bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of A Disintegrin And Metalloproteinase 10 (ADAM10) in dendritic cells dampens type 2 immune responses.
Authors: Damle Sheela , Martin Rebecca , Conrad Daniel H 
Published: January 2023

Abstract
Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Current therapeutic strategies focus on management of disease symptoms, but are unable to control disease initiation. Previous reports from our lab demonstrated a reduction in type 2 (Th2) immune responses with ADAM10 inhibition. Thus, we sought to understand the role of ADAM10 in immune cells involved in Th2 responses, specifically dendritic cells (DCs). We generated mice which have ADAM10 deleted from DCs using mice that express Cre recombinase driven by the CD11c promoter (A10DCKO mice). We used a house dust mite (HDM) extract model of allergic airway inflammation and demonstrated a drastic reduction in airway resistance in the A10DCKOs as well as a reduction in eosinophils. We also found a reduction in Th2 cytokine expression, HDM specific IgG1 antibody, and lung inflammation in the A10DCKOs. After administration of inhaled antigen we found a significant reduction in antigen specific T cell proliferation in the spleen of the A10DCKOs, but no difference in the mediastinal lymph nodes. To understand the mechanism and given the importance of ADAM10 in Notch signaling, we compared the phenotype of the A10DCKOs to published reports of Notch2 DC-specific KOs. The A10DCKOs had a similar reduction in total conventional, CD172+, and CD172+ ESAM+ DCs in the spleen. However, we saw no decreases in other DC populations in the spleen and mesenteric lymph node demonstrated in the Notch2 KO, indicating a role for ADAM10 separate from Notch2 signaling. Overall, these results point to a mechanism of action of an ADAM10 inhibitor and a novel strategy for modulating Th2 immune responses.
Autocrine and paracrine cytokine feedback augment the production of Th2-associated cytokines.
Authors: Olson Matthew Richard , Kaplan Mark H 
Published: January 2023

Abstract
The Type 2 cytokines (including cytokines from Th2 and Th9 cells) play a critical role in priming of the humoral response, immunity to parasites, and the induction of allergic disease. It has been proposed that unlike Type 1 cytokines (i.e. IFN-γ), the induction of Type 2 cytokines is cell autonomous and requires no additional signals for optimal cytokine production. Contrary to this notion, we found that the addition of golgi transport inhibitors that block cytokine secretion (i.e. monensin (Mon) and brefeldin A (BFA)) during stimulation significantly impaired the induction of Type 2, but not Type 1 cytokine mRNA and protein production. These data suggest that the release of cytokines by activated Th cells is uniquely required for further production of Type 2 cytokines. Mon and BFA strongly inhibited the release of IL-2 after stimulation and blockade of IL-2 during activation in the absence of golgi inhibitors significantly diminished Type 2 cytokine production. Further, transduction of cells with a constitutively active STAT5 negated the need for additional IL-2 signaling in driving Type 2 cytokine transcription, suggesting that STAT5 is the primary mediator of IL-2-driven gene expression. Interestingly, both autocrine and paracrine IL-2 production were capable of driving maximal Type 2 cytokine production. Taken together, these data indicate a novel role for IL-2 feedback in promoting Type 2 cytokine production and likely in promoting allergic inflammation.
Crisaborole Topical Ointment, 2%, a novel nonsteroidal, anti-inflammatory, topical, phosphodiesterase 4 inhibitor, reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults with mild-to-moderate atopic dermatitis
Authors: Zane Lee Thomas , Hebert Adelaide A. , Eichenfield Lawrence F. , Lebwohl Mark G. , Paller Amy S. , Simpson Eric L. , Tom Wynnis L. , Hughes Matty H. 
Published: January 2023

