bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and function of IL-1 receptor type 2 (IL-1RII) regulating human Th17 responses
Authors: Lee Won-Woo , Kim Dong Hyun , Cho Sunjung
Published: January 2023

Th17 cells are a unique subset of proinflammatory cells conferring protection against extracellular bacteria and fungi, but have been also implicated in the pathogenesis of many autoimmune diseases. IL-1β is critical for the differentiation, expansion, in vivo survival, and effector function of Th17 cells. Among components of IL-1 receptor (IL-1R), decoy IL-1RII is a negative regulator of functional IL-1RI-mediated IL-1β signaling. Given its preferential expression on Treg cells, IL-1RII has been suggested to play a role for controlling the Th17 and Treg balance. However, little is known about a molecular mechanism underlying IL-1RII expression and its contribution to modulation of Th17 responses. Here, we found that IL-1RI and IL-1RII expression were rapidly induced by memory CD4+ T cells after stimulation with TCR alone. Cyclosporin A reduced IL-1RII expression, whereas an augmented FOXP3 was associated with enhanced IL-1RII expression. This finding was corroborated by in vitro assays using NFAT inhibitor, dNP2-VIVIT and an inhibitor of FOXP3/NFAT1 interaction, peptide FOXP3 393–403. Moreover, reporter assay suggests that NFAT/FOXP3 binding sites in IL-1RII promoter are critical for its transcription. At day 2 post-stimulation, there were three distinct subsets; IL-1RI+IL-1RII−, IL-1RI+IL-1RII+, and IL- 1RI−IL-1RII− CD4+ T cells, having unique features including cytokine production profile, the expression of Tregassociated genes, and responsiveness to IL-1β, suggesting a pivotal regulatory role of IL-1RII for human Th17 responses. Our findings will be beneficial to understanding a modulatory mechanism on Th17 response and IL- 1β-mediated IL-1R signaling contributing to pathogenesis of autoimmune diseases.
Endogenous antisense RNA and dysregulation of CD39 expression in inflammatory bowel disease
Authors: Longhi Maria Serena , Harshe Rasika , Xie Anyan , Zhang Haohai , Robles Rene' J. , Mukherjee Samiran , Vuerich Marta , Moss Alan C. , Robson Simon C.
Published: January 2023

CD39 is an ectonucleotidase that hydrolyzes extracellular ATP/ADP to generate immunosuppressive adenosine. CD39 is expressed by Tregs, where it contributes to immunosuppression; and by a subset of effector Th17 cells where it limits pathogenicity.

CD39 is regulated at the genetic level via single nucleotide polymorphisms in non-coding regions of the gene. These are associated with decreased CD39 expression and with predisposition to Crohn’s disease. CD39 is also regulated at transcriptional level through the activation of pathways involving the aryl-hydrocarbon-receptor and O2. We have noted the presence of antisense RNA at the 3’ end of the human CD39/ENTPD1 gene. Hence, another form of regulation might be operational at post-transcriptional level and could relate to the presence of endogenous antisense RNAs.

CD39-specific antisense levels were increased in Treg and Th17 cells obtained from the peripheral blood of Crohn’s patients over controls. CD39 antisense is largely localized in the cell nucleus. CD39 expression was at low levels in both cell types in Crohn’s. When testing lamina propria-derived cells, we noted higher CD39 expression and lower antisense levels in Th17 cells isolated from non-inflamed bioptic areas over inflamed areas. Functional analysis revealed that antisense silencing by FANA oligos (AumBiotec) resulted in consequent CD39 upregulation.

In conclusion, our data indicate that regulation of CD39 antisense RNA impacts Treg suppression and Th17 cell modulation of pathogenic potential in Crohn’s disease. Inhibition/blockade of antisense should be considered as a novel therapeutic strategy to restore CD39 along with immune homeostasis in Crohn’s disease and other inflammatory conditions.
Effect of an anti-inflammation treatment on ligature-induced experimental periodontitis
Authors: Hu Anka , Pan keqing , Han Xiaozhe
Published: January 2023

Objective

Inflammation-related immune responses and bone metabolism lead to extensive tooth loss in periodontitis. This study is to investigate the effect of anti-inflammation treatment in vitro and on ligature-induced experimental periodontitis in vivo.

Methods

Splenocytes were isolated from C57BL/6J mice and cultured for 48 hours under the following conditions: control, lipopolysaccharide (LPS) (1 μg/ml), LPS(1 μg/ml)+fenofibrate (1, 10, 50, 100 μM). The mRNA level and secreted protein level of TNF-α expression were detected by RT-qPCR and ELISA respectively. Silk ligatues (7–0) were tied around both maxillary second molars of C57BL/6J mice for two weeks. Optimized dose of fenofibrate (100 μM) and vehicle control were injected into contralateral side of palatal gingiva on days 3, 6 and 9. The palatal gingival tissues and maxillary bone were collected on day 14 to determine expressions of TNF-α, IL1, RANKL/OPG and periodontal bone resorption respectively.

Results

TNF-α expressions of cultured spleen B cells were significantly increased in the presence of LPS when compared with control group, and significantly reduced by fenofibrate treatment in a dose-dependent manner from (1–100 μM). Gingival mRNA levels of TNF-α, IL1 and the ratio of RANKL/OPG were significantly decreased after injection of fenofibrate, when compared to the control side (p<0.05). The periodontal bone loss were significantly decreased on the side with injection of fenofibrate, as compared to the control side (p<0.05).

