Soluble Interleukin-2 Receptor Alpha Research Articles

Elevated circulating soluble interleukin-2 receptor (sCD25) level is associated with prefrontal excitatory-inhibitory imbalance in individuals with chronic pain: A proton MRS study

Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance. In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA+ (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC. We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA+. Greater prefrontal Glx/GABA+ was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA+ on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing. Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.

Estimation of plasma soluble interleukin-2 receptor alpha chain level in adults with acute myeloid leukemia

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a clonal malignant condition of immature hematopoietic cells, characterized by clonal proliferation of abnormal cells (blasts) in the marrow leading to impairment of the normal blood cell production giving rise to failure of the bone marrow. Soluble interleukin-2 (IL-2) receptor alpha chain is a protein that is involved in the assembly of the high-affinity IL-2 receptor, and it has a critical role in controlling immune system homeostasis. The overexpression of sIL-2RA was investigated in many hematopoietic malignancies, and it was correlated with poor outcome. OJECTIVES: The aim of this study was to assess the sIL-2RA level as a prognostic factor and assess its impact on survival and if it can be used as a targeted treatment for a better outcome. MATERIALS AND METHODS: Sixty newly diagnosed adults with AML before starting therapy were included in the study, and they were followed up for 6 months to document survival status. Thirty healthy adults were taken as a control group. Using an enzyme-linked immunosorbent assay, the plasma sIL-2RA level was measured. Statistical analysis was done using Microsoft Excel 2019 and version 26 SPSS statistical software. P <0.05 was considered statistically significant. RESULTS: A considerable difference in the plasma sIL-2RA level between AML patients and controls also was more elevated in patients who died after 6-month follow-up. According to the blast percentage, total white blood cell count, and M0-M2 subgroups, the sIL-2RA level correlated positively. Irrelevant association was found regarding the patients’ age, the count of platelet, and the hemoglobin. CONCLUSIONS: Plasma sIL-2RA level is higher in AML patients than the control group at the time of diagnosis. Patients with a high level of plasma sIL-2RA have an inferior (overall survival) and poor outcome. SIL-2RA level is higher in M0-M2 subgroups than other subtypes. There is a significant association between sIL-2RA level and the absolute count of leukemic blasts.

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

BackgroundNon-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that...

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 & 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 & Class IV) than non-proliferative lupus nephritis (Class V) at baseline (3934.3 ± 1095.2, 3934.3 ± 1095.2 & 1801.98 ± 205.8 pg/L respectively) and levels were decreased significantly 6 months after treatment (p <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.

Relationships between levels of endocrine-disrupting chemicals and immune markers in maternal circulation during mid-pregnancy

Background and Aim: Prenatal exposure to endocrine-disrupting chemicals (EDCs) has been linked to child neurodevelopmental disorders. Maternal immune activation during pregnancy is associated with adverse child developmental outcomes. Whether EDCs influence maternal immune physiology is unclear. Methods: We analyzed data from general population controls (n=439) of the Early Markers for Autism (EMA) Study, a case-control study of children born during 2000-2003 in Southern California. Eleven polychlorinated biphenyls (PCBs), 6 brominated flame retardants (BFRs), 2 organochlorine pesticides (OCPs), 6 polyfluoroalkyl substances (PFAS), and 22 cytokines/chemokines were measured in maternal serum samples collected 15-20 weeks into pregnancy. We assessed individual relationships between log-transformed EDC levels and immune markers with spearman correlations and adjusted linear regression models. We further explored overall associations of EDC mixtures with specific immune markers using Bayesian kernel machine regression (BKMR). Results: After adjustment for false-discovery rate, 28 correlations between EDCs and maternal immune markers were statistically significant (spearman rho ranging from -0.25 to 0.24). These top correlations comprised 14 chemicals (9 PCBs, 3 PFAS, 1 BFR, and 1 OCP), and 8 immune markers. In adjusted linear models, all PCBs were inversely associated with levels of soluble interleukin-2 receptor alpha (sIL-2ra), with PCB99 showing the strongest relationship (adj-β[95%CI]: -0.48[-0.69, -0.27]). In BKMR, increasing all congeners in the PCB mixture from their 50th to their 95th percentiles was associated with decreased sIL-2ra (adj-β[95%CrI]: -0.43[-0.84, -0.02] and PCB99 had the highest relative importance in this mixture. Among other EDCs, p,p´-DDE, an OCP, was inversely associated with multiple markers (IL-12p40, IL-13, and IL-1ra). In contrast, others, such as Et-FOSAA, a PFAS, were positively associated with multiple immune markers, including IL-12p70, GM-CSF, IL-1ra, and IL-10. Conclusions: These findings suggest that specific EDCs may affect diverse immune and inflammatory pathways during pregnancy. These relationships may have implications for child development. Keywords: EDCs; prenatal; immune

Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma.

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

Interleukin-2 receptor alpha as a biomarker for nonalcoholic fatty liver disease diagnosis.

Two recent studies in the adult and pediatric Nonalcoholic Steatohepatitis-Clinical Research Network (NASH-CRN) cohorts have shown that soluble interleukin-2 receptor alpha (IL2RA) levels increased with fibrosis severity. However, no hepatic study has been conducted in Asian morbidly obese patients who underwent bariatric surgery. In this study, we proposed IL2RA as a biomarker for nonalcoholic fatty liver disease (NAFLD) diagnosis and performed immunohistochemistry (IHC) staining of IL2RA. This prospective cohort study enrolled 123 morbidly obese patients who underwent bariatric surgery at Taipei Medical University Hospital from October 2016 to June 2018. During bariatric surgery, all patients underwent a wedge liver biopsy under laparoscopic guidance. The diagnoses of NASH and liver fibrosis were made histologically. In IHC of IL2RA, the number of lymphocytes with IL2RA immunoreactivity was counted in five high-power fields (×400, total: 1.19 mm2). Among the 123 patients, the mean age was 35.5 years, mean body mass index (BMI) was 40.6 kg/m2, 87 (70.7%) were female, 25 (20.7%) had diabetes mellitus, and 57 (46.3%; 11 with non-NAFLD and 46 with steatosis) and 66 (53.7%) were included in the non-NASH and NASH groups, respectively. The NASH group had higher IHC of IL2RA than the non-NASH group. In multivariate analysis, IHC of IL2RA (odds ratio, 1.025; 95% confidence interval, 1.006-1.045; p = 0.011) and alanine aminotransferase (ALT; odds ratio, 1.045; 95% confidence interval, 1.018-1.073; p = 0.001) were the independent factors associated with NASH. The area under the receiver operating curve of IL2RA IHC for NASH was 0.627 at the cutoff value of 82 (p = 0.0113). IL2RA is significantly associated with NASH in morbidly obese patients and would be a useful biomarker for NASH diagnosis.

Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms.

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. Further, patients with T1D have 3–4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.

Measurement of the concentration of serum soluble interleukin-2 receptor alpha chain in dogs with lymphoma

Soluble interleukin-2 receptor (sIL-2r) is released directly from the surface of lymphocytes expressing interleukin-2 receptor alpha chain (CD25), and its serum concentration has been found to reflect the prognosis of human lymphoproliferative malignancies. In this study, we demonstrated the presence of sIL-2r in canine serum and developed a specific sandwich enzyme-linked immunosorbent assay (ELISA) to quantify the concentration of canine serum sIL-2r. In the immunoprecipitation (IP) assay, CD25 protein weighing approximately 45 kDa was detected in canine serum, smaller than the membrane-bound CD25 (approximately 55 kDa). To measure the concentration of serum sIL-2r in dogs, an ELISA system was developed. Serum sIL-2r levels were significantly higher in dogs with multicentric high-grade B-cell lymphoma before therapy than that in healthy dogs. Serum sIL-2r concentration was also found to be elevated in a proportion of dogs with other types of lymphoma. Changes in serum sIL-2r levels generally paralleled the changes in mass and lymph node size in dogs with high-grade B-cell lymphoma. This study demonstrated that serum sIL-2r level would be a marker to monitor tumour growth and regression in canine lymphoma.

