Soluble Interleukin-2 Research Articles

Soluble Interleukin 2 Receptor as a Potential Biomarker for Immune Checkpoint Inhibitor Nephritis (ICI-AIN)

Soluble Interleukin 2 Receptor as a Potential Biomarker for Immune Checkpoint Inhibitor Nephritis (ICI-AIN)

Association of Soluble IL-1 Receptor Type 2 with Recovery of Left Ventricular Function and Clinical Outcomes in Acute Myocardial Infarction.

The role of soluble interleukin-1 receptor type 2 (sIL-1R2) in acute myocardial infarction (AMI) remains undocumented. In the present study, we aimed to evaluate the possible associations of sIL-1R2 with left ventricular (LV) function, remodeling and future clinical events in the setting of AMI. Circulating sIL-1R2 levels were quantified after percutaneous coronary intervention (PCI) on day 1 of hospital admission for 204 AMI patients, and upon enrollment of 204 healthy controls. Echocardiography was conducted in the acute phase and at 12-month follow-up. Adverse clinical events were registered after 12 months. Circulating sIL-1R2 levels were significantly higher in AMI patients than in healthy controls (medians respectively 6652.81 pg/mL, 3799.13 pg/mL, p 0.0001). AMI patients with sIL-1R2 levels less than the median had a larger proportion of worsened LV ejection fraction [a decrease in LV ejection fraction (LVEF) of more than 10% units] and reduced LVEF (a final LVEF 50%). After multivariate adjustment, sIL-1R2 levels less than the median were associated with an increased risk of worsened LVEF [odds ratio (OR): 3.7, 95% confidence interval (CI): 1.6-8.5, p = 0.002] and reduced LVEF at 12 months (OR: 2.1, 95% CI: 1.1-4.3, p = 0.035). Moreover, low sIL-1R2 levels were associated with an increased risk of having an adverse clinical event during the first 12 months after AMI [hazard ratio (HR): 2.5, 95% CI: 1.0-6.1, p = 0.039]. Low levels of circulating sIL-1R2 were associated with impaired recovery of LV function and adverse clinical outcomes in AMI patients. These findings might contribute to understanding the important role of sIL-1R2 in postinfarction inflammation.

Clinical Significance Of Serum And Urine Soluble Interleukin 2 Receptor, C-Reactive Protein, Cystatin C, and Serum and Urine Creatinine in Renal Transplant Patients

Cytokines play a major role in the inflammatory and allo-specific components of allograft rejection, and in the migration of cells into graft tissue. IL-2 binding of sIL-2R plays a major role in T cell activation. It is suggested that high urinary sIL-2R (U/sIL-2R) in the first 3-5 post-transplant days identified the patient sub-group at risk of developing acute rejection (RX). However, it was difficult to distinguish between RX and infection (INFX) as both of these factors can potentially affect serum sIL-2R (S/sIL-2R) and U/sIL-2R concentrations independent of actual production rates. The aims of this study were to validate and extend previous findings of the use of sIL-2R in renal transplantation, to investigate other protein markers currently used such as serum C-reactive protein (CRP), serum cystatin C (cys. C), and serum and urine creatinine (S/creat. and UCRE) and attempt to differentiate RX from INFX. SIL-2R ELISA kit was validated and used to establish reference ranges in healthy donors, transplant (TX) recipients, and renal disease controls. These values were compared with serial estimations of S/sIL-2R and U/sIL-2R of patients post-TX. Levels of serum CRP, cys. C, S/creat. and UCRE were also investigated in the renal disease control and 21 TX subjects to determine if a panel of investigation would have enhanced clinical diagnosis. RX and INFX were determined retrospectively on an “intention to treat” basis. Results show that sIL-2R levels in normal serum and urine subjects are lower than in disease controls, that CRP and cys C are good indicators of RX as well as U/sIL-2R and S/sIL-2R, that UCRE is not a good marker of differentiation, and that stratifying levels of these markers according to treatment differentiated RX from INFX.

Blockade of the protease ADAM17 ameliorates experimental pancreatitis

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice-which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression-and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17/IL-6 trans-signaling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.

Evaluation of clinical and laboratory characteristics of patients with cutaneous sarcoidosis: A single-center retrospective cohort study.

