Tumor Necrosis Factor receptor-II Research Articles

Sex-Specific Pathways From Prenatal Maternal Inflammation to Adolescent Depressive Symptoms

Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the association between prenatal inflammation and offspring depression in adolescence has yet to be examined. To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations. This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023. Levels of inflammatory biomarkers (interleukin 6 [IL-6], IL-8, IL-1 receptor antagonist [IL-1RA], and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy. Self-reported depressive symptoms at adolescent follow-up. A total of 674 mothers (mean [SD] age, 28.1 [5.9] years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75). In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.

Study protocol on effectiveness of yoga practice on composite biomarker age predictors (yBioAge) in an elderly Indian cohort- two-armed open label randomized controlled trial

IntroductionThe recent development of robust indices to quantify biological aging, along with the dynamic epidemiological transitions of population aging generate the unmet need to examine the extent up to which potential interventions can delay, halt or temporarily modulate aging trajectories.Methods and analysisThe study is a two-armed, open label randomised controlled trial. We aim to recruit 166 subjects, aged 60–75 years from the residential communities and old age clubs in Bangalore city, India, who will undergo randomisation into intervention or control arms (1:1). Intervention will include yoga sessions tailored for the older adults, 1 h per day for 5 days a week, spread for 12 months. Data would be collected at the baseline, 26th week and 52nd week. The primary outcome of the study is estimation in biological age with yoga practice. The secondary outcomes will include cardinal mechanistic indicators of aging- telomere length, interleukin-6 (IL-6), tumor necrosis factor receptor II (TNF-RII), high sensitivity c-reactive protein (hsCRP)], insulin signaling [insulin and IGF1], renal function [cystatin], senescence [growth differentiating factor 15 (GDF-15)] and cardiovascular function [N-terminal B-type natriuretic peptides (NT-proBNP)]. Analyses will be by intention-to-treat model.Ethics & disseminationThe study is approved by the Institutional Ethics Committee of Swami Vivekananda Yoga Anusandhana Samsthana University, Bangalore (ID:RES/IEC-SVYASA/242/2022). Written informed consent will be obtained from each participant prior to inclusion.Trial registration numberCTRI/2022/07/044442.

Abstract 18418: Osteoprotegerin Mediates T-Cell Response in Myocardial Wound Healing Post-Ischemic Injury

Introduction: Myocardial Infarction (MI) triggers an inflammatory response associated with cardiac wound healing. T-regulatory cells (Tregs) play a crucial role in the MI heart during this inflammatory response via their regulation of cardiac repair and function. Stimulating and sustaining the pro-reparative T cell response after MI would aid in preserving cardiac structure and function. Cortical Bone derived Stem Cells (CBSCs) possess a diverse array of inflammatory signaling molecules that can influence the inflammatory microenvironment of the heart after MI. A paracrine factor, Osteoprotegerin (OPG), is abundantly present in CBSCs, but it is unknown if OPG can mediate Tregs in myocardial injury. Hypothesis: CBSCs-derived Osteoprotegerin can regulate cardiac wound healing post-MI by modulating T cell response. Methods and Results: T cells exposed to CBSC secretome underwent an upregulation of a Treg population (p≤0.0001) characterized by the expression of Tumor Necrosis Factor Receptor II (TNFRII). Further investigation into the CBSC secretome highlighted OPG as a potent signaling molecule responsible for inducing TNFRII+ Tregs (p≤0.0001) measured by FACS analysis. siRNA-mediated depletion of OPG studies showed compromised TNFRII+ Treg induction (p≤0.0001). In vivo studies, adult FoxP3-GFP (12-16 week) mice underwent left anterior descending artery ligation followed by intramyocardial injection of CBSCs, Mesenchymal Stem Cells (MSCs), or vehicle (saline) along the infarct border zone. Resident T-lymphocyte populations were assessed at 1- and 8-weeks post-MI via flow cytometry. CBSC-treated hearts yielded a greater prevalence of TNFRII+ Tregs at 1- and 8-weeks following MI compared to MSCs (p≤0.01; p≤0.0001) and vehicle (p≤0.0001; p≤0.05). CBSC induction following MI reduced infarct size compared to the vehicle (p≤0.05). Ablation of the Treg population in the ischemic zone following MI increased infarct size and solicited adverse cardiac remodeling (p≤0.05). Conclusion: Osteoprotegerin can promote cardiac wound healing by facilitating the expansion and preservation of pro-reparative TNFRII+ Tregs.

