Heterogeneity of cerebral atrophic rate in mild cognitive impairment and its interactive association with proteins related to microglia activity on longitudinal cognitive changes.

BACKGROUND: Heterogeneity of cerebral atrophic rate commonly exists in mild cognitive impairment (MCI), which may be associated with microglia-involved neuropathology and have an influence on cognitive outcomes. OBJECTIVE: We aim to explore the heterogeneity of cerebral atrophic rate among MCI and its association with plasma proteins related to microglia activity, with further investigation of their interaction effects on long-term cognition. SUBJECTS: A total of 630 MCI subjects in the ADNI database were included, of which 260 subjects were available with baseline data on plasma proteins. METHODS: Group-based multi-trajectory modeling (GBMT) was used to identify the latent classes with heterogeneous cerebral atrophic rates. Associations between latent classes and plasma proteins related to microglia activity were investigated with generalized linear models. Linear mixed effect models (LME) were implemented to explore the interaction effects between proteins related to microglia activity and identified latent classes on longitudinal cognitive changes. RESULTS: Two latent classes were identified and labeled as the slow-atrophy class and the fast-atrophy class. Associations were found between such heterogeneity of atrophic rates and plasma proteins related to microglia activity, especially AXL receptor tyrosine kinase (AXL), CD40 antigen (CD40), and tumor necrosis factor receptor-like 2 (TNF-R2). Interaction effects on longitudinal cognitive changes showed that higher CD40 was associated with faster cognitive decline in the slow-atrophy class and higher AXL or TNF-R2 was associated with slower cognitive decline in the fast-atrophy class. CONCLUSIONS: Heterogeneity of atrophic rates at the MCI stage is associated with several plasma proteins related to microglia activity, which show either protective or adverse effects on long-term cognition depending on the variability of atrophic rates.

Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults.

BACKGROUND: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD. METHODS: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers. RESULTS: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = -0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = -0.335, p = 0.002). No other associations were found. LIMITATION: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center. CONCLUSION: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.

Genetic factors associated with age-related macular degeneration modulating plasma inflammatory biomarker levels in patients with AIDS.

INTRODUCTION: Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS. MATERIALS AND METHODS: Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1). RESULTS: In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels. CONCLUSIONS: Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Association of inflammatory markers with muscle and cognitive function in early and late-aging older adults.

OBJECTIVES: Age-related loss in muscle and cognitive function is common in older adults. Numerous studies have suggested that inflammation contributes to the decline in physical performance and increased frailty in older adults. We sought to investigate the relationship of inflammatory markers, including CRP, IL-6, IL-10, TNF-α, TNFR1, and TNFR2, with muscle and cognitive function in frail early-aging and non-frail late-aging older adults. DESIGN: Secondary analysis of a cross-sectional study. SETTINGS AND PARTICIPANTS: Two hundred community-dwelling older men and women were included. They had been recruited in two groups based on age and functional status: 100 early-agers (age 65-75, who had poor functional status, and more co-morbidities) and 100 late-agers (older than 75 years, who were healthier and had better functional status). MEASUREMENTS: We assessed CRP, IL-6, IL-10, TNF-α, TNFR1, TNFR2, grip strength, Short Physical Performance Battery (SPPB) score, and cognitive function. We used correlation coefficients, partial correlations, and regression modeling adjusted for age, BMI, gender, and exercise frequency. RESULTS: The mean age in the two groups were 70.4 and 83.2, respectively. In regression models adjusting for age, BMI, gender and exercise frequency, early-agers demonstrated significant associations between inflammatory markers and outcomes. Each mg/dl of CRP was associated with (regression coefficient ± standard error) -0.6 ± 0.2 kg in grip strength (p = 0.0023). Similarly, each pg/mL of TNF-α was associated with -1.4 ± 0.7 (p = 0.0454), each 500 pg/mL of TNFR1 was associated with -1.9 ± 0.6 (p = 0.0008), and each 500 pg/mL of TNFR2 was associated with -0.5 ± 0.2 (p = 0.0098) in grip strength. Each 500 pg/mL of TNFR1 was associated with -0.4 ± 0.2 point in SPPB (p = 0.0207) and each pg/mL in IL-10 with 0.2 ± 0.1 point in MoCA (p = 0.0475). In late-agers, no significant correlation was found between any of the inflammatory markers and functional outcomes. CONCLUSION: In early-agers with frailty and more co-morbidities, the inflammatory markers CRP, TNF-α, TNFR1, and TNFR2 were associated with grip strength, TNFR1 was correlated with physical performance, and IL-10 was correlated with cognitive function. However, in healthier late-agers, no relationship was found between inflammatory markers and muscle or cognitive function. Our findings suggest presence of a relationship between inflammation and loss of muscle performance and cognitive function in frailer and sicker individuals, regardless of their chronological age.