BackgroundCutaneous sarcoidosis is a relatively rare disease whose clinical manifestations include red-brown macules, plaques, papules and subcutaneous nodules. The skin changes may also be restricted to pre-existing scars. Cutaneous sarcoidosis can be associated with systemic organ involvement.ObjectivesAim of this retrospective study was to longitudinally investigate clinical and laboratory findings in patients with cutaneous sarcoidosis.MethodsPatients (>18 years) with histologically confirmed cutaneous sarcoidosis between January 2014 and December 2020 were included. Patient demographics, clinical features, laboratory and radiological findings, management, clinical outcomes and co-morbidities associated with cutaneous sarcoidosis were analyzed.ResultsThirty-seven patients with cutaneous sarcoidosis were identified, of whom 57% were female. The most common clinical phenotype of cutaneous sarcoidosis was papular sarcoidosis (n = 16), while plaques and nodules were present in 9 patients. In contrast, subcutaneous (n = 1) and scar-associated sarcoidosis (n = 1) were rare. Of patients with systemic disease, the cutaneous disease followed, preceded, and coincided with the development of systemic sarcoidosis in 2, 9, and 12 patients, respectively. Levels of soluble interleukin (IL)-2 receptor, angiotensin converting enzyme (ACE), and C-reactive protein (CRP) were elevated, in 76%, 21%, and 50% of the tested patients respectively and predicted systemic involvement. Hypercalcemia was present in 6% of patients. Female sex and younger age (<54 years) were significantly associated with systemic manifestations.ConlcusionsCutaneous sarcoidosis was frequently associated with additional systemic involvement, particularly when present in young females. 24 % of patients with cutaneous sarcoidosis developed additional organ involvement during follow-up.

Serum Soluble Interleukin 2 Receptor Alpha vs. Urinary Parameter and Serum Immunological Markers as a Monitoring Tool of Treatment Response of Lupus Nephritis and their Relation to Lupus Nephritis Class on Renal Biopsy

Background: Lupus Nephritis (LN) is one of the most common and serious manifestations in SLE patients that causes significant morbidity and mortality. Current conventional biomarkers for LN are sometimes unable to predict treatment response of lupus nephritis. Recently serum soluble interleukin-2 receptor alpha (sIL-2 R alpha) is shown to be a good marker to predict treatment response of LN. Objective: To compare serum sIL-2R alpha with other commonly used markers as a marker of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with lupus nephritis after kidney biopsy were included in this study. Serum soluble interleukin-2 receptor alpha, 24 hrs UTP, anti-dsDNA, complements level (C3 &amp; C4) were measured in all patient at baseline, 3-months and 6- months after treatment. Serum soluble interleukin-2 receptor alpha level was measured by ELISA and is expressed as pg/mg. Serum sIL-2R alpha as well as conventional biomarker value were compared before and after treatment and in between treatment response and non-response group. Results: Serum sIL-2R alpha levels were significantly higher in patients of proliferative lupus nephritis (Class III &amp; Class IV) than non-proliferative lupus nephritis (Class V) at baseline (3934.3 ± 1095.2, 3934.3 ± 1095.2 &amp; 1801.98 ± 205.8 pg/L respectively) and levels were decreased significantly 6 months after treatment (p &lt;0.001). Serum sIL-2R alpha levels were also significantly higher in non-remission proliferative group then remission proliferative group (4071.60 ± 769.91 vs 5169.20 ± 394.76) with p value 0.008 at baseline. In contrast no significant difference were observed for 24 hrs UTP levels at baseline between this group which suggest that serum sIL-2R alpha are more sensitive marker than 24 hrs UTP in predicting treatment response of lupus nephritis. Conclusions: Serum sIL-2R alpha might be a valuable serological biomarker to diagnose and to predict and monitor the treatment response of lupus nephritis.

A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities.

Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: • The homodimeric structure of F4RLI facilitates its easy production processes and quality control. • The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. • F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.

Increased sIL-2Rα leads to obstruction of IL-2 biological function and Treg cells differentiation in SLE patients via binding to IL-2.

