bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial Ischemia/Reperfusion injury is mediated by polymorphonuclear neutrophils through direct activation of Phospholipase D (PLD) and mTOR
Authors: Ganesan Ramya , Henkels Karen M , Pavlov Vasile I , Stahl Gregory L , Gomez-Cambronero Julian 
Published: January 2023

Abstract
During ischemia/reperfusion injury (I/RI), leukocytes release cytokines and exacerbate inflammation causing cardiac dysfunction, while neutrophils produce oxygen radicals that worsen the initial myocardial infarction. Phospholipase D is a cell membrane remodeling and signaling protein implicated in the pathology of I/RI. We analyzed I/RI by ejection fraction, infarct size and serum Troponin levels in wild-type, PLD1−/− and PLD2−/− mice. PLD-deficient mice or inhibition of PLD in WT mice protected against I/RI. Removing PLD2 yielded a slightly better outcome, suggesting PLD2 contributed more to the injury than PLD1, particularly at longer (&gt;4 h) reperfusion times. Three cell signaling mechanisms were investigated: mTOR pathway, Aurora Kinase A and Cyclin-D3. Gene expression of the mTOR pathway was increased in response to I/RI in WT mice and abrogated in PLD-KO mice suggesting PLD augmented mTOR pathway during IR/I. PLD1−/− mice have lower expression of CCND3/Aurora Kinase A, while PLD2−/− mice expressed more phospho-CyclinD3. We detected neutrophil-associated Ly6G after adoptive transfer of bone marrow neutrophils during I/RI. Myocardial PMN accumulation was increased following I/R and PLD inhibitors abrogated PMN accumulation. Less myocardial PMN accumulation was observed in PLD-KO mice following IR/I. Adoptive transfer of fluorescently labeled PLD2−/− or PLD1−/−PMN into PLD1−/− or PLD2−/− mice, respectively, demonstrated that PLD1 containing (PLD2−/−) PMNs accumulated more significantly in the myocardium following I/RI. This study demonstrates for the first time the specific mechanistic contribution of mammalian PLD1 and PLD2 to MI/R injury in a murine model and their role in neutrophil infiltration.
Antigen-specific transendocytosis of CD40 ligand accompanies T cell help for B cells
Authors: Gardell Jennifer L , Parker David C 
Published: January 2023

Abstract
It has been known for decades that the delivery of T cell help to B cells is antigen-specific, MHC-restricted, and depends on CD40L. However the mechanisms by which CD40L, a transmembrane cytokine, is delivered to the T cell surface and engages CD40 on antigen-presenting B cells remains to be determined. It has been thought that when a T cell recognizes an antigen-presenting B cell, CD40L expressed on the T cell surface engages with CD40 on the surface of B cells as long as the cells remain conjugated. We show for the first time that CD40L does not remain on the surface of the T cell, but is transferred to and endocytosed by B cells receiving T cell help. Transfer of CD40L is nearly absent from bystander B cells that are not presenting antigen. It was recently discovered that peptide-MHC engaged TCRs are deposited on B cells in microvesicles at the immunological synapse. Our data suggest that CD40L might be deposited in a similar manner as a secreted vesicle. CD40-engaged CD40L on vesicles could allow for sustained signaling in antigen-presenting B cells despite the brief interactions with helper T cells that occur in vivo in germinal centers.
RGC-32 regulates TGF-β extracellular matrix production in multiple sclerosis.
Authors: Tatomir Alexandru , Tegla Cosmin A , Cudrici Cornelia D , Boodhoo Dallas , Martin Alvaro , Mekala Armugam , Rus Violeta , Badea Tudor C , Rus Horea 
Published: January 2023

Abstract
Extracellular matrix (ECM) deposition in demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and modify immune responses. RGC-32 plays an important role in mediation of TGF-β downstream effects, but its role in ECM deposition and gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we examined the role of RGC-32 in mediation of ECM production and reactive astrocyte marker α-smooth muscle actin (α-SMA) expression. In MS lesions, collagen I, IV and V were found to be expressed by astrocytes which were also expressing RGC-32. In cultured astrocytes, α-SMA, collagens I, IV, V and fibronectin were significantly induced at 18 h of stimulation with TGF-β. Next, we silenced RGC-32 expression by transfecting astrocytes with siRGC-32 and compared the effect of this treatment to that of control siRNA. The RGC-32 siRNA effectively decreased the mRNA and protein RGC-32 expression by 90% when compared to astrocytes transfected with control siRNA. RGC-32 silencing resulted in a significant reduction in TGF-β- induced collagens I, IV, V and fibronectin expression. Using astrocytes isolated from RGC-32 knockout (KO) mice, we found that TGF-β- induced collagen IV and α-SMA expression were significantly reduced in RGC-32 KO when compared with wild type mice. Our data also indicate that RGC-32 plays an important role in the TGF-β-mediated induction of ECM and is also required for the transition of astrocytes to a reactive state. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.
The role of ILC2s in neonatal type 2 immunity bias and allergen sensitization
Authors: Steer Catherine A. , Allinger Patricia , Takei Fumio 
Published: January 2023