Abstract
Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus and eczematous lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, anti-inflammatory, topical, phosphodiesterase 4 inhibitor for the treatment of AD. Here, we present the impact of crisaborole on pruritus and signs of AD evaluated as supportive efficacy endpoints for 2 Phase 3 studies (301, 302). Patients ≥2 years old with mild-to-moderate AD were enrolled in 2 double-blind, vehicle-controlled, multicenter Phase 3 studies of identical design. Patients were randomized 2:1 to receive crisaborole or vehicle twice daily for 28 days. Supportive efficacy endpoints examined severity of pruritus (measured twice daily) and signs of AD (measured weekly) on a 4-point scale (None [0] to Severe [3]). Success was defined for pruritus or each sign or symptom of AD as achievement of None (0) or Mild (1) with ≥1-grade improvement from baseline. Improvement in pruritus was achieved sooner in crisaborole-treated patients than vehicle-treated patients (pooled data: median, 1.37 vs 1.70 days; P = 0.001). A greater proportion of crisaborole-treated patients achieved success for all clinical signs of AD by Day 29 (301, 302; erythema: 62.8% vs 46.1%; 54.9% vs 33.9%; induration/papulation: 57.7% vs 54.8%; −51.9% vs 40.2%; exudation: 41.0% vs 33.3%; 38.1% vs 27.2%; excoriation: 63.0% vs 51.8%; 57.2% vs 44.2%; lichenification: 51.7% vs 46.5%; 51.4% vs 35.3%). In 2 large Phase 3 studies, crisaborole demonstrated early relief of pruritus and showed improvement in all measured signs of AD. Crisaborole Topical Ointment, 2%, may represent a safe and efficacious treatment for patients ≥2 years with mild-to-moderate AD.
FcγRIII signaling promotes IL-33-dependent monocyte migration to the lung extravascular space.
Authors: Camacho Daniel F , Tjota Melissa Yuwono , Turnquist Heth R , Sperling Anne I 
Published: January 2023

Abstract
IL-33 is implicated in type 2 inflammatory processes, including allergic asthma. Our group previously demonstrated that two Th2 stimuli, allergen-specific IgG immune complexes (ICs) and house dust mite extract (HDM), signal through FcRγ-associated receptors on antigen presenting cells to upregulate IL-33 and induce type 2 allergic airway inflammation. In this study, we find that monocytes from WT, but not IL-33−/− or FcγRIII−/− mice, accumulate in the lung extravascular space within 18 hours of OVA-IC challenge. Exogenous IL-33 treatment in the airways is sufficient to restore monocyte accumulation in the IL-33−/− mice. Further, treatment with pertussis toxin abolishes IL-33-dependent monocyte accumulation, a finding consistent with GPCR-dependent migration of these cells. Our findings suggest that during allergic sensitization, activation of the FcRγ signaling pathway promotes IL-33- and GPCR-dependent monocyte migration to the lung extravascular space, where monocytes may then contribute to type 2 allergic inflammation.
Airway epithelial cells promote allergic sensitization to cockroach allergen through GM-CSF production
Authors: Sheih Alyssa , Ziegler Steven F 
Published: January 2023

Abstract
Allergic asthma is an inflammatory disease of the airways driven by an overactive immune response against allergens. Allergen-specific TH2 cells are critical to the pathogenesis of asthma but factors controlling the initiation of TH2 responses are not well understood. The emerging picture is one that points to a role for airway epithelial cells (AECs) and epithelial-derived cytokines in promoting TH2 immunity to allergens. However, allergens are structurally diverse and can elicit different epithelial-derived cytokines. Thus, there are multiple pathways that lead to TH2 immunity and mechanisms of sensitization that are unique to individual allergens remain to be elucidated. Cockroach allergen (CRA) is an environmental allergen that is strongly associated with the incidence of allergic asthma. Despite its clinical importance, very little is known about the molecular and cellular pathways involved in allergic sensitization to CRA. To determine the mechanisms that regulate allergic sensitization to CRA, we intranasally sensitized and challenged mice with CRA to induce allergic airway inflammation with hallmark features of asthma. Using this model, we demonstrate that allergic sensitization to CRA requires activation of AECs. MyD88 deletion in AECs reduced allergic airway response to CRA as well as production of GM-CSF during sensitization. Using a neutralizing antibody against GM-CSF, we showed that GM-CSF is essential for TH2 priming and allergic sensitization to CRA, likely through activation of dendritic cells. When GM-CSF was intranasally delivered during sensitization, TH2-mediated eosinophilia was restored in the absence of MyD88. Thus, AECs promote allergic sensitization to CRA through production of GM-CSF.
Towards a non-allergenic peptide mix containing the T cell epitopes of the clinically most relevant house dust mite allergens for tolerance induction
Authors: Huang Huey-Jy , Curin Mirela , Banerjee Srinita , Chen Kuan-Wei , Garmatiuk Tetiana , Resch Yvonne , Campana Raffaela , Focke-Tejkl Margarete , Valenta Rudolf , Vrtala Susanne 
Published: January 2023

