bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the HVEM-BTLA-CD160-LIGHT network in Psoriasis
Authors: Sedy John R , Veny Marisol , Nguyen Jennifer , Balmert M Olivia , Niemela Nichole , Norris Paula S , Ware Carl F 
Published: January 2023

Abstract
Genetic studies have identified heritable linkages to psoriasis. However, complete identification of psoriasis susceptibility loci remains elusive. We have identified the HVEM-BTLA-CD160-LIGHT pathway as a critical regulator of innate and adaptive cell function in several autoimmune diseases, and recently in a mouse model of experimental psoriasis. Specifically, we have shown that the inhibitory receptor BTLA regulates the activity of innate γδ T cells, correlating with worsened dermatitis in BTLA-deficient animals, and attenuated disease in animals treated with agonistic BTLA antibodies. Additionally, our data indicates that the TNF receptor protein HVEM activates CD160 receptors in innate cells, promoting inflammatory signaling. More recently we have observed that skin inflammation is also worsened in animals lacking the TNF ligand for HVEM, LIGHT. In order to promote anti-inflammatory activities of HVEM, we sought to develop ligand specific biologics that could selectively engage inhibitory pathways through BTLA. Our initial studies showed that wild-type HVEM-Fc worsens disease. Additionally, we find that LIGHT-specific proteins that block HVEM-LIGHT interactions also worsen disease, consistent with our results in LIGHT-deficient animals, and identifying a unique regulatory role for LIGHT in skin inflammation. Finally, animals treated with proteins specific for BTLA and CD160 show reduced pathology compared to animals treated with wild-type HVEM-Fc. Through our efforts to synthesize ligand specific HVEM biologics, we have shown how select ablation of HVEM ligands can result in both pro- and anti-inflammatory signaling that can be targeted for the development of therapeutics for inflammatory diseases.
The nature and role of autoimmunity in cystic fibrosis lung immunopathology
Authors: Skopelja Sladjana , Hamilton JoNell , Jones Jonathan D. , Ashare Alix , Gifford Alex H. , Rigby William F.C. 
Published: January 2023

Abstract
Cystic Fibrosis (CF) arises due to the altered activity of the CF transmembrane regulator (CFTR) protein. While the lung disease in CF is associated with chronic infection by Pseudomonas aeruginosa (PA), identical CFTR mutations exhibit considerable clinical variability. To elucidate this, we evaluated the autoantibody response to bactericidal permeability-increasing protein (BPI) and anti-citrullinated proteins (ACPA) in CF patients (n=38) and compared it with the autoantibody profile in sera from Rheumatoid Arthritis (RA) patients (n=50), given the association of airway inflammation with ACPA induction in RA. The presence of ACPA was restricted to RA patients; no antibodies to BPI were seen. In contrast, 42% of CF patients had anti-BPI IgG, but no ACPA. Contrary to ACPA, the autoantibodies to BPI did not bind to post-translationally modified epitopes but mapped to the protein C-terminus (CT-BPI). Patients with high levels of anti-BPI IgG exhibited worse lung function (lower FEV1), the presence of anti-Cif antibodies (CFTR inhibitory factor), and the absence of the homozygous F508del CFTR mutation. Neutrophil incubation with PA led to the cleavage of BPI into a ~32kDa fragment corresponding to CT-BPI, in an elastase dependent process. In addition, anti-BPI IgG levels were higher in patients harboring the more pathogenic (mucoid) PA strain infection. These findings prompt the model that autoantibody responses reflect greater impairment of PA clearance, which is the hallmark of this chronic inflammatory disorder. Alternatively, given that no clear association between bacterial colonization and CF disease severity exists, the model that autoantibodies independently exacerbate CF lung pathology merits consideration.
Identifying the human B cell population that produces atheroprotective natural antibodies
Authors: Buchta Claire M , McSkimming Chantel C , Taylor Angela M , McNamara Coleen A 
Published: January 2023

