bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adeno-associated viral vector-mediated ATPase gene transfer alleviates asthmatic airway inflammation in OVA-sensitized mice model
Authors: Kuo Ming-Ling 
Published: January 2023

Abstract
Bronchial asthma is a chronic inflammatory disorder of the airway characterized by airway hyperresponsiveness (AHR), pulmonary eosinophilia, elevated serum IgE, and dysregulated T helper (Th) 2 cytokines. It is becoming urgent to identify target molecules for the preventive and therapeutic purpose. ATP accumulation in bronchoalveolar lavage fluid (BALF) of asthmatic subjects indicates that extracellular ATP and the downstream responses are involved. ATP is tightly regulated by CD39, a nucleoside triphosphate diphosphohydrolase (ATPase) encoded by entpd1. Upregulated BALF ATP levels and decreased CD39 RNA were accompanied with asthmatic cardinal features in ovalbumin (OVA)-sensitized mice. Recombinant adeno-associated virus (rAAV) has been developed to carry exogenous genes with safe and low toxic therapeutic potential. The different serotypes and tropisms of AAVs benefit tissue specific gene targeting. This study aims to determine whether lung-targeting rAAV carrying CD39 (AAV/CD39) is able to reduce extracellular ATP in BALF and inhibit the OVA-induced allergic inflammation in an asthmatic murine model. rAAV vectors were administrated into the lungs of mice 3 days before the first OVA exposure. The data indicate that ATP levels in BALF were downregulated accompanied with rescued CD39 expression. The administration of AAV/CD39 was able to suppress AHR, pulmonary eosinophilia, and the production of IL-5 and IL-13 from OVA-activated mediastinal lymph nodes (MLNs) cells. IL-33 in BALF was also reduced. These data indicate that the attenuation of asthmatic airway inflammation may affect innate lymphoid cells (ILC) 2 activation. Thus, ATP level could be a potential target for asthma gene therapy.
Targeting MARCKS phosphorylation site domain shows therapeutic potential for allergic asthma
Authors: Lee Chen-Chen , Chen Ching-Hsien , Lee Ko-Wei , Shu Wen-Chi , Kenyon NIcholas , Wang Chien-Neng , Wu Reen 
Published: January 2023

Abstract
Prevalence of asthma is increased all over the world, especially in Taiwan, study analyzed data of 997,729 enrolees from the National Health Insurance register from 2000 to 2007, the prevalence of asthma increase from 2.9% to 11.9%. Various signaling pathways and mechanisms have been identified and targeted for therapeutic application. Among them, one treatment, based on the use of MANS peptide, which is corresponding to the myristoylated N-terminal 24-amino acid portion of the MARCKS (myristoylated alanine-rich C kinase substrates) protein, to compete MARCKS’ binding to membrane has produced useful results. There is a lack of information regarding to the level/activity of phosphorylated MARCKS (p-MARCKS) in allergic asthma. It is also unclear if this activity can be directly suppressed for the allergic asthma treatment application. In this study, we have found elevated p-MARCKS in most of asthmatic tissues from human as well as from the animal model. This elevation can be directly suppressed by a peptide, MPS, targeting MARCKS phosphorylation site domain, prior to allergen sensitization. In addition, MPS pre-treatment also suppressed all of the symptoms associated with allergic airway asthma, which includes a reduction of inflammatory cells influx and TH2 cytokine presence in the lumen, and also a reduction of airway mucous cell metaplasia and airway hyperreactivity. In addition to inhibition of TH2 responses, lung dendritic cells migrate to mediastinal lymph nodes also decreased by MPS treatment. These results suggest that MARCKS phosphorylation site domain is a potential therapeutic target for the treatment of allergic asthma.
Natural killer cells regulate allergic lung inflammation by acting on group 2 innate lymphoid cells.
Authors: Jaffar Zeina , Ferrini Maria , Roberts Kevan 
Published: January 2023