Triptolide attenuates inhibition of ankylosing spondylitis-derived mesenchymal stem cells on the osteoclastogenesis through modulating exosomal transfer of circ-0110634.

BackgroundAnkylosing spondylitis (AS) is featured by chronic inflammation of the sacroiliac joints and spine as well as pathological new bone formation. Osteoclastogenesis is a critical part in the development of bone formation. Circular RNAs (circRNAs) are recent research hotspot in the RNA field while rarely reported in osteoclastogenesis.MethodsAS mesenchymal stem cells (ASMSCs) and healthy donor mesenchymal stem cells (HDMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs). RT-qPCR was applied to detect the expression level of circ-0110634 in different exosomes. TRAP staining and TRAP activity detection were performed to identify the effect of circ-0110634 overexpression on osteoclastogenesis. Bioinformatics analysis and mechanism investigation were conducted to explore the downstream molecular mechanism of circ-0110634.ResultsThe effect of ASMSCs on PBMCs osteoclastogenesis is weaker than that of HDMSCs. Circ-0110634 had higher expression in ASMSCs exosomes than HDMSCs exosomes. Circ-0110634 overexpression suppressed the osteoclastogenesis. Circ-0110634 bound to both TNF receptor associated factor 2 (TRAF2) and tumor necrosis factor receptor II (TNFRII). Circ-0110634 also accelerated the dimerization of TRAF2 to induce TRAF2 ubiquitination and degradation. Circ-0110634 repressed the interplay between TRAF2 and TNFRII to inactivate the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) pathways. Triptolide promoted the osteoclastogenesis of ASMSCs exosomes-treated PBMCs via decreasing the exosomal transference of circ-0110634 in a dose-dependent manner. Consistently, triptolide treatment stimulated osteoclastogenesis to alleviate the arthritis of DBA/1 mice through suppressing circ-0110634.ConclusionOur study confirmed that triptolide targets circ-0110634 to ease the burden of AS patients.The Translational potential of this articleThis study suggests triptolide targets circ-0110634 to regulate osteoclastogenesis, which provides a novel potential target in triptolide treatment for AS patients.

Systemic inflammation and risk of all-cause mortality after invasive breast cancer diagnosis among Hispanic and non-Hispanic white women from New Mexico

IntroductionSoluble tumor necrosis factor receptor-II (sTNF-R2), a pro-inflammatory biomarker, is associated with obesity and breast cancer (BC). The association between sTNF-R2 and risk of mortality after BC has not been studied, specifically among Hispanic women, an at-risk population due to their high prevalence of obesity and poor prognosis. We examined the association between sTNF-R2 and mortality among Hispanic and non-Hispanic white (NHW) BC survivors. MethodsA total of 397 invasive BC survivors (96 Hispanic, 301 NHW) contributed baseline interview data and blood samples. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression models adjusting for clinical factors including body mass index. ResultsAfter a median follow-up time of 13 years, 133 deaths occurred. The association between high vs low levels of plasma sTNF-R2 and mortality was not statistically significant overall (HR, 1.32; 95% CI 0.89–1.98). However, when stratified the mortality risk among Hispanic women was nearly 3-fold (HR, 2.83; 95% CI 1.21–6.63), while risk among NHW women was attenuated (HR, 0.99; 95% CI 0.61–1.61) (p-interaction=0.10). ConclusionOur results suggest Hispanic BC survivors with high sTNF-R2 levels may have increased risk of mortality and could inform targeted interventions to reduce inflammation and improve outcomes.

