bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scavenger receptor BI attenuates IL-17-dependent neutrophilic inflammation in asthma.
Authors: Reece Sky W. , Kilburg-Basnyat Brita , Gilliard Andrea , Hodge Myles , Luo Bin , Madenspacher Jennifer , Cook Donald , Fessler Michael , Gowdy Kymberly M. 
Published: January 2023

Abstract
Asthma impacts over 24 million people and costs about $56 billion annually in the United States. Airway neutrophil accumulation and high levels of IL-17 are characteristic of severe asthma. However, mechanisms underlying IL-17/neutrophilic inflammation in severe asthma remain poorly defined. Scavenger receptor class B type I (SR-BI) is a multi-recognition receptor that regulates cholesterol trafficking. We previously reported SR-BI dampens pulmonary innate immune responses during bacterial pneumonia, but the role of SR-BI in asthma is unknown. We hypothesize pulmonary SR-BI expression is protective against house dust mite (HDM)-induced IL-17-dependent neutrophilic asthma. SR-BI+/+ and SR-BI−/− mice were sensitized with 10 μg HDM by oropharyngeal aspiration on day 0 and 7, and challenged with 2 μg HDM on day 14, 15, 16. Airway inflammation and cytokine production were quantified on day 17. SR-BI−/− mice had increased neutrophils but decreased eosinophils in bronchoalveolar lavage (BAL) after HDM challenge compared to SR-BI+/+ mice. BAL levels of neutrophil chemoattractants CXCL1, CXCL2 and CXCL5 were not significantly different between SR-BI+/+ and SR-BI−/− mice. SR-BI−/− mice had increased pulmonary IL-17A and GM-CSF production and decreased IL-5 production. To identify cellular sources of airspace IL-17, single cells isolated from lung were labeled with antibodies for flow cytometry. IL-17A increased in neutrophils (CD45+Ly6G+) and macrophages (CD45+CD64+CD11b−CD11c+) but not T cells (CD45+CD4+) of asthmatic SR-BI−/− mice suggesting myeloid cells rather than Th17 cells as sources of IL-17. Overall, SR-BI expression in the lung suppresses neutrophilic inflammation and IL-17 production in HDM-induced asthma model.
PKCλ/ι regulates Th17 cells and house dust mite-induced allergic airway inflammation
Authors: Yang Jun-Qi , Dong Panpan , Yang Yingying , Zhou Wei , Mei Congjin , Guo Fukun , Zheng Yi 
Published: January 2023

Abstract
Asthma is a chronic airway inflammatory disease affecting millions of people in the world. CD4+ T helper cells play central roles in its pathogenesis. We have reported that atypical protein kinase PKCλ/ι regulates Th2 differentiation and function. Recently, we found that PKCλ/ι was involved in the regulation of Th17 differentiation and function. PKCλ/ι-deficient CD4+ T cells showed impaired ability to differentiate into Th17 cells in vitro under Th17-polarizing culture conditions. The secretion of IL-17, IL-17F, IL21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-polarizing and Th17-polarizing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorgt, key Th17 transcription factors. On the other hand, PKCλ/ι did not affect the development and induction of regulatory T (Treg) cells. In order to study the in vivo roles of PKCλ/ι-Th17 axis, we applied a murine model of house dust mites (HDM)-induced allergic airway inflammation, in which Th17 cells and neutrophils are dominant responder among others. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 and Th2 effector cytokines, such as IL-17, IL-4, IL-5 and IL-13 were inhibited in the bronchoalveolar lavage fluids. Their mRNA levels in the lungs were also significantly downregulated. Thus, PKCλ/ι emerges as an important regulator of Th17 differentiation and allergic airway inflammation. Further investigations are underway to explore the underlying molecular mechanisms.
Resveratrol treatment alters lung microbiome in the murine ovalbumin-induced asthma model by increasing mucus-degrading Akkermansia muciniphila.
Authors: Alharris Esraah Sattar , Alghetaa Hasan F. , Busbee Philip Brandon , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Asthma is a chronic inflammatory disease that involves the narrowing of the lung airways and excessive mucus production. Resveratrol (RES), a polyphenolic stilbene, is known to control asthmatic attacks via different molecular mechanisms. However, no studies have examined the effect of resveratrol on the microbiome in the ovalbumin (OVA)-induced asthma mouse model. In this study, we induced asthma in BALB/c mice by injecting OVA followed by 7 days treatment with RES. Plethysmography showed that the expiratory resistance in the lung tissue was significantly reduced in the RES treated group, while mean volume, peak expiratory flow, and frequency of respiration was increased. Histopathological examination of the lungs of the RES-treated group showed significant reduction in inflammatory cell infiltration and led to restoration of normal lung tissue architecture. In addition, there were significant increases in the expression of the genes encoding tight-junction molecules (claudin-1 and cadherin-18) in the RES-treated group. We performed 16S rRNA microbial analysis of cecal flushes and pulmonary tissues, which showed that RES treatment alters the gut microbiome by significantly increasing the level of Bacteroides acidifaciens spp. compared to disease controls. In addition, there was a significant increase in Akkermansia muciniphila (AM) species within the lungs after RES treatment. AM is a gram-negative, non-spore-forming bacterium known to induce mucus degradation. Since asthma is characterized by an increase in mucus in the lungs, we concluded that RES improves asthma in OVA-induced mouse model by significantly increasing AM and preventing mucus build-up in the lungs.
IκB kinase β inhibitor, BMS-345541, suppresses the dendritic cell response in a murine model of allergic airway inflammation
Authors: Gregorczyk Izabela , Maślanka Tomasz 
Published: January 2023

