients with JIA between the ages of 6 and 18 were consented and enrolled for collection of SF from the knee and venous blood. Blood and SF leukocytes were analyzed by flow cytometry. Platelet-free plasma and debris-free SF supernatant were obtained by dual centrifugation and a 20-plex chemiluminescent assay (Meso Scale Discovery) was used to quantify cytokines.

Results
We report data on blood and SF collected at the same visit from 7 JIA patients. JIA subtypes represented were psoriatic (N=1), oligoarticular extended (N=1), oligoarticular persistent (N=2) and polyarticular (N=3) arthritis; all rheumatoid factor-negative. CD3 expression was decreased on SF compared to blood T-cells. Concomitantly, expression of the CD3-inhibitory enzyme arginase was increased on SF compared to blood neutrophils and macrophages. However, arginase-rich primary granules were not significantly exocytosed by SF neutrophils. Finally, we measured high levels of neutrophil chemoattractants (IL-8, G-CSF, and IL-1α) in SF compared to plasma.

Conclusions
Neutrophils are recruited to the joints of JIA patients and accumulate arginase on their surface, presumably released from tertiary, but not primary, granules. Arginase activity in the SF may lead to CD3 downregulation and T-cell inhibition, potentially in an effort to limit autoimmune complications.
-Brucella induction of RIDD activity promotes intracellular parasitism by subverting BLOS1-controlled immune defense
Authors: de Figueiredo Paul , Wells Kelsey , He Kai , Pandey Aseem , Cabello Ana-Lucia , Gomez Gabriel , Rice-FIcht Allison , Sze Sing-hoi , Qian Xiaoning , Ficht Thomas A 
Published: January 2023

Abstract
The intracellular bacterial pathogen and biothreat agent Brucella is the causative agent of brucellosis, a global zoonotic disease that is associated with acute and chronic symptoms in humans and animals. The mechanisms by which the pathogen colonizes host cells remain obscure. Here, we demonstrate that infection activates the regulated IRE1-dependent decay (RIDD) of mRNA encoding BLOS1 (biogenesis of lysosome-related organelles 1 subunit 1), a protein that promotes endosome-lysosome fusion. RIDD-deficient host cells as well as mice harboring a RIDD-incompetent variant of IRE1a displayed resistance to infection. Moreover, host cells carrying a RIDD resistant variant of BLOS1 displayed enhanced trafficking of the pathogen to lysosomes, and increased resistance to intracellular parasitism. Finally, cells harboring mutations in BLOS1 displayed increased susceptibility. Taken together, the data demonstrate that host RIDD activity on BLOS1 transcripts regulate Brucella intracellular parasitism by disrupting BLOS1-directed lysosomal trafficking activity, thereby promoting maintenance of the pathogen’s replicative niche in the endoplasmic reticulum.
Clearance of Plasmodium falciparum-infected red blood cells by NK cells and monocytes
Authors: Sekar Padmapriya , Arora Gunjan , Long Eric O 
Published: January 2023

Abstract
Antibodies naturally acquired during repeated exposure to the parasite Plasmodium falciparum are essential for control of blood-stage malaria. NK cells are innate immune cells with an important role in containing viral infections and tumor growth, mainly by direct cytotoxicity and inflammatory cytokine production. Recently, we reported that primary human NK cells lyse Plasmodium falciparum-infected red blood cells (iRBCs) via antibody-dependent cellular cytotoxicity (ADCC) in presence of IgG isolated from adults living in a malaria-endemic region. This NK-mediated lysis results in inhibition of parasite growth in vitro. Live imaging showed release of parasitophorous vacuoles (PV) from iRBCs after incubation with NK cells. Many of these PVs gave propidium iodide-positive signals, suggesting loss of viability of P. falciparum inside the PVs after NK-mediated iRBC lysis. I am interested to know whether and how PVs are eliminated and postulate that monocytes play a role in clearance of PVs, thereby reducing the inflammatory response. To observe the interaction of NK cells and monocytes with PVs, I isolated PVs from iRBCs by mild saponin treatment and mechanical disruption of RBC membranes. Purified PVs bind IgG isolated from adults living in a malaria-endemic region, showing that adults develop antibodies against Plasmodium antigens at the surface of PVs. Preliminary live imaging experiments show phagocytosis of PVs by monocytes. Currently I am testing the contribution of Fc receptors on monocytes to phagocytosis of PVs and the interaction of NK cells with PVs.
Bcl3 dependent regulation of Dendritic Cell function in Toxoplasma gondii infection
Authors: Guha June , Claudio Estefania , Jankovic Dragana , Siebenlist Ulrich 
Published: January 2023