Conclusion

An anti-inflammation treatment, fenofibrate, inhibited the inflammation and periodontal bone loss in ligature-induced experimental periodontitis.
Gαq deficiency accelerates the onset of experimental lupus
Authors: He Yan , Qian Hongyan , Shi Guixiu
Published: January 2023

Systemic lupus erythematosus is related to abnormal expression of type I interferon signature genes and characterized by a variety of clinical manifestations and autoantibody production. Tetramethylpentadecane (TMPD), also called as pristine, induced a murine model of systemic lupus erythematosus. Taking pristine to genetically normal mice results in the production of lupus-like autoantibodies and glomerulonephritis, similar to human lupus nephritis. Our previous studies have shown a crucial role of Gαq in immune system. In this study, we treated Gnaq+/− mice with pristane using C57BL/6 mice as controls. Gnaq+/− mice developed antinuclear antibodies earlier than the control mice; also, their titers were higher than the controls. pDCs were increased in the peritoneal lavage fluid of Gnaq+/− mice injected for 7 days compared to controls. Th1 and Th17 cells both were increased significantly in injected Gnaq+/− mice after a month. Gnaq+/− mice took place into more severe kidney damage than controls. Together all, our findings demonstrate that Gαq deficiency accelerated lupus occurrence.
Inflammation in PTSD is a consequence of dysregulated WNT signaling orchestrated by long non-coding RNA LINC00926 and lysine methyltransferase MLL1
Authors: Bam Marpe , YANG XIAOMING , Nagarkatti Prakash S , Nagarkatti Mitzi
Published: January 2023

Posttraumatic Stress Disorder patients experience chronic inflammation. It is not known whether immune dysregulation causes PTSD or the psychiatric imbalance occurs first. Moreover, little is known about the molecular mechanisms involved in the immune dysregulation. Our past work indicates the involvement of epigenetic mechanisms such as histone methylation in the regulation of inflammation in PTSD. By employing RNA-Seq, we identified upregulated expression of WNT10B and LINC00926 in the PBMCs of PTSD. Thus, we hypothesized that LINC00926 overexpression in PTSD results in increased H3K4me3 (gene activating histone methylation) around the promoter of WNT10B leading to its upregulation which in turn, regulated the elevated expression of inflammatory cytokines like IFNg and IL17. Thus, we first confirmed the interaction between LINC00926 and the histone H3K4 methyltransferase, MLL1. Then, by in vitro knockdown of LINC00926 we confirmed lowered expression of WNT10B implying that the interaction between LINC00926 and MLL1 possibly leads to increased H3K4me3 on WNT10B promoter and thereby its upregulation. Following this, we confirmed increased H3K4me3 around WNT10B promotor of PTSD patients by ChIP-Seq. Finally, we confirmed that upregulated WNT10B indeed contributed to the elevated expression of IFNg and IL17. In conclusion, our data implies that upregulation of LINC00926 in PTSD leads to inflammatory state by a mechanism that involves interaction with MLL1 resulting in increased H3K4me3 around WNT10B promotor and, eventually leads to elevated expression of proinflammatory cytokines. Our report is the first to show that inflammation in PTSD is a result of altered epigenetic mechanism involving LINC00926 and WNT10B.
Alternative Macrophage Programming After Clot Phagocytosis
Authors: Schenkel Alan , Aragon Jordon , Mills Cole , Glennon Moriah , Garcia Niko , LaFleur Caitie , Horn Kadi
Published: January 2023

Repair program(s) in "alternatively activated" macrophages can help with short-term wound responses after sterile damage events. Clot resolution by fibrinolysis and phagocytosis by tissue macrophages can activate anti-inflammatory and pro-fibrotic signals like Transforming Growth Factor- β. It has been hypothesized by the late Andrew Tager and Rachel Chambers that some forms of human pulmonary fibrosis may involve chronic alveolar damage, leakage of blood components, clots, and subsequent pro-fibrotic events that then fail to remodel back to normal alveolar structure. We found evidence of chronic bleeds and hemosiderin-positive macrophages in the lungs of Platelet Endothelial Cell Adhesion Molecule-1 deficient mice that developed a progressive and fatal pulmonary fibrosis. We are testing this hypothesis in vitro using murine broncho-alveolar macrophages exposed to aged clots. Interestingly, fresh blood and clots were not efficiently phagocytosed by the murine myeloid leukemia cell line RAW264 nor by broncho-alveolar macrophages. Clots needed to be aged for two days first. Ingestion also causes the macrophages to become fluorescent, which is a useful way to assess phagocytosis. We are now developing mRNA sequencing protocols to assess the gene programs of macrophages over time.
Alpha2B-adrenergic receptor regulates neutrophil recruitment in MSU-induced peritoneal inflammation
Authors: WEI YINGYING , Duan Lihua , Chen Jie , Rao Xiaoquan , Tao Ying , Zhong Jixin
Published: January 2023

Gout is one of the most common metabolic disorders in human and its disease activity has been associated with sympathetic nervous system. α2B-adrenergic receptor (α2BAR), a subtype of α2 adrenergic receptor, have a critical role in many diseases. However, the role of α2BAR in the pathogenesis of gout remains unclear. Here, we assessed the effects and mechanisms of α2BAR on the MSU-induced peritonitis that mimics human gout by using the α2BAR-overexpressing mice (α2BAR-Tg). We found that the number of recruited neutrophils was significantly increased in the α2BAR-Tg mice after MSU treatment, when compared with wild type mice. In contrast, the number of macrophages was not changed. Importantly, there is no difference in the IL-1β levels and caspase-1 activity between wild type and α2BAR-Tg mice in the gout animal model. Notably, the enhanced neutrophil migration in α2BAR-Tg mice was dependent on the expression of α2BAR on neutrophils, but not the expression in other tissues or cells. In vitro experiments confirmed the promotive effect of α2BAR on neutrophil migration. In conclusion, our data provide direct evidence that α2BAR plays a critical role in neutrophil migration and MSU-induced inflammation. Thus, α2BAR might serve as a promising therapeutic target for gout.
22q11.2 Deletion Syndrome (DiGeorge) and Mutations in Forkhead Box N1 (FOXN1) cause a Thymic Hypoplasia through distinct Developmental Processes
Authors: van Oers Nicolai S , Du Qiumei , Huynh Larry , Coskun Fatma , Dozmorov Igor , Raj Prithvi , Khan Shaheen , Wysocki Christian , Markert Mary Louise , de la Morena Maria Teresa
Published: January 2023