Preliminary Results of a Combined Score Based on sIL2-Rα and TIM-3 Levels Assayed Early After Hematopoietic Transplantation.

Assays of cytokines in the plasma at the onset of graft-vs. -host disease (GVHD) can predict disease severity and treatment-related mortality (TRM); however, the optimal time during which cytokines should be tested and the specific panel of cytokines with the highest predictive ability remain unknown. We chose a predefined time point, 18 days after hematopoietic stem cell transplantation (HSCT), to measure the levels of six cytokines in the plasma: soluble interleukin-2 receptor alpha (sIL2-Rα), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), suppression of tumorigenicity-2 (ST-2), intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-γ), and interleukin-6 (IL-6). The study included 95 patients, who underwent allogeneic hematopoietic transplantation at our institution. Plasma levels of sIL2-Rα and TIM-3, measured as continuous data, had predictive value for overall survival (sIL2-Rα, p = 0.002; TIM-3, p = 0.0007), while TRM could be predicted by sIL2-Rα (p = 0.0005), IFN-gamma (p = 0.01), and IL-6 (p = 0.0001). No cytokine was associated with the risk of relapse. Patients were categorized into groups, according to cytokine thresholds determined by receiver operating characteristic curve analysis (sIL2-Rα ≤ or > 8,100 pg/ml; TIM-3 ≤ or > 950 pg/ml) and multivariate analysis was conducted. High levels of both TIM-3 and sIL2-Rα were significant predictors of poor survival [TIM-3 > 950 pg/ml: hazard ratio (HR) = 6.214 (95% CI 1.939–19.910), p = 0.002 and sIL2-Rα > 8.100 pg/ml: HR = 2.644 (95% CI 1.308–5.347), p = 0.006]. Using these cutoff thresholds, we constructed a composite scoring system that could distinguish three different groups of patients with varying rates of TRM: high risk, 41.7%; intermediate risk, 10.8%; and low risk, 7.1% (Gray's test: p = 0.001). If confirmed in a validation cohort, this composite scoring system could be used to guide the modulation of post-transplant immune suppressive therapy.

Association of soluble interleukin-2 receptor alpha with laboratory parameters and clinical findings of hemophagocytic lymphohistiocytosis patients: The first report from South of Iran.

INTRODUCTION:Hemophagocytic lymphohistiocytosis (HLH) is caused by overactivation of immune system. Gene mutations, infections, malignant, and autoimmune trigger the development of the disease.MATERIALS AND METHODS:Clinical data and peripheral blood samples of 21 patients suspected of HLH were collected in Shiraz Medical Centers 2017–2018. Peripheral blood samples were analyzed for soluble interleukin-2 receptor alpha (sIL2Rα) marker (sCD25), and the results were compared with 36 normal controls as well as comparison with clinical findings and other laboratory parameters.RESULTS:Twenty-one patients (11 males and 10 females) with an average age of 5.2 were investigated. In this study, peripheral blood samples were taken from 16 newly diagnosed patients before treatment, and five were posttreatment blood samples. The mean sIL2Rα level before treatment in 16 patients was 9023 pg/ml. The mean peripheral blood sample of the 36 controls was 3025 pg/ml. The mean of the five posttreatment samples was 4198 pg/ml. Significant difference between pretreatment and the control group was observed. However, no significant difference was detected between after treatment samples and the control group. By comparing the sIL2Rα levels between patients with increased aspartate aminotransaminase (AST) and patients with normal AST level, there was a significant difference in the amount of IL2Rα level.CONCLUSION:This study highlights the importance of IL2Rα marker in the diagnosis and follow-up, during treatment and suppression. Furthermore, a significant difference with respect to AST level requires further investigation.

