bluuebunny/crossref_metadata_2025_split huggingface dataset:
A serum CNS-specific protein fingerprint predictive of clinical relapses and disease development of multiple sclerosis
Authors: Raphael Itay , Gomez-Rivera Francisco , Huizar Carol Chase , Gupta Rishein , Arulanandam Bernard , Forsthuber Thomas 
Published: January 2023

Abstract
There is a critical need in MS to develop biomarkers to improve early diagnosis, predict imminent disease relapses, and optimize treatment responses. In MS, central nervous system (CNS) inflammation results in damage to neuronal tissues and disruption of blood-brain barrier integrity, and ultimately to leakage of CNS-specific proteins (CSPs) into serum. Therefore, altered serum levels of CSPs could be promising biomarkers of MS. Based on our previous discovery of CSP expression waves in brain tissue of mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model for human MS, we investigated a subset of CSPs which have human-homologs in longitudinal serum specimens from individual mice in this model. Herein, we establish a pre-onset serum CSP expression wave that enabled prediction of clinical onset of EAE and stratification of subjects into diseased versus healthy. Importantly, we demonstrate that the pre-onset serum CSP wave was not affected by adjuvants and microbial infection, thereby has high sensitivity and specificity for a neuroinflammatory disease. Moreover, we identify differences in serum protein expression between active and passive immunization of EAE revealing hitherto not appreciated differences for disease induction mechanisms. The results provide proof of concept for the development serum CSP waves as biomarkers of MS, specifically for early detection and prediction of the onset of clinical relapse.
A Role for the CD27-CD70 Pathway in T Cell Driven Skin Inflammation
Authors: Remedios Kelly Anne , Zirak Bahar , Rosenblum Michael D 
Published: January 2023

Abstract
The CD27-CD70 costimulatory pathway plays important roles in T cell function and has been implicated in multiple autoimmune diseases. It is currently unknown whether this costimulatory pathway influences T cell responses in the skin. To study the role of CD27 in CD4 T cells, we have utilized the previously described K5 TGO model of inducible tissue-antigen expression. In this model, mice with both K5 and TGO transgenes allow the expression of the model antigen ovalbumin (ova) to be stringently induced or extinguished in the epidermis through the application or withdrawal of doxycycline. After turning on antigen, the transfer of WT ova-specific CD4 (OTII) T cells into K5/TGO recipients induces an inflammatory dermatitis characterized by scaling and neutrophil influx. When CD27-deficient OTII T cells were transferred, skin disease was attenuated and neutrophil influx was decreased. CD27 costimulation promoted T cell accumulation in the skin draining lymph nodes and skin and IL-2 and IFNg production upon restimulation ex vivo. Using in vivo competition experiments, we found that CD27 promoted CD4 responses in a cell-intrinsic manner. CD27 had minimal effect on early T cell activation and proliferation but seemed instead to be involved in promoting survival. Our studies highlight a previously un-identified role for the CD27 pathway in promoting CD4 T cell responses in the skin.
PKC-θ is dispensable for OX40L-induced TCR-independent Treg proliferation
Authors: Alharshawi Khaled , Marinelarena Alejandra , Kumar Prabhakaran , El-Sayed Osama , Bhattacharya Palash , Sun Zuoming , Epstein Alan L. , Prabhakar Bellur S. 
Published: January 2023

Abstract
Previously, we have shown that GM-CSF-induced Bone marrow-derived dendritic cells (G-BMDCs), upon co-culture with splenic CD4+ T cells, have the capability to induce preferential proliferation of regulatory T cells (Tregs) in TCR-independent and OX40L/OX40 dependent manner. In this study we investigated the signaling involved in this Treg proliferation induced by G-BMDCs. Firstly, using splenic CD4+ T cells from OX40 deficient mice and G-BMDCs from WT mice, we confirmed the important role of OX40L/OX40 interaction in Treg expansion. Since OX40 stimulation in the absence of TCR engagement has been reported to induce the assembly of a signalosome involving PKC-θ, we investigated the requirement of PKC-θ in our Treg proliferation mechanism. Interestingly, PKC-θ deficient-CD4+ T cells showed impaired Treg proliferation upon co-culture with WT G-BMDCs. However, this defect in proliferation could be rescued upon IL-2 addition suggesting that PKC-θ was dispensable for Treg proliferation. We further demonstrated that PKC-θ was essential for T-effectors to provide IL-2, which was required for OX40L/OX40-induced Treg proliferation. Furthermore, injecting WT, OX40- deficient, and PKC-θ-deficient mice with soluble OX40L, we established that OX40L/OX40 signaling was sufficient to induce in vivo expansion of Tregs in WT and PKC- deficient mice, but not in OX40-deficient mice. Finally, our data suggested a possible involvement of TRAF1 in Tregs, downstream of OX40 activation.
Modified low density lipoprotein (mLDL) uptake by B cells alters B cell phenotype and impacts atherosclerosis.
Authors: Waseem Tayab , Gjurich Breanne , Butcher Matthew , Alekseev Andrei , Nurieva Roza , Galkina Elena 
Published: January 2023

