bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated frequency of producing IL-17A Neutrophils in peripheral blood from patients with RA
Authors: Gonzalez-Orozco Maria , Juarez-Estrada Ana , Vazquez-Castellanos Gabriel , Barbosa-Cobos Rosa Elda , Limon-Camacho Leonardo , Ortiz-Navarrete Vianney 
Published: January 2023

Abstract

Introduction
Rheumatoid Arthritis (RA) is a systemic and chronic inflammatory disease, which affects 1–1.5% of population worldwide. Synovial membrane, cartilage and bone are the main sites affected by inflammation. The inflammatory process in RA leads to increased production of inflammatory cytokines IL-8, TNF-a, IL-6, IL-1b, IL-15, IL-18 e IL-17A in synovial fluid and serum. In addition to Th17, others cells such as gd T cells, iNKTs, mast cells and neutrophils also produce IL-17A. In mouse model of RA, IL-17A producing neutrophils seems to be important for the onset of the disease. Thus, we hypothesize that the population of IL-17A producing neutrophils is increased in patients with RA.

Objective
To analyze the frequency of IL-17A producing neutrophils in peripheral blood of patients with RA.

Methods
Peripheral blood from 68 patients with rheumatoid arthritis and 15 healthy donors has been collected, erythrocytes were lysed and peripheral blood leukocytes were stained for surface marker CD177 and for intracellular detection of IL-17A. Cells were analyzed by flow cytometry. It was also evaluated the frequency TH17 cells by flow cytometry using standard protocol.

Results
IL-17A producing neutrophils are increased in peripheral blood of patients with RA (0–19.5% Mean 1.66%) compared with healthy donors where no neutrophils IL-17A+ were observed (0–0.1% mean 0.05%). Surprisingly, Th17 cells were not detected in peripheral blood of patients with RA.

Conclusion
Neutrophils might be the most important source of IL-17A during the inflammatory response observed in patients with RA since we do not detect TH17 cells in these patients.
Antibody to HA4 of gingipain of Porphyromonas gingivalis is a possible biomarker for rheumatoid arthritis
Authors: Tsay Gregory J , Siao Shih-Hong , Lee Yi-Hsuan , Sun Justin , Chang Yu-Chao , Chen Jonathan , Lan Joung-Liang , Chang Jinghua Tsai , Zouali Moncef 
Published: January 2023

Abstract
Porphyromonas gingivalis (Pg) may play a role in the pathogenesis of rheumatoid arthritis (RA). Arg-gingipain A (RgpA), one of the virulence factors of Pg contains catalytic domain, hemagglutinin domain and sub-hemagglutinin domain including HA-1, HA-2 &HA-3, and HA-4. We detected the antibody against hemaglutinin domain (anti-HA), catalytic domain, HA-1, HA-2 &HA-3, and HA-4 in patients with autoimmune diseases and periodontitis by ELISA and Western blot

Methods
RgpA hemagglutinin domain and its subdomains were cloned respectively. ELISAs and Western blot using these recombinant proteins were developed and antibody reactivities examined in patients with RA, SLE, healthy normal controls, and individuals with PD.

Results
By ELISA, no serum from patients with RA, PD or normal controls was found to react with RgpA catalytic domain. In analysis of anti-RgpA hemagglutinin domain antibodies, 42 of 155 RA patients (27.1%), 16 of 48 PD patients (33.33%) were found to react with RgpA hemagglutinin domain. Anti-HA1 antibody, 39 of 155 RA patiens (25.16%), 6 of 48 PD patients (12.5%). Anti-HA2&3 antibody, 43 of 155 RA patients (27.74%), 10 of 48 PD patients (20.83%). Anti-HA4 antibody, 51 of 155 RA patients (32.9%), 2 of 36 SLE patients (5.56%), 7 of 48 PD patients (14.58%).
By Western Blot, serum from patients with both RA and PD reacted to HA (150kDa), HA1 (72kDa), and HA2/3 (45kDa), respectively. But only serum from patients with RA reacted to HA4(55kDa), not serum from patients with PD, SLE or healthy controls.