Elevated Plasma sIL-2Rα Levels in Primary Myelofibrosis Play a Distinct Role on Disease Progression in JAK2V617F and Calr Mutants

Background: Plasma soluble interleukin-2 receptor alpha (sIL-2Rα), that is released from the cell surface of activated T and B lymphocytes, is one of the best markers of immune activation. High levels of sIL-2Rα have been correlated with poor prognosis in different types of cancers. In patients with primary myelofibrosis (PMF) elevated plasma levels of the receptor are associated with risk of blast transformation and death. In this study we aimed to analyze how increased levels of sIL-2Rα mark the disease progression to improve our knowledge on the immune regulation of the disease. Methods: sIL-2Rα plasma concentration values were obtained by a commercial immunoassay (R&D Systems), according to the Manufacturer's Instructions, and expressed in pg/ml. Health care data of persons with PMF were obtained from the data-base of the Center for the Study of Myelofibrosis at the IRCCS Policlinico S. Matteo Foundation in Pavia. We excluded persons treated with disease-modifying drugs at any time before or on the date of base-cohort entry, and persons with acute inflammatory diseases, autoimmune diseases, other neoplasms, and severe liver or renal dysfunction. The final study cohort consisted of 300 subjects. Thirty-four healthy normal subjects matched for age and sex represented the control group. The study was approved by the local Ethic Committee, and was conducted complying with the principles of the Declaration of Helsinki. Results: In patients with PMF, plasma sIL-2Rα values ranged from 275 to 13,860 pg/ml, with a mean value of 1693 ± 1529 pg/mL standard deviation (SD). sIL2Rα metrics in healthy controls were: mean, 740 ± 346 pg/mL (SD), range, 207 to 1718 pg/mL. Difference in plasma sIL2Rα levels between subjects with PMF and normals was significant (P<0.001). In the analyses, we used a cut-off point of 1300 pg/mL based on the distribution of sIL-2Rα in normal subjects (upper 95th centile). Based on this cut-off, 51.1% individuals with PMF had elevated sIL-2Rα levels. At a cross-sectional analysis, in JAK2V617F mutated subjects, increasing sIL2-Rα levels were associated with clinical and hematological parameters that vary with disease progression, like decreasing hemoglobin and platelet count, increasing spleen size, white blood cell (WBC) count, frequency of circulating blood blasts and hematopoietic stem and progenitor (HSP)-CD34+ cells. The correlation coefficient of sIL-2Rα with these parameters ranged fom 0.27 to 0.41. In CALR mutated patients, the association of increased sIL-2Rα levels with decreased platelet count, increased frequency of circulating HSP-CD34+ cells, WBC count and blasts no longer remained. After a median follow-up of 61 months (range 2-178), out of the 108 patients analyzed at diagnosis, 32 (29.6%) developed severe anemia (Hb < 10 g/dL), 23 (21.3%) massive splenomegaly (spleen > 10 cm from the left costal margin), 26 (24.1%) leukocytosis (WBC >12 x109/L), and 22 (20.4%) an alarming number of HSP-CD34+ cells in PB (>100 x 106/L). Moreover, 10 (9.2%) received an allogeneic hematopoietic stem cell transplantation (HSCT), 15 (13.8%) incurred in blast transformation (BT), and 8 (7.4%) died. In patients with JAK2V617F mutation, having elevated level of sIL-2Rα gave a higher risk of incurring in severe anemia (hazard ratio (HR), 3.70, 95% CI, 1.31-10; P=0.009), large splenomegaly (HR, 8.33; 95% CI, 2.12-33.3; P=0.002) and alarming HSP-CD34+ cells (HR, 4.14; 95% CI, 1.02-20; P=0.050). Moreover, JAK2V617F mutants with elevated levels of sIL-2Rα had higher risk of death than those with non-elevated sIL-2Rα (HR, 9.09; 95% CI, 1.75-50; P=0.008). On the contrary, in CALR mutants no interaction with the levels of sIL-2Rα and risk of disease progression was evidenced. By using a composite endpoint that considered death for any cause, BT or HSCT, PMF patients with JAK2V617F mutation carrying an elevated sIL-2Rα presented a shorter time to event as compared to those with non-elevated sIL-2Rα (P=0.011), while in CALR mutants this difference disappeared (P=0.80) (Figure). Conclusion: The results of this study give a strong proof of concept that the immune landscape of PMF is associated with the presence/absence of JAK2V617F or CALR mutation. Acquiring direct evidence that elevated levels of sIL-2Rα represents an immune- mediated modality of disease progression in JAK2V617F but not in CALR mutated patients opens new areas of investigation towards an individualized therapeutic approach of PMF. Figure Disclosures No relevant conflicts of interest to declare.