Abstract LB081: Systemic inflammation is associated with increased risk of mortality after invasive breast cancer among Hispanic women from New Mexico

Abstract Introduction: Soluble tumor necrosis factor receptor-II (sTNF-R2), a circulating pro-inflammatory biomarker, has been found to associated with obesity and increased risk of breast cancer. No studies to date have examined the association between sTNF-R2 and risk of mortality among Hispanic breast cancer survivors, an at-risk population due to their high prevalence of obesity and poor prognosis. The current study examined the long-term effects of sTNF-R2 on risk of mortality among Hispanic and non-Hispanic white (NHW) breast cancer survivors from the New Mexico Health Eating Activity and Lifestyle Study. Methods: A total of 397 invasive breast cancer survivors (96 Hispanic, 301 NHW) contributed data for the present study. Women with breast cancer diagnosed between July 1996 and March 1999 were ascertained through the National Cancer Institute's Surveillance Epidemiology and End Results registry in New Mexico. Baseline demographic characteristics, anthropometric measures, and blood samples were collected approximately 5 months post diagnosis by trained interviewers. Plasma levels of sTNF-R2 were assayed and measures were log-transformed to conform to normality. The main predictor of low (referent) vs high sTNF-R2 levels was based on the median value. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the associations between sTNF-R2 and all-cause mortality were calculated using Cox proportional hazards regression models overall and by ethnicity. Models were adjusted for age at diagnosis, education, breast cancer stage, treatment, and body mass index (BMI). Results: A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. While Hispanic women had higher baseline BMI (mean= 27.21, standard deviation (SD)= 5.83) compared to NHW women (mean= 25.68, SD= 5.36) (p< 0.001), significant differences by ethnicity for sTNF-R2 levels were not observed. In models adjusted for ethnicity and other covariates, the association between high vs low levels of plasma sTNF-R2 and risk of mortality was not statistically significant among all women (HR, 1.36; 95% CI 0.90-2.03). However, in models stratified by ethnicity, Hispanic women had increased risk of mortality of almost 3-fold (HR, 2.83; 95% CI 1.21-6.63), while the association among NHW women was attenuated and was not statistically significant (HR, 0.99; 95% CI 0.61-1.61). The statistical interaction between sTNF-R2 and ethnicity with risk of mortality was not statistically significant (p= 0.10). Conclusion: Our study results suggest Hispanic breast cancer survivors with high levels of systemic inflammation measured by sTNF-R2 are at increased risk of mortality. These results could inform targeted intervention studies to decrease inflammation and reduce risk of mortality among this at-risk population. Citation Format: Avonne E. Connor, Stephanie D. Boone, Kathy B. Baumgartner, Richard N. Baumgartner. Systemic inflammation is associated with increased risk of mortality after invasive breast cancer among Hispanic women from New Mexico [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB081.

Relationships Between Age, Frailty, Length of Care Home Residence and Biomarkers of Immunity and Inflammation in Older Care Home Residents in the United Kingdom.

Aging is associated with changes to the immune system, collectively termed immunosenescence and inflammageing. However, the relationships among age, frailty, and immune parameters in older people resident in care homes are not well described. We assessed immune and inflammatory parameters in 184 United Kingdom care home residents aged over 65 years and how they relate to age, frailty index, and length of care home residence. Linear regression was used to identify the independent contribution of age, frailty, and length of care home residence to the various immune parameters as dependent variables. Participants had a mean age (±SD) of 85.3 ± 7.5 years, had been residing in the care home for a mean (±SD) of 1.9 ± 2.2 years at the time of study commencement, and 40.7% were severely frail. Length of care home residence and frailty index were correlated but age and frailty index and age and length of care home residence were not significantly correlated. All components of the full blood count, apart from total lymphocytes, were within the reference range; 31% of participants had blood lymphocyte numbers below the lower value of the reference range. Among the components of the full blood count, platelet numbers were positively associated with frailty index. Amongst plasma inflammatory markers, C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1ra), soluble E-selectin and interferon gamma-induced protein 10 (IP-10) were positively associated with frailty. Plasma soluble vascular cell adhesion molecule 1 (sVCAM-1), IP-10 and tumor necrosis factor receptor II (TNFRII) were positively associated with age. Plasma monocyte chemoattractant protein 1 was positively associated with length of care home residence. Frailty was an independent predictor of platelet numbers, plasma CRP, IL-1ra, IP-10, and sE-selectin. Age was an independent predictor of activated monocytes and plasma IP-10, TNFRII and sVCAM-1. Length of care home residence was an independent predictor of plasma MCP-1. This study concludes that there are independent links between increased frailty and inflammation and between increased age and inflammation amongst older people resident in care homes in the United Kingdom. Since, inflammation is known to contribute to morbidity and mortality in older people, the causes and consequences of inflammation in this population should be further explored.