Conclusion
Only Serum from patients with RA recognize HA4. HA4 at the C-terminal domain of RgpA hemagglutinin of Pg is a target of RA. Anti-HA4 antibody is a candidate predictive biomarker for RA.
Neuropsychiatric symptoms of patients with systemic lupus erythematosus caused by intracisternal deposited lupus IgG through meningitis
Authors: Deng Guo-Min , Xie Changhao , Guo Yacong , Fang Xang , Qiao Wei 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by high levels of autoantibodies and multi-organ tissue damage. Although neuropsychiatric symptoms are frequent in patients with SLE, its pathogenesis remains unclear. In this study, we investigated pathogenesis of neuropsychiatric symptoms in SLE patients. We analyzed the medical records of 1131 patients with SLE and conducted animal experiments. We found that fifty-nine patients showed NPSLE clinical manifestation including headaches, seizure disorder, cognitive dysfunction, cerebrovascular disease, etc. Lupus-prone mice spontaneously develop meningitis and apoptosis of neurons. IgG is a major contributor in meningitis. This meningitis depends on the dose of IgG, but is not associated with the kind of autoantibody and disease activity. Monocyte/macrophage and TNF play important role in the development of this meningitis. Lupus IgG induces the apoptosis of neurons directly. The deposited IgG in brain tissue exerts an important role in the pathogenesis of NPSLE. This finding will promote the development of an effective therapeutic strategy for NPSLE patients.
IL-17 signaling inducibly degrades ABIN1, a constitutive inhibitor of inflammatory signaling
Authors: Cruz Juan Agustin , Childs Erin , Amatya Nilesh , Simpson-Abelson Michelle , Garg Abhishek , Beyaert Rudi , Aneskievich Brian , Ma Averil , Gaffen Sarah L 
Published: January 2023

Abstract
IL-17 is a pro-inflammatory cytokine that drives autoimmune diseases and promotes immunity to fungi. IL-17 binding to the IL-17 receptor initiates recruitment of adaptor proteins that activate NF-κB. IL-17 also induces expression of A20, a feedback inhibitor that restricts NF-κB activation and limits IL-17-dependent inflammation. ABIN1 is an A20 binding protein that has been implicated in autoimmunity in human genetic studies, so we hypothesized that ABIN1 might also play a role in restricting IL-17-dependent signaling. Indeed, ABIN1 inhibited the IL-17 pathway based on RNA silencing analyses. Specifically, the expression of the IL-17-dependent gene lipocalin 2 (Lcn2) increased at both basal levels and after stimulation upon ABIN1 knockdown. Consistently, reconstitution of ABIN1-deficient fibroblasts with ABIN1 also decreased both Lcn2 expression and promoter activation. However, while ABIN1 mRNA increased after IL-17A stimulation, ABIN1 protein progressively decreased following its inducible phosphorylation. Although feedback loops are commonly seen in signaling pathways, differential regulation of mRNA and protein of the same gene are not as common. Thus, we now propose that ABIN1 serves as a constitutive inhibitor of NF-κB signaling. While ABIN1 mRNA is induced by NF-κB at the mRNA level, removal of the ABIN1 protein is required to initiate signal transduction. Unexpectedly, we discovered that A20 is dispensable for both IL-17-mediated degradation of ABIN1 and for ABIN1-dependent inhibition of IL-17 signaling. Altogether, these findings suggest that ABIN1 is a tonic NF-κB inhibitor, and that IL-17 signaling induces its degradation independently of A20 to enhance expression of NF-κB-dependent genes such as Lcn2.
Th17 cells modulate the LN microenvironment through IL-17 dependent regulation of fibroblastic reticular cells
Authors: Majumder Saikat , Revu Shankar , Du Fang , McGeachy Mandy J 
Published: January 2023