Abstract
Atherosclerosis is a multifaceted chronic inflammatory disease characterized by the accumulation of modified lipoproteins and immune cells in the aortic wall and vascular dysfunction. The uptake of modified low density lipoproteins (mLDL) by MFs plays an important role in atherosclerosis through the modulation of cholesterol metabolism and MF activation. To date, the impact of mLDL on B cell phenotype and functions is unaddressed. We show that B cells can uptake acetylated and oxidized LDL (acLDL and oxLDL, respectively) via a dynamin-dependent pathway in a concentration, time, and temperature-dependent manner. Assessment of the transcriptional profiles of in vivo acLDL+ B cells and acLDL- B cells by RNAseq suggests that acLDL+ B cells assume an anergic like phenotype. Anergy plays an important role in keeping autoreactive B cells in a state of unresponsiveness and the loss of anergy contributes to the development of autoimmune diseases. Currently, nothing is known about the role and regulation of B cell anergy in atherosclerosis. We show here for the first time that GRAIL, an E3 ubiquitin ligase associated with T cell tolerance, is expressed in B cells. To determine whether B cell-specific GRAIL expression plays a role in atherosclerosis, we performed adoptive transfer of GRAIL-deficient or GRAIL-sufficient B cells into B-cell-deficient mice on apolipoprotein-E deficient background (uM−/− Apoe−/−) mice and examined atherogenesis after 8 weeks of western diet feeding. B cell-specific GRAIL-deficiency supported plaque burden and orchestrated inflammation in the aortic wall. These data suggest that there is a specific mechanism by which B cells recognize mLDL and regulate their anergy-dependent response to mLDL in atherosclerosis.
The endogenous regulator IL-27 suppresses Th2 and Th17 responses in the kidney to ameliorate renal fibrosis in a model of obstructive kidney disease
Authors: Muallem Gaia , Aronson Lillian , Hunter Christopher A 
Published: January 2023

Abstract
Chronic kidney disease (CKD) is a major healthcare issue, causing significant morbidity and mortality as well as high healthcare costs. Early detection of CKD and prevention of disease progression are important strategies for management, and accordingly an improved understanding of fibrotic processes is a critical focus of kidney research. Aberrant immune responses promote fibrosis in the kidney, and exploring the endogenous regulators of these pathways has relevant implications for clinical therapies. Consistent with other organ systems, CD4+ T cell production of the cytokines IL-4, IL-13, and IL-17 has been associated with renal fibrosis in preclinical models of disease, and alternatively activated macrophages (AAMs) have been shown to promote fibrosis in the kidney. The cytokine interleukin-27 (IL-27) limits the magnitude of T cell responses, and our data indicate that after unilateral ureteral obstruction (UUO) mice deficient in IL-27 develop increased kidney fibrosis that is associated with the emergence of Th2 and Th17 responses as well as an increase in alternative activation of macrophages. Therefore, IL-27 is an endogenous regulator that limits clinically relevant immune pathways in the kidney and has potential as an important diagnostic and therapeutic tool in the management of renal fibrosis.
T cell responses to exercise stress do not adequately model those from tactical stress events
Authors: Siedlik Jacob A , Deckert Jake A , Bhatta Anuja , Dunbar Amanda J , Gigliotti Nicole M , Chan Marcia A , Benedict Stephen H , Vardiman John P , Gallagher Philip M 
Published: January 2023