Patients with 22q11.2 deletion syndrome and those with mutations in the Forkhead Box N1(FOXN1) transcription factor (Nude/SCID) can both present with a thymic hypoplasia that results in a severe T cell lymphopenia. In both clinical conditions, the thymic anlage fails to develop properly within the 3rdpharyngeal pouch during embryogenesis. We characterized the development of the thymus in mouse models of 22q11.2 deletion syndrome (22q11.2del) and a new set of mice with mutations in Foxn1that genocopied a SCID patient with novel compound heterozygous mutations in FOXN1. Both sets of mice develop hypoplastic thymic lobes. An analysis of thymopoiesis in embryos revealed distinct development problems. The hypoplastic thymii from the 22q11.2del mice were primarily sized restricted, with normal percentages of all thymocyte subsets apparent. This contrasted a severe deficiency of thymocytes due to the Foxn1mutations, which primarily affected the development and expansion of thymic epithelial cells. Comparative gene expression analyses of e13.5 fetal thymii revealed differentially regulated transcripts that define the basis of the hypoplasia. A dysregulated mesenchymal cell signature was apparent in the 22q11.2del model, which contrasted the epithelial transcript disruption due to the Foxn1mutations. These results suggest different strategies are necessary to correct the thymic tissue abnormalities in patients who present with thymic hypoplasias due to their congenital disorders.
Small intestinal lamina propria immune cells dyshomeostasis is associated with alcoholic steatohepatitis in the mouse
Authors: Hao Liuyi , Zhong Wei , Sun Xinguo , Zhou Zhanxiang
Published: January 2023

The intestine represents the largest compartment of the immune system. Small intestinal lamina propria (SILP) immune processes are increasingly implicated in controlling disease development in the body. We have shown that reduction of tight junction proteins, system dysbiosis, and endotoxins translocation to the liver accounts for alcohol-induced steatohepatitis. However, the underlying mechanisms are still unclear. The present study investigated the effects of SILP antigen presenting cells dyshomeostasis on the pathogenesis of alcoholic steatohepatitis. Alcohol-induced liver inflammation was analyzed by inflammatory immune cells infiltration and proinflammatory cytokine gene expression. Chronic alcohol exposure (8 weeks) not only cause enteric dysbiosis but also increased plasma endotoxins (LPS) levels. The frequency of CD64-CD45+MHCII+CD11chi dendritic cells and CD64+F4/80+CD11b+ macrophage were both increased in SILP after chronic alcohol exposure. Further analysis demonstrated that alcohol exposure differently regulates CD103+ and CD103- dendritic cells subsets ratio. Intestinal IL-12p70 was significantly decreased after alcohol exposure. alcohol feeding also increased th2 cells but decreased th1 cells in SILP. The present study demonstrated that small intestinal immune cells activation may account for alcohol-induced dysbiosis, and thereby being a pathophysiological factor in the development of alcoholic steatohepatitis.
Identification of Peripheral Immune Mechanisms playing a protective role in Alzheimer's Disease progression
Authors: Agrawal Anshu , Baulch Janet , Acharya Munjal , Agrawal Sudhanshu
Published: January 2023

Alzheimer’s disease (AD) has become the most common form of dementia in the elderly. Recent studies have highlighted the role of inflammation and the immune system in the etiology of AD. However, there is a key gap in knowledge regarding the immune processes in healthy aged individuals as compared to AD patients. We have recently demonstrated that healthy aged subjects display a weak immune/inflammatory response to Amyloid beta–Aβ peptide (1–42) characterized by high IgM antibody responses. In contrast, MCI or AD patients exhibit high levels of IgG antibody against Aβ indicative of a strong immune response. IL-21, an inflammatory cytokine that enhances the differentiation of B cells and facilitates the class switching of IgM to IgG antibodies, is also upregulated in the plasma of AD patients compared to healthy aged controls. In support of these human data, our pre-clinical in vivo experiments using the 5xFAD mouse model of AD also display increased immune activation as compared to age-matched control mice. Similar to humans, we observed a decreased IgM and increased IgG response against Aβ. Furthermore the increased IgM antibody response correlated negatively with cognitive dysfunction. In addition, we also observed an increase in the proportions of T follicular helper (Tfh) cells which secrete IL-21, and enhance the B cell class switch to IgG antibodies in AD mice. In summary, our data indicate that weak immune/inflammatory response against Aβ is protective and facilitates the clearance of Aβ without inducing damaging levels of inflammation. In contrast, strong immune/inflammatory response against Aβ such as those observed in MCI and AD subjects and mice enhance inflammation and aid AD progression.
IL-35+ regulatory immune cells in diabetic nephropathy
Authors: Singh Kailash , Luo Zhenkan , Carlsson Per-Ola , Hansell Peter , Sandler Stellan
Published: January 2023

Diabetes causes an elevation of the blood glucose level and a long-term hyperglycemia contributes to kidney damage, i.e. diabetic nephropathy (DN). DN exhibits signs of inflammation and infiltration of mononuclear cells in kidney. Regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic antigen presenting cells (tolAPCs) maintain the homestasis of the immune system, specifically by producing anti-inflammatory cytokine IL-35. Despite intensive research the role of Tregs, Bregs and tol APCs and IL-35 is not yet clear. Herein, we investigated the role of these immune cells in mice and patients.