Abstract
B cells act in a subset-dependent fashion in the development of murine atherosclerosis: conventional B-2 cells are atherogenic, while B-1 B cells have atheroprotective functions, mainly through production of IgM natural antibodies. Many of these antibodies are specific for oxidation-specific epitopes (OSE) such as malondialdehyde (MDA) on LDL and block macrophage uptake of oxidized lipids, preventing foam cell formation. In human subjects, high levels of plasma IgM to MDA-LDL are associated with reduced coronary artery disease and cardiovascular events; however the human B cell subset that produces these antibodies has not yet been identified. Recently, a putative human B-1 cell (CD20+CD27+CD43+) was defined. In PBMC from a cohort of human subjects presenting with cardiovascular disease, we show that expression of the chemokine receptor CXCR4 on human B-1 cells (n=54) positively correlated with plasma levels of IgM to MDA-LDL (p=0.004) and is inversely associated with coronary artery plaque volume as measured by intravascular ultrasound (IVUS) (p=0.0001). Using CyTOF mass cytometry technology, we demonstrate that CXCR4 expression was localized to a specific subset of human B-1 cells, suggesting that these cells may have distinct effector functions. Additionally, we developed biotinylated MDA-LDL and demonstrate that MDA-LDL showed enriched binding to a subset of IgM+ human B-1 cells, suggesting that these cells are responsible for producing IgM to MDA-LDL. Ongoing experiments will examine antibody production from these cells. Identification of the human cell type that produces IgM to MDA-LDL has the potential to lead to the development of strategies to enhance production of this atheroprotective antibody.
Uterine NK cells of preeclamptic patients express reduced Fas
Authors: Loewendorf-Snead Andrea I , Nguyen Tina A , Kahn Daniel A 
Published: January 2023

Abstract
Preeclampsia, a disease of pregnancy, despite extensive investigation has escaped a defining mechanism, though risk factors suggest underlying immunopathology. A lymphocytic infiltrate of the decidua includes the specialized uterine NK cells. Uterine NK cells have distinct phenotype and function and are essential for healthy pregnancy.
After UCLA IRB approval (#11-002962), patients with normal and preeclamptic third trimester pregnancies undergoing cesarean section were recruited for sampling of maternal peripheral blood, and endometrium at the time of delivery. Lymphocyte populations and functionality were characterized using flow cytometry and in-vitro re-stimulation assays.
As expected, we found increased proportions of CD56hi CD16- uterine NK cells in the endometrial decidua compared to the peripheral blood of the same patient. Only uterine NK cells exclusively displayed an activated (CD69+) phenotype. In preeclamptic patients, the percentage of peripheral NK cells expressing Fas was significantly increased whereas Fas expression was decreased on uterine NK cells (CD56+CD16−). Interestingly, intracellular cytokine production of uterine NK cells is similar in healthy and preeclamptic patients (Perforin A, Granzyme A, IFNγ). While proportions of γδ T cells isolated from the decidua are similar in healthy and preeclamptic patients, γδ T cells from the decidua of preeclamptic patients displayed reduced expression of CD127 and CD27. This pattern along with reduced Granzyme A-expression suggests reduced functionality similar to the exhaustion observed in αβ T cells in the context of persistent inflammatory stimulation.
Using dimensionality reduction techniques on cross project phospho-flow data to cluster patients based on signaling patterns
Authors: Couse Michael , Wang Weiqi , Holmes Tyson , Maecker Holden T 
Published: January 2023

Abstract
Phospho-flow is an assay that measures the phosphorylation level of various cellular proteins on a per cell basis. This approach allows researchers to apply numerous stimulations and measure the phosphorylation level in a variety of cell types for each patient, thus creating a patient specific signaling “fingerprint”. This technique has been used to identify perturbations underlying a single disease, however little work has been done to compare these “fingerprints” across diseases. In this study, we compile phospho-flow data performed at the Stanford Human Immune Monitoring Center (HIMC) and use dimensionality reduction techniques to cluster patient’s “fingerprints” from a variety of diseases.
The HIMC provides immune monitoring assays and catalogs these assays on the Stanford Data Miner (SDM), a data repository with mining tools that allows for the upload and integration of clinical and demographic data as well as data from HIMC assays. Through this, we were able to sort on only phospho-flow studies and subsequently extract the data from 164 patients comprising 11 different conditions. Each sample received 7 different stimulations; 3 STAT proteins were measured in 8 cell types totaling over 27,000 data points.
Through principal component analysis we are able to see distinct clustering of patients by disease when graphing the 1st 3 components. This clustering picture is validated when looking at the clustering that occurs through analysis by tSNE and unsupervised hierarchical clustering. Next, we isolated the top loadings from the first three principal components to identify the signaling pathways driving the clustering. Specific signaling pathways were identified to explain differences seen between diseases and within diseases.
Intravenous rasburicase-induced immune tolerance is associated with depletion of specific lymphocytes and up-regulation of regulatory T cells
Authors: Xu Hui , Mills Frederick , Max Edward E 
Published: January 2023