Abstract
Military training environments are rigorous, requiring service members to endure not only physical and psychological stress but also sleep deprivation, caloric restriction, and severe thermic challenges. The convention has been to use immunoendocrine responses induced by various exercise regimens to generalize results to the layered stress environments of wartime. The purpose of this study was to determine whether exercise models are accurate representations of the physiologic response to the stress experienced in an operational environment. To achieve this aim we identified changes in T cell proliferative capacity (costimulation through CD3+CD28 or stimulation with PHA) and relevant immunoendocrine interactions following an environment comparable to that experienced in Basic Combat Training. An increased proliferation response was observed post-exercise in T cells isolated from whole blood in the layered stress group with those increases still significant at 6 h post-exercise. In contrast, the moderate exercise group saw no significant changes in proliferative ability immediately after exercise exhibiting what could be expressed as a characteristic exercise response. Analyses of serum stress hormones, immunomodulatory cytokines, and immunoglobulins -G, -M, and -A failed to reveal any correlated variations that could clarify the T cell findings. These data suggest that exposure to a high stress environment leads to increased T cell proliferation that appears to be independent of changes in stress hormone concentrations and immunomodulatory cytokines. We submit that variations in exercise intensity and duration do not necessarily approximate military operational or tactical stress responses.
IL-23 mediated skin inflammation is dependent on the expansion and function of RORγt expressing cells
Authors: Gauld Stephen B , Wang Yibing , Gauvin Donna , Huang Susan , Lays Laura , Lippert Stephanie , Edelmayer Rebecca , Wetter Joseph , Salte Katherine , Olson Lauren , Namovic Marian , Donnelly-Roberts Diana , Su Zhi , Scott Victoria , Honore Prisca , McGaraughty Steven , Kort Michael 
Published: January 2023

Abstract
While playing an important role in host defense against extracellular pathogens, the IL-23/IL-17 axis is inherently linked to autoimmune disease. Biologic therapies have been developed that target the p19 subunit of IL-23 and IL-17A or IL-17R; and show remarkable efficacy against a range of autoimmune conditions including Psoriasis (PsO). Despite this clinical validation, the cellular pathways induced by IL-23 remain poorly defined. In order to better understand the role of RORγt in this pathway, we administered a potent and selective inhibitor of RORγt in a model of IL-23 mediated skin inflammation, which closely models human PsO. Looking specifically at skin, to differentiate from previous studies, we show that the accumulation of RORγt expressing cells is an early event following exogenous IL-23 exposure. Expansion of these RORγt expressing cells paralleled disease progression (inflammation) with both αβ and γδ T cells contributing to this population. Inhibition of RORγt with a novel small molecule inverse agonist significantly attenuated ear inflammation and histological endpoints related to human PsO. Furthermore, use of this compound attenuated both the accumulation of RORγt positive cells and their effector function (IL-17A production). Finally, inhibition of RORγt had profound downstream consequences, leading to significant recovery of keratinocyte dysregulation and normalization of anti-microbial gene expression. Collectively our studies confirm that RORγt expressing cells are an early feature of IL-23 mediated skin inflammation, reside predominantly in the T cell compartment, and play an active role in keratinocyte biology and disease pathology.
Sphingosine kinase 2 deletion in CD4+ T cells protects against kidney fibrosis
Authors: Perry Heather , Bajwa Amandeep , Huang Liping , Okusa Mark D 
Published: January 2023