Abstract
House dust mites are one of the most important allergen sources. Der p 1, Der p 2, Der p 5, Der p 7, Der p 21 and Der p 23 are the clinically most important house dust mite (HDM) allergens. The aim of this study was to define a mix of non-allergenic T cell epitope-containing peptides of these allergens for tolerance induction. According to the amino acid sequences of these allergens, we synthesized and purified 33 overlapping peptides covering the complete sequences of Der p 1, 2, 5, 7, 21 and 23. The peptides were tested for IgE and IgG reactivity with sera from HDM allergic patients in ELISA. PBMCs from 27 HDM allergic and 10 non-HDM allergic individuals were incubated with the synthetic peptides and T cell proliferation was measured using a CFSE dilution-based assay. The peptides could be purified in large amounts. They lacked secondary structure but most of them remained soluble in physiological buffers. ELISA assays indicated that most peptides from Derp 1, 2, 5, 7, 21 and 23 lacked IgE reactivity and thus were non-allergenic. T cell proliferation assays identified 12 predominant epitopes in the Der p allergens. Our data indicates that a reasonable number of non-allergenic peptides including the sequences and thus T cell epitopes of the clinically most relevant house dust mite allergens can be defined for prevention of HDM allergy by tolerance induction.
Blocking CD28 signal in steroid resistant asthma
Authors: Mori Akio , Kouyama Satoshi , Yamaguchi Miyako , Kinoshita Arisa , Kamide Yosuke , Hayashi Hiroaki , Watai Kentaro , Mitsui Chihiro , Oshikata Chiyako , Sekiya Kiyoshi , Tsuburai Takahiro , Fukutomi Yuma , Taniguchi Masami , Ohtomo Takayuki , Kaminuma Osamu 
Published: January 2023

Abstract
To investigate the mechanism of steroid resistance in severe asthma, effect of CD28 signal blockade on T cell activation and asthma model was analyzed.
PBMC obtained from mild (steroid sensitive, SS), steroid dependent (SD), and steroid resistant (SR) asthmatics were stimulated with mitogens. Der f 2-specific Th clones were established and effects of glucocorticoids (GCs) on the proliferation and cytokine synthesis were analyzed. Steroid responsiveness of murine Th clones reactive to ovalbumin were analyzed. Unprimed BALB/c mice were transferred with these clones and then antigen challenged. Effect of GC on BALF eosinophilia was evaluated. CTLA4-Ig was administered through nasal inhalation or venous injection.
IL-5 production by PBMC of SS asthmatics was significantly reduced after ICS administration, but that of SD asthma remained high. IC50 values for the suppression of cytokine synthesis and proliferation responses by dexamethasone was not different among SS, SD, or SR asthmatics. Addition of CD28 signal induced steroid resistance in IL-2 and PI-3 kinase dependent manner. Murine SS and SR Th clones were selected based on the steroid sensitivity of their proliferation responses in vitro. Airway infiltration of eosinophils and lymphocytes of mice transferred with SS clones were effectively inhibited by GC. In contrast, those of mice transferred with SR clones were not significantly inhibited. Administration of CTLA4-Ig significantly suppressed the proliferation of GC-treated SR clones in vitro, and the BALF eosinophilia of mice transferred with SR clones in vivo.
Costimulatory signal mediated through CD28 seems crucial for the induction of steroid resistance and might be a target for therapeutic intervention.
TGFBR1M318R+/− Knock-In mice recapitulate the immune phenotypes of Loeys-Dietz syndrome.
Authors: Laky Karen , Guerrerio Anthony , Weissler Katherine A , Frischmeyer-Guerrerio Pamela 
Published: January 2023

Abstract
Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder caused by mutations in genes encoding proteins in the transforming growth factor beta (TGFβ) signaling pathway. Patients heterozygous for a point mutation in the kinase domain of TGFβR1 (TGFBR1M318R) exhibit classic manifestations of LDS. Mice with this mutation were made with the hope that an animal model of LDS will lead to better understanding of the mechanisms underlying LDS symptoms. TGFBR1M318R+/− mice exhibit the hallmark skeletal and cardiovascular phenotypes of LDS. We sought to determine if TGFBR1M318R+/− mice also recapitulate the immune phenotypes characteristic of LDS. We find that like their human counterparts, TGFBR1M318R+/− mice spontaneously develop elevated serum IgE and eosinophilic esophagitis (EoE), characterized by esophageal dilation, increased collagen, food impaction, and increased infiltration of eosinophils, T cells, mast cells, and myeloid antigen presenting cells. We made bone marrow (BM) chimeras to determine whether altered TGFβR signaling in hematopoietic and/or stromal cells led to EoE. Both irradiated TGFBR1M318R+/− mice reconstituted with WT BM, and WT mice reconstituted with TGFBR1M318R+/− BM had EoE 8 weeks post-reconstitution, indicating that aberrant TGFβ signaling in either BM-derived or non-hematopoietic cells can be associated with EoE, but that neither is absolutely required. To determine which hematopoietic cells are essential to the development of EoE we generated RAG2−/− TGFBR1M318R+/− mice and found that they too developed EoE, demonstrating that neither T or B cells were essential. Using TGFBR1M318R+/− mice to study the immune pathology of LDS should lead to better therapeutic strategies for the treatment of EoE.
Whole Exome Sequencing (WES) of a Small IPEX-like Patient Cohort results in High Hit Rate and Supports Focusing on the Usual Suspects.
Authors: Hagin David , Ochs Hans D , Torgerson Troy R 
Published: January 2023