Abstract
Therapeutic proteins can be potent agents for treating serious diseases, but in many patients these proteins provoke antibody responses that blunt therapeutic efficacy. Intravenous administration of high doses of some proteins induces immune tolerance, but the mechanisms behind this effect are poorly understood. As a model to study tolerance induction in mice, we used Rasburicase, a commercial recombinant uricase used for treatment of hyperuricemia. Intraperitoneal (i.p.) injection of Rasburicase without or with alum provoked a clear anti-Rasburicase antibody response, but intravenous (i.v.) injection did not. The lack of response to i.v. Rasburicase was apparently due to active immune suppression, since i.v.-treated mice showed blunted antibody and reduced T cell responses to subsequent i.p. injections of Rasburicase. This blunted response was associated with a decrease in Rasburicase-specific B cells and T cell proliferation, and an increase in proportion of CD4+ FoxP3+ regulatory T cells (Treg). We examined the number of lymphocytes in peripheral blood after Rasburicase i.v. injection. Intravenous injection of rasburicase temporary reduced numbers of B cells and T cells, but robustly depleted Rasburicase-specific B cells in blood. Further results showed that rasburicase i.v. injection decreased the number of lymphocytes by inducing apoptosis of B cells and activated T cells. Thus, our data suggests that Rasburicase i.v. injection-induced apoptosis and depletion of lymphocytes and up-regulation of Treg cells play important roles in the intravenous therapeutic protein-induced immune tolerance.
Chemokine production by regulatory T cells is required for therapeutic attenuation of autoimmunity and allograft rejection
Authors: Pesenacker Anne M , Patterson Scott J , Wang Adele Y , Mojibian Majid , Morishita Kim , Tan Rusung , Kieffer Timothy J , Verchere C Bruce , Panagiotopoulos Constadina , Levings Megan K 
Published: January 2023

Abstract
Regulatory T cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and non-harmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require Tregs to be near their targets of suppression, but how Treg-to-target proximity is controlled is unknown. We found that Tregs produce chemokines to attract CD4+ and CD8+ T cells close to their proximity in vitro and in vivo. Mouse and human lineage committed Tregs, as well as murine in vitro induced Tregs, produced CCL3 and CCL4 at message and protein level. Chemokine producing Tregs had an activated Treg phenotype with high expression of multiple proteins associated with suppressive function. Furthermore the human CCL3 and CCL4 promoter could be transactivated by FOXP3. In vitro and in vivo migration experiments indicated that CCR5 was the major receptor required by target cells. CCL3 and CCL4 deficient Tregs were impaired in their ability to prevent experimental autoimmune encephalomyelitis or islet allograft rejection, but suppressive in a standard in vitro assay. Moreover, Tregs from subjects with established type 1 were impaired in their ability to produce CCL3 and CCL4. These results demonstrate a previously unknown facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their in vivo function and therapeutic effect in autoimmunity and transplantation.
Functional angiotensin and bradykinin receptors are expressed on primary human mast cells
Authors: Fukuoka Yoshihiro , Hite Michelle R , Schwartz Lawrence B 
Published: January 2023

Abstract

Purpose
The role of mast cells (MCs) has traditionally been recognized as an effector cell for IgE-mediated allergic diseases, involving ~20% of USA citizens. However, everyone has MCs, indicating their involvement in biologic and pathobiologic conditions beyond allergy. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor (AT1R) blockers are used to treat cardiovascular disorders such as hypertension, while a bradykinin type 2 receptor (B2R) inhibitor is used to treat attacks of hereditary angioedema. We examined the expression and biological function of AT1R, B2R and B1R on primary human MCs.

Methods
MCs were dispersed from fresh surgical human skin obtained from CHTN, and placed into culture with SCF (100 ng/ml) for 4–8 weeks. FACS analysis, western blotting, qRT-PCR, degranulation (β-hexosaminidase release), cytokine/chemokine secretion of IL-6, IL-8 and CCL5, nitric oxide (NO) production (DAF-AM diacetate) were measured.