Circulating TNF-RII, IP-10 and HGF are associated with severity of COVID-19 in oncologic patients.

The COVID-19 patients showed hyperinflammatory response depending on the severity of the disease but little have been reported about this response in oncologic patients that also were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sixty-five circulating cytokines/chemokines were quantified in 15 oncologic patients, just after SARS-CoV-2 infection and fourteen days later, and their levels were compared in patients who required hospitalisation by COVID-19 versus non-hospitalised patients. A higher median age of 72 years (range 61-83) in oncologic patients after SARS-CoV-2 infection was associated with hospitalisation requirement by COVID-19 versus a median age of 49 years (20-75) observed in the non-hospitalised oncologic patients (p = 0.008). Moreover, oncologic patients at metastatic stage or with lung cancer were significantly associated with hospitalisation by COVID-19 (p = 0.044). None of these hospitalised patients required ICU treatment. Higher basal levels of tumour necrosis factor receptor II (TNF-RII), interferon-γ (IFNγ)-induced protein 10 (IP-10) and hepatocyte growth factor (HGF) in plasma were significantly observed in oncologic patients who required hospitalisation by COVID-19. Higher TNF-RII, IP-10 and HGF levels after the SARS-CoV-2 infection in oncologic patients could be used as biomarkers of COVID-19 severity associated with hospitalisation requirements.

Soluble tumor necrosis factor receptor 2 is associated with progressive diabetic kidney disease in patients with type 2 diabetes mellitus.

BACKGROUND: Chronic low-grade inflammation is considered one of the major mechanisms for the progression of diabetic kidney disease. We investigated the prognostic value of circulating soluble tumor necrosis factor receptor 2 (sTNFR2) for early nephropathy in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 364 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 were followed up for a median of 4 years. Renal outcomes were defined as a composite of either or both a >30% decline in the eGFR and/or albuminuria stage progression determined with consecutive tests. RESULTS: Seventy-three patients developed renal composite events. Serum concentrations of sTNFR2 were strongly associated with the risk of renal function decline and progressive changes in albuminuria. Through a receiver operating characteristic curve analysis, a serum sTNFR2 level of 1.608 ng/mL was adopted as the discriminator value for predicting renal outcomes (area under the curve 0.63, 95% confidence interval 0.57-0.70, p < 0.001), yielding a sensitivity of 75.3% and a specificity of 51.2%. The association of sTNFR2 levels ≥1.608 ng/mL to renal outcomes was significant after adjusting for relevant variables (hazard ratio 2.27, 95% confidence interval 1.23-4.20, p = 0.009) and remained consistent across subgroups stratified by age, sex, systolic blood pressure, eGFR, albuminuria, and the use of renin-angiotensin system blockers. CONCLUSIONS: Higher circulating levels of sTNFR2 are independently associated with an eGFR decline and progressive albuminuria in patients with type 2 diabetes.

Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia.

Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL.

Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries.

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.

AIMS/HYPOTHESIS: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). METHODS: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. RESULTS: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. CONCLUSIONS/INTERPRETATION: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.

Cognitive Function, Sarcopenia, and Inflammation Are Strongly Associated with Frailty: A Framingham Cohort Study.