The circulating concentration of IL-35 was lower in T1D patients with DN and without DN than healthy controls. Proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower but IL-17+Tregs were higher in patients with DN compared to healthy controls, suggesting a phenotypic shift of Tregs. The proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower in kidneys of diabetic mice. Furthermore, IFN-gamma+ Tregs were higher in kidneys of diabetic mice, indicating a phenotypic shift of Treg cells.

After the administration of IL-35 in diabetic mice the mice became normoglycemic and had a lowered albumin creatinine ratio compared to control mice. The IL-IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were increased in IL-35 treated mice. IFN-gamma+Tregs were decreased and the number of Foxp3+ cells was decreased, and mononuclear cells infiltration was also decreased in kidneys of IL-35 treated mice.

Our data suggest that IL-35+ regulatory immune cells are impaired in DN and systemic administration of IL-35 prevents the development of DN in mouse models of DN.
Genetic Immune Pathologies Are Common in Azerbaijan
Authors: Fazal Nadeem , Ibrahimova Shalala , Mammadova Vafa , Aliyeva Gunay , Nasrullayeva Gulnara
Published: January 2023

Genetic immune pathologies are common in Azerbaijan. Primary immune deficiencies (PID) include more than 300 rare congenital diseases. There are more than 250 genes known to be involved in different immune disorders, especially in PID. Around 30% of patients are not diagnosed on time despite having clinical and laboratory evidences. Primary immunodeficiency disorders may be caused by mutations in one or several specific genes. The exact diagnosis of PID patients requires genetic analysis. The diagnosis is not always made timely because genetic tests are not carried out in many countries like Azerbaijan and are quite expensive. We present data of clinical and genetic analyses PIDs in Azerbaijan. During 2010–2019 we studied 111 PID patients. Genetic results obtained from 18 of these patients revealed that the mutations were located mainly in 7 groups of genes. These genetic mutations had clinical manifestations in the form of PID variants, i.e., WAS syndrome, X link agammaglobulinemia, HIGM syndrome, and Ataxia-Telangiectasia. AT patients were analyzed through linkage analysis with D11S384, D11S2179 and D11S1294 genetic markers. Immune analyses included; phenotyping of leucocyte subset in peripheral blood, serum IgM, IgG, IgA, IgE levels, phagocytic activity of neutrophils by NBT. Additional tests such as X-ray, computer tomography and ultrasound investigations were used. Genotyping of mutations was performed through sequence-based methods. In PID patients mutations in the following genes were identified; CCCG>C deletion on TBX1 gene, c.12_13insGG hemizygous mutation on exon 1 of WAS gene, Gln234stop mutation and T>A SNP on 100614289 location of BTKgene, c.6010C>T and c.6671G>A mutations on LRBAgene, c.135T>A on CD40LGgene.
Glucocorticoid induced leucine zipper is inversely related with neuroinflammation in the brain
Authors: Lynch Nicholas McChesney , Wong Junmei , Srinivasan Mythily
Published: January 2023

Glucocorticoids (GC) are steroid hormones secreted as the end-product of the neuroendocrine stress cascade. Absence or elevated GC mediate neurotoxic responses, suggesting that a narrow window ranging from physiological to slightly high GC mediate protective responses. The beneficial effects are attributed to the transactivation of regulatory proteins and inhibition mediated by glucocorticoid receptor interactions with other cofactors. Elevated GC accelerate beta amyloid (Aβ ) plaque formation and tau phosphorylation, aggregates of which upregulate reactive oxygen species in vulnerable neurons. The oxidative stress negatively regulates glucocorticoid receptor, preventing suppression of the transcriptional factor, nuclear factor-κ B (NF-κ B) by GC. The ensuing inflammatory distress enhance further Aβ accumulation initiating a vicious cycle. The glucocorticoid induced leucine zipper (GILZ) is a gene strongly upregulated by GC and mediates many of the anti-inflammatory and anti-proliferative effects of GC. Mechanistically GILZ inhibits NF-κ B by binding the p65 subunit of NF-κ B in the cytoplasm and thereby prevent transactivation of inflammatory and apoptosis mediators. Although GILZ is constitutively expressed in many tissues including the brain, the expression has been shown to occur with varying dynamics suggesting that the local milieu modulates its expression with consequent effects on cellular responses. Here we investigated the expression profile of GILZ in lipopolysaccharide mediated neuroinflammation model of Alzheimer’s disease. Our data suggest that the GILZ expression is downregulated in neuroinflammation correlating inversely with the pro-inflammatory cytokines and innate immune responses.
Adaptive immune cell activation in acute pediatric traumatic brain injury
Authors: Ortega Sterling B , Torres Vaneesa O , Tian Fenghua , Poinsatte Katie , Tweed Jefferson , Greenwell Cynthia , Windsor Jana , Raman Lakshmi , Miles Darryl , Stowe Ann
Published: January 2023