Results
FACS analysis and western blotting showed the AT1R and B2R are expressed on MCs. Angiotensin II (0.1–10 μM) and bradykinin (BK, 0.1–2 μM) stimulated MCs to release cytokines (1–4 ng/ml) which was inhibited by specific inhibitors. BK also stimulated the production of NO. Both the B2R and B1R are up-regulated by TNFα (10 ng/ml for 3 days), leading to enhanced activation of MCs by BK (1 μM) and desArg-LysBK (1 μM). Exposure of MCs to angiotensin II (2 μM), angiotensin (1–7)(10 μM) or ACEI (ramipril 1 μM) also enhanced cytokine secretion triggered by low concentration of BK (0.03–0.25 μM).

Conclusion
These findings suggest functional interactions of AT1R, B2R, ACE and Mas on human MCs, providing novel roles for MCs in cardiovascular, inflammatory and allergic disorders.
The effect of LPS on CD103 expression on dendritic cells
Authors: Brassard Julyanne , Bernatchez Emilie , Langlois Anick , Blanchet Marie-Renée 
Published: January 2023

Abstract
Control of the intensity and duration of the pulmonary immune response is crucial in homeostasis maintenance in the lung. Dendritic cells (DCs), the main antigen presentation population in the lung, play a crucial role in these mechanisms. Notably, CD103+ DCs play a regulatory role while CD11b+ DCs are considered pro-inflammatory cells. Therefore, the balance between these two important DC populations is crucial in homeostasis maintenance and host-defense. However, the mechanisms regulating this tight balance remain poorly understood. Preliminary data obtained in our laboratory showed that Saccharopolyspora rectivirgula exposure downregulates CD103+ DCs levels in vivo as early as 18h following antigen exposure, impacting the pro/anti-inflammatory DC balance. However, the mechanisms involved in this response are still undefined. As TNF is an important pro-inflammatory cytokine secreted rapidly in response to antigens (such as LPS), lung- and spleen-isolated DCs were stimulated in vitro for 18h with increasing concentrations of TNF and LPS. Flow cytometry and qRT-PCR analysis demonstrated that CD103 protein and mRNA expression are downregulated following stimulation. The percentage of CD103+ DCs was also decreased in vivo 18h after mouse LPS exposure (mouse model). Furthermore, exposure of Cd103−/− mice to LPS led to an impaired resolution of airway inflammation and return to homeostasis, supporting the importance of CD103 expression for homeostasis maintenance in the lung in response to antigens. Our results suggest that modulation of CD103 expression in response to antigens is a crucial step in host defense and homeostasis maintenance in the lung.
NLRX1 attenuates damage following traumatic brain injury through negatively regulating NF-κB signaling
Authors: Allen Irving C , Meza Armand , Brickler Thomas , Coutermarsh-Ott Sheryl , Ives Angela , Bertke Andrea , Theus Michelle 
Published: January 2023

Abstract
Mechanical trauma to the CNS results in the disruption of the cellular microenvironment leading to massive necrotic and apoptotic loss of neuronal and glia populations. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity and free radial release contribute to neural tissue damage. Members of the NLR family of pattern recognition receptors are essential mediators of the host immune response. Recently, our lab and others identified a novel sub-group of NLRs that function as negative regulators of inflammation. One of the members of this sub-group, NLRX1, is a potent regulator of interferon, NF-κB, ROS production and autophagy. Thus, we hypothesized that NLRX1 attenuates Traumatic Brain Injury (TBI) through the negative regulation of overzealous innate immune system signaling. To evaluate this hypothesis, we utilized Nlrx1−/− mice in a controlled cortical impact (CCI) injury model. The Nlrx1−/− mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. We also observed significant proliferation of microglia within the Nlrx1−/− lesions compared to wild type animals. Mechanistically, our data indicates that NLRX1 attenuates TBI progression through the microglia compartment via negative regulation of NF-κB signaling and IL-6 production. Together, our data extends the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identifies this highly novel NLR as a significant modulator of TBI progression.
BTLA+ dendritic cells govern induction of extrathymic regulatory T cells and tolerance.
Authors: Jones Andrew , Bourque Jessica , Opejin Adeleye , Gross Cindy , Hawiger Daniel 
Published: January 2023