BACKGROUND: Frailty is an important contributor to morbidity and mortality in chronic liver disease. Understanding the contributors to frailty has the potential to identify individuals at risk for frailty and may potentially provide targets for frailty-modifying interventions. We evaluated the relationship among cognitive function, inflammation, and sarcopenia and frailty. METHODS: Using cohorts from the Framingham Heart Study (2011-2014), we evaluated for factors associated with frailty. Exposures included cognitive tests (combined Trails A/B test, Animal Naming Test, and combined Digit Span Forward/Backward test), inflammation (interleukin-6 and tumor necrosis factor receptor II), and sarcopenia (creatinine-to-cystatin C ratio). We performed linear and logistic regression to identify the relationship between these exposures and the Liver Frailty Index (LFI). RESULTS: The study population (N = 1208) had a median age of 70 years, was 56% female, and 48.5% had evidence of liver disease. The combined Trails A/B test (ß 0.05, P < .001), creatinine-to-cystatin C (ß -0.17, P = .006), and both inflammatory markers, interleukin-6 levels (ß 0.16, P = .002) and tumor necrosis factor receptor II (ß 0.21, P = .04), were independently associated with the LFI. Using an LFI cutoff of ≥4.5 to define frailty, Trails A/B (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.37), Animal Naming Test (OR 0.64, 95% CI 0.42-0.97), sarcopenia (OR 0.10, 95% CI 0.01-0.73), and interleukin-6 (OR 4.99, 95% CI 1.03-15.53) were all associated with frailty. Although liver disease did not modify the relationship between the LFI and the Trails A/B test, interleukin-6 was significantly associated with the LFI only in the presence of liver disease. CONCLUSIONS: Cognitive performance, inflammation, and sarcopenia, each highly prevalent in cirrhosis, are associated with the LFI in this population-based study of persons without cirrhosis. Further research is warranted for interventions aiming to prevent frailty by tailoring their approach to the patient's underlying risk factors.

Disordered glycemic control in women with type 2 diabetes is associated with increased TNF receptor-2 levels.

BACKGROUND: Evidence implicates tumor necrosis factor (TNF) in the pathophysiology of Type 2 Diabetes (T2D) through unclear mechanisms. We hypothesized that disordered glycemic control leads to TNF activation and increases in soluble-TNF (sTNF) and its receptors-1 (sTNFR1) and -2 (sTNFR2). METHODS: We characterized 265 T2D and non-diabetic Latin American subjects and assessed the relationship between the TNF system and fasting plasma glucose (FPG), hemoglobin-A1C (A1C), insulin (FPI), C-peptide and HOMA-Beta. RESULTS: sTNF and sTNFR2 but not sTNFR1 levels were higher in T2D than non-diabetics (P<0.0001). In T2D, sTNFR2 was associated with A1C and C-peptide (R2=0.354, b=0.504, P<0.0001; b=0.167, P=0.049). Also, T2D patients with disordered glycemic control had increased sTNFR2 levels that correlated with FPG (Rho:0.393, P<0.001), A1C (Rho:0.451, P<0.001) and HOMA-Beta (Rho:-0.308, P=0.005); events not observed in T2D patients with adequate glycemic control. Furthermore, sex-based comparative analyses of T2D patients showed that women compared to men had higher sTNFR2 levels (P=0.017) that correlated with FPG, A1C, FPI and HOMA-Beta. CONCLUSIONS: Disordered glycemic control is associated with sTNF and sTNFR2. sTNFR2 levels were higher in T2D women than men. Thus, increased sTNFR2 levels may be an important biomarker for disordered glucose and inflammatory complications in T2D patients and women in particular.

Umbilical Cord-derived Mesenchymal Stem Cells modulate TNF and soluble TNF Receptor 2 (sTNFR2) in COVID-19 ARDS patients.

