Serum sIL-2R Levels Research Articles

Role of periostin in evaluating the responsiveness of allergic patients to allergen-specific immunotherapy

Objectives: Allergen-specific immunotherapy (AIT) has been considered the most effective treatment for IgE mediated allergies, especially respiratory allergies. Several biomarkers have been developed to evaluate the clinical efficacy of AIT, yet none of them have been thoroughly validated. So our objective here is to investigate the usefulness of periostin as a biomaker for monitoring the efficacy of allergen immunotherapy. Materials and methods: This study included 46 healthy non-atopic volunteers and 46 patients with allergic rhinitis (AR). They were sensitized only to date palm pollen. The participants were tested by skin prick test and total serum IgE levels were measured. Serum samples were collected from healthy subjects and allergic patients before and after the one-year AIT. Serum levels of periostin, eotaxin, and sIL-2R were estimated by ELISA. Symptom scores in the allergic patients were also evaluated before and after completing one year AIT. Results: There is a significant increase in serum levels of IgE, periostin, sIL-2R, and eotaxin in allergic patients as compared to healthy controls. Symptom scores, sIL-2R and serum periostin levels were significantly decreased after one-year AIT in AR patients. Conclusion: Periostin can be used as a biomarker to evaluate AIT efficacy in AR patients. Bangladesh Journal of Medical Science Vol. 21(1) 2022 Page : 184-190

Comparison of serum sIL-2R and LDH levels in patients with intravascular large B-cell lymphoma and patients with advanced stage diffuse large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVL) is a rare type of lymphoma characterized by tumor growth selectively within the vessels. The 5th edition of the World Health Organization classification defines IVL as a large B-cell lymphoma, the same as diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Since the clinical manifestations of IVL are nonspecific, the diagnosis is time-consuming, and the course is often fatal. Serum soluble interleukin-2 receptor (sIL-2R) and serum lactate dehydrogenase (LDH) levels are known to be elevated in a variety of lymphomas. However, the mechanism of sIL-2R elevation in B-cell lymphomas is not fully understood. In this study, we analyzed the serum level of laboratory findings, including sIL-2R and LDH, as well as the presence of B symptoms in 39 patients with IVL, and compared them with 56 patients with stage IV DLBCL. Both sIL-2R and LDH levels were significantly higher in IVL than in DLBCL (p = 0.035 and p = 0.002, respectively). In IVL, there were no significant differences in both sIL-2R and LDH levels between patients with and without B symptoms (p = 0.206 and p = 0.441, respectively). However, in DLBCL, both sIL-2R and LDH levels were significantly higher in the presence of B symptoms (p = 0.001 and p < 0.001, respectively). The high sIL-2R and LDH levels in IVL may be related to the peripheral blood microenvironment, but further studies are needed to verify this.

Association of high serum soluble interleukin 2 receptor levels with risk of adverse events in patients with cardiac sarcoidosis

Abstract Background Sarcoidosis is a systemic granulomatous disease that affects multiple organs. Among these, the presence of cardiac involvement is recognised as a determinant of worse clinical outcomes. Soluble interleukin 2 receptor (sIL-2R) is a potentially useful biomarker in the diagnosis and evaluation of disease severity in patients with sarcoidosis. However, it remains to be seen whether sIL-2R is associated with the severity and activity of disease in patients with cardiac sarcoidosis (CS). Purpose The aims of this study were to investigate whether sIL-2R was associated with clinical outcomes and to clarify the relationship between sIL-2R levels and disease activity evaluated by 18F-fluorideoxyglucose in positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with CS. Methods We examined 101 consecutive patients with CS who were admitted to our University HospitalbetweenMay 2003 and February 2020. Patients who had no data of serum sIL-2R levels before initiation of immunosuppressive therapy (n=18) were excluded. Ultimately, 83 patients were examined in this study. The primary outcome was a composite of advanced atrioventricular block (AVB), ventricular tachycardia or ventricular fibrillation (VT/VF), heart failure hospitalisation, and all-cause death. Inflammatory activity in the myocardium and lymph nodes were assessed by18F-FDG PET/CT. We used a published program to analyse the cardiac metabolic activity (CMA), and total lymph node glycolysis (TLyG), which are quantitative measures of FDG volume-intensity. Results During a median follow-up period of 2.96 (interquartile range 2.24–4.27) years, the primary outcome occurred in 24 patients (29%), including 1 advanced AVB, 13 VT/VF, 5 hospitalisations for heart failure, and 5 all-cause deaths. Kaplan-Meier analyses showed that the primary outcome occurred more frequently in patients with higher sIL-2R levels (&amp;gt;538 U/mL, the median) than in those with lower sIL-2R levels (Figure). A multivariable Cox regression analysis revealed that a higher sIL-2R level was independently associated with an increased subsequent risk of adverse events (hazard ratio 3.71, 95% confidence interval 1.63–8.44, p=0.002), even after adjustments for age, plasma B-type natriuretic peptide, estimated glomerular filtration rate, left ventricular ejection fraction, and late gadolinium enhancement, which are known to be strong determinants of worse clinical outcomes in patients with CS (Table). Furthermore, sIL-2R levels were significantly correlated with TLyG, the inflammatory activity in lymph nodes (r=0.346, p=0.003) but not with CMA, the inflammatory activity in myocardium (r=0.131, p=0.27). Conclusions Increased sIL-2R is associated with worse long-term clinical outcomes accompanied by increased systemic inflammatory activity in CS patients. These findings suggest the importance of assessing sIL-2R as a surrogate marker for further risk stratification in these patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science