Abstract PO-176: Obesity, breast cancer treatment, and systemic inflammation: A cross- sectional analysis of Hispanic and non-Hispanic white breast cancer survivors from New Mexico

Abstract Background: Circulating markers of systemic inflammation have been found to be important long-term prognostic factors for breast cancer (BC). Studies have shown that obesity measured by percent body fat is the most significant predictor of inflammation in BC survivors. Specific BC treatments may also stimulate both local and systemic increases in inflammation. Little is known about the impact of other body size measures and BC treatment effects on inflammation among Hispanic BC survivors, an at-risk population due to their high prevalence of obesity and poor prognosis. Objective: We examined the associations between body size measures, BC treatment, and odds of systemic inflammation measured by soluble tumor necrosis factor receptor-II (sTNF-R2), a circulating pro-inflammatory biomarker, among Hispanic and non-Hispanic white (NHW) women diagnosed with breast cancer (stages I-IIIa) from the New Mexico Health, Eating, Activity, and Lifestyle cohort. Methods: A total of 397 BC survivors (96 Hispanic, 301 NHW) contributed data for the present study. Women with BC diagnosed between July 1996 and March 1999 were ascertained through the National Cancer Institute’s Surveillance Epidemiology and End Results registry in New Mexico. Baseline demographic characteristics, anthropometric measures, and blood samples were collected approximately 5 months post diagnosis by trained interviewers. Plasma levels of sTNF-R2 were assayed and measures were log-transformed to conform to normality. The study outcome of low vs high sTNF-R2 levels was based on the median value. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models and were stratified by ethnicity. Results: There were higher proportions of women with high compared to low sTNF-R2 levels and the following obesity measures: high percent body fat (≥35%), high body mass index (BMI) (≥30 kg/m2), and high waist-hip ratio (>0.85). No significant differences were observed by sTNF-R2 levels and ethnicity or treatment. In multivariable models, we observed significant positive associations among women with high body fat percentage (compared to < 35%) (OR= 1.62, 95% CI 1.01-2.60) and morbid obesity (BMI ≥35 kg/m2 compared to BMI< 35 kg/m2) (OR= 4.16, 95% CI 1.43-12.10). High waist-hip ratio was not significantly associated with sTNF-R2. While current tamoxifen use was not associated with sTNF-R2, we did find that women who received radiation and chemotherapy were 2 times more likely to have high sTNF-R2 levels compared to women who did not have chemotherapy and radiation (OR= 2.04, 95% CI 1.03-4.01). Our results were not significantly modified by ethnicity. Conclusion: BC survivors with high body fat percentage and extreme BMI have increased odds of systemic inflammation measured by sTNF-R2. Survivors treated with chemotherapy and radiation are also more likely to experience systemic inflammation. Future studies will examine the long-term effects of these associations on poor prognosis. Citation Format: Avonne E. Connor, Kala Visvanathan, Stephanie D. Boone, Kathy B. Baumgartner, Richard N. Baumgartner. Obesity, breast cancer treatment, and systemic inflammation: A cross- sectional analysis of Hispanic and non-Hispanic white breast cancer survivors from New Mexico [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-176.

Inflammatory Biomarkers, Hematopoietic Stem Cells, and Symptoms in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy.