Abstract
In allergic asthma, inhalation of airborne allergens such as the house dust mite (HDM) effectively activates both innate and adaptive immunity in the lung. Endogenously generated cannabinoids and eicosanoids (acting via CB2 or PGI2-IP receptors, respectively) play important roles in both homeostatic and inflammatory processes including allergic airway inflammation. In this study, HDM responses in CB2 receptor–deficient (CB2−/−) or IP−/− mice were compared with wild type (WT) counterparts. Surprisingly, both CB2−/− and IP−/− mice had increased numbers of pulmonary natural killer cells (NK cells) producing IFN-γ that was inversely associated with the number of group 2 innate lymphoid cells (ILC2s) expressing IL-33Rα and IL-13 compared with WT animals. Remarkably, CB2−/− or IP−/− mice were less responsive to HDM challenge than WT counterparts since intranasal instillation of the allergen induced markedly reduced levels of airway eosinophils, CD4+ lymphocyte infiltration, and mucus production, as well as depressed levels of type 2 cytokines. NK cells and their production of IFN-γ were responsible for such attenuated inflammatory responses because depletion of NK cells or inhibition of IFN-γ production in vivo in CB2−/− or IP−/− mice restored both the HDM-induced allergic inflammation and ILC2 numbers in the lungs. Collectively, these data demonstrate a role for these eicosanoids in regulating the number and properties of NK cells resident in lung tissue and reveal a crucial role for NK cells in the regulation of lung tissue ILC2s and the development of allergic lung inflammatory responses.
The Role of Myristoylated, Alanine-rich C-kinase Substrate (MARCKS) in a Murine Model of Chronic Airway Inflammation
Authors: Wang Chien-Neng 
Published: January 2023

Abstract
Severe asthma, a complicate chronic lung inflammation. Several chronic inflammatory cells that involved in the inflammatory responses, such as macrophages, neutrophils, and eosinophils, produce large amounts of ROS, the excess level of ROS would increase lung inflammation and lung injury. In fact, this inflammation is well controlled by steroid, but some subset of patients these glucocorticoids are less effective. Neutrophil recruitment is a prominent feature of acute exacerbations of chronic asthma. In patients with difficult-to-control asthma, neutrophilic inflammation rather than eosinophils often predominate.
Myristoylated alanine-rich C kinase substrate (MARCKS), is a protein kinase C (PKC) substrate. MARCKS also plays a crucial role that phosphorylation of MARCKS by PKC leads its release from plasma membrane into the cytosol, participating in regulating cell migration such as macrophage and neutrophil. We found that increase of airway MARCKS phosphorylation in asthmatic patients and murine model of chronic steroid-resistance allergic asthma. In this report, our observations indicate that 1) targeting of MARCKS phosphorylation inhibited chronic asthmatic symptoms, such as eosinophil and neutrophil infiltrate into lung. MPS peptide inhibits mucus production, collagen deposition and airway hyperresponsiveness rather than steroid-resistance group; 2) targeting of MARCKS phosphorylation decreased IFN-r, IL-4, IL-17A, IL-33, eotaxin and KC production. MPS peptide also inhibit NADPH oxidase DUOX-1, 2 protein expression and end product 3-nitrotyrosine production; We found that MPS peptide shows a therapeutic potential for steroid-resistance allergic asthma.
Antibodies to a peptide derived from EBNA-1 may be a potential biomarker for SLE
Authors: Spatz Linda A. , Hajtovic Sabastian , Singh Divya 
Published: January 2023

Abstract
The Epstein Barr virus (EBV) has been associated with the autoimmune disease Systemic lupus erythematosus (SLE). We previously demonstrated that mice injected with EBNA-1, a major nuclear protein of EBV, develop anti-dsDNA antibodies that cross-react with EBNA-1. We generated two monoclonal antibodies, 3D4 and 16D2, from EBNA-1 injected mice, and showed that they bind to both EBNA-1 and dsDNA. We also identified a peptide, PFM-15, in EBNA-1 (PQPGPLRESIVCYFM) that is recognized by 3D4 and 16D2. We hypothesize that this peptide can act as a molecular mimic of dsDNA and elicit antibodies to EBNA-1 that cross-react with dsDNA in some individuals who develop lupus. In the present study, we screened the sera of 17 lupus patients and 19 healthy individuals to determine if they have antibodies to PFM-15. We observed a highly significant increase (p&lt;.05) in the number of SLE patients that have antibodies to PFM-15 compared to the number of healthy individuals with these antibodies. Furthermore, statistical analysis revealed that the anti-PFM-15 test has an 80% positive predictive value for SLE suggesting potential to be used diagnostically to detect a subset of patients with lupus. We also observed that 75% of the lupus patients tested, who had antibodies to PFM-15, also had antibodies to dsDNA and a moderately strong correlation was observed between the level of antibodies to PFM and dsDNA in these patients. This is consistent with our observation that antibodies to PFM-15 cross-react with dsDNA. These studies suggest that antibodies to PFM-15 may be a useful biomarker for a subset of patients exposed to EBV who develop lupus. Future studies with a much larger cohort of patients and controls will be needed to confirm this.
Profiling Autoantibodies in Idiopathic Inflammatory Myopathies
Authors: Li Quanzhen , Wang Li , Zhu Chengsong , Yan Mei , Zuo Xiaoxia , Zhang Huali 
Published: January 2023

Abstract

Objects
To screen autoantibodies (autoAbs) in sera of Idiopathic Inflammatory Myositis (IIM) patients and to assess their clinical significance for diagnosis, classification and disease activity evaluation.