Abstract
Integrins play a critical role in the function and migration of Th17 cells in CNS, and blockade of inflammatory T cell migration is used therapeutically in multiple sclerosis. Our previously published data demonstrated a critical role for αvβ3 in driving encephalitogenic Th17 cell migration in experimental autoimmune encephalomyelitis (EAE), in an IL-23R-dependent manner. Herein, we show that fibronectin, a ligand for integrin αvβ3, is significantly upregulated in the dLNs of EAE mice. Strikingly, the expression of fibronectin in dLN was significantly reduced in IL23R−/− mice following immunization. Fibronectin expression increased in dLNs during the progression of EAE with similar kinetics but delayed peak compared to IL-17. Since IL23R regulates IL-17 production, we analyzed LN from IL-17−/− and IL17Ra−/− mice immunized for EAE, and observed a similar defect in fibronectin expression in the absence of IL-17 signaling. CD45−gp38+CD31− fibroblastic reticular cells (FRCs) in the T cell zone are the major producers of fibronectin in the dLNs, and these stromal cells expand during EAE. Although IL-17RA−/− LN appeared similarly enlarged following immunization, indicating an inflammatory response, the number of FRCs was decreased in immunized IL17Ra−/− LN, corresponding to decreased fibronectin. Taken together, our data suggests that during priming of the immune response, and before migrating to their peripheral target tissue, Th17 cells modulate the local LN environment in which they are activated through production of IL-17 to promote FRCs expansion and induction of ECM. This could have long-term consequences in the host upon future infectious challenge, as well as influencing chronicity of Th17-mediated autoimmune disease.
Visualizing antigen-specific CD8 T cell dynamics in the small intestine
Authors: Thompson Emily A , Mitchell Jason , Beura Lalit K , Nelson Christine , Fife Brian T , Vezys Vaiva 
Published: January 2023

Abstract
The small intestine (SI) represents the largest mucosal barrier between the environment and the host. As such, the SI limits both normal and pathogenic microbe invasion and must balance immune tolerance and activation. CD8ab T cells constitute a dominant lymphocyte population in the SI and contribute to both of these processes but detailed investigation into their in situ behavior in response to various stimuli is lacking. We visualized Ag-specific CD8 T cell migration in the SI using two-photon microscopy to understand CD8 T cell immunosurveillance. We found that pathogen-specific CD8 T cells are initially slowed early after infection but regain motility directly after Ag clearance. At a memory time point, CD8 T cells exhibited slower migration concurrent with acquisition of a resident memory phenotype. Current studies are focused on determining what is required for CD8 T cell motility throughout the course of infection. Additionally, as tolerance reversal and expansion of self-specific CD8 T cells has recently become a focus of cancer therapy, we characterized in situ behavior of self-specific CD8 T cells. Using a mouse expressing a model Ag in the SI as a self-protein, we observed self-specific CD8 T cells before and after tolerance reversal. Tolerant CD8 T cells migrate significantly faster than pathogen-specific cells at acute time points after infection. Contrastingly, ex-tolerant CD8 T cells were comparable to pathogen-specific CD8 T cells indicating that indeed their in situ scanning behavior had been altered upon tolerance reversal. These observations have provided valuable insight into CD8 T cell motility within the SI and can inform targeted treatment options and vaccines to ensure effective immunosurveillance of this tissue.
HDAC3 controls homeostasis of retina-resident microglia derived from embryonic precursors
Authors: Mi Xiaofan , Yao Yi , Liu Queping , Kumar Ashok , Gao Hua , Zhou Li , Mi Qing-Sheng 
Published: January 2023