BackgroundFatigue and insomnia are common symptoms experienced by breast cancer patients undergoing adjuvant radiation therapy (RT), yet the underlying mechanisms of these symptoms are unclear. In particular, the roles of hematopoietic stem cells (HSCs) and inflammatory cytokines remain to be elucidated.MethodsBreast cancer patients (n = 147) completed questionnaires to longitudinally assess symptoms before, during, and after adjuvant RT. Phlebotomies were performed prior to RT, at the second and fifth treatment fractions, end of treatment (EOT), and 1 month after completing RT, assessing for CD34+, CD45+, full hematology, and 17 inflammatory cytokines. The associations between symptoms and all biomarkers were evaluated. All statistical tests were 2-sided.ResultsGeneral fatigue and insomnia worsened with RT, with peak levels observed at EOT, which remained statistically significant even after controlling for anxiety and depression (P < .05 for all). CD34+, CD45+, white blood cell, and lymphocyte counts decreased, with the lowest levels also observed at EOT (P < .001). Fatigue and insomnia were associated with changes in both interferon γ-induced protein 10 (IP-10) - (P = .03 and P = .01, respectively) and tumor necrosis factor receptor II (TNF-RII) (P = .02 and P = .006, respectively), while mental fatigue was associated with increased matrix metalloproteinases-2 (MMP-2) levels (P = .03). Patients who received prior chemotherapy demonstrated statistically significantly greater severity in all symptoms, with lower baseline HSC levels.ConclusionsThis is the first longitudinal study to examine linkages between symptoms, HSCs, and cytokines, demonstrating that fatigue and insomnia shared associations with increasing serum levels of IP-10 and TNF-RII, and mental fatigue was associated with increasing serum levels of MMP-2. Our findings highlight opportunities for further research into mechanisms and potential interventions for these symptoms.

Ephedrine enhances HIV-1 reactivation from latency through elevating tumor necrosis factor receptor II (TNFRII) expression

HIV-1 persists during antiretroviral therapy (ART) due to long-lived and proliferating latently-infected host cells, with the outcome being an incomplete cure. The latently-infected cells, or reservoir cells, are transcriptionally absent and invisible to the immune response. Elimination of latency is one strategy in activating virus production, making it visible to immune clearance. We previously showed that Ephedrae herba reactivated HIV-1 from latency. In this study, we used ephedrine, a major component of Ephedra herba, to reactivate HIV-1 from latency. The results showed that ephedrine enhances HIV-1 reactivation in the presence of TNFα. Combination treatment demonstrates a synergistic effect of HIV-1 reactivation compared to TNFα alone. Ephedrine treatment shows a higher TNFRII expression level, which is related to increased HIV-1 reactivation. However, the mechanism of ephedrine in HIV-1 reactivation is still unclear, and may be related to TNFRII receptor expression. Our results indicate that ephedrine enhances HIV-1 reactivation from latency in combination with TNFα treatment. This new reagent could be a promising latency reversal agent (LRA).

Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter

ObjectiveMaternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. MethodParticipants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9–11, mothers completed a questionnaire assessing psychological symptoms. ResultsMultivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. ConclusionThese findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.

Development of a biomarker panel to predict cardiac resynchronization therapy response: Results from the SMART-AV trial

Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

Differential T Cell Levels of Tumor Necrosis Factor Receptor-II in Children With Autism.

Autism spectrum disorders (ASD) are characterized by impairments in verbal and non-verbal communication, in social interactions, and often accompanied by stereotypical interests and behaviors. A role for immune dysfunction has long been implicated in ASD pathophysiology, behavioral severity, and co-morbidities. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been associated with ASD in some studies but little is known about its receptors. There are two receptors for TNFα, with TNFRI relaying many of the signals from TNFα, especially those that are rapid, whilst TNFRII relays later more long-term effects of TNFα. Proteolytic cleavage can lead to the soluble versions of these receptors which can neutralize the effects of TNFα. Here, we determined levels of TNFα and its receptors in 36 children with a confirmed diagnosis of ASD and 27 confirmed typically developing (TD) controls, 2–5 years-of-age. Children with ASD had higher levels of TNFRII on T cells compared to controls following cell stimulation. Levels of sTNFRII were decreased in cell supernatants following stimulation in ASD. Overall these data corroborate the role of inflammatory events in ASD and align with previous studies that have shown differential changes in cellular adaptive immunity in children with ASD. Future longitudinal analyzes of cellular immune function and downstream signaling from immune receptors will help further delineate the role of inflammation in ASD.