Methods
IgG and IgM autoAbs were comprehensively profiled from 138 IIM patients, 70 SLE, 50 SSc and 100 normal controls (NC) using a customized autoantigen array bearing 125 myositis-specific antigens (MSA) and other autoantigens. Western blot and Immunoprecipitation were used for autoAb verification. The profile of autoAbs and correlation with clinical criteria were evaluated.

Results
78% IIM patients showed positive reactivity to at least 1 MSA. The autoAbs which exhibited high prevalence in IIM are anti- Jo-1 (24.6%), MDA5 (23.2%), SAE2 (13%), SRP54 (11.6%) and DNA polymerase II (8.7%). We identified the autoAb clusters that best distinguish the 3 autoimmune disease: anti-Jo-1 and anti-MDA5 for IIM, and anti-CENP-A&B and Scl-70 for SSc, and anti-chromatin/Nucleosome, anti-dsDNA, and anti-Sm/SmD for SLE. The coexistence of MSA autoAbs was observed in IIM with about 35% IIM patients carried more than 2 MSA autoAbs. The IIM patients who developed interstitial lung disease (ILD) exhibited significantly higher autoAbs against Jo-1, MDA5, Mi-2, Ro-SSA and Trptophanyl compared with the IIM without ILD (&lt;0.05). The IIM patients who carried positive autoAbs against JS, TIF1γ, Mitochondrial antigen and La/SSB showed a significantly higher risk of malignancy (p&lt;0.05). Based on autoAbs, we established an autoAb score for IIM prediction and evaluation.

Conclusion
Autoantibody profiling revealed distinct and heterogenic autoAbs in IIM which are potential biomarker for diagnosis, prognosis and classification of the disease.
The respective contributions of P2X7 receptor variants to the development of psoriasiform dermatitis
Authors: Yang Yin , Killeen Meaghan E. , Diaz-Perez Julio A. , Mathers Alicia R. 
Published: January 2023

Abstract
Psoriasis is a chronic inflammatory cutaneous disease caused by environmental triggers in genetically predisposed individuals which account for 2–3% of the world population. However, the mechanisms contributing to the initialization of psoriasis are largely unknown. ATP is a particularly interesting candidate that, via P2X7 receptor (P2X7R) signaling, can activate NF-κB and the IL-23/IL-17 axis, both of which have been shown to be critical in psoriasis pathogenesis. Moreover, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. Specifically, we have determined that the canonical P2X7R variant A (P2X7RA) is expressed comparably in both lesional psoriatic tissues and normal human skin. However, it is the alternatively spliced P2X7R variant B (P2X7RB) that is highly expressed in human psoriatic lesions. P2X7RB is widely distributed in human tissues and P2X7RB activation enhances cellular proliferation, decreases ATP-induced apoptosis, and in heterotrimers potentiates the inflammatory responses induced by P2X7RA. Importantly, our studies have established that signaling through the P2X7R induces an acute psoriasiform dermatitis in mice. Thus, our ongoing work is focusing on the specific role of P2X7R variants in inflammatory diseases. We confirmed in human blood derived DCs that signaling through the P2X7RB can induce proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, to same degree as P2X7RA. In conclusion, this work provides a basic mechanistic insight into local inflammation induced following purinergic signaling through the P2X7R that is likely involved in the pathogenesis and potential treatment of many cutaneous inflammatory diseases.
Characterization and isolation of rhesus macaque eosinophils
Authors: Legrand Fanny , Stokes Kindra , Hong So Gun , Tocheny Claire , Mayer-Barber Katrin , Dunbar Cynthia E. , Klion Amy D. 
Published: January 2023