Abstract
Progressive fibrosis, a hallmark of chronic kidney disease (CKD), can occur following an acute insult such as ischemia-reperfusion injury (IRI). Sphingosine kinase 2 (Sphk2) deletion in CD4+ T cells protects from folic acid-induced fibrosis; an effect mediated IFNγ. Mitochondrial metabolism has emerged to be important in CD4+ T cell function. We hypothesized that Sphk2 regulates mitochondrial function and IFNγ production in CD4+ T cells in protection against IRI induced fibrosis.
CD4+ T cells were isolated from WT, Sphk2−/− or Sphk2−/− Ifng−/− mice and adoptively transferred to WT mice prior to unilateral IRI. After 14 days, plasma creatinine (PCr) was quantified as a measure of kidney function and kidney transcript levels of a fibrosis marker αSMA (Acta2) was quantified by RT-qPCR. Mitochondrial function was assessed by Seahorse and TMRE uptake by flow cytometry.
WT mice that received Sphk2−/− CD4+ T cells had better kidney function indicated by a reduced PCr level (0.68 +/− 0.01, n = 3) compared to vehicle (0.99 +/− 0.07, n = 4), WT (0.86 +/− 0.04, n = 3), and Sphk2−/− Ifng−/− (1.16 +/− 0.06, n = 4) CD4+ T cells. Additionally, Sphk2−/− CD4+ T cell recipients had reduced transcript levels of Acta2. Naïve and effector Sphk2−/− CD4+ T cells had increased basal oxygen consumption rate compared to WT CD4+ T cells. Effector Sphk2−/− CD4+ T cells had increased TMRE fluorescence compared to WT control CD4+ T cells.
Sphk2−/− CD4+ T cells protect against IRI induced decline in kidney function and fibrosis, an effect mediated by production of IFNγ. Additionally, deletion of Sphk2 may promote mitochondrial function and effector CD4+ T cell function. Thus, targeting the Sphk2 pathway in T cell adoptive therapy may be a therapeutic strategy in the treatment of CKD.
A brain-specific chemokine, FAM19A5, inhibits RANKL-induced osteoclast formation
Authors: Park MinYoung , Lee Ha Young , Kim Hyeung Sik , Lee Mingyu , Kim Ye Seon , Seong Jae Young , Bae Yoe-Sik 
Published: January 2023

Abstract
Since osteoclast plays a key role in bone resorption, the identification of novel molecules that regulate osteoclastogenesis has been important issue. A neurokine or brain-specific chemokine, FAM19A5, a member of C-C chemokine family, is mainly expressed in central nervous system. In this study, we found that FAM19A5 strongly stimulated chemotactic migration of mouse bone marrow-derived macrophages (BMDM). FAM19A5 also markedly stimulated the activation of protein kinase B (Akt) and ERK, resulting in phosphorylation of the kinases in BMDM. FAM19A5 also blocks RANKL-induced osteoclastogenesis. It was confirmed by tartrate-resistant acid phosphatase (TRAP) staining and osteoclast-related gene level. Collectively, we suggest that FAM19A5 can act as a new ligand that regulates chemotactic migration of BMDM and osteoclastogenesis.
CD1a on Langerhans cells controls inflammatory skin diseases.
Authors: Kim Ji Hyung , Hu Yu , Winau Florian 
Published: January 2023

Abstract
In contrast to conventional T cells that recognize peptides on MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. The abundant expression of CD1a hallmarks Langerhans cells in the skin, a subtype of dendritic cell (DC) with antigen-presenting functions. CD1a is able to bind and display a broad spectrum of lipid antigens derived from exogenous sources, such as bacteria, or host origin. The complex immune system of the skin is critically involved in responses to extrinsic insults like allergens, as well as in autoimmune diseases, such as psoriasis. However, the in vivo role of CD1a on Langerhans cells remains enigmatic since CD1a is lacking in mice. Using CD1a-transgenic mice, we show that the lipidic substance urushiol from the plant poison ivy induces severe skin inflammation in a CD1a-dependent fashion. The immune response is driven by CD1a-expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL-17 and IL-22. Among different urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a model for psoriasis, CD1a massively amplified inflammation mediated by Th17 cells reactive with self lipid antigens from skin. Strikingly, treatment with blocking antibodies versus CD1a fully abrogated skin inflammation. Patients suffering from psoriasis showed strong inflammatory T cell activation in response to CD1a. Thus, we propose CD1a as a potential target for future therapeutic strategies against inflammatory skin diseases.
A self-glycerophospholipid suppresses immunity and inflammation via recruitment of Ly6C+ myeloid cells
Authors: Singh Ram Raj , Prasad Priti , Tran Cynthia , Halder Ramesh 
Published: January 2023