Biological variation of immunological blood biomarkers in healthy individuals and quality goals for biomarker tests

BackgroundCytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers.ResultsEstimates of intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were examined for blood immunological biomarkers. Biomarkers with CVI < 10% for both genders were CD3, CD4, and CD8 T-cells, serum levels of soluble cluster of differentiation 14 (sCD14), sCD163, and soluble glycoprotein 130 (sgp130). The CVI for serum levels of adiponectin, interleukin-1 receptor antagonist (IL-1Ra), macrophage inflammatory protein 1 beta (MIP-1β), soluble CD40 Ligand (sCD40L), soluble interleukin-2 receptor alpha (sIL-2Rα), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor II (sTNF-RII), and tumor necrosis factor alpha (TNF-α) were between 11 and 20%. Biomarkers with CVG < 20% were CD3 T-cell, and serum concentrations of sCD14, sCD40L, and sgp130. The biomarkers with CVG > 40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα.ConclusionThe biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CVI was relatively small while CVG was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient’s test result with previous ones may be more useful than the usage of conventional reference values.

Hemophagocytic Lymphohistiocytosis and Infections: An Update.

Hemophagocytic Lymphohistiocytosis and Infections: An Update.

The Immunology of Macrophage Activation Syndrome.

Synonymous with secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus (SLE). Clinical and laboratory features of MAS include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic coagulopathy, and liver dysfunction. Soluble interleukin-2 receptor alpha chain (sCD25) and sCD163 may be elevated, and histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining. A common hypothesis as to the pathophysiology of many cases of MAS proposes a defect in lymphocyte cytolytic activity. Specific heterozygous gene mutations in familial HLH-associated cytolytic pathway genes (e.g., PRF1, UNC13D) have been linked to a substantial subset of MAS patients. In addition, the pro-inflammatory cytokine environment, particularly IL-6, has been shown to decrease NK cell cytolytic function. The inability of NK cells and cytolytic CD8 T cells to lyse infected and otherwise activated antigen presenting cells results in prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a pro-inflammatory cytokine cascade. The cytokine storm results in activation of macrophages, causing hemophagocytosis, as well as contributing to multi-organ dysfunction. In addition to macrophages, dendritic cells likely play a critical role in antigen presentation to cytolytic lymphocytes, as well as contributing to cytokine expression. Several cytokines, including tumor necrosis factor, interferon-gamma, and numerous interleukins (i.e., IL-1, IL-6, IL-18, IL-33), have been implicated in the cytokine cascade. In addition to broadly immunosuppressive therapies, novel cytokine targeted treatments are being explored to dampen the overly active immune response that is responsible for much of the pathology seen in MAS.

Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides.

Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (Treg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8+ T cells co-cultured with IL-2-stimulated CD4+ T cells that had been pretreated with CMD178 compared to CD8+ cells co-cultured with untreated IL-2-stimulated CD4+ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit Treg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.