Abstract
IPEX (Immune dysregulation Polyendocrinopathy Enteropathy X-linked) syndrome is caused by mutations in FOXP3. The term IPEX-Like is used to describe patients with features of IPEX syndrome and normal FOXP3 sequencing. A cohort of 15 IPEX-like patients was submitted for WES and analyzed in search for underlying monogenic defects. Potential causative mutations were identified in 46% (7/15). Major clinical features and mutations identified are presented below. Despite an obvious analysis bias, the high prevalence of previously described causative genes supports a two-step approach for studying a defined population, starting with targeted sequencing of relevant genes followed by trio WES of unsolved cases.
Clinical SymptomsGeneMutationsIEnteropathy, FTT, Autoimmune cytopenias, T1D, LAD, Recurrent infections, Antibody deficiency.CTLA4Heterozygous c.410C&gt;Tp.Pro137LeuIIAutoimmune cytopenias, Enteropathy, FTT, LAD, Recurrent infections.LRBAHomozygousc.2617_2620del CTCTp.Leu873fsIIIEnteropathy, Lymphocytic pneumonitis, Short stature, Eczema, Recurrent infections.STAT3Heterozygous c.1243G&gt;Cp.Glu415GlnIVEnteropathy, FTT, Lymphopenia, LAD and SplenomegalyTTC7ACompound heterozygous:c.1817A&gt;G p.Lys606Argc.2086T&gt;Cp.Ser696ProVEnteropathy, FTT, transient leukopenia. Two siblings died of severe enteropathy.MYO5BHomozygousc.946G&gt;Ap.Gly316ArgVIEnteropathy, Autoimmune cytopenias, Eczema, ArthritisCTLA4Heterozygousc.436G&gt;Ap.Gly146ArgVIIT1D, Thyroid disease, Enteropathy, Glomerulonephritis, Eczema, Fungal osteomyelitisFOXP3Hemizygous splice site mutation:c.712G&gt;CT1D – Type 1 Diabetes, LAD – Lymphadenopathy, FTT – Failure To Thrive, ICH – Intracranial Hemorrhage.
Developing a T cell:Dendritic cell co-culture system to predict idiosyncratic drug induced hypersensitivity reactions
Authors: Oropallo Michael A , Shang Jackie , Ke Zhenlian , Gonzalez Raymond James , Sistare Frank D. , Lebron Jose , Monroe James J. 
Published: January 2023