Abstract
Neonatal immunity is largely type 2, potentially dampening damaging inflammatory type 1 immunity. Without early correction from gradual microbial type 1 stimulation, type 2 immunity may become overactive, resulting in allergic disease. Exposure to inhaled allergens during the neonatal period may sensitize individuals resulting in the development of allergic lung disease. Our lab has characterized group 2 innate lymphoid cells (ILC2s) in mouse lungs, which upon exposure to inhaled allergens, produce IL-5 and IL-13 and drive type 2 lung inflammation. We investigated whether ILC2s play a role in neonatal type 2 bias and allergen sensitization. Mouse lung ILC2s rapidly develop and 10 day old (D10) pups had more ILC2s than adults. D10 ILC2s appeared to be activated due to intracellular IL-13 and IL-5 expression and eosinophil lung infiltration, not observed in ILC2-deficient pups. ILC2 numbers are high in D10 lung-draining lymph nodes but not in the spleen or liver. ILC2s may be driving Th2-biased cell differentiation, as intranasal (IN) OVA-antigen treatment into D10 OTII pups results in significantly more IL-4+IL-13+ CD4+ T cells in the lung-draining LN after 6 days compared to adult OTII mice. Moreover, upon IN protease-allergen papain treatment at D10 and then again 4 weeks later, higher numbers of LN Th2 cells were present compared to similarly treated adults. Importantly, IL-33-deficient D10 pups, had fewer activated ILC2s and little eosinophil lung infiltration, suggesting that neonatal ILC2s activated by endogenous IL-33, produce type 2 cytokines resulting in type 2-biased lung immunity. Therefore, ILC2s may play a role in the neonatal sensitization of individuals, causing the development of allergic lung inflammation in adults.
Characterizing immune responses in severe T-cell mediated adverse drug reaction.
Authors: Konvinse Katherine Chanel , White Katie , Pavlos Rebecca , Redwood Alec , Trubiano Jason , Ergen Elizabeth , Mallal Simon Alexander , Phillips Elizabeth J 
Published: January 2023

Abstract
Severe immune-mediated adverse drug reactions (IM-ADRs) significantly impact patient outcome and inflict substantial cost on healthcare and drug development. Many of these T-cell mediated reactions are now known to be class I and/or class II HLA restricted, however, the minority of patients carrying an HLA risk allele will develop an IM-ADR. To help define the specific immunopathogenesis of these T-cell mediated drug reactions, a biobank of cryopreserved PBMCs and blister fluid/skin biopsies has been developed from HLA class I and II genotyped patients with IM-ADRs (Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN), abacavir hypersensitivity, and drug reaction with eosinophilia and systemic symptoms (DRESS)) at various time points from their acute reaction. Causative drugs included antibiotics, antiretrovirals, anticonvulsants and allopurinol. Overnight gamma interferon ELISpot assay proved sensitive to identify dose-dependent drug responses at different time points during and following the acute IM-ADR. We used intracellular cytokine staining and cell sorting to identify drug specific CD137+/CD69+ activated CD8+ and CD4+ T cells. Single cell and bulk TCR sequencing was performed to compare activated and non-activated populations of T cells in the presence and absence of drug. Immune responses differed according to the drug, clinical phenotype/tissue specificity, time from drug reaction, CD4+ and/or CD8+ dependency, and the oligoclonality of drug specific T-cell populations.
Eosinophil lineage commitment and IL-5-dependent expansion is regulated by IL-33 in mice
Authors: Johnston Laura K , Hsu Chia-Lin , Krier-Burris Rebecca A. , Chhiba Krishan D. , Chien Karen B. , McKenzie Andrew , Berdnikovs Sergejs , Bryce Paul J. 
Published: January 2023