Abstract
Membrane lipids function as essential components of biological membranes, as signaling molecules, and as energy storage molecules. Phosphatidic acid is a vital membrane lipid that serves as a precursor for the synthesis of all acylglycerol lipids in the cell. Phosphatidic acid participates in a wide range of cellular processes, including cytoskeletal organization, secretion, endocytosis, and cell proliferation. Here, we examined the effect of phosphatidic acid on myeloid cells and its ability to modulate tumor immunity and inflammatory disease. We found that in vivo administration of phosphatidic acid protected against immune mediated liver inflammation induced by concanavalin A, but worsened tumor spread in the B16F10 melanoma lung metastasis model. Phosphatidic acid reduced pro-inflammatory cytokines but increased anti-inflammatory cytokine interleukin-10 in the liver. Phosphatidic acid did so by inducing the mobilization and migration from the bone marrow to peripheral organs of Ly6C+ myeloid cells that upon adoptive transfer protected against autoimmune liver inflammation. Our novel observations indicating immune suppressive functions of phosphatidic acid may have wide implications for a variety of conditions with altered lipid metabolism and inflammation such as atherosclerosis and autoimmune disease and conditions with local or systemic alterations in phosphatidic acid such as osteoarthritis and Alzheimer’s disease.
Neutrophil polarization in the airways of infants with bronchiolitis
Authors: Cavallaro Elena C , Liang Kar-Kate , Forsyth Kevin D , Dixon Dani-Louise 
Published: January 2023

Abstract
Pulmonary neutrophilia is observed in pediatric patients with viral-induced bronchiolitis. Despite an alleviation in clinical symptoms, our findings suggest that airway neutrophil infiltration and activation does not appear to resolve by discharge in hospitalized infants. The recent identification of neutrophil plasticity and polarization into distinct phenotypic pro-inflammatory (N1) and immunosuppressive (N2) subsets provides an unexplored avenue for regulation of the neutrophilic inflammatory response in bronchiolitis. Admission nasopharyngeal aspirate (NPA) samples were assessed from twelve bronchiolitic infants presenting to Flinders Medical Centre, Adelaide, Australia in 2013. An overall strong positive correlation between N2 soluble mediator TGF-β1 and the percentage of neutrophils stained for N2 marker MMP-9 was observed; with no correlation observed between TGF-β1 and neutrophils positive for N1 marker ICAM-1. In 2015 and 2016, eleven bronchiolitic infants provided consecutive NPAs across hospitalization. In both cohorts, concentrations of active TGF-β1 detected were comparable to levels previously identified to significantly suppress neutrophil activity in vitro (&gt;1 pg/mL). Temporal assessment of neutrophil polarization is underway. The detection of pre-established neutrophil polarizing mediators, and the correlation of these mediators with different neutrophilic subsets within NPAs indicates a potential N1/N2 paradigm occurring within the airways of bronchiolitic infants. Further investigation is merited, with analyses over disease trajectory and by disease severity required to assess biological significance.
Majie Pingchuan Cataplasm Regulates Thymic Stromal Lymphopoietin in Rats with Asthma
Authors: Wang Xueqian , Cheng Fafeng , Zhu Wenxiang , Yin Xiangjun , Liu Yuanjun , Li Changxiang , Ma Chongyang , Kong Hui , Wang Qingguo 
Published: January 2023

Abstract
As a new type of external preparations, cataplasm is widely used in clinical practice. In this study, we aimed to explore the efficacy and mechanism of Majie Pingchuan Cataplasm (MJPC) on asthma. By treating the brown-norway asthmatic rats with MJPC, it was found that the incubation period was significantly longer compared with rats injected with dexamethasone (P&lt;0.05); in addition, the airway smooth muscle spasm was relieved compared with the asthmatic rats (P&lt;0.05); it was observed that the number of inflammatory cells (such as eosinophils and neutrophils) was reduced both in the blood and lung tissue (P&lt;0.05). The efficacy of MJPC was also explored in vitro. Components of MJPC had an antagonistic effect on the tracheal smooth muscle contraction of guinea pigs induced with histamine phosphate and acetylcholine chloride. It has been proven that thymic stromal lymphopoietin (TSLP) plays an important role in the pathogenesis of atopic dermatitis and asthma. So we hypothesized that TSLP may be an important regulator of immune system in the skin and lung. In this study, TSLP levels in different tissues were detected to explore the mechanism of MJPC in the treatment of asthma. The results showed that expressions of TSLP in the lung tissue, skin, bronchoalveolar lavage fluid and serum were significant lower in the MJPC group compared with the model group (P&lt;0.05). Our study confirmed that MJPC has a therapeutic effect on asthma in rats, it can not only play a role in blood after percutaneous absorption, but also regulate the skin immune system to achieve the treatment of asthma by affecting the expression of TSLP in local skin.