Traumatic brain injury (TBI) is mediated by mechanical injury to the brain resulting in tissue shearing, and characterized by neuronal injury and inflammation. We hypothesize that TBI activates brain-targeting immune responses which can induce secondary neuronal injury. Blood and cerebral spinal fluid (external ventricular drain, EVD) were collected from pediatric TBI patients (pTBI, 1–18 yrs.) at days 1, 3 and 5 following TBI and EVD placement. The blood from sick controls (0–18 yrs, no CNS injury) were collected at day 1 post injury. pTBI patients exhibited a higher quantity of leukocytes (CD45+) relative to controls (p=0.01) on day 1 post-TBI, indicating an immediate and robust immune modulation due to CNS injury, that decreased at days 3 and 5, relative to day 1. Major subsets of adaptive immune cells (CD3, CD4, CD8, and CD19) did not exhibit altered cellularity relative to controls but activated adaptive T cells (CD4+CD161+and CD8+CD161+) were substantially higher at day 1 versus controls. Neuronal autoreactivity was evaluated by labeling peripheral blood mononuclear cells with carboxyfluorescein succinimidyl ester (CFSE) and culturing with neuronal and control antigens. Response to antigen was determined by dilution of CFSE (proliferation) and expression of CD25 (activation). Autoreactivity analysis of pTBI patients revealed a decrease in the CD4 T-cell responses to CNS antigens relative to sick control patients. Interestingly, the CD8 T-cell analysis revealed CNS-specific autoimmune responses absent in pTBI patients which were present in sick controls. Based on these initial observations, we hypothesize that the adaptive immune system is activated upon TBI and can potentially target CNS resident cells in young patients.
Coronary artery bypass grafting surgery is associated with immunoparalysis of monocytes and dendritic cells
Authors: Perros Alexis J , Esguerra-Lallen Arlanna , Rooks Kelly , Chong Fenny N , Engkilde-Pedersen Sanne , Faddy Helen M , Hewlett Elise , Naidoo Rishendran , Tung John-Paul , Fraser John F , Tesar Peter , Ziegenfuss Marc , Smith Susan , O'Brien Donalee , Flower Robert L , Dean Melinda M
Published: January 2023

Background

Exposure of patient blood to the bypass circuitry and re-perfusion of the heart at the end of coronary artery bypass grafting (CABG) is associated with activation of leucocytes, the complement cascade and cytokine secretion. Dendritic cells (DC) and monocytes are immunoregulatory cells that may be impacted by CABG contributing to an altered immune status. This study investigated changes in the DC and monocyte immune profile in CABG patients at 5 time-points: admission, peri-operative, ICU, day 3 (D3) and day 5 (D5).

Methods

At each time point, freshly collected whole blood from 50 CABG patients was used in an ex-vivo whole blood culture model. Lipopolysaccharide (LPS) was added in parallel to model an infectious complication. Expression of DC and monocyte co-stimulatory and adhesion molecules and production of intracellular inflammatory mediators was measured via flow cytometry.

Results

CABG resulted in significant perturbation of monocyte and DC responses. DC and monocytes were immunoparalysed as evidenced by failure to respond to LPS stimulation. Modulation of DC and monocyte costimulatory and adhesion molecule expression and inflammatory mediator production was associated with prolonged length of stay in intensive care and post-operative atrial fibrillation. While DC and monocyte expression of co-stimulatory and adhesion molecules recovered towards baseline by D5 post-surgery, their capacity to produce inflammatory mediators did not.

Conclusions

DC and monocyte responses were significantly impaired following CABG. Use of an ex-vivo model to assess immune competency of cardiac surgery patients may provide a tool for the early prediction of adverse outcomes.
Relationship between autoimmunity and lifestyle
Authors: Kimura Koki
Published: January 2023

Introduction

Health promotion is important to prevent functional deterioration of our advanced immune system. The purpose of the present study was to examine the factors associated with the number of times an individual contracts cold and number of days it takes to recover.

Methods

The subjects were 38 healthy females. We used a questionnaire format to survey the dietary patterns and activity levels of the subjects. The dietary patterns were assessed by examining the average meal content consumed per week over the last 1–2 months and meal consumption, including nutritional content and other factors. The activity levels represented the average duration of physical activity per day and exercise duration per week (4 intensity levels: 3≤ metabolic equivalents (METs) <4, 4≤ METs <6, 6≤ METs <8, 8 ≤ METs ≤15).

Results

The mean number of times an individual contracts cold annually was 2.0 ± 1.3 times and number of days it takes to recover was 3.2 ± 1.3 days. The results of the examination of factors associated with the number of times an individual contracts cold annually revealed a significant difference for BMI (r=0.333, P<0.05). In addition, a significant correlation was observed between the number of days it takes to recover from the cold and cholesterol intake (r=0.393, P<0.05). The coping mechanisms used when contracting cold were as follows: going to the hospital (32%); taking over-the-counter medicine (42%); waiting for natural recovery (26%).

Conclusions

This study showed that there was a significant correlation between number of times an individual contracts cold and BMI. In addition, a significant correlation was observed between the number of days it takes to recover from the cold and cholesterol intake.
Differential activation of an innate immune signaling pathway in lymphocytes from patients with multiple sclerosis
Authors: Carrithers Michael D
Published: January 2023

Prior work demonstrated that epithelial V-like antigen (EVA), a cell surface adhesion molecule, is expressed in lymphocytes and is necessary for the efficacy of anti-alpha4integrin treatment of experimental autoimmune encephalomyelitis (EAE), a mouse model of human multiple sclerosis (MS). EVA deficiency is associated with a severe clinical phenotype of EAE in the presence or absence of treatment. Recent work demonstrates that EVA, which is encoded by the mpzl2 gene, also regulates expression of the anti-viral oligoadenylate synthase genes, Oas1 and Oas2. Here the EVA signaling pathway was assessed in patients with MS and healthy controls from the UIC Neuroimmunology Biobank. The goal of this initiative is to assess individual variation in innate immune responses that are associated with severe phenotypes of multiple sclerosis (MS) in underrepresented racial and ethnic minority groups. In response to treatment with the Tlr7/8 agonist R848, peripheral blood lymphocytes from MS patients demonstrated an increase in mpzl2 expression that was not observed in healthy controls. In addition, racial and ethnic differences were observed in the expression of Oas1and Oas2 genes. It is hypothesized that differential innate immune activation of these transcriptional pathways are novel biomarkers and modifiers of disease severity in MS.