Sperm Protein 17 Expression by Murine Epithelial Ovarian Cancer Cells and Its Impact on Tumor Progression.

The cancer testis antigen sperm protein 17 (Sp17) is a promising antigenic target in epithelial ovarian cancer (EOC) vaccine development. However, its role in ovarian cancer is unclear. We isolated and expanded Sp17+ and Sp17− clones from the murine EOC cell line ID8, and compared their in-vitro cell growth characteristics and in-vivo tumorigenicity. We also examined the potential co-expression of molecules that may influence cancer cell survival and interaction with immune cells. These include stimulatory and immunosuppressive molecules, such as major histocompatibility class I molecules (MHC I), MHC II, cytotoxic T lymphocyte associated antigen-4 (CTLA-4), CD73, CD39, tumor necrosis factor receptor II (TNFRII), signal transducer and activator of transcription 3 (STAT3) and programmed death-ligand 1 (PD-L1). Whilst the presence of Sp17 was not correlated with the ID8 cell proliferation/growth capacity in vitro, it was critical to enable progressive tumor formation in vivo. Flow cytometry revealed that Sp17+ ID8 cells displayed higher expression of both STAT3 and PD-L1, whilst MHC II expression was lower. Moreover, Sp17high (PD-L1+MHCII−) cell populations showed significantly enhanced resistance to Paclitaxel-induced cell death in vitro compared to Sp17low (PD-L1−MHCII+) cells, which was associated in turn with increased STAT3 expression. Together, the data support Sp17 as a factor associated with in-vivo tumor progression and chemo-resistance, validating it as a suitable target for vaccine development.

Specific Pro-Inflammatory Signaling Pathways are Induced in Patients with Cardiac Sarcoidosis; Potential Prognostic/Therapeutic Applications

Introduction While cardiac imaging has improved the diagnosis and risk assessment for cardiac sarcoidosis, treatment regimens have consisted of generalized heart failure (HF) therapies and non-specific anti-inflammatory regimens. Thus, improvements in identifying the relative progression of this cardiovascular condition as well as identifying more specific therapeutic targets are necessary. The overall goal of this study was to perform high sensitivity plasma profiling of specific inflammatory pathways in patients with suspected cardiac sarcoidosis. Hypothesis Using large format arrays, specific inflammatory signaling cascades will be upregulated in cardiac sarcoid patients when compared to age matched referent normal subjects. Methods Plasma samples were collected from patients with biopsy confirmed sarcoidosis undergoing F-18 fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) (n=32; age 32-75 yrs) and compared to referent normal subjects. Using a high sensitivity, automated multiplex array, soluble cytokine receptor profiles (an index of cytokine activation) were measured and then indexed to referent normal values (Table). As a composite, soluble receptor levels for interleukin (IL)-1, -2, and epidermal growth factor (EGFR) were increased in sarcoid patients. In those patients with cardiac inflammation (FDG uptake), IL-1RII and IL-2Ra subtype receptor levels were higher when compared to no cardiac inflammation as was the soluble tumor necrosis factor receptor-II. Conclusions The novel finding from this study was the identification of increased activation of a cluster of soluble receptors, which not only augment inflammatory cell maturation but also transmigration in patients with sarcoidosis and cardiac involvement. The specific change in a cluster of IL receptors may hold prognostic value in cardiac sarcoidosis as well as the potential for more specific therapeutic targeting.

Elevated Circulating Osteoprotegerin Levels in the Plasma of Hemodialyzed Patients With Severe Artery Calcification.