Abstract
Microglia are tissue resident macrophages of the central nervous system (CNS) that function in CNS maintenance and innate immune defense. Macrophages are mediators of immune threshold and thus implicated in disease pathogenesis. Compared to research efforts on CNS microglia, relatively little is known about microglial development or homeostasis in the retina. Histone deacetylases (HDACs) are enzymes known to regulate gene expression by modifying chromatin structure. Here, we use a murine model with conditional deletion of HDAC3 induced by Colony Stimulating Factor 1 Receptor (Csf1r) Cre to determine the consequence of HDAC3 depletion on microglial development and homeostasis in the retina. Macrophages were identified using CD11b and F4/80 markers. Retinal microglial populations were assessed in mice at embryonic day 14.5 (E14.5) as well as at birth and 4-weeks old. A population of CD11b+F4/80bright retinal microglia were identified as early as E14.5, indicating that retinal microglia are derived from seeding of embryonic progenitors from the yolk sac or fetal liver. Although the frequency of retinal microglia was comparable at embryonic stage and at birth, it was significantly reduced (P = 0.008) in HDAC3 KO mice at 4 weeks old. Moreover, retinal microglia were partially radio-resistant, and could be repopulated by fetal liver cells transferred from WT but not HDAC3 KO embryos. This is the first report to show that retina-resident microglia are derived from embryonic precursors and that HDAC3 controls microglial homeostasis in adult retina. HDAC3 may serve as a promising therapeutic target for microglial immune-reactive pathologies such as age-related macular degeneration.
Utilizing self-specific CD8 T cells for the treatment of cancer
Authors: Nelson Christine , Quarnstrom Clare , Thompson Emily , Vezys Vaiva 
Published: January 2023

Abstract
CD8 T cells are potent effectors that monitor the body for infections as well as malignancies. CD8 T cell infiltration into tumors is correlated with better prognoses in many cancers. However, the tumor microenvironment is often toleragenic, which treatments like checkpoint inhibitors seek to overcome. Such treatments have been met with some success, but their benefits remain elusive for a subset of patients. Using a strict model of tolerance to intestinal self-antigen, we show that newly activated CD8 T cells respond best to checkpoint blockade therapy, while CD8 T cells in a toleragenic environment, even for a short time, do not respond. We have developed a therapeutic vaccination strategy that generates a targeted CD8 T cell response with renewed susceptibility to checkpoint blockade. Using heterologous prime boost vaccination model, we have refined tolerance reversal to a subset of self-antigen specific CD8 T cells, and eliminated the need for broadly immunostimulatory treatments. This model has been used to reverse tolerance in CD8 T cells specific for engineered antigens in the small intestine as well as naturally occurring self-antigens in the skin. The expanded populations of skin-specific CD8 T cells can be utilized for the treatment of melanoma. These melanocyte-specific CD8 T cells are functional and generate tissue resident memory (Trm) populations throughout the body, including the skin. Additionally, melanocyte-specific CD8 T cells can cooperate with neo-antigen specific CD8 T cells to aid in tumor clearance. By investigating tolerance reversal in self-specific CD8 T cells we have uncovered ways to improve upon current anti-cancer treatments and developed potentially translatable anti-cancer vaccine strategies.
Intestinal homeostasis governed by mesenchymal stromal cells
Authors: Nagashima Kazuki , Takayanagi Hiroshi 
Published: January 2023

Abstract
The mammalian intestine harbors numerous bacteria and contains a large number of immune cells. A continuous dialogue between immune cells and luminal microbes is critical for the maintenance of the intestinal homeostasis. The intestinal epithelium is a single-layered cell sheet that separates numerous microbes and the immune system. The appropriate development and maintenance of the epithelium are essential for the clearance of pathogens and the prevention of excess immune responses against commensal microbes. Microfold (M) cells are epithelial cells specialized for bacterial sampling and initiate germinal center formation and IgA production in the gut associated lymphoid tissues (GALTs). Here, we show that previously unrecognized mesenchymal stromal cells regulate an epithelial function and induce IgA production in the GALTs. The impairment of these mesenchymal stromal cells caused a reduction in IgA production against commensal bacteria, resulting in the altered composition of the gut microbiota. These results suggest that these mesenchymal stromal cells contribute to the maintenance of the intestinal homeostasis.
IL-13Rα2 modulates inflammatory and metabolic effects of IL-33 by regulation of tissue IL-13 responses
Authors: Duffen Jennifer Parker , Zhang Melvin , Hammerman Katherine , Morin Jeffrey , Nocka Karl , Kasaian Marion 
Published: January 2023