OBJECTIVE: We aimed at explaining the mechanism of therapeutic effect of Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in subjects with COVID-19 Acute Respiratory Distress Syndrome (ARDS). Patients with COVID-19 ARDS present with a hyperinflammatory response characterized by high levels of circulating pro-inflammatory mediators, including tumor necrosis factor α and ß (TNFα and TNFß). Inflammatory functions of these TNFs can be inhibited by soluble TNF Receptor 2 (sTNFR2). In patients with COVID-19 ARDS, UC-MSC appear to impart a robust anti-inflammatory effect, and treatment is associated with remarkable clinical improvements. We investigated the levels of TNFα, TNFß and sTNFR2 in blood plasma samples collected from subjects with COVID-19 ARDS enrolled in our trial of UC-MSC treatment. PATIENTS AND METHODS: We analyzed plasma samples from subjects with COVID-19 ARDS (n=24) enrolled in a Phase 1/2a randomized controlled trial of UC-MSC treatment. Plasma samples were obtained at Day 0 (baseline, before UC-MSC or control infusion), and Day 6 post infusion. Plasma concentrations of sTNFR2, TNFα, and TNFß were evaluated using a quantitative multiplex protein array. RESULTS: Our data indicate that at Day 6 after infusion, UC-MSC recipients develop significantly increased levels of plasma sTNFR2 and significantly decreased levels of TNFα and TNFß, compared to controls. CONCLUSIONS: These observations suggest that sTNFR2 plays a mechanistic role in mediating UC-MSC effect on TNFα and TNFß plasma levels, determining a decrease in inflammation in COVID-19 ARDS.

Cross-sectional study of plasma Axl, ferritin, IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium.

OBJECTIVE: To evaluate the performance of 4 plasma protein markers for detecting disease activity in childhood-onset systemic lupus erythematosus (SLE) patients. METHODS: Eighty-three consecutive pediatric patients fulfilling ≥4 ACR criteria for SLE and twenty-five healthy controls were prospectively recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using SLEDAI-2000 score. Fifty-seven patients had clinically active SLE (SLEDAI score ≥4, or having a flare). RESULTS: The plasma concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE. Plasma Axl levels were significantly higher in active renal versus active non-renal SLE patients. Levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores. Levels of Axl, IFGBP4 and sTNFR2 inversely correlated with plasma complement C3 levels. Only plasma Axl and ferritin levels correlated with degree of proteinuria. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA antibody titer or decreased C3. Ferritin and IGFBP4 levels were more specific for concurrent active lupus nephritis than anti-dsDNA or C3. Plasma ferritin was the best monitor of global SLE activity, followed by C3 then Axl, while both Axl and C3 were best monitors of clinical lupus nephritis activity. CONCLUSION: In childhood-onset SLE patients, plasma ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these plasma markers should be explored further in longitudinal cohorts of SLE patients.

Leukocyte TNFR1 and TNFR2 Expression Contributes to the Peripheral Immune Response in Cases with Ischemic Stroke.

Tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2) have been found in brain parenchyma of stroke patients, and plasma levels are increased in the acute phase of stroke. We evaluated associations between TNFR1 and TNFR2 plasma levels and stroke severity, infarct size, and functional outcome. Furthermore, we examined cellular expression of TNFR1 and TNFR2 on leukocyte subpopulations to explore the origin of the increased receptor levels. Blood samples were taken from 33 acute ischemic stroke patients and 10 healthy controls. TNFR1 and TNFR2 plasma concentrations were measured and correlated against the Scandinavian Stroke Scale at admission, infarct volume, and the modified Rankin Scale score three months after stroke onset. Classical, intermediate, and non-classical monocytes as well as neutrophils were purified, and cellular expression of TNFR1 and TNFR2 was examined using flow cytometry. TNFR1 and TNFR2 plasma levels were both increased after ischemic stroke, but we found no correlation with patient outcome measurements. Compared to healthy controls, ischemic stroke patients had decreased non-classical monocyte and neutrophil populations expressing TNFR1 and increased neutrophils expressing TNFR2, and decreased non-classical populations co-expressing both TNFR1 and TNFR2. This study supports the hypothesis of an acute immunological response orchestrated by the peripheral immune system following an ischemic stroke. However, the origin of the increased TNFR1 and TNFR2 plasma levels could not be clearly linked to peripheral monocytes or neutrophils. Future studies are needed and will help clarify the potential role as treatment target.