BackgroundThe decrease of IL-2 level is believed to play an important role in the disease occurrence and development of SLE, but the relevant mechanisms have not been fully clarified. Many studies have found that the level of soluble interleukin 2 receptor α (sIL-2Rα) in SLE patients is significantly increased. Considering the fact that sIL-2Rα has the ability to bind IL-2, we want to know whether the increased sIL-2Rα has some impact on the level and function of IL-2 in SLE patients.MethodsNew onset SLE patients, treated SLE patients and healthy volunteers were recruited. The levels of serum IL-2, IL-2 mRNA in CD3+ T cells and serum sIL-2Rα were detected and compared in these subjects. Two mixed solid-phase sandwich ELISA system were designed to measure exclusively the heterodimers complex of sIL-2Rα/IL-2. The sera from SLE patients were pretreated with or without immune complex dissociation solution and detected for IL-2 levels. IL-2 standard or serum from HCs were used to co-incubate with recombinant sIL-2Rα or serum samples with high levels of sIL-2Rα and detected for IL-2 levels by ELISA. The inhibitory effect of sIL-2Rα on IL-2 biological activity was investigated by CTLL-2 cell proliferation assay. The frequencies and absolute counts of Treg cells were detected by flow cytometry before and after the addition of recombinant sIL-2Rα.ResultsThe levels of serum IL-2 in SLE patients were significantly decreased and negatively correlated with SLEDAI. However, there was no significant difference in IL-2 mRNA levels in CD3+ T cells between SLE patients and healthy controls. The levels of serum sIL-2Rα in SLE patients were significantly increased, positively correlated with the SLEDAI and negatively correlated with the levels of serum IL-2. sIL-2Rα was shown to bind to IL-2 to form immune complex, resulting in false reduction in the detection level of serum IL-2 and significant decrease in biological activity of IL-2. The increase of sIL-2Rα was demonstrated to be one of the important mechanisms for the obstruction of Treg cells differentiation in SLE patients.ConclusionIncreased serum sIL-2Rα can bind to IL-2, leading to obstruction of IL-2 activity and Treg cells differentiation.

Hyperinflammatory syndrome resembling haemophagocytic lymphohistiocytosis following axicabtagene ciloleucel and brexucabtagene autoleucel.

Haemophagocytic lymphohistiocytosis-like toxicity following chimeric antigen receptor T cells (CAR-HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR-HLH after infusion of brexucabtagene autoleucel (n= 2) or axicabtagene ciloleucel (n= 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)-2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C-reactive protein and IL-6. Clinical improvement following treatment with anakinra (n=2) and ruxolitinib (n=1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life-saving treatment for CAR-HLH.

The Predicting Role of Serum TSGF and sIL-2R for the Lymph Node Metastasis of Papillary Thyroid Carcinoma.

Objective To explore the clinical utility of tumor-specific growth factor (TSGF) and the soluble interleukin-2 (IL-2) receptor (sIL-2R) as immune-related factors for predicting lymph node metastases (LNM) of papillary thyroid carcinoma (PTC). Methods A total of 206 patients with PTC subjected to curative surgery were enrolled. All patients had complete medical records. Serum levels of TSGF were detected using Automatic Biochemistry Analyzer and the serum sIL-2R concentration was detected by enzyme-linked immunosorbent assay (ELISA). Furthermore, we analyzed the relationship between the two indicators and the clinicopathological characteristics and assessed their effect on lymphatic metastasis in patients with PTC by logistic regression analysis. Results Receiver operating characteristic (ROC) analysis revealed that the determined cut-off value of serum TSGF and sIL-2R was 63.35 U/mL and 507 U/mL, respectively. Serum TSGF was associated with focality (χ2 = 4.97, P = 0.026) and lymphatic metastasis (χ2 = 4.154, P = 0.042), while serum sIL-2R was remarkably related to gender (χ2 = 4.464, P = 0.035). Univariate logistic regression analysis indicated that age, tumor size, serum TSGF level, capsule invasion, and nodular goiter were the lymphatic metastasis-related factor of PTC. Multivariate regression analysis revealed that age > 45 years was a protective factor (OR: 0.4, 95% CI: 0.206-0.777, P = 0.007). Conversely, larger tumor size (OR: 4.594, 95% CI: 2.127-9.921, P = 0.000), higher serum TSGF levels (OR: 1.888, 95% CI: 1.009-3.533, P = 0.047), and capsule invasion (OR: 1.939, 95% CI: 1.009-3.726, P = 0.047) were associated with an increased risk of LNM. Conclusion Serum TSGF levels were identified as an independent factor for LNM in patients with PTC.