Human Pegivirus (HPgV) Infection and Lymphoma Risk and Prognosis: A Study from North America

Background. HPgV (previously called GBV-C) is a single-stranded RNA virus belonging to the Flaviviridae, and is the most closely related human virus to the Hepatitis C virus. HPgV is transmitted through parenteral, sexual and perinatal routes and replicates in vitro in T and B-lymphocytes. Active infection lasts months to years and viremia can be detected in plasma by real time (RT)-PCR methods. HPgV viremia has been linked to risk of non-Hodgkin lymphoma in some previous studies, but these have had a limited number of cases. In the largest study conducted to date, we evaluated the association of HPgV viremia and viremic load (VL) with risk of developing lymphoma, overall and by major subtypes, in the Mayo Clinic Case-Control Study of Lymphoma. Because the virus has also been associated with better prognosis in the setting of co-infection with HIV in many studies, we further assessed the association of HPgV with prognosis. Finally, to better understand the association of HPgV with lymphoma risk we correlated the HPgV status with circulating levels of selected cytokines in a subset of our controls.Methods. To assess the role of HPgV in lymphoma risk (etiology), we used risk factor data and banked plasma samples (stored at -80°C) from 2094 lymphoma cases newly diagnosed from 2002-2009 and 1572 frequency matched controls. Plasma samples (blind to case/control status) were tested for HPgV RNA by RT-PCR, and those with RNA concentrations < 5,000 genome equivalents/ml were confirmed using nested RT-PCR methods. We used unconditional logistic regression model to estimate odds ratio (ORs) and 95% confidence intervals (CI) for the association of HPgV status (negative/positive) and VL (tertiles among positive controls) with lymphoma risk, adjusted for age and sex. To assess the role of HPgV in lymphoma outcome (prognosis), we used 2948 cases from the Iowa/Mayo Molecular Epidemiology Resource, a prospective cohort study of newly diagnosed lymphoma patients (included all cases from the case-control study). We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% CI for the association of HPgV viremia status and VL with event-free (EFS) and overall (OS) survival, adjusted for clinical and treatment variables. Circulating serum cytokines in 379 controls with HPgV data were analyzed using the Luminex-100 system Version 1.7. Data were acquired using STar Station software and analysis was performed using the MasterPlex QT 1.0 system.Results. The mean age of cases was 61 years, and 58.2% were male, while the mean age of controls was 63 years, and 51.1% were male; 78 (5.0%) controls and 211 (10.1%) cases were HPgV positive. There was a positive association of HPgV viremia with risk of lymphoma overall (OR = 2.14; 95% CI 1.63-2.80; p <0.0001), and for all major subtypes except HL and CLL/SLL (Table). Further adjustment for history of hepatitis, transfusion, autoimmune disease, atopy, family history of lymphoma, farming, obesity, smoking, alcohol use, or sun exposure did not confound these results, and results were consistent when excluding plasma samples (38%) collected after initiation of treatment. There was no dose-response association of VL with overall lymphoma risk: compared to HPgV negative, OR = 1.8 for lowest tertile (95% CI 0.58-5.97), OR = 4.3 for middle tertile (95% CI 0.97-19.6), and OR = 2.5 for highest tertile (95% CI 0.95-6.97). In the control group, median levels of serum sIL2-R (p=0.04), MIP1α (p=0.03) and MIG (p=0.02) were significantly higher in HPgV viremia positive compared to HPgV negative controls. In contrast to the analysis for risk, there was no association of HPgV viremia with EFS (HR = 1.00; 95% CI 0.85-1.18) or OS (HR = 0.97; 95% CI 0.79-1.20) for lymphoma overall, nor for any of the subtypes (Table). Likewise, there was no association of EFS or OS with viremic load.Conclusion. HPgV infection was associated with the overall risk of lymphoma, as well as most of the major NHL subtypes except CLL/SLL and HL, and this was not confounded by other lymphoma risk factors. However, there was no association of HPgV status with prognosis. Among controls, HPgV viremia was associated with higher levels of IL-2R, MIP1α and MIG, which were previously associated with risk of DLBCL and FL in a case-control analysis, and suggests potential mechanistic pathways for further exploration. These data support the hypothesis for a role for this virus in the etiology of multiple lymphoma subtypes. [Display omitted] DisclosuresNowakowski:Nanostring: Research Funding; Bayer: Consultancy, Research Funding; Abbvie: Consultancy; Genetech: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; celgene: Consultancy, Research Funding; pharmacyclics: Consultancy. Ansell:Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Celldex: Research Funding. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering .

Relationship between levels of serum gastric inhibitory polypeptide (GIP), soluble interleukin-2 receptor (sIL-2R), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and disease condition and prognosis of patients with severe acute pancreatitis.

To explore the relationship between levels of serum gastric inhibitory polypeptide (GIP), soluble interleukin-2 receptor (sIL-2R), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and the disease condition and prognosis in patients with severe acute pancreatitis (SAP). A total of 52 patients with SAP (SAP group) and 50 patients with mild acute pancreatitis (MAP group) admitted to Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China between April 2017 and December 2019 were included in the present study. A further 50 people who had received a healthy physical examination during the same period constituted the healthy control group. The levels of serum GIP, sIL-2R, and sTREM-1 were measured. The levels of serum GIP, sIL-2R, and sTREM-1 were compared among the SAP, MAP and healthy control groups, and the severity of disease (Ranson scoring system) was compared between the SAP and MAP groups. Pearson correlation analysis was used to analyze the correlation between the levels of serum GIP, sIL-2R, and sTREM-1 with the Ranson scores in the SAP group. A receiver operating characteristic (ROC) curve was drawn to evaluate the predictive efficacy of serum GIP, sIL-2R, and sTREM-1 on prognosis. The levels of serum GIP, sIL-2R, and sTREM-1 in the SAP and MAP groups were higher than those in the healthy control group, and the levels in the SAP group were higher than those in the MAP group. The Pearson correlation analysis showed that the levels of serum GIP, sIL-2R, and sTREM-1 in the SAP group were positively correlated with Ranson scores. The levels of serum GIP, sIL-2R, and sTREM-1 in the survival group were lower than those in the deceased group. The ROC curve showed that the best cut-off values of serum GIP, sIL-2R, and sTREM-1 in predicting prognostic survival were 167.040 pg/mL, 70.840 pg/mL, and 128.325 ng/mL, respectively. The levels of serum GIP, sIL-2R, and sTREM-1 are closely related to the severity of illness in patients with SAP and can be used as reference indicators for assessing the onset of SAP and predicting prognosis.

Interrelationships Between Serum Levels of Procalcitonin and Inflammatory Markers in Patients Who Visited a General Medicine Department.

Various laboratory markers of inflammation are utilized in general practice, but their clinical diagnostic significance is often ambiguous. In the present study, we determined the clinical significance of the examination of serum levels of procalcitonin (PCT) by comparing the PCT levels with the levels of other inflammatory markers, based on a retrospective review of 332 PCT-positive patients, including cases of bacterial infection (20.5%), non-specific inflammation (20.8%), neoplasm (9.9%), connective tissue diseases (8.4%), and non-bacterial infection (7.2%), were analyzed. The serum PCT level was highest in the bacterial infection group (1.94 ng/ml) followed by the non-specific inflammatory group (0.58 ng/ml) and neoplastic diseases group (0.34 ng/ml). The serum PCT level was positively correlated with serum levels of C-reactive protein (rho=0.62), soluble interleukin-2 receptor (sIL-2R; rho=0.69), and ferritin, the plasma level of D-dimer, and white blood cell count, and negatively correlated with the serum albumin level (rho=-0.52), hemoglobin concentration, and platelet count. The serum PCT level showed a stronger positive correlation with the serum sIL-2R level than the other biomarkers. The results suggest that an increased PCT level may indicate not only an infectious state but also a non-bacterial inflammatory condition in the diagnostic process in general practice.

Serum checkpoint molecules in patients with IgG4-related disease (IgG4-RD)

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4+ plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements.MethodsSerum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD.ResultsIn untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy.ConclusionSerum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.

Interrelationships Between Serum Levels of Procalcitonin and Inflammatory Markers