Abstract
In experimental models of obesity, IL-13 can overcome insulin resistance by promoting eosinophilic inflammation and M2 macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine, and by IL-33, which triggers release of IL-13. We propose that elevation of tissue IL-13 levels resulting from IL-13Rα2 deficiency, with or without IL-33 administration, counteracts the metabolic stress of obesity produced by a high fat diet. IL-13Rα2 expression was found to be elevated in adipose tissue of obese mice. Mice deficient in IL-13Rα2 had high expression of M2 markers in adipose tissue, consistent with increased IL-13 activity. IL-33 administration raised serum and tissue IL-13 concentrations, produced splenomegaly, elevated tissue eosinophils, macrophages, and ILC2s, and induced an inflammatory gene expression signature in adipose tissue. IL-33 reduced body weight, adipocyte size and fasting blood glucose to a greater extent in IL-13Rα2-deficient mice compared to wild-type littermates, and these changes were attenuated in mice lacking IL-13. In contrast, IL-33-induced splenomegaly and eosinophilia were exacerbated in the absence of IL-13, associated with impaired induction of the soluble decoy receptor, ST2, and unrestrained IL-33 activity. In the context of high fat diet, IL-33 administration resulted in damaging systemic inflammation, which was enhanced in IL-13Rα2-deficient mice. These findings suggest that IL-13Rα2 regulation of tissue IL-13 levels can result in a skewed M2 bias under conditions of metabolic stress, and implicate IL-13Rα2 as a critical checkpoint to limit adverse effects of the IL-33/IL-13 axis.
Deciphering the role of Interleukin-33, a Janus-Faced cytokine, in mast cell-mediated responses in allergic asthma using systems immunological methodologies
Authors: Pushparaj Peter Natesan , Rasool Mahmood , Naseer Muhammad Imran , Abuzenadah Adel , Chaudhary Adeel , Al-Qahtani Mohammed , Gauthaman Kalamegam 
Published: January 2023

Abstract
The prevalence of Allergy and Asthma has been increasing over the past decade, and about 300 million people suffer from these diseases worldwide. Interleukin-33 (IL-33), an Interleukin-1 family of cytokine, binds with the IL-33 receptor (IL-33R) to elicit an array of molecular and cellular processes in immune cells. Here, we have studied the role of IL-33 in mast cell-mediated responses and its impact on allergic asthma using systems immunological methodologies. We have obtained all the microarray datasets from the Gene Expression Omnibus (GEO) related to the IL-33 treated mast cells and allergic asthma. The datasets were analyzed using Genespring GX12.6 (Agilent Technologies, USA) to classify the differentially expressed genes (P&lt;0.05) compared to untreated controls. The ingenuity pathway analysis (Qiagen, USA) of the IL-33 triggered differentially expressed genes in mast cells have revealed that the canonical pathways such as T-helper cell differentiation, the role of macrophages, fibroblasts, endothelial cells in autoimmunity, and chemokine signaling were significantly (P&lt;0.05) upregulated. Besides, in-depth analyses of the IL-33 induced differentially expressed genes in mast cells and allergic asthma, using the comparison analysis module in IPA, showed a significant attenuation in HCK and other related signaling networks. However, the stimulation of both Th1 and Th2 associated cytokines by IL-33 could differentially regulate allergic asthma. Thus, IL-33 is a Janus-Faced cytokine in mast cell mediated allergic responses and, hence, requires further in vitro and in vivo studies to evaluate the therapeutic importance.
The role of eosinophils in adipose tissue inflammation and metabolic function
Authors: Bolus William Reid , Gutierrez Dario , Anderson-Baucum Emily , Kennedy Arion , Hasty Alyssa 
Published: January 2023