Serum soluble interleukin-7 receptor alpha levels are negatively correlated with the simultaneous activity of antineutrophil cytoplasmic antibody-associated vasculitis.

This study investigated whether serum soluble interleukin-7 receptor alpha (sIL-7Rα) levels could reflect the simultaneous activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Sixty patients with AAV were included in this study. AAV-related variables and clinical and laboratory data were collected at the two-time points (at early high and late low BVAS) for each patient along with blood sampling. Serum sIL-7Rα levels and the populations of CD3+CD4+ and CD3+CD8+ T cells expressing membranous IL-7Rα (mIL-7Rα) were compared between patients at different time points and between patients and healthy controls. Serum sIL-7Rα levels were significantly lower in AAV patients at early high BVAS than in those at late low BVAS, and the direction of change in serum sIL-7Rα levels increased as BVAS decreased. Serum sIL-7Rα levels were inversely correlated with BVAS, erythrocyte sedimentation rate and C-reactive protein levels. In addition, serum sIL-7Rα levels in AAV patients at early high BVAS exhibited significantly lower levels than those in healthy controls. Particularly, AAV patients at early high BVAS showed significantly increased populations of CD3+ T cells and CD3+CD8+ T cells expressing mIL-7Rα compared to those at late low BVAS. This study demonstrated that not only serum sIL-7Rα levels but also the populations of CD3+ and CD3+CD8+ T cells expressing m IL-7Rα were negatively correlated with simultaneous BVAS in patients with AAV. Therefore, we suggest that serum sIL-7Rα levels can be an additional and useful biomarker for assessing the simultaneous activity of AAV.

SOCS3 limits TNF and endotoxin-induced endothelial dysfunction by blocking a required autocrine interleukin-6 signal in human endothelial cells.

Increased circulating levels of soluble interleukin (IL)-6 receptor α (sIL-6Rα) are commonly observed during inflammatory responses, allowing for IL-6 signaling in cells that express the ubiquitous receptor subunit gp130 but not IL-6Rα, such as endothelial cells. Activation of Toll-like receptor (TLR)-4 or the tumor necrosis factor (TNF) receptor leads to NF-κB-dependent increases in endothelial IL-6 expression. Thus, we hypothesize that danger signals may induce autocrine IL-6 signaling within the endothelium via sIL-6Rα-mediated trans-signaling. In support of this hypothesis, we recently demonstrated that conditional deletion in the endothelium of the IL-6 signaling inhibitor SOCS3 leads to rapid mortality in mice challenged with the TLR-4 agonist endotoxin through increases in vascular leakage, thrombosis, leukocyte adhesion, and a type I-like interferon response. Here, we sought to directly test a role for sIL-6Rα in LPS-treated human umbilical vein and dermal blood microvascular endothelial cells. We show that cotreatment with sIL-6Rα dramatically increases the loss of barrier function and the expression of COX2 and tissue factor mRNA levels induced by LPS. This cotreatment led to strong activation of STAT1 and STAT3 while not affecting LPS-induced activation of p38 and NF-κB signaling. Similar results were obtained when sIL-6Rα was added to a TNF challenge. JAK inhibition by pretreatment with ruxolitinib or by SOCS3 overexpression blunted LPS and sIL-6R synergistic effects, whereas SOCS3 knockdown further increased the response. Together, these findings demonstrate that IL-6 signaling downstream of NF-κB activation leads to a strong endothelial activation and may explain the acute endotheliopathy observed during critical illness.

Serum biomarker panel diagnostics in pancreatic ductal adenocarcinoma: the clinical utility of soluble interleukins, IFN-γ, TNF-α and PD-1/PD-L1 in comparison to established serum tumor markers