Abstract
Dendritic cells (DCs) initiate immunity and also antigen-specific tolerance mediated by extrathymic regulatory T (Treg) cells that prevent subsequent T cell priming. It remains unclear how DCs regulate induction of such tolerance. Here we report that T cell activation by CD11c+ DCs in steady state had no lasting impact on subsequent immune responses and resulted in neither induction of Treg cells, nor priming of autoimmune T cells. Our studies further revealed that efficient induction of Treg cells required BTLA expressed specifically in DEC205+ CD8+ CD11c+ DCs. Ligation of HVEM, a receptor of BTLA, in Foxp3neg T cells promoted Foxp3 expression through upregulation of CD5. In contrast, T cells activated in the absence of BTLA and HVEM-mediated functions, remained CD5lo and therefore failed to resist the inhibition of Foxp3 expression in response to effector-differentiating cytokines. Thus only T cells specifically stimulated by BTLA+ DCs efficiently converted into Treg cells that mediated antigen-specific tolerance.
Anti-inflammatory role of cannabinoid receptor type 1 antagonist AM251 in high fat diet-induced obesity— a focus on microRNAs.
Authors: Miranda Kathryn , Mehrpouya-Bahrami Pegah , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Obesity is a major health problem in the U.S. that continues to increase in prevalence. Excessive calorie consumption leads to expansion of adipose tissue through both hypertrophy and hyperplasia. As a result, adipocytes die and macrophages infiltrate into the adipose tissue to repair damage. Activation and infiltration of immune cells contribute to the chronic low-grade inflammation present in obesity. Immune cells express cannabinoid receptors that regulate inflammation. In this study, a mouse model of high fat diet-induced obesity was used to determine the effect the CB1 receptor antagonist AM251 has on adipose tissue inflammation. C57BL6 mice were fed a high fat diet (HFD) for twelve weeks to induce obesity and then given AM251 (10mg/kg/day) oral gavage for four weeks while continuing HFD. Treatment improved metabolic parameters while reducing fat mass and pro-inflammatory cytokine production. To further investigate the anti-inflammatory effects of AM251, infiltrating F4/80+ cells were isolated from epididymal fat and used for microRNA microarray. Nine miRNAs were differentially expressed as a result of AM251 treatment. These miRNAs were analyzed using Ingenuity Pathway Analysis software (Qiagen) and were found to significantly affect the “Inflammatory Disease and Inflammatory Response” pathways. Upregulated miRNAs such as miR-466i-3p were found to target macrophage polarization genes including Pik3r1. The current study suggests that CB1 antagonists may mediate anti-inflammatory effects and amelioration of obesity through regulation of miRNA expression.
(Supported in parts by NIH grants P01AT003961, R01AT006888, R01ES019313, R01MH094755, P20GM103641, and Veterans Affairs Merit Award BX001357.)
microRNAs profile expression in a mouse model of lupus triggered by lipids associated in non-bilayer phospholipid arrangements
Authors: Zarate Luz Angela , Wong Carlos , Bustos Israel , Resendiz Albany , Landa Carla , Pedroza Abraham , Wong Carlos , Perez Carlos , Baeza Isabel 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic multifactorial autoimmune disease; its pathology is mainly attributed to auto-antibodies that cause inflammation and tissue damage. Our group proposed that lipids associated in non-bilayer phospholipid arrangements (NPA) are involved in the development of SLE. BALB/c mice developed a disease very similar to human SLE when they received Mn2+ or drugs chlorpromazine, procainamide (which stabilize NPA in the plasma membrane), or liposomes bearing NPA induced by these drugs or by Mn2+. Recently, we found that the gene expression profile of mice with lupus was different to that found in healthy mice and was similar to patients with SLE: in mice with lupus genes involved in presentation of exogenous antigens, antibody production and TLR4 and NOD2 signaling and some genes encoded for complement proteins were over-expressed, while genes for NK cell recognition and apoptosis were under-expressed. In the present study, we used the mouse immunopathology miScriptTM miRNA PCR Array in order to compare mature microRNA profile between mice with lupus and healthy mice. The results indicated 9 microRNAs deregulated, 4 microRNAs were underexpressed (miR-155, miR-146b, miR-23, miR-let-7d) which can regulate positively transcription of RNAs associated with IL-6, IL-1 and 5 microRNAs were overexpressed (miR-205, miR-200a, miR-18a, miR-207 and miR-574) which can regulate negatively transcription of RNAs associated with apoptosis and T cell response. This results were validated used TaqMan microRNA Assays and were similar to those found in human LES. Then this study highlight the importance of microRNAs in regulate immune process that has implications in the pathogenesis of LES an inflammatory disease.