Abstract
Pharmacological IκB kinase (IKK) inhibition could be an effective therapeutic strategy for the prevention and treatment of allergic asthma. Recently, we have demonstrated that a selective inhibitor of IKKβ prevented allergic asthma in a mouse model through inhibition of CD4+ effector T cell responses in the lung-draining mediastinal lymph nodes (MLNs). However, the precise mechanism responsible for this effect was not been fully elucidated. The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway inflammation (AAI). The study attempts to shed light on the involvement of DCs in the anti-asthmatic action of BMS-345541 (BMS), i.e. a selective inhibitor of IKKβ. We studied the effect of a 7-day treatment with BMS on the development of AAI and the absolute count of CD11chighCD11b+CD103− (CD11b+) and CD11chighCD11b−CD103+(CD103+) DCs in the MLNs and lungs of OVA-sensitized/challenged mice. The absolute count of CD11b+ and CD103+ DCs was increased in the MLNs of untreated OVA-immunized mice. Moreover, the absolute number of CD11b+, but not CD103+, DCs was increased in the lungs of these mice. BMS reduced, but did not fully prevent, the OVA-induced increase in the count of migratory CD11b+ DCs in the MLNs. In turn, administration of this agent prevented the OVA-induced increase in absolute counts of CD103+ DCs in the MLNs and CD11b+ DCs in the lungs. Treatment with BMS protected the lungs from OVA-induced AAI. These results strongly suggest that one of the mechanisms, and probably a key one, underlying the anti-asthmatic action of IKKβ inhibitors is the suppression of the formation of inflammatory DCs at the inflammatory site and their accumulation in the draining lymph nodes.
Intratracheal ovalbumin administration induces colitis through the IFN-γ
Authors: SHIN DA SOM , Jung Kyoung-Hwa , Bae Hyunsu 
Published: January 2023

Abstract
Recent studies it has reported an increased incidence of inflammatory bowel disease (IBD) in patients with pulmonary diseases. Despite clinical and epidemiological studies of the interplay between colitis and asthma, the diseases’ related underlying echanisms remain unclear. In this study, we evaluated the development of colitis in a model of allergic airway inflammation. We revealed that intratracheal chronic ovalubmin (OVA) exposure induces colitis and allergic airway inflammation. Interestingly, induction of colitis was largely regulated by Th1, rather than Th2 responses, whereas allergic airway inflammation was primarily mediated by Th2 responses. Experiments T-bet−/− and Ifng−/− mice deficient mice confirmed that IFN-γ is a major mediator involved in OVA-induced colitis. These findings broaden current understanding of allergen induced colitis pathology and could play a role in the development of novel clinical treatment strategies for asthmatic patients who are at risk of developing colitis.
Lupus susceptibility gene Esrrg regulates Treg development and suppressive function through mitochondrial metabolism
Authors: Li Wei , Choi Seung-Chul , Titov Anton , Abboud Georges , Morel Laurence 
Published: January 2023