PurposeNovel biomarkers to better predict outcome and select the best therapeutic strategy for the individual patient are necessary for pancreatic ductal adenocarcinoma (PDAC).MethodsUsing a panel assay, multiple biomarkers (IFN-γ, IL-10, IL-6, IL-8, TNF-α, CEA, CA 19–9, CYFRA 21–1, HE4, PD-1 and PD-L1 levels) were measured in serum samples of 162 patients with resected, locally advanced and metastatic PDAC in this retrospective single-center study. Optimal cut-off values to differentiate prognostic subgroups with significantly different overall survival (OS) were determined by receiver operator characteristics and Youden Index analysis. Marker levels were assessed before the start of chemotherapy and correlated with OS by univariate and multivariate Cox analysis.ResultsMedian OS for resected patients was 28.2 months, for locally advanced patients 17.9 months and for patients with metastatic disease 8.6 months. CYFRA 21–1 and IL-8 discriminated metastatic from locally advanced patients best (AUC 0.85 and AUC 0.81, respectively). In univariate analyses, multiple markers showed prognostic relevance in the various subgroups. However, multivariate Cox models comprised only CYFRA 21–1 in the resected group (HR 1.37, p = 0.015), IL-10 in locally advanced PDAC (HR 10.01, p = 0.014), as well as CYFRA 21–1 and CA 19–9 in metastatic PDAC (p = 0.008 and p = 0.010) as an independent prognostic marker for overall survival.ConclusionIL-10 levels may have independent prognostic value in locally advanced PDAC, whereas CYFRA 21–1 levels are prognostic after PDAC surgery. CYFRA 21–1 and IL-8 have been identified to best discriminate metastatic from locally advanced patients.

Association between IL-23R rs11209026 Gene polymorphism and soluble interleukin 23 receptor (△9) in Iraqi patients with and without lupus nephritis

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the uncontrolled formation of antibodies, overproduction of pro-inflammatory cytokines with a genetic background that is poorly understood. This case-control study comprised 80 SLE patients, SLE patients who met the American College of Rheumatology (ACR) criteria (40 SLE and 40 LN groups), and 40 healthy controls. All participants' serum IL-23R levels were determined using an enzyme-linked immunosorbent assay (ELISA). 40 patients (20 SLE and 20 LN groups) and 12 age- and sex-matched healthy controls were genotyped for IL-23R gene polymorphisms (rs11209026 G&gt;A) by direct DNA sequencing. As for sIL-23R levels, the results showed non-significant differences between the groups of the patients (0.18(0.11-7.50) vs 0.17(0.12- 3.73) (P= 0.751) in SLE and LN, respectively) and the control group (0.17 (0.12-2.69) (P=0.713) vs (P=0.934) in SLE and LN, respectively). Analysis of the rs11209026 sequencing results showed that most patients and the control group share the same genotype, which is GG, and that the A allele is underrepresented in the studied groups, as the AA genotype did not appear in the results. Our results suggest that rs11209026 affects the production of the soluble form of IL-23R.

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner.

Interferon gamma (IFN-γ) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-γ pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-γ receptor (IFN-γ-R). However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR−/− bone marrow chimeric model, this study showed that non-hematopoietic IFN-γ response is critical for development of FHL hepatitis in LCMV-infected Prf1−/− mice. Lack of hepatic IFN-γ responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-γ non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-γ response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-γ, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.

Role of Neuron-Specific Enolase in the Diagnosis and Disease Monitoring of Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. The diagnosis of sarcoidosis is based on clinicopathologic findings accompanied by the formation of granulomas in multiple organs, including the lung. Although angiotensin-converting enzyme (ACE) and soluble interleukin 2 receptor (sIL-2R) are traditionally used for the diagnosis of sarcoidosis, specific diagnostic markers remain to be determined. In the current study, we found that serum neuron-specific enolase (NSE) levels were elevated in patients with sarcoidosis. Serum NSE levels were positively correlated with serum ACE and sIL-2R levels. The sensitivity of NSE alone was modest, but its combination with sIL-2R and ACE had the highest sensitivity compared to those of each single marker. When comparing serum NSE and pro-gastrin-releasing peptide (ProGRP) levels in SCLC patients with those in patients with sarcoidosis and nonsarcoidotic benign diseases, serum NSE could be used to distinguish SCLC from sarcoidosis and nonsarcoidosis by setting at a cutoff value of 17.0 ng/ml with a sensitivity of 73.5% and a specificity of 90.2%, which were comparable to those of ProGRP. Serum NSE levels were associated with organ involvement and were higher in sarcoidosis patients who had been treated with oral corticosteroid (OCS) than in those who had never received OCS therapies; there was a positive association between elevated serum NSE levels and OCS use. Increased concentrations of serum NSE in patients at the nonremission phase decreased after spontaneous remission, whereas serum NSE levels fluctuated in accordance with serum ACE or sIL-2R levels during the follow-up period in patients with sarcoidosis. These findings suggest that NSE could be a marker for the diagnosis and monitoring of the clinical outcome of patients with sarcoidosis.