We studied the correlations between circulating osteoprotegerin (OPG) level and radial artery calcification (RAC) assessed histologically and carotid artery intima-media thickness (CCA-IMT). Moreover, we studied the relationship between OPG levels and all-cause and cardiovascular (CV) mortality during a 5-year observation period. The study comprised 59 CKD patients (36 hemodialyzed (HD), 23 predialysis). The biochemical parameters included: creatinine, calcium, phosphate, intact parathormone, C-reactive protein, interleukin-6, tumor necrosis factor receptor II (TNFRII), transforming growth factor-β, hepatocyte growth factor, fibroblast growth factor 23, osteonectin (ON), osteopontin, osteoprotegerin, and osteocalcin. CCA-IMT and the presence of atherosclerotic plaques was assessed by ultrasound. Fragments of radial artery obtained during creation of HD access were prepared for microscopy and stained for calcifications with alizarin red. RAC was detected in 34 patients (58%). In multiple regression adjusted for dialysis status, TNFRII, ON and Framingham risk score (FRS) were identified as the independent predictors of OPG. Serum OPG above the median value of 7.55 pmol/L significantly predicted the presence of RAC in simple logistic regression (OR 5.33; 95%CI 1.39-20.4; P = 0.012) and in multiple logistic regression adjusted for FRS, dialysis status and CCA-IMT values (OR 6.56; 95%CI 1.06-40.6; P = 0.036). OPG levels above the median were associated with higher CCA-IMT values (1.02 ± 0.10 vs. 0.86 ± 0.13; P < 0.001) and predicted the presence of atherosclerotic plaques in carotid artery (OR 14.4; 95%CI 2.84-72.9; P < 0.001), independently of FRS, dialysis status and RAC. In this study, elevated serum OPG levels correlated with higher CCA-IMT, the presence of atherosclerotic plaques and the severity of the RAC independently of each other. During follow-up, 25 patients (42%) died, including 21 due to CV causes. In multiple Cox regression, OPG above the median predicted overall survival independently of dialysis status, Framingham risk score, CCA-IMT above the median value, and the presence of atherosclerotic plaques in CCA, but not independently of RAC. We postulate that circulating OPG may play a dual role as a marker for both medial arterial calcification and atherosclerosis, hence it seems to be a valuable tool for assessing CV risk in patients with CKD. OPG might be an early indicator of all-cause mortality in CKD patients with advanced medial arterial calcification.

Reduced Recovery of Depression in Female T Allele Carriers of TNF-RII rs1061622 at Earlier Stage after Wenchuan Earthquake.

Objective: The aim of current study was to explore longitudinally the prevalence, severity, potential factors, and predictors of depression among Chinese Han adolescent survivors with different genotypes of tumor necrosis factor receptor-II (TNF-RII) rs1061622 after the 2008 Wenchuan earthquake. Method: TNF-RII rs1061622 variants were examined by polymerase chain reaction–restriction fragment length polymorphism and verified by DNA sequencing. Depression symptoms were assessed by Beck Depression Inventory (BDI) among 439 high school students at 6, 12, and 18 months after the earthquake. Results: No significant differences were observed in depression prevalence and BDI scores between the TT homozygotes and the G allele carriers in both the male and female subjects. However, the female TT homozygotes had a higher depression prevalence than the male TT homozygotes at 6, 12, and 18 months, whereas the female G allele carriers had a higher depression prevalence than the male G allele carriers only at 6 and 12 months after the earthquake. Moreover, BDI scores declined in the male subjects with both genotypes and only in the female G allele carriers at 12 months when compared with those at 6 months. Furthermore, the predictors of depression severity or potential factors of depression prevalence were different between the G allele carriers and the TT homozygotes at different times after the earthquake. Conclusion: It is concluded that the association of TNF-RII rs1061622 with depression is longitudinally different in Chinese Han adolescents after the 2008 Wenchuan earthquake. The T allele may be associated with reduced recovery of depression in female adolescents in the earlier stage of depression rehabilitation.

Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood.