Abstract
Estrogen-Related Receptor Gamma (Esrrg) is the candidate gene for the Sle1c2 susceptibility locus, which encodes the orphan nuclear receptor ERR-g, in the NZM2410 mouse model of Systemic Lupus Erythematosus (SLE). Congenic C57BL/6 (B6) mice expressing this locus have an increased IFN-g production and dysregulated metabolism in their CD4 T cells, but the role of ERR-g in CD4 T cells is still unclear. In muscle, heart, iPSCs, pancreatic β cells and neurons, Esrrg has been identified as a major regulator of mitochondrial metabolism. We generated Treg conditional Esrrg knockout mice Foxp3cre Esrrgf/f (Esrrg-KO) and compared CD4+ T cells between Esrrg-KO and B6 mice. Tregs from Esrrg-KO mice showed a reduced expression of Foxp3 and CD25, and other markers associated with Treg suppressive activity. Esrrg-KO mice demonstrated non-Treg global CD4 T cell activation, including the increased frequency and number of CD69 and T effector memory cells, as well as increased spontaneous T follicular helper (Tfh) cells and decreased T follicular regulatory (Tfr) cell frequencies. In the T-dependent NP-KLH immunization, Esrrg-KO mice produced increased Tfh and germinal center B cells and less Tfr, which led to high affinity anti-NP IgG. Esrrg-deficiency in Tregs significantly altered the expression of genes and metabolites, ATP, NAD+ and ROS, involved in mitochondria function. Esrrg-KO mice also exhibited a high expression of mTORC1 and Hif1-a, a pathway that is known to destabilize Foxp3 expression. Finally, Esrrg-deficiency decreased both respiration and glycolysis in Tregs. These results demonstrate that Esrrg-deficiency results in defective mitochondrial function in Tregs, which leads to defective Tregs and global CD4 T cell hyperactivation.
Immunological and electrophysiological characterization of T-cell subsets in inflammatory bowel diseases
Authors: Tajti Gabor , Palatka Karoly , Hajdu Peter , Szanto Tibor Gabor , Panyi Gyorgy 
Published: January 2023

Abstract
Crohn’s Disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characteristic of massive T-cell infiltration of the affected GI tract. CD is Th1-Th17 dominant whilst UC is considered as a Th2-Th17 prevailing disease.
It is also known that ion channels play a crucial role in T-cell physiology and the expression profile is different among T-cell subsets. This differential expression allows ion channel-specific targeting of autoimmune diseases (e.g. psoriasis).
Motivated by these findings we set out experiments to characterize the infiltration of inflamed GI tract by various T-cell subsets along with the subtype specific expression of ion channels in these cells.
We isolated T-cells from biopsy specimens and blood samples of therapy naïve IBD patients (under the ethical approval of the Medical Research Council of Hungary). Following enzymatic (0.5 mg/ml collagenase IV and 250 IU/ml DNAse I) and mechanical disruption, T-cell subsets were separated using flow cytometry. Preliminary results indicate the following proportions of subsets in biopsy samples (% of CD4+ cells): 22.3% Th1, 16.0% Th2 and 25.1% Th17 in CD, while 17.0% Th1, 19.1% Th2, and 16.4% Th17 in UC. We developed electrophysiological techniques to monitor the activity of Kv1.3 and KCa3.1 channels whereas intracellular calcium imaging is used to characterize the functional expression of CRAC, TRPA1 and TRPV1 channels.
Patients included in the study will be monitored for therapy follow-up: changes of T-cell subset distribution and ion channel function of subsets will be determined. Our main goal is to identify novel targets for IBD therapy that is of great importance if we consider that even the modern biological therapies often turn into ineffectiveness.
Selective inhibition of Tfh cells by a small molecule inhibitor abrogates progression of experimental inflammatory arthritis
Authors: Zhang Xin , Migliore Frank , Hellmers Linh , Bradley Sedrick , Zakem Jerald , Davis William , You Zongbing , Quinet Robert 
Published: January 2023

Abstract

Background
Rheumatoidarthritis (RA) is an inflammatory autoimmune disease characterized by T cell infiltration in the joints and autoantibody production. T follicular helper (Tfh) cells are a unique subset of CD4+ T cells regulating antibody production in B cell follicle. Our previous studies have showed that increased circulating Tfh cells were correlated with anti-CCP antibody titer and disease activity in active RA patients, indicating that Tfh cells may play an important role in RA pathogenesis. Here we investigate the therapeutic potential of a small molecule inhibitor targeting Tfh cells (SMI-Tfh) in mice with collagen-induced arthritis (CIA).