Abstract
With the recent increase in targeted therapies for the treatment of eosinophil-associated disorders, the availability of animal models that mimic human eosinophil responses is a priority. Although murine models have been useful in this regard, differences in eosinophil biology and pathogenesis between humans and mice have limited their utility in some settings. Rhesus macaques provide a potential solution to this problem. Multi-parameter flow cytometry was used to compare the surface phenotype of human and rhesus macaque eosinophils in whole blood. Based on the findings, a strategy for magnetic bead purification of rhesus eosinophils was devised. Activation of purified eosinophils was assessed by surface staining with anti-CD69 antibody, and function was evaluated in a standard chemotaxis assay. Similar to human eosinophils, rhesus macaque eosinophils were found to express EPX and functional CCR3. Siglec-8 expression was not detected. Rhesus neutrophils do not express CD16, the surface marker most commonly used for eosinophil purification in humans. Purity was established by counting 300 cells on cytospin slides stained with Diff-Quik and by flow cytometry. Rhesus eosinophils were isolated from six Rhesus monkeys by Ficoll sedimentation followed by immunomagnetic negative selection using anti-CD64 antibody. Purity of &gt;90% was achieved in 2 animals. Purified eosinophils were not activated, as assessed by CD69 expression, and chemotaxis to eotaxin was preserved. These data provide a comprehensive comparison of the surface expression patterns of human and rhesus granulocytes and a method for purification of viable and functional rhesus eosinophils for in vitro studies.
Autoreactive-prone CD21lo B cells increased in scleroderma patients with interstitial lung disease
Authors: Vowell Katherine Nicholas , Wilfong Erin M. , Crofford Leslie J. , Kendall Peggy L. 
Published: January 2023

Abstract
Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by fibrosis of the skin and vital organs. The pathogenesis of SSc is unknown, but detection of autoantibodies in &gt;90% of SSc patients suggests that B lymphocytes play a role. Therefore, we explored B cell phenotypes in SSc patients using fluorescence cytometry and the multi-dimensional unsupervised analysis tool viSNE. We found that compared to healthy controls, SSc patients had significantly higher proportions of an autoreactive-prone B cell subset identified by low expression of CD21 (CD21lo). Previously, circulating CD21lo B cells were shown to express autoantibodies and were increased in other autoimmune diseases. When considering the clinical phenotypes of the SSc patients, we found that the frequency of CD21lo B cells was only increased in SSc patients with interstitial lung disease (ILD). ILD is a complication of SSc that is associated with increased morbidity and mortality. To our knowledge, this is the first time that a peripheral blood B cell subset has been identified in association with ILD in patients with a systemic autoimmune disease. We investigated the signaling properties of these anergic cells and found lower expression of Bruton’s tyrosine kinase (BTK) in CD21lo B cells compared to normal B cells. This was surprising, as BTK is thought to be overexpressed in autoimmunity, but may indicate that the anergic state is due in part to suppression of BTK-mediated signaling. Our data suggest that CD21lo B cells should be investigated for their role in SSc pathogenesis, and for their utility as a biomarker of ILD. In addition, these findings demonstrate a potential mechanism by which B cell depleting therapy may specifically benefit SSc patients with ILD.
Direct correlation between plasma microbial translocation and autoantibodies in first-degree relatives of patients with systemic lupus erythematosus
Authors: Jiang Wei , Ogunrinde Elizabeth , Zhou Zejun , Kamen Dianne , Oates Jim , Li Quanzhen , Alexander Alekseyenko , Gilkeson Gary S. 
Published: January 2023

Abstract

Background
The process of events underlying autoantibody production in systemic lupus erythematosus (SLE) is unknown.

Methods
Plasma from 36 female African-Americans (18 unrelated healthy controls (UHCs) and 18 first-degree relatives of SLE patients (FDRs)) were assessed for autoantibodies by autoantibody array, lipopolysaccharide (LPS) levels by the limulus amebocyte assay and microbiome by 16S rDNA analysis.

Results
Compared to UHCs, FDRs exhibited elevated plasma autoantibody levels but not similar total IgGs. The median plasma IgGs were 346 (interquartile range, 236–465) and 480 (286–891) for anti-double strand DNA (anti-dsDNA, P = 0.04, Mann-Whitney U-test), 3422 (2863–4076) and 4815 (3447–8464) for anti-single strand DNA (anti-ssDNA, P = 0.03), and 4593 (4050–5521) and 4714 (4004–5278) for total IgGs (P = 0.95), in UHCs and FDRs respectively. Furthermore, parent/child of patients exhibited elevated plasma LPS compared to UHCs. Plasma LPS levels were 59.1 (53.3–68.6) and 71.2 (62.2–80.4) for UHCs and parent/child of patients respectively (P = 0.03). Notably, plasma LPS was positively correlated with IgG anti-dsDNA (r = 0.53, P = 0.02, Spearman correlation) and anti-ssDNA (r = 0.53, P = 0.02) in FDRs but not in UHCs (P &gt; 0.70). Plasma microbiome revealed a reduced diversity (P &lt; 0.02) and lower abundance of Streptococcaceae (unadjusted P = 0.01, adjusted for multiple comparisons P = 0.10) in FDRs compared to UHCs. The ratios of Firmicutes to Bacteroidetes were 6.75 (0.66–42.5) in UHCs and 3.37 (0.63–22.5) in FDRs but did not achieve significance.