Endobronchial ultrasound-guided transbronchial needle aspiration facilitating diagnosis of sarcoidosis in a breast cancer patient with multiple lymphadenopathy: a case report

BackgroundSarcoidosis is a benign systemic granulomatous disorder of unknown etiology. Cell-mediated immunity disorder is often found in sarcoidosis patients, and an association between malignant tumors and sarcoidosis has been suggested. Sarcoidosis and malignant disease can occur simultaneously or sequentially, leading to misdiagnosis and mistreatment. Sarcoidosis is diagnosed clinically, radiologically, and histologically. We report herein a case of sarcoidosis diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration from the mediastinal lymph nodes of a breast cancer patient.Case presentationThe patient was a 70-year-old Asian woman who presented with right breast tumor. A 20-mm movable mass was identified in the inferolateral quadrant of the right breast, and mammography revealed a spiculated mass with calcification. Ultrasonography revealed a mass with internal hypoechogenicity, and biopsy revealed estrogen receptor-positive, human epidermal growth factor receptor 2-positive invasive ductal carcinoma. Positron emission tomography/computed tomography showed multiple lymphadenopathy including mediastinal lymph nodes, with fluorodeoxyglucose accumulation in those nodes suggesting breast cancer metastases. Endobronchial ultrasound-guided transbronchial needle aspiration of a mediastinal lymph node revealed noncaseous epithelioid granuloma. Due to a history of uveitis and elevated soluble interleukin 2 receptor, lymphadenopathy due to sarcoidosis and stage IIA breast cancer were diagnosed. Right partial mastectomy and axillary lymph node dissection were performed after preoperative chemotherapy. No exacerbation of sarcoidosis symptoms has been observed during treatment.ConclusionWe report a case of breast cancer in which sarcoidosis could be diagnosed based on endobronchial ultrasound-guided transbronchial needle aspiration, a history of uveitis, and elevated soluble interleukin 2 receptor despite fluorodeoxyglucose positron emission tomography/computed tomography suggesting multiple lymph node metastases. This report emphasizes the importance of differential diagnosis of lymph node involvements in cancer patients.

Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options.

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy.

Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

Peculiarities of iron metabolism in patients with breast cancer before adjuvant chemotherapy

Introduction. Numerous studies using multivariate analysis have confirmed the relationship between low hemoglobin and / or hypoxia of tumor tissue with a worsening prognosis.The study objective was to assess the state of iron metabolism in breast cancer patients in the perioperative period, before conducting adjuvant chemotherapy for adequate administration of iron and recombinant erythropoietins preparations.Materials and methods. The object of the study included 17 breast cancer patients with a relatively favorable prognosis, with luminal types A and B (Her 2 / neu positive or negative), three times negative type. The examination was carried out in the postoperative period, before the first course of adjuvant chemotherapy. The main metabolites of ferrokinetics were studied: hepcidin 25 (GP25), ferritin, soluble transferrin receptors, transferin, iron, erythropoietin, C-reactive protein and interleukin 6 indicators.Results. In patients with breast cancer, even before adjuvant chemotherapy, a violation of iron metabolism was revealed. Anemic syndrome (AS) with iron deficiency erythroproiesis was diagnosed in 29.4 % of them. In most of them, AS was accompanied by a deficiency of endogenous erythropoietin. Iron deficiency anemia was more common; functional iron deficiency (FID) was found in some patients. In contrast to patients with iron deficiency anemia, patients with FID had a significant concentrations of GP25, C-reactive protein, and interleukin 6 and ferritin were within the upper limit of normal. It should be noted that GP25 hyperexression was observed not only in breast cancer patients with FID, but also in patients without laboratory signs of anemia, which did not exclude the latent stage of AS.Conclusion. To achieve the effectiveness of the treatment of AS, a comprehensive and personalized approach is required. Iron preparations are prescribed to restore iron metabolism; recombinant erythropoietins preparations are used to increase the rate of erythrocyte formation during chemotherapy. The same treatment regimen is justified for the correction of AS with FID. However, the strategy for future treatment of FID is associated with the use of GP25 antagonists (in order to overcome the retention of iron in the reticuloendothelial system), hormones or cytokines that can effectively stimulate erythropoiesis in AS with impaired iron metabolism.