Abstract
Adipose tissue (AT) inflammation in obesity is mediated by immune cells and correlates with metabolic disorders (e.g. insulin resistance & type 2 diabetes). After the seminal 2011 paper by Wu et al., implicating eosinophils improve AT health, a series of studies sought to define mechanisms of this initial discovery. In lean AT, eosinophils are abundant & promote M2-like macrophages (MΦ). In obesity the proportion of AT eosinophils declines, concomitant with increased inflammation & M1-like MΦ. Using eosinophil deficient mice (ΔdblGATA) fed high fat diet, Wu et al. showed a lack of AT eosinophils correlated with increased weight & impaired glucose tolerance. In contrast, IL-5 transgenic (IL5tg) mice with excess AT eosinophils weigh less & have improved glucose tolerance. We recently published that CCR2−/− mice have an unexpected surge in AT eosinophils during obesity, associated with M2MΦs, but without the metabolic benefits of IL-5tg mice. This was the first study to link CCR2 function & AT eosinophil accumulation. In new studies, we elevated AT eosinophils via injections of IL-5 protein. The elevated AT eosinophils were not able to reduce weight or improve glucose tolerance. Thus, the mere presence of AT eosinophils is insufficient to alter metabolic heath. Eosinophils are not traditionally viewed as very plastic cells (like MΦs), however eosinophils of metabolic tissues such as AT & the GI tract may indeed respond differently than classically understood eosinophils of parasitic infections & allergy/asthma. Our data suggest the phenotype of AT eosinophils, and not just their quantity, is responsible for their impact on AT health, providing impetus for future studies to determine whether eosinophils also demonstrate plasticity.
Diffusional analysis of cytokines in lymph node tissue on a microfluidic chip
Authors: Ross Ashley E , Pompano Rebecca R 
Published: January 2023

Abstract
Cytokines must diffuse between immune synapses, to neighboring cells, and across the lymph node in order to propagate specific immune responses. However, cytokine diffusion in the tissue environment has never been measured, making it difficult to model cell-cell signaling or the localization of cytokine therapeutics. Here, we analyzed the diffusion of TNF-α, IFN-γ, and IL-2, selected because they have central roles in immunity, they represent two different structural classes, and they vary in molecular weight and multimerization. We utilized a microfluidic platform to deliver picogram quantities of fluorescently labelled cytokines to specific regions of 300-μm thick slices of live murine lymph node tissue ex vivo and analyzed spread by fluorescent microscopy. The analysis method was compared to FRAP and microinjection techniques by analyzing diffusion of 10 kDa and 40 kDa Dextrans in both agarose and tissue slices. With the device, we were able to analyze diffusion of cytokines within the B-cell and T-cell zones of the tissue separately. On average, both TNF-α and IFN-γ diffused at the same rate in both the T-cell and B-cell zone (TNF-α: 2.5 ± 0.8 and 2.5 ± 1.6 × 10−7 cm2/s and IFN-γ: 6.0 ± 1.8 and 4.9 ± 1.5 × 10−7 cm2/s respectively, n = 7–9, p &gt; 0.05); however, IL-2 diffused more rapidly in the T-cell zone (8.1 ±1.1 × 10−7 cm2/s, n = 7–8) than in the B-cell zone (4.5 ± 0.3 × 10−7 cm2/s, n = 7–8) yet the difference was not significant (p&gt;0.05). Variation in diffusion between different zones suggests that cytokines interact differently within specific environments. This data provides the first diffusional analysis of cytokines in intact lymph node tissue and validates a new method to enhance the understanding of cell signaling kinetics.