Methods
CIA was induced in DBA/1 mice by immunization with chicken type II collagen. Following the onset of clinical arthritis, mice were treated with SMI-Tfh (50mg/kg/day) for 10 days. Arthritis progression was monitored daily and recorded by the paw swollenness. Blood, spleen, and affected paws were collected at the end of the study. Tfh cells were examined and defined by CD4+CXCR5+ICOS+via flow cytometry and further confirmed by immunohistochemistry staining in spleen.

Results
Mice developed arthritis four weeks after immunization with type II collagen. Treatment with SMI-Tfh significantly reduced the disease progression/activity in mice with CIA. SMI-Tfh significantly inhibited the frequency of Tfh cells in spleen (P&lt;0.01), but not the frequency of circulating Tfh cells in CIA mice (P&gt;0.05).

Conclusion
The small molecule inhibitor SMI-Tfh selectively inhibits Tfh cells and abrogates progression/activity of inflammatory arthritis in CIA mouse model. Treatment with SMI-Tfh in CIA mice provides a potential strategy for joint protection and may be beneficial in RA patients.
Autoimmune regulator gene supports maternal-fetal immune tolerance during early pregnancy
Authors: Gillis-Buck Eva Mae , Bautista Jhoanne L. , Anderson Mark S. , MacKenzie Tippi C. 
Published: January 2023

Abstract
Numerous mechanisms protect against immune responses between the mother and her fetus in order to maintain a healthy pregnancy. The autoimmune regulator gene (AIRE) is a crucial component of tolerance to self-antigens, but its relevance for maternal-fetal tolerance has not yet been explored. AIRE contributes to both central and peripheral tolerance via the presentation of tissue specific antigens (TSAs), leading to clonal deletion of self-reactive T cells. These TSAs include placental antigens, which we call “distant self” antigens, since they are encoded in the maternal genome, but have not been expressed since the mother was herself an embryo with a placenta. We hypothesize that maternal tolerance of “distant self” placental TSAs are critical for successful embryo implantation and development. To test this, we ablated AIRE-expressing cells during the first nine days of mouse pregnancy using an AIRE-diphtheria toxin receptor (DTR) model. We found significantly smaller litter sizes (p&lt;0.0001) and smaller embryos in a subset of AIRE-DTR pregnancies (30% of N=10), compared to wildtype (WT) pregnancies given DT (N=11). Flow cytometry of maternal tissues showed AIRE-DTR pregnancies had significantly more CD4+ T cells and fewer FoxP3+ T regs in the uterus, and more CD25+CD4+ T cells in maternal peripheral lymph nodes. AIRE-DTR mice were also less likely to be pregnant after a confirmed plug (rate of pregnancy on embryonic day 9.5: 67% AIRE-DTR vs 92% WT), suggesting decreased fertility or early pregnancy loss. Thus, AIRE-expressing cells may provide an additional mechanism of maternal-fetal tolerance by deleting reactive maternal T cells and promoting maternal T reg differentiation at the maternal-fetal interface.
The Benzathine Penicillin G (BPG) Reformulation Preferences Study - Samoa
Authors: Sika-Paotonu Dianne , Viali Satupa’itea , Naseri Leausa Toleafoa Take K. , So’o Fui Le’apai Tu’ua Ilaoa Asofou , Lameko Toleafoa Viali , Punivalu Monalisa , Maiava Fuatai , Ah-Ching Salausa John , Tiatia Ramona , Sung Yun K. , Zonneveld Rebecca , Poot Betty , Norris Pauline , Betty Bryan , Thornley Craig , Eddie Barbara , Wineera-Parai Ranei , Baker Michael , Carapetis Jonathan 
Published: January 2023