Abstract
Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis and eczema. While IL-5 is necessary for the maturation of eosinophil progenitors (EoP) into mature eosinophils (EoM), the signals that promote commitment to the eosinophil lineage are unknown. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in the peripheral tissues. Recently, ST2 expression was described on hematopoietic stem cells, where its function remains unclear. Here, we sought to determine whether IL-33 and ST2 contribute to hematopoietic lineage decisions. We found that both IL-33- and ST2-deficient mice exhibited diminished peripheral blood eosinophils at baseline. Correspondingly, IL-33 administration increased EoM as well as IL-5 in the blood and bone marrow in WT and IL-33-deficient but not ST2-deficient mice. Blocking IL-5 with a neutralizing antibody prevented IL-33-expanded EoP from maturing into EoM, while transgenic overexpression of IL-5 in ST2-deficient mice resulted in significantly lower hypereosinophilia than transgenic IL-5 mice. Finally, we observed that IL-33, but not IL-5, specifically expanded EoP and upregulated IL-5Rα on EoP as well as increased IL-5 after bone marrow was cultured for three days. Our findings identify a basal defect in eosinophilopoiesis in IL-33- and ST2-deficient mice. Furthermore, we establish unappreciated roles for IL-33 and ST2 in eosinophil development via progenitor regulation and define a mechanism whereby IL-33 licenses commitment into the eosinophil lineage by driving both responsiveness to IL-5 and IL-5 production.
Blockade of the Neogenin-RGMb-BMP signaling hub inhibits allergen-induced airway hyperreactivity
Authors: Yu Sanhong , leung Krystle , Kim Hye-Yeung , Xiao Yanping , Albacker Lee A , Lee Hyun-Jun , Umetsu Dale T , Freeman Gordon J , Dekruyff Rosemarie H 
Published: January 2023

Abstract
Bronchial asthma is associated with type 2 immune responses induced by components of adaptive as well as innate immunity. Although innate cytokines such as IL-25 have been shown to play a key role in development of airway hyperreactivity (AHR), little is known of innate molecules that regulate IL-25-mediated airway inflammation. We found that blockade of repulsive guidance molecule b (RGMb) in an experimental murine model of asthma blocked the development of AHR, a cardinal feature of asthma, and that RGMb is expressed on F4/80+CD11b+CD11cneg macrophages (RGMb+ macrophages), which accumulated in the lungs of OVA-sensitized and challenged mice, but not in naïve mice. Moreover, we found that a large fraction of the RGMb+ macrophages expressed the IL-25 receptor, IL-17RB, and produced IL-13. IL-25 was critical for the development of AHR in our model, since mice deficient in IL-17RB did not develop AHR. Finally, treatment with anti-RGMb mAb during the challenge phase of the protocol after allergen sensitization effectively prevented the development of AHR and airway inflammation, suggesting for the first time that RGMb+ cells, including RGMb+ macrophages, play critical roles in allergen-induced asthma.
Targeting the immune system with subtype-selective GABAA receptor modulator to alleviate asthma symptoms.
Authors: Nieman Amanda N , Forkuo Gloria S. , Guthrie Margaret L. , Yuan Nina Y. , Yu Olivia B. , Kodali Revathi , Zahn Nicolas M. , Jahan Rajwana , Stephen Michael R. , Poe Michael M. , Hartzler Benjamin , Emala Charles W. , Cook James M. , Arnold Leggy A. 
Published: January 2023

AbstractInflammation is one of the main characteristics of asthma in addition to mucus metaplasia and airway hyperresponsiveness due to muscle constriction. Therefore, current asthma treatments include corticosteroids, which are associated with many negative side effects1. Recently, small molecule modulators of the γ-aminobutyric acid receptor (GABAAR) have been shown to reduce inflammation and induce airway smooth muscle relaxation2,3. GABAARs are expressed in the neurons to moderate neuronal firing. However other cell types have distinct arrangements of GABAAR subtypes as well, which can be targeted with subtype-selective GABAAR modulators. Our study hypothesizes that compounds targeting GABAARs bearing the α4 subunit will predominantly target airway smooth muscle cells and immune cells. We have developed two subtype-selective GABAAR modulators, Xhe-III-74EE and Xhe-III-74A. Investigations with T cells showed reduced IL-2 levels for treated cells. In addition, both compounds reduced cellular rapid cytoplasmic calcium release upon activation. In vivo studies showed that XHE-III-74A was able to reduce eosinophilia in an ovalbumin sensitized and challenged (Ova S/C) model.
Memory ILC2s and type 2 lung inflammation
Authors: Martinez-Gonzalez Itziar , Mathae Laura , Gahedi Maryam , Steer Catherine , Poon Grace FT , Takei Fumio 
Published: January 2023