Tumor necrosis factor superfamily molecules are increased in behavioral variant frontotemporal dementia and correlate with cortical atrophy: An exploratory investigation.

Frontotemporal dementia (FTD) is the second most frequent cause of young-onset dementia. Even though immune-mediated and neuroinflammatory factors have been recognized as potential pathophysiological mechanisms, the role of specific immune molecules, such as the tumor necrosis factor (TNF) superfamily, remains elusive. The aim of this study was to investigate TNF Superfamily Molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], soluble TNF receptor type 1 [sTNFRI] and soluble TNF receptor type 2 [sTNFRII]) in patients with behavioral variant FTD (bvFTD) and controls, and to explore potential associations with clinical parameters and brain atrophy. This study included two groups of participants matched for age, sex and schooling years: patients with probable bvFTD (n = 17, mean age = 64.9 years, 6 women/11 men) and healthy controls (HC, n = 17; mean age = 63.9 years, 10 women/7 men). All participants underwent comprehensive cognitive assessment and structural brain imaging with 3 T magnetic resonance imaging. Plasma levels of TNF, TWEAK, sTNFRI and sTNFRII were determined by ELISA. We conducted voxel-based morphometry analyses to investigate correlations between grey matter (GM) atrophy and plasma levels of TNF, TWEAK, sTNFRI and sTNFRII within bvFTD group. Compared to HC, bvFTD patients had lower cognitive scores and marked frontotemporal atrophy. Patients with bvFTD had significantly higher plasma levels of TNF (p < 0.0001), sTNFRI (p < 0.001), and sTNFRII (p < 0.0001), and similar levels of TWEAK in comparison with controls. The levels of sTNFRII were positively correlated with GM atrophy involving temporal poles, precuneus and cerebellum in bvFTD patients, while the levels of TWEAK positively correlated with right superior temporal gyrus. Our results implicate TNF superfamily in the pathophysiology of FTD.

Predictive Significance of Serum Interferon-Inducible Protein Score for Response to Treatment in Systemic Sclerosis-Related Interstitial Lung Disease.

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, ß2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3ß) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. RESULTS: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). CONCLUSION: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Association between circulating tumor necrosis factor receptors and oral bacterium in patients receiving hemodialysis: a cross-sectional study.

BACKGROUND: High levels of tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2), markers of inflammation, have been reported as significant predictors of mortality in hemodialysis patients. Porphyromonas gingivalis is a major pathogenic bacterium involved in periodontitis, which induces systemic inflammation. We investigated the association between the abundance of P. gingivalis in saliva and serum TNFR levels in hemodialysis patients. METHODS: A cross-sectional study was conducted on 121 hemodialysis patients visiting a clinic in the Tokyo metropolitan area. Medical interviews and examinations, comprehensive dental examinations, bacterial examinations for P. gingivalis in saliva, and measurements of circulating TNFR levels were conducted. Multiple linear regression analysis was performed to evaluate the association between the number of P. gingivalis and circulating TNFR levels. RESULTS: TNFR1 and TNFR2 were positively correlated with high-sensitivity C-reactive protein (hsCRP). Severe periodontitis was significantly associated with the number of P. gingivalis in saliva but not serum TNFR levels. The number of P. gingivalis was significantly associated with both TNFR1 and TNFR2 levels in sera after adjusting for age, sex, body mass index, smoking status, history of diabetes, prior cardiovascular disease events, serum levels of hsCRP and albumin, and severity of periodontitis [for TNFR1: coefficient 0.76, 95% confidence interval (CI) 0.14-1.37, p = 0.02; for TNFR2: coefficient 0.95, 95% CI 0.09-1.80, p = 0.03]. CONCLUSION: Circulating TNFR levels are associated with the number of P. gingivalis in saliva after adjusting for relevant clinical factors.

Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function.

AIMS/INTRODUCTION: Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin-to-creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. MATERIALS AND METHODS: This was a cross-sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 . The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. RESULTS: Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60-89 mL/min/1.73 m2 , and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60-89 mL/min/1.73 m2 ) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. CONCLUSIONS: The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.