Abstract
Acute Rheumatic Fever (ARF) is an autoimmune condition caused by untreated group A streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Multiple or severe attacks of ARF can cause cardiac damage known as rheumatic heart disease (RHD). In Australia, New Zealand (NZ) and the Pacific Region, the disease burden of ARF and RHD amongst Indigenous and Pacific communities is one of the highest in the world, usually affecting children and young adults. The most effective recommended management for ARF requires monthly intramuscular injections of 1.2 million units of Benzathine Penicillin G (BPG) known as secondary prophylaxis (SP) for 10 years or more. The goal of SP is to prevent GAS infections that may lead to the recurrence of ARF. Even with these monthly BPG injections, adherence to SP schedules are usually low due to the frequency and duration of injection, pain and access to proper and timely healthcare. A less painful and longer acting BPG formulation would ideally help prevent recurrence of ARF and improve compliance rates to this schedule with improved understanding of barriers and novel approaches to BPG delivery urgently needed. To better understand the BPG reformulation preferences of children/teens currently receiving monthly BPG intramuscular injections, and that of their families and healthcare providers who administer BPG, three software applications will be developed from pre-existing applications that have been optimized for use in target populations in New Zealand. This will be the first time software applications have been used to collect qualitative and quantitative data on individual preferences for BPG formulations and dosing regimens in Samoa.
T cell receptor mining of RNA-Seq data to gain insight into inflammatory responses: correlative studies compare the αβ to the γδ T cell infiltrate in psoriasis
Authors: Marusina Alina I. , Merleev Alexander A. , Shimoda Michiko , Maverakis Emanual 
Published: January 2023

Abstract
γδ T cells have been proposed to play a major role in the pathophysiology of psoriasis and other immune-mediated skin diseases. T cell repertoire analysis is one method of characterizing the T cell component of an immune response. Although traditionally conducted on T cell receptor (TCR)-dedicated PCR products, with the appropriate bioinformatics pipeline and sequencing depth, T cell repertoire analysis can also be performed directly on RNA-Seq data sets, allowing for informative correlative studies to be performed in parallel. To compare the role of γδ versus αβ T cells in psoriasis, we have chosen to mine psoriasis and healthy control skin RNA-Seq data sets for TCR receptor sequences. Unlike prior studies, our results are validated in four independently collected datasets.
We demonstrate that in the setting of psoriasis, TCRγ and TCR δ-mapped reads are only a small fraction of their TCR α and TCR β counterparts. Although we identified several TCR sequences that were found in multiple skin samples, none were associated with HLA-Cw6. We also observed an increase in TCR repertoire diversity in psoriatic biopsies, demonstrating the polyclonal nature of the T cell infiltrate in psoriasis. Analysis of CDR3 sequences were also conducted revealing no psoriasis-associated public CDR3 sequences. A meta-analysis revealed a statistically significant link between the of TRAJ23 usage in psoriasis and the psoriasis-associated cytokine IL17A. TRGV5, a TCR γ segment, was also associated with psoriasis but correlated instead with IL36A.
This work highlights novel strategies for characterizing tissue-infiltrating T cells from RNA-Seq data sets, an approach with broad applications in the fields of autoimmunity and cancer immunotherapy.
Regulation of NKT cell function by a 0.1 Mbp interval on chromosome 1 encompassing Fcgr3
Authors: DeVault Victoria L. , Malagic Murisa , Mei Linda , Dienz Oliver , Lilley Graham W.J. , Benoit Patrick , Ather Jennifer L. , Poynter Matthew E. , Boyson Jonathan E. 
Published: January 2023

Abstract
NKT cells play a critical role in tissue-specific immune responses by rapidly producing cytokines in response to glycolipid stimulation. We previously reported that host genetic background played a substantial role in the NKT cell response to the agonist glycolipid α-galactosylceramide (αGalCer). A 6.6 Mbp region on chromosome 1 was identified as a major regulator of the NKT cell cytokine response between C57BL/6 (B6) and 129X1/SvJ mice. To fine-map this locus, we generated several B6.129 congenic lines with overlapping 129X1/SvJ intervals from 0.1 to 1.1 Mbp, and assessed the response of NKT cells to αGalCer. An analysis of serum and intracellular cytokine production after αGalCer challenge revealed significantly reduced levels of all cytokines tested in the B6.129c3 (c3) congenic strain that possessed the minimal 129 interval containing 5 genes. In vitro analysis of sorted splenic NKT cells indicated that the reduced cytokine production was NKT cell-intrinsic. In addition, we observed significantly fewer thymic NKT cells in the B6.129c3 congenic mice suggesting that the c3 interval may also regulate NKT cell development. Analysis of candidate genes within the c3 interval revealed a 5-fold increase in Fcgr3 gene expression on c3 NKT cells, which was associated with increased expression of FcγR3 protein on B6.129c3 NKT, NK and neutrophils. Taken together, these data identify the c3 interval as a novel locus regulating the response of NKT cells to glycosphingolipid, and reveal a link between this phenotype and an expression polymorphism that regulates Fcgr3 expression.