Abstract
Group 2 innate lymphoid cells (ILC2s) are critical mediators of allergic lung inflammation. Upon protease allergen encounter, epithelial-derived IL-33 activates ILC2s to produce large amounts of type 2 inflammatory cytokines. ILC2-derived cytokines induce T helper 2 (Th2) cell-independent allergic lung inflammation. Upon activation a subset of lung ILC2s becomes long-lived memory cells. Memory ILC2s are more sensitive and respond stronger to unrelated allergen encounters. Gene expression analysis and transfer experiments show that the high responsiveness is due to intrinsic changes in memory ILC2s. Indeed, memory ILC2s not only respond to IL-33 but also become responsive to the alarmin IL-25. Finally, memory ILC2s promote early Th2 differentiation in the draining lymph node, which leads to a stronger memory T cell response. On the other hand, the generation and maintenance of memory ILC2s is T-cell independent. Understanding the regulation of memory ILC2s may lead to the development of novel therapies for allergic diseases.
IRF5 as an upstream regulator of severe steroid-refractory asthma.
Authors: Oriss Timothy B , Morse Christina M , Raundhal Mahesh Ramdas , Huff Rachael E , Hannum Rachel , Ray Prabir , Ray Anuradha 
Published: January 2023

Abstract
Severe, corticosteroid (CS)-refractory asthma is a significant problem both clinically and in terms of economic impact. A CS-responsive T helper-type 2 (Th2)/Type 2 response is a feature of milder asthma. However, we recently reported heightened airway type 1 (IFN-γ) and type 17 (IL-17) immune responses along with detectable Th2 response in &gt;50% of clinically diagnosed severe asthma cases in adults in the context of CS treatment. In macrophages, the transcription factor IRF5 was previously shown to promote the expression of Type 1/17-inducing cytokines. However, its role in promoting the expression of these cytokines in dendritic cells (DCs), which would impact T helper cell differentiation, has not been studied. Thus, to determine the role of IRF5 in eliciting a CS-refractory severe asthma phenotype, we utilized our newly established model of severe asthma, in which IFN-γ plays an important role in increased airway hyperresponsiveness (AHR), and which is poorly responsive to CS mimicking human disease. Using WT and IRF5−/− mice subjected to the severe asthma model, we show that IRF5 is required to promote Th1 and Th17 immune responses and importantly, also plays a role in increased AHR. In the absence of IRF5, reduced Th1/Th17 responses were associated with decreased expression of the type-1/17-promoting cytokines IL-12 and IL-6 in lung DCs. Also, using bronchoalveolar lavage (BAL) cells, we detected higher IRF5 expression in human severe versus milder asthma. Therefore, IRF5 may represent a potential target for therapeutic intervention in CS-refractory human severe asthma with a strong Th1/Th17 immunobiologic component.
Effects of Complement C4 Gene Copy-Number Variations, Gene Size Dichotomy and C4A-Deficiency on Genetic Risk and Clinical Presentation of East-Asian and European Systemic Lupus Erythematosus (SLE)
Authors: Yu Chack Yung , Chen Ji Yih , Wu Yee Ling , Mok Mo Yin , Wu Yeong-Jian Jan , Lintner Katherine E. , Wang Chin-Man , Chung Erwin K. , Yang Yan , Zhou Bi , Wang Huanyu , Yu Denise J.H.C. , Alhomosh Alaaedin , Jones Karla , Spencer Charles H. , Nagaraja Haikady N. , Lau Yu Long , Lau Chak-Sing 
Published: January 2023