Abstract Various laboratory markers are utilized in general practice to detect inflammation, and procalcitonin (PCT) has also been routinely measured in many patients as a marker of bacterial infection and sepsis. An increase in PCT starts before an increase in C-reactive protein (CRP), and PCT level is useful not only for the diagnosis of bacterial infection, sepsis, as an indicator of the severity and prognosis of systemic inflammatory diseases, and is also useful for determination of the response to individual treatment. PCT is a precursor of calcitonin and PCT is not produced in a healthy state but is produced by various tissues in septic conditions. Since there are many patients with elevated levels of PCT due to nonbacterial causes, the levels of serum PCT have been apt to be used for a marker for the early detection of not only bacterial infection but also many inflammatory and/or febrile disorders including fever of unknown origin (FUO) in the clinical setting of general medicine. Here we attempted to clarify the differences and similarities of inflammatory markers for a clinical setting. We retrospectively reviewed 359 patients in whom serum PCT had been measured. According to our earlier study, the patients were categorized into 7 groups: bacterial, non-bacterial infection, non-specific inflammation, neoplasm, connective tissue disease (CTD), drug-induced diseases, and unidentified causes. Data for 332 PCT-positive cases including cases of bacterial infection (20.5%), non-specific inflammation (20.8%), neoplasm (9.9%), CTD (8.4%), and non-bacterial infection (7.2%) were used for analysis. Serum PCT level was highest in the bacterial infection group (1.94 ng/ml) followed by the non-specific inflammatory group (0.58 ng/ml) and neoplastic diseases group (0.34 ng/ml). Of note, serum PCT level was positively correlated with serum levels of C-reactive protein (R2=0.39), soluble interleukin-2 receptor (sIL-2R; R2=0.48), and ferritin, plasma level of D-dimer level and white blood cell count, whereas it was negatively correlated with serum albumin level (R2=0.27), hemoglobin concentration and platelet count. The result of the strongly positive correlation with serum level of sIL-2R suggested that an increased serum PCT level may indicate not only an inflammatory state but also a neoplastic state such as malignant lymphomas in the diagnostic process of various inflammatory disorders in a clinical setting of general practice for diagnosing febrile conditions.

Pretreatment levels of serum soluble interleukin-2 receptor are useful in selecting the treatment regimen for newly diagnosed advanced-stage follicular lymphoma with low tumor burden.

High pre-treatment serum soluble interleukin-2 receptor (sIL-2R) levels are associated with poor overall survival (OS) of patients with newly diagnosed follicular lymphoma (FL). We evaluated the usefulness of pre-treatment sIL-2R levels in selecting a treatment regimen for advanced-stage FL with low tumor burden (FL-LTB). This retrospective, multicenter observational study enrolled consecutive patients who received a rituximab-containing regimen for newly diagnosed advanced stage FL-LTB (grade 1-3a) between 2008 and 2018. We applied a previously reported cut-off value of 1800IU/mL for sIL-2R. A total of 211 patients were eligible for the analysis. Among patients with high sIL-2R (47 patients, 22.3%), the OS rates for patients treated by rituximab monotherapy (R-mono) (11 patients) were significantly lower than those treated by rituximab-combination chemotherapy (R-chemo) (36 patients): 5-year OS rates were 66.7% and 94.4%, respectively (P = 0.007). Among patients with low sIL-2R (164 patients, 77.7%), OS rates were comparably good between the R-mono group (34 patients) and the R-chemo group (130 patients): 5-year OS rates were 100% and 98.3%, respectively (P = 0.38). Our results suggest that R-chemo may yield better OS than R-mono for patients with newly diagnosed advanced-stage FL-LTB and high pre-treatment serum sIL-2R levels.

Serum Soluble Interleukin-2 Receptor as a Potential Biomarker for Immune-related Adverse Events.

Biomarkers for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) are required. We encountered a patient whose skin irAE fluctuated in parallel with serum soluble interleukin-2 receptor (sIL-2R). We examined 15 patients with cancer who received ICIs. Serum sIL-2R levels before and during ICI treatment were measured. The sIL-2R levels of preserved serum samples from another five patients who developed grade 3 irAEs were measured. Twelve patients showed no significant changes in sIL-2R levels during ICI treatment. Baseline serum sIL-2R levels in three patients increased beyond the normal range before the second cycle. These three patients had grade ≥2 irAEs at the second cycle treatment visit, supporting our hypothesis. Furthermore, at diagnosis of irAEs, the sIL-2R levels of all preserved samples from patients with grade 3 irAEs were significantly elevated. Serum sIL-2R is a promising biomarker for the diagnosis of irAEs.

Validation of systemic parameters for the diagnosis of ocular sarcoidosis.

Ocular sarcoidosis is diagnosed based on suggestive intraocular findings and systemic investigations. In this study, we assessed the clinical usefulness of systemic parameters in the diagnosis of ocular sarcoidosis. A retrospective study. This study included 79 cases (19 men, 60 women) with ocular sarcoidosis who visited Hokkaido University Hospital from 2011 to 2015 and were followed up for more than one year. The control group was 91 cases of other uveitis (38 men, 53 women). All cases underwent blood examination for the measurement of angiotensin-converting enzyme (ACE), Krebs von den Lungen-6 (KL-6), soluble interleukin-2 receptor (sIL-2R), and calcium (Ca) levels. Bilateral hilar lymphadenopathy (BHL) was also examined by plain chest X-ray and contrasting chest computed tomography