High serum levels of soluble interleukin-2 receptor (sIL2-R), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) are associated with adverse clinical features and predict poor outcome in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with heterogeneous outcomes. To improve accuracy of the international prognostic index score, new biological variables are being investigated. The aim of this study was to determine the prognostic significance of serum levels of different cytokines, namely soluble interleukin-2 receptor (sIL2-R), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF). We analyzed 197 de novo DLBCL patients (91 M/106 F; median age 66 years) treated with immunochemotherapy in a single institution. Serum cytokine determination was performed with ELISA, using the upper normal values as cut-offs. sIL-2R, IL-6 and TNF were elevated in 133, 130 and 144 cases, respectively. Elevation of each of these cytokines correlated with worse performance status, presence of B symptoms, advanced stage, elevated LDH and β2-microglobulin (P<0.03) and lower complete remission rate (P<0.001). Elevated levels of serum sIL-2R and TNF were significantly associated with shorter progression-free (PFS) and overall survival (OS), while elevated IL-6 only with shorter PFS. Early death (<4months from diagnosis) strongly correlated with elevated cytokines. Determination of serum cytokines levels is simple and adds information regarding risk of early death, response to therapy, and outcome.

Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease.

Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65-77).

Novel inflammatory markers associated with cognitive performance: Singapore Longitudinal Ageing Studies

We identified and validated several novel inflammatory markers of cognitive performance in community-living older persons. An exploratory study (n = 83) correlated 177 inflammatory markers assayed by Luminex with the Mini–Mental State Examination (MMSE) and identified 8 inflammatory markers for enzyme-linked immunosorbent assay (ELISA) and correlations with MMSE, Montreal Cognitive Assessment (MoCA), and cognitive impairment in the validation study (n = 139). The validation study replicated the significant associations of soluble interleukin-2 receptor alpha chain (sIL-2Rα; p = 0.050), soluble tumor necrosis factor receptor 2 (sTNFR2; p = 0.002) and soluble glycoprotein 130 (sgp130; p = 0.026) with MMSE, and sIL-2Rα (p = 0.019) and sgp130 (p < 0.001) with MoCA. Significant trends of associations of tertiles of sgp130, sIL-2Rα, and sTNFR2 were found with cognitive impairment. Highly elevated estimates of association of high versus low tertiles were obtained for sgp130 (odds ratio [OR] = 4.24, 95% confidence interval [CI] 0.96–18.8), sIL-2Rα (OR = 3.94, 95% CI 0.83–18.7), and sTNFR2 (OR = 7.58, 95% CI 1.19–48.1). sgp130, sTNFR2, and sIL-2Rα are promising inflammatory markers of low cognitive performance for further investigation.

Sexual Dimorphisms of Adrenal Steroids, Sex Hormones, and Immunological Biomarkers and Possible Risk Factors for Developing Rheumatoid Arthritis.

Innate immunity and immunological biomarkers are believed to be interrelated with sex hormones and other neuroendocrine factors. Sexual dimorphism mechanisms may be operating in certain rheumatic and inflammatory diseases which occur more frequently in women than men, as rheumatoid arthritis (RA). Less data have been available on altered interrelations of the combined neuroendocrine and immune (NEI) systems as risk factors for development of certain diseases. In this study, serological interrelations of NEI biomarkers are analyzed before symptomatic onset of RA (pre-RA) versus control (CN) subjects, stratified by sex. Sexual dimorphism was found in serum levels of acute serum amyloid A (ASAA), soluble interleukin-2 receptor alpha (sIL-2Rα), and soluble tumor necrosis factor receptor 1 (sTNF-R1). Multiple steroidal and hormonal (neuroendocrine) factors also showed highly (p < 0.001) significant sexual dimorphism in their assayed values, but less for cortisol (p = 0.012), and not for 17-hydroxyprogesterone (p = 0.176). After stratification by sex and risk of developing RA, differential NEI correlational patterns were observed in the interplay of the NEI systems between the pre-RA and CN groups, which deserve further investigation.