Abstract
The atypical IκB family member Bcl-3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in nuclei, thereby either positively or negatively modulating transcription in a context-dependent manner. Bcl-3 is critical for host resistance to Toxoplasma gondii and Bcl-3-deficient mice succumbed within 3–5 weeks after infection, correlating with an apparently impaired Th1-type adaptive immune response rather than a defect in the innate immune response. Surprisingly, mice lacking Bcl-3 in CD11c+ dendritic cells (DC) were as susceptible as mice globally deficient for Bcl-3, demonstrating that Bcl-3 is required in these cells to prime protective T-cell-mediated immunity to T. gondii. It remains to be determined however whether conventional or monocyte derived DCs are critical mediators of a successful T cell response against the invading pathogen.
We generated mice specifically lacking Bcl-3 in conventional DCs (Zbtb46 cre knockout [KO]) or in monocyte derived cells, including monocyte derived DCs (LysM cre KO). Surprisingly, both conditional KO strains were as susceptible to T. gondii infection as CD11c+ conditional or total KO mice. Interestingly, we detected the presence of a unique subpopulation of conventional DCs that expressed the monocytic markers CD64 and Ly6C in infected spleen and various tissues including lung. Furthermore, this population was reduced in the absence of Bcl3. This hybrid DC population may have a crucial role in the T cell responses after infection, in particular in the generation of inflammatory cytokines such as IFNg, a cytokine which is indispensable for host protection.
IκBζ regulates NLRP3 inflammasome activation
Authors: Ahn Huijeong , Lee Geun-Shik 
Published: January 2023

Abstract
Inflammasome activation induces the maturation and secretion of interleukin (IL)-1β and -18, and is dependent on NF-κB signaling to induce the transcription of the inflammasome components, called the priming step. This study elucidated the role of IκBζ, an atypical IκBs (inhibitor of κB) and a coactivator of NF-κB target genes, on the activation of inflammasome. Bone marrow-derived macrophages (BMDMs) that originated from IκBζ-encoding Nfkbiz gene depletion mice presented a defect in NLRP3 inflammasome activation. In addition, the Nfkbiz+/− and Nfkbiz−/− mice significantly attenuated serum IL-1β secretion in response to a monosodium urate injection, a NLRP3 trigger, when compared with Nfkbiz−+/+ mice. The lack of IκBζ in BMDMs produced a disability in the expression of Nlrp3 and pro-Il1β mRNAs during the priming step. In addition, ectopic IκBζ expression enhanced the Nlrp3 promoter activity. Overall, IκBζ controlled the activation of NLRP3 inflammasome by upregulating the Nlrp3 gene during the priming step.
Tyrosine Phosphorylation of NLRP3 by Src Family Protein Tyrosine Kinase Lyn Suppresses NLRP3 Inflammasome Activation
Authors: Xiao Yizhi , Tang Juan , Lin Guoxin , Guo Hui , Zhang Jian 
Published: January 2023

Abstract
The NLRP3 inflammasome is a multi-protein complex that triggers the activation of inflammatory caspase-1 and the maturation of IL-1β in response to microbes and danger signals in host cells. However, how the NLRP3 inflammasome is regulated is not fully understood. Here, we show that NLRP3 is tyrosine phosphorylated upon activation of the NLRP3 inflammasome, and that NLRP3 tyrosine phosphorylation correlates with its ubiquitination. Further, we identified Lyn as the protein tyrosine kinase that phosphorylates NLRP3 at Tyr 918, which facilitates its ubiquitination and proteasome-mediated degradation. Consistent with these data, NLRP3 tyrosine phosphorylation and ubiquitination is abrogated in macrophages lacking Lyn, which correlates with heightened IL-1 production. Therefore, our data demonstrate that Lyn-mediated tyrosine phosphorylation of NLRP3 is a prerequisite for its ubiquitination, thus dampening NLRP3 inflammasome activity.