This work was funded by the Evelyn Garcia Research Fund at the University of Illinois College of Medicine, Chicago.
Sexual dimorphism in the physiological response of the Apoe
−/− atherosclerosis model to sleep fragmentation
Authors: Moriarty Alina K , Waseem Tayab , Keeter William Coles , Edemobi Stefan , Pham Michael , Sanford Larry , Wellman Laurie , Galkina Elena
Published: January 2023

Sleep fragmentation (SF) is tightly correlated with the development of chronic low grade inflammatory diseases such as, type 2 diabetes and atherosclerosis; however, the exact relationship between SF and atherogenesis is unknown. Little evidence exists regarding the origin of sex differences in sleep behavior. While the role of gender has been studied in atherosclerosis, the impact of gender in SF-associated atherogenesis is not known. Recently, we have shown that high fat diet (HFD) fed male Apolipoprotein E-deficient (Apoe−/−)mice on SF unexpectedly experienced premature death, with 80% of males not surviving past week 2 of SF, while 80% of females survived past week 8 under the same conditions. To investigate the gender effects, male and female Apoe−/− mice were fed a HFD and SF for 10 days. Following HFD and SF, male mice, but not female Apoe−/− mice had enlarged hearts and lymph nodes, as well as peritoneal bleeding. Further, SF resulted in a significantly higher amount of circulating LPS and alterations in the immune composition of bone marrow (BM), blood, and lymph nodes (LN) in male HFD fed Apoe−/− mice vs SF female Apoe−/− mice. We detected a significant decrease in myeloid cells in the BM and blood, as well as a decrease in the percentage of T and B cells in the LN of HFD fed-SF males’ vs diet matched SF females. Interestingly, when male Apoe−/− mice were administered 17b-estradiol orally, in supplement with HFD feeding and SF, they survived past the 14 day death window. Altogether, SF alters the immune response in male atherosclerotic Apoe−/− mice resulting in early death. Our data suggests that the hormonal landscape in female Apoe−/− mice protects against SF-induced premature death via estrogen-dependent mechanisms.
Cell bound complement activation products alone and in combination with low serum complement C3 or C4 have superior diagnostic performance in systemic lupus erythematosus
Authors: Weinstein Arthur , Wallace Daniel J , Putterman Chaim , Arriens Cristina , Askanase Anca , Kalunian Kenneth C , Collins Christopher E , Saxena Amit , Massarotti Elena M , Alexander Roberta Vezza , Ibarra Claudia , Chatham Winn , Ramsey-Goldman Rosalind , Narain Sonali , Chandra Tarun , Ahearn Joseph , Manzi Susan , Dervieux Thierry
Published: January 2023

BACKGROUND

Cell-bound complement activation products (CB-CAPs) are sensitive and specific diagnostic markers of systemic lupus erythematosus (SLE). We compared the performance of CB-CAPs to low serum complement C3 or C4 in distinguishing SLE from other rheumatic diseases and healthy individuals.

METHODS

Adult subjects (n=1200) were enrolled from multiple academic centers, including SLE (498), healthy individuals (252) and subjects with other rheumatic diseases (450). Erythrocyte bound C4d [EC4d] and B-Lymphocyte bound C4d [BC4d] were quantitated using flow cytometry. Serum C3 and C4 levels were determined using immunoturbidimetry. Measurements included sensitivity, specificity, area under the curve (AUC) of the receiver operating characteristic curve (ROC) and Youden Index, for each marker as well as combinations.

RESULTS

Abnormal CB-CAPs status yielded 62% sensitivity with 88% specificity in distinguishing SLE from the group with other diseases compared to low C3/C4 status − 38% sensitivity, 93% specificity. Youden index was 0.492±0.03 for CB-CAPs compared to 0.313±0.03 for low C3/C4 (p<0.01). AUC was higher with BC4d (0.72) than with EC4d (0.68; p<0.01), low C3 (0.62; p<0.01), low C4 (0.62; p<0.01) and low C3 and/or C4 levels (0.66; p<0.01).

The cumulative complement scoring system yielded higher AUC (0.81). A score with greater than 1 complement abnormality yielded 45% sensitivity and 98% specificity.

CONCLUSION

Our data suggests that CB-CAPs have greater diagnostic performance than low serum complement C3/C4. The combination of these complement abnormalities in a composite complement score is superior in distinguishing SLE from other rheumatic diseases and healthy individuals.
Chronic inflammation associated with obesity exacerbates bone loss in mice
Authors: Fields Travis , Ramanan Meera , Rayalam Srujana , Shashidharamurthy Rangaiah
Published: January 2023