Conclusion
Taken together, these results indicate a possible role for plasma microbial translocation and microbiome composition in autoantibody development in SLE.
Role of Vps33B in regulation of inflammatory responses
Authors: McDaniel Margaret , Tracy Charles , Kramer Helmut , Pasare Chandrashekhar 
Published: January 2023

Abstract
Macrophages and dendritic cells use pattern recognition receptors (PRRs) to sense their surroundings and respond to pathogenic stimuli. Engagement of PRRs, such as Toll-like receptors (TLRs), results in accelerated phagocytosis of cargo, activation of anti-microbial responses, and induction of phagosomal and endosomal maturation. Endo/phagosomal maturation and endo/phagolysosome fusion likely plays a critical role in regulation of TLR signaling and outcome of inflammatory responses following microbial recognition. Previous work in the lab has shown that Vps (Vacuolar protein sorting) 33B specifically regulates endosomal maturation following TLR activation, thus influencing the outcome of downstream signaling. In the absence of Vps33B, drosophila hemocytes and mouse macrophages elicit an enormous inflammatory response to live or dead bacterial challenge, yet are unable to degrade the bacterial cargo. This exaggerated immune response is a direct result of accumulated TLRs and ligands that continue to signal while stuck in late endosomal compartments. We have now discovered that this inability to degrade pathogenic cargo has critical implications for adaptive immunity. Absence of Vps33B leads to enhanced maturation of DCs, yet these DCs are unable to effectively prime CD4 T cells, presumably due to lack of processing endocytosed cargo. Mice that specifically lack Vps33B in DCs were unable to activate antigen-specific CD4 T cells in vivo, leading to defective Th1 and Th17 priming. Collectively, our results suggest an important role for Vps33B in both innate and adaptive immune responses. Further work will elucidate the molecular mechanisms of regulation of Vps33B downstream of TLRs and its impact on host immunity.
ILC2-derived IL-13 likely promotes development of peanut allergy
Authors: Krempski James W. , Iijima Koji , Kobayashi Takao , Kita Hirohito 
Published: January 2023

Abstract

Background
Peanut (PN) allergies are life-long diseases that cause severe anaphylactic responses to affected individuals. Allergic immune responses are typically mediated by CD4+ T cells producing type 2 cytokines. However, there is little information available regarding the immunological mechanisms that initiate the development of PN allergen-specific T cells and production of PN specific-IgE (PN-IgE).

Goal
The goal of this study was to elucidate the mechanisms involved in initiation of peanut allergy.

Results
Naïve BALB/c mice (wt) chronically exposed intranasally (i.n.) to PNf developed PN allergy as demonstrated by increased serum levels of PN-IgE as well as acute anaphylactic response when challenged intraperitoneally with PN extract. Acute i.n. exposure of naïve mice to PNf increased the lung levels of IL-13. By using IL-13eGFP reporter mice, we found that group 2 innate lymphoid cells (ILC2s) produce IL-13 when mice are exposed to PNf. Further, IL-13−/− mice showed significant decrease in the numbers of follicular helper T cells in dLNs and serum levels of PN-IgE relative to wild type (wt) mice. When naïve mice were exposed daily to PNf for 2 days, wt mice showed a significant increase in the numbers of dendritic cells (DCs) in the lung dLN; in contrast, overall dLN cellularity as well as number of DCs was decreased in IL-13−/− mice. Furthermore, there were fewer CD11c+ MHC2+ DCs in dLN of IL-13−/− mice, indicating a role for IL-13 in maturation of DCs.

Conclusions
Our findings show that airway exposure to PN induces allergy sensitization by mechanisms involving ILC2-derived IL-13 that mediate the migration and maturation of lung DCs to the dLN. The interplay between ILC2s and DCs are likely critical for development of peanut allergy.