Aging is characterized by deleterious immune and metabolic changes, but the onset of these changes is unknown. We measured immune and metabolic biomarkers in adults beginning at age 30. To our knowledge, this is the first study to evaluate these biomarkers in adults aged 30 to over 80. Biomarkers were quantified in 961 adults. Tumor necrosis factor alpha (TNF-α), tumor necrosis factor receptor I (TNFR-I), tumor necrosis factor receptor II (TNFR-II), interleukin (IL)-2, IL-6, VCAM-I, D-Dimer, G-CSF, regulated on activation, normal T cell expressed and secreted (RANTES), matrix metalloproteinase-3 (MMP-3), adiponectin, and paraoxonase activity were measured by ELISA. Acylcarnitines and amino acids (AAs) were measured by mass spectrometry and reduced to a single factor using principal components analysis (PCA). Glycine was analyzed separately. The relationship between age and biomarkers was analyzed by linear regression with sex, race, and body mass index (BMI) as covariates. Age was positively correlated with TNF-α, TNFR-I, TNFR-II, IL-6, IL-2, VCAM-1, D-Dimer, MMP-3, adiponectin, acylcarnitines, and AAs. Age was negative correlated with G-CSF, RANTES, and paraoxonase activity. BMI was significant for all biomarkers except IL-2, VCAM-1, RANTES, paraoxonase activity, and the AA factor. Excluding MMP-3, greater BMI was associated with potentially adverse changes in biomarker concentrations. Age-related changes in immune and metabolic biomarkers, known to be associated with poor outcomes in older adults, begin as early as the thirties.

Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis.

Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II (TNFRII) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. A novel mouse TNFRII-selective fusion protein (EHD2-sc-mTNFR2 ) was generated by genetic engineering. Mouse T cells were incubated together with interleukin-2 and/or EHD2-sc-mTNFR2 , and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen-induced arthritis (CIA) were treated with EHD2-sc-mTNFR2 or saline, and the therapeutic effects were monitored and characterized. Selective activation of TNFRII was found to expand both CD4+ and CD8+ Treg cells. Moreover, TNFRII activation elevated the number of CD4+CD25+ and CD8+CD25+ Treg cells and increased the number of FoxP3-expressing cells in CD8+, but not CD4+, Treg cells, indicating different mechanisms of TNFRII-induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD2-sc-mTNFR2 led to the expansion of both CD4+ and CD8+ Treg cells invivo and induced antiinflammatory responses that alleviated arthritis. Our findings support the use of TNFRII-selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.

Periodontitis May Restrain the Mandibular Bone Healing via Disturbing Osteogenic and Osteoclastic Balance.

Periodontitis has been advocated as a systematic chronic low-grade infection burden. However, the relationship between periodontitis and bone defect healing has not been elucidated. One hundred and eight male Wister rats were randomly assigned into three groups: control (healthy) group, periodontitis group, and periodontitis plus human tumor necrosis factor receptorII:IgG Fc fusion protein (rhTNFR:Fc) group. The experimental periodontitis model was established by ligaturing with orthodontic wire and silk suture plus local administration of 20μl of lipopolysaccharide (LPS). Mandibular bone defects in size of 4 × 2 × 1mm were created for all the rats and rhTNFR:Fc subcutaneously injected at neck at a dose of 2.5mg/kg every 3days for the periodontitis plus rhTNFR:Fc group. The gene and protein expressions of bone-related markers in the healing tissue were monitored and new bone formation was histologically evaluated. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine the number of osteoclasts. The results showed that the mRNA and protein expressions of osteogenesis-related markers were significantly lower while nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) gene expression was significantly higher in the periodontitis group. The periodontitis group showed decreased new bone formation and increased number of osteoclasts when compared to the control group. However, there was no significant difference between the periodontitis plus rhTNFR:Fc group and the control group. These results demonstrated that periodontitis may restrain the mandibular bone healing via disturbing osteogenic and osteoclastic balance in which tumor necrosis factor-α (TNF-α) could act as a leverage.