Dysfunctional adipose tissue characterized by abnormal inflammatory cytokine production during obesity, is linked to several metabolic disorders including bone loss. An increase in bone fracture incidence due to increased rates of obesity is becoming a significant new health concern. However, it is still obscure whether obesity accelerates bone loss. Herein, we have investigated the systemic weight gain, cytokine production, bone turnover markers and femur bone micro-architecture in high-fat diet (HFD) fed obese mice. HFD mice exhibited excessive visceral fat accumulation (2.4 fold) in the peritoneal cavity and increased body weight (2.1 fold) compared to regular chow diet (RCD) fed mice. The serum levels of pro-inflammatory cytokine IL-6 was increased approximately 8-fold in HFD mice compared to RCD mice. The serum bone turnover marker, C-terminal telopeptides of collagen (CTx), was almost 2-fold higher in HFD mice compared to RCD mice. Further, radiological studies from micro computed tomography (micro-CT) of femur suggests that HFD mice exhibited considerably reduced bone volume fraction (BV/TV) and cortical thickness compared to RCD mice. These results suggest the chronic inflammation associated with many metabolic disorders such as obesity may accelerate bone loss.
CD40 function in immune development and response: Cell type requirements and cytoplasmic domain function
Authors: Lu Ying , Chiang Jeffrey , Zhang Ray , Alkhaleel Farrah , Hodes Richard J
Published: January 2023

CD40 is a TNFR family member and serves as a costimulatory molecule expressed on multiple antigen presenting cell (APC) lineages. The functional significance of CD40 expression is illustrated by human disease and mouse models of life-threatening immune deficiency. CD40-CD40L deficiency affects multiple aspects of immune development and response. However, cell type-specific requirements for CD40 and requirements for CD40 signaling domains have not been comprehensively analyzed. In this study, we use conditional CD40 knockout mice to study cell type requirements and generated CD40 intracellular domain mutants by CRISPR to determine domain-specific functions. CD40 expression on B cells but not DC is required for CD40 dependent superantigen-specific negative selection and for T-cell dependent class-switched antibody responses. TRAF2/3 binding domains of CD40 are critical for these CD40 functions, while deletion of putative TRAF6 binding domain had minimal effect. In contrast, in vivo priming of cytokine-producing T cells depends on CD40 expression on DC but not B cells and requires both TRAF2/3 and TRAF6 domains. CD40 expression on both B cells and DC is required for maximal autoimmune EAE disease induced by recombinant human MOG (rhMOG), and both TRAF2/3 and TRAF6 domains of CD40 are required for this autoimmune response. Initial results indicate that CD40 on thymic epithelial cells and DC contributes to negative selection of tissue restricted antigen-binding T cells. These results identify different CD40-dependent APC requirements and suggest distinct CD40 signaling pathways for specific immune responses. Analysis of the linkage between cell type-specific CD40 function and intracellular signaling is under study.
Brain-Thymus communication is a novel immunosuppressive feature of neurological insults
Authors: Ayasoufi Katayoun , Pfaller Christian K , Khadka Roman H , Jin Fang , Johnson Aaron J.
Published: January 2023

Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma mutiforme (GBM) causes mortality and leads to failure of therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus; a primary immune organ. Specifically, we evaluated the effects on the thymus following physical injury with intracranial PBS injection, intracranial (ic) Theiler’s Murine Encephalomyelitis Virus infection, intracranial injection with lipopolysaccharide, CNS tumors (B16 melanoma and GL261 glioma ic), and seizure induction with intraperitoneal Kainic acid injection. These insults resulted in significant thymic involution that is reversible upon clearance of the neurological insult. The extent of thymic involution correlated with the extent of brain injury. Further analysis of the brain-thymus axis in mice with GL261 gliomas was conducted using RNA-Seq. Principle component analysis of RNA-Seq data revealed unbiased separation of thymi of naïve and glioma harboring mice, suggesting that thymus is directly affected by brain injury. To determine the extent to which thymic involution was caused by a soluble factor, we employed parabiosis. This approach demonstrated a soluble factor is responsible for thymic involution. These findings are the first demonstration that neurological insults ubiquitously contribute to immune suppression. We also provide evidence that thymic involution is mediated by a soluble factor, the identification of which could be critical for ameliorating the effect of neurological injuries on immune suppression.
A role for group 2 innate lymphoid cells in muscular dystrophy
Authors: Kastenschmidt Jenna
Published: January 2023

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder characterized by progressive myofiber degeneration and chronic inflammation. Asynchronous and continuous bouts of injury dysregulate the immune response to injured myofibers, exacerbating muscle degeneration and impairing regeneration. In contrast, activation of type 2 immunity during acute injury is required for efficient muscle regeneration. Evidence in the literature suggests a similar type 2 immune response is activated in dystrophic muscle, but is dysregulated by competing degenerative inflammatory responses. However, the regulation of type 2 immunity in dystrophic muscle is largely unknown. A recently identified subset of immune cells, group 2 innate lymphoid cells (ILC2), were shown to potently regulate type 2 immunity and promote tissue repair. In this study, we found that muscle ILC2s were increased in number and expressed higher levels of interleukin-5 (IL-5) in mdx mice compared to wildtype controls, indicating that muscle degeneration activates ILC2s. In vivo expansion of ILC2s using IL-2/anti-IL-2 complex (IL-2c) and IL-33 enhanced type 2 cytokine expression in mdx skeletal muscle and increased the cross-sectional area of regenerating myofibers, suggesting that ILC2s enhance muscle regeneration through the upregulation of type 2 cytokines. In addition, loss-and gain-of-function experiments demonstrated that ILC2s promote the skeletal muscle recruitment of eosinophils, an innate immune cell population previously shown to promote muscle regeneration. Collectively our data support a working model in which ILC2s promote skeletal muscle regeneration by enhancing type 2 immunity (i.e. eosinophilia and increased type 2 cytokines).
AhR ligands differentially affect thymus and peripheral lymphoid organs by targeting T cells and their functions leading to pro- or anti-inflammatory responses
Authors: Singh Narendra Prasad , Miranda Kathryn , Jackson Dominique , Sumpter Steilan , Singh Udai P , Nagarkatti Mitzi , Nagarkatti Prakash
Published: January 2023