Abstract
Human complement C4 is complex with multiple layers of diversity. This study aims to elucidate the copy-number variations (CNVs) of C4A and C4B in disease risk of SLE, and compare the basis of race-specific C4A-deficiency in East-Asians (EA) and Europeans. Our study-populations included (a) 999 EA-SLE patients and 1,347 healthy subjects; and (b) 232 European SLE patients and 500 healthy subjects. Variations in gene copy-numbers (GCNs) for total C4, C4A, C4B, long and short genes were determined and validated by independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein that is concurrent with C4A-deficiency. In EA, strong protective effects for high GCNs of total C4 and C4A against SLE were notable; low and medium GCNs of total C4 and C4A, and the absence of short genes were risk factors for SLE. Homozygous C4A-deficiency was infrequent but had an odds-ratio (OR) of 12.4 (p=0.0015) in SLE. Low serum complement levels were strongly associated with low GCNs of total C4 (OR=3.27, p=7.0×10−7) and C4B (OR=2.55, p=2.5×10−5). Patients with low complement had high frequencies of anti-dsDNA (OR=4.96, p=9.7×10−17), hemolytic anemia (OR=3.89, p=3.6×10−10) and renal disease (OR=2.18, p=8.5×10−6). The monomodular-short haplotype with C4A-deficiency and in linkage-disequilibrium with HLA-DRB1*0301 prevalent in Europeans was scarce in EA. Instead, most EA-subjects with C4A-deficiency shared a recombinant haplotype with bimodular-LS encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA-sequencing revealed the E920K polymorphism for C4B96. In conclusion, C4 CNVs and C4A-deficiency are important in the risk and manifestations of East-Asian and European SLE.
TRAF1 in regulation of T cell responses and inflammation
Authors: Edilova Maria , Abdul-Sater Ali A. , Clouthier Derek , Watts Tania H 
Published: January 2023

Abstract
TNFR associated factor one (TRAF1) is a signaling adaptor that links a subset of tumor necrosis factor receptors to downstream survival signaling through NF-kB and MAP kinases. TRAF1 is critical for survival signaling downstream of 4-1BB but its role downstream of TNFR2 has been controversial. Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs3761847, in an intronic segment of the TRAF1 gene as contributing to susceptibility to and severity of Rheumatoid arthritis. However, the effect of this SNP on TRAF1 expression or T cell biology have not been examined to date. To avoid the complications of chronic inflammation, we chose to examine the effect of this common SNP on TRAF1 levels and function in healthy donors. Samples were collected from 80 healthy donors and TRAF1 levels and cytokines measured by intracellular flow cytometry on T cells from resting and anti-CD3/CD28 treated PBMC. Individuals homozygous for the risk polymorphism (GG) exhibited significantly lower TRAF1 protein levels in T cells than donors with the disease resistant (AA) genotype. However, the frequency of naïve, memory and regulatory T cell subsets was indistinguishable between AA and GG donors. T cells from the disease susceptible donor T cells produced less IFNγ, TNFα and IL-2 upon stimulation. Work is in progress to investigate how TRAF1 specifically impacts TNFR2 signaling in T cells. Taken together, our data suggest that the TRAF1 SNP results in lower TRAF1 protein and lower cytokine production by T cells, supporting the evidence that TRAF1 has a net positive role in T cell cytokine production. However, these data also present a paradox of how lower TRAF1 protein levels contribute to increased inflammatory disease.
Epithelial ErbB2 activity determines thymus homeostasis and T cell maturation
Authors: Agrawal Tanvi , Chan Win-yan , Sage Elizabeth , Kolluri Krishna , Sladen Paul , Sturges Gabrielle , Vallath Sabarinath , Janes Samuel , Coles Mark , Ambler Carrie , Brown Jeremy , Giangreco Adam 
Published: January 2023

Abstract
Thymus involution, the age-dependent loss in organ structure and functionality, promotes increased immune dysfunction in humans, causing increased susceptibility to opportunistic infections, peripheral autoimmunity and reduced vaccine efficacy. Despite this, the mechanisms that regulate thymus involution remain incompletely understood. This has resulted in a lack of clinically approved therapies capable of reversing age-associated thymus involution. Here, we identify that thymic epithelial cell (TEC) specific ErbB2 activity determines thymus homeostasis and T cell maturation.
In these studies, we use a conditionally regulated bitransgenic mouse model in which a dominant-active ErbB2 transgene is expressed in keratin14 positive TECs following doxycycline administration. We show that increased ErbB2 expression causes rapid onset of thymus atrophy that resembles age-associated involution. Specific changes include destruction of thymic cortico-medullary boundaries, abnormal TEC differentiation, reduced thymus size and cellularity, and abnormal T cell differentiation. Using foetal thymus organ cultures derived from wild type and bitransgenic animals, we confirm that these phenotypes are due to TEC autonomous ErbB2 expression. Finally, we establish that treating aged mice with the clinically approved Erbb2 inhibitor Lapatinib restores thymus function, improves Streptococcus pneumoniae vaccine efficacy, and promotes infection resistance.
Overall, these results demonstrate a previously unknown role for ErbB2 in adult thymus homeostasis and suggest the potential translational relevance of ErbB2 inhibition as a means to reduce or reverse age-associated thymus involution.