Abstract
Idiosyncratic drug induced hypersensitivy reactions (IDHR)s pose a significant safety risk to patients. Indeed, IDHRs have been associated with severe, life-threatening conditions such as Stevens Johnson syndrome, Toxic epidermal necrolysis, and hepatotoxicity. Though drug-induced immune system activation is often implicated in IDHRs, the mechanisms by which this occurs are poorly understood and likely involve formation of drug metabolites or haptens. Furthermore, pre-clinical models often fail to detect the potential of drugs to cause these reactions. Thus, there is a need to create models that can 1) examine how drugs or drug byproducts activate the immune system and 2) predict the potential of drugs to induce IDHRs before they are evaluated in clinical trials. To that end, we have examined the in vitro activation of T cells by autologous monocyte derived dendritic cells (DC)s in the presence of drugs that are associated with IDHR. In concert with previous findings, IDHR associated drugs induce T cell proliferation. Additionally, T cells stimulated by IDHR associated drugs upregulate cell surface markers of activation including CD71, CD69, CD45RO, CD25, and MHC-II. Importantly, we have begun to explore how drug metabolites formed either during T cell:DC co-culture or during culture with hepatocytes influence DC presentation and T cell activation.
NK cell phenotype and proliferation in Systemic Lupus Erythematosus
Authors: Hudspeth Kelly L , Shu Wang , Wang Jingya , Rahman Saifur , Smith Michael A , Casey Kerry Anne , Stephens Geoffrey L , Sanjuan Miguel A ,   Autoimmunity Molecular Team, Hasni Sarfaraz A , Ettinger Rachel , Siegel Richard M 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder whose pathology appears to involve many immune cell types. While it is clear that autoantibody producing B cells as well as CD4+ T cell help are key contributors to disease, little is known regarding the role of innate lymphoid cells such as Natural Killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multicolor flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki-67, which was not found in healthy donors. Only a moderate increase of Ki-67 was observed on other immune cell types such as total CD4+, CD8+ T cells or CD19+ B cells in the same donors. Increased NK cell proliferation was found to correlate with clinical parameters. Furthermore, proteomics analysis and auto-antibody arrays revealed significant correlations between NK cell expression of Ki-67 and specific serum protein biomarkers, as well as SLE associated auto-antibodies. These results will contribute to the understanding of the mechanistic role of NK cells in immune-mediated pathology of SLE.
Immunoprofiling determines survival and guides therapy in sepsis
Authors: Valentine Catherine , Bergerat Agnes 
Published: January 2023

Abstract

Objectives
The host immune response during sepsis is still not well understood. Our goal was to examine different mediators of immune function to determine mechanistic explanations for the immune dysfunction observed in sepsis, and determine if blockade of PD-L1 would alter survival in sepsis

Methods
Outbred CD-1 mice underwent cecal ligation and puncture (CLP) to induce sepsis. 24h post-CLP, Il-6 levels were measured by ELISA. Splenocytes were analyzed by flow cytometry for expression of MHCII, CSM, and other cell surface markers. Additional mice were treated 6h post CLP with anti PD-L1 and followed for survival.

Results
Mice were stratified into groups predicted to live (P-Live) or die (P-Die) on the basis of plasma IL-6. Although both groups of mice had increased expression of PD-L1 on splenic monocytes relative to healthy mice, P-Die mice expressed higher levels relative to P-Live mice. P-Die mice had higher levels of MHCII compared to the P-Live group. CD28 and CD40L expression was higher on lymphocytes in P-Live mice. CD4 and CD8 cells had higher levels of CD69 in the P-Die mice compared to P-Live, whereas IL-2r was increased in P-Live compared to healthy mice, but unchanged in P-Die mice. Surprisingly, P-Live mice that received anti PD-L1 had a significantly higher mortality than mice treated with isotype.

Conclusions
Studies of CSM, MHCII and activation markers in P-Live vs. P-Die mice demonstrate variability during the host response in sepsis. Cells in P-Die mice are capable of presenting antigen, but induce apoptosis of lymphocytes via PD-L1. Lymphocytes in P-Die mice show evidence of decreased function. Immunoprofiling of septic patients will identify survivors vs. non-survivors and guide appropriate immunotherapy of sepsis
B cells respond via germinal centers to produce anti-lipid IgG antibodies in a murine model of lupus
Authors: Baeza Carlos Wong , Mora Albany Resendiz , Tescucano Alonso , Landa Carla , Zarate Luz Angela , Wong Carlos , Baeza Isabel , Romo Leopoldo Flores 
Published: January 2023

Abstract
Anti-lipid IgG antibodies are produced in some mycobacterial infections and autoimmune diseases (lupus, anti-phospholipid syndrome). However, few studies have addressed the mechanisms that lead to the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a mouse model of lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membrane of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which are involved in the development of the disease. We used this model of lupus to investigate the in vivo mechanisms that lead to the production of anti-lipid IgG antibodies. B cells are activated, in response to most protein antigens, via germinal centers or extrafollicular reactions. In germinal centers, a T cell-dependent response leads to isotype switch, somatic hypermutation, affinity maturation and memory generation, whereas these events do not usually occur in extrafollicular reactions. In this mouse model of lupus induced by chlorpromazine-stabilized NPA, we found plasma cells producing NPA-specific IgGs in the inguinal lymph nodes, the spleen, and bone marrow of mice. We also found a significant number of germinal center B cells specific for NPA in the inguinal lymph nodes and the spleen, and we demonstrated the presence of NPA in these same germinal centers. In contrast, we found very few extrafollicular reaction B cells specific for NPA. Altogether, our data suggest that, in this murine model of lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.