TCDD, FICZ, and Resveratrol (RES) are potent ligands of aryl hydrocarbon receptor (AhR). TCDD is well known to cause thymic atrophy but the effects of FICZ and RES have not been studied to date. In the current study, we investigated the effect of AhR ligands in vivo. We chose these AhR ligands for their different origin-TCDD, an environmental contaminant, FICZ, endogenously generated, and RES, found in plant products. To this end, C57BL/6 mice were treated with vehicle (corn oil) or TCDD (10 μg/kg bw) or FICZ (10 μg/kg bw) or RES (100 mg/kg bw) by oral gavage. Three days post treatment, thymi and spleens were harvested and stained with fluorochrome-labelled Abs against various T cell surface markers and analyzed by flow cytometry. We observed significant effect of TCDD on decreasing thymic weight and thymic cellularity, when compared to vehicle. FICZ, on the other hand, had no significant effect on thymus. RES, however, significantly caused increase in thymic weight as well as thymic cellularity. Upon analysis of various T cell populations in the thymus, TCDD caused significant downregulation of almost all the markers (CD3, CD4, CD8, CD25, CD44, and αβTCR) whereas, FICZ and RES had moderate effects on thymic T cell subpopulations. Upon analysis of spleen, all the three AhR ligands had mixed effects. We observed significant effect of TCDD and RES in generation of Tregs, when compared to vehicle. FICZ, on the other hand, suppressed Tregs but significantly increased Th17 cells. Together, our studies suggest that although TCDD, FICZ, and RES are AhR ligands, they had different effects on both thymus and spleen. TCDD and RES had role in inducing immune suppression by generating more Tregs, whereas, FICZ had a role in inflammation by generating more Th17 cells.
Roles of Toll-like Receptors in Regulating Fibroblastic Reticular Cells Pathobiology during Sepsis
Authors: Deng Meihong , Li Yiming , Chen Tianmeng , Chen Kong , Billiar Timothy R
Published: January 2023

Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in peritoneal fat, play immune-regulatory roles in the host defense. However, the mechanisms underlying the regulation of FRC pathobiology, especially in response to Toll-like receptor (TLR) signaling is unclear. Therefore, we aimed to understand the roles of TLR signaling in FRC pathobiology during sepsis. FALC cells were isolated from mesenteric adipose tissue in wild-type mice before and after cecal ligation and puncture (CLP). The transcriptomic profile of FALC cells were assessed using single cell RNA sequencing. Notably, FRCs were a major population of FALC cells (50 +/− 10.2 % in control, 30 +/− 8.6% in CLP). One population of FRCs were identified in control mice, and two populations of FRCs were identified in CLP mice. According to gene set enrichment analysis, FRCs after CLP are enriched in gene expression associated with inflammatory response and chemotaxis. Interestingly, activation of TLR4 (LPS) and TLR3 (Poly I:C) signaling in mesenteric adipose tissue derived FRCs significantly increased the expression of chemokines known to attract neutrophils (Cxcl2 and Cxcl5), monocytes (Cxcl3), and lymphocytes (Cxcl13 and Ccl20), while activation of TLR9 (ODN1518) significantly decreased these chemokine gene expressions. Importantly, we found similar regulatory effects of TLR3, 4, and 9 on chemokine production in human adipose tissue-derived FRCs. Together, our results indicate that TLRs plays critical roles in regulating chemokine production by FRCs. These data form a knowledge basis upon which to design new therapeutic strategies of FRC-based treatments for sepsis.
Astragaloside IV, the major bioactive component of Astragalus membranaceus (Fisch.) Radix, attenuates airway inflammation by modulating Th2 cytokines, STAT6 and ROR-γτ transcription factors in an asthmatic mouse model
Authors: Shen Chao-Bin , Gu Yan-Ni , Wang Song , Yu Lan
Published: January 2023

OBJECTIVE

Astragaloside IV (AS-IV), the major bioactive component of Astragalus membranaceus (Fisch.) Radix, possesses anti-inflammatory, regular immunological balance and other pharmacological properties. Although Astragalus is associated with immunoregulatory functions of allergic diseases, the pathophysiological mechanisms of AS-IV action in allergic inflammatory lung disease have not been examined. This study aims to explore the mechanisms of how AS-IV suppresses airway inflammation in bronchial asthma by inhibiting the inflammatory cytokines and transcription factors pathway.

METHODS

A total of 40 BALB/c male mice were selected and divided into control, asthma, AS-IV and dexamethasone groups. Ovalbumin-induced mouse asthma model was established. HE staining were conducted to observe the pulmonary pathological changes. ELISA was adopted for the levels of IFN-γ, IL-5, IL-13, IL-17A and TGF-β, qRT-PCR for the transcription factors mRNA expressions of GATA-3, STAT6, T-bet, RORγt, and Foxp3.

RESULTS

Compared with the control group, the asthma group had irregular tissue structure and severe inflammation, increases in maximal pulmonary resistance. AS-IV strongly suppressed levels of Th2 cytokines IL-5 and IL-13 in lung homogenate, but it upregulated T-bet and Foxp-3 mRNA expression in lungs. AS-IV exerted immunomodulatory effects through downregulation of STAT6, RORγt and GATA-3 expression.

CONCLUSION

These results suggest that the anti-asthmatic activity of AS-IV may occur by the suppression of IL-5, and IL-13 production through inhibition of the STAT6 and RORγt signaling pathways. Our results suggest that AS-IV can be a novel therapeutic component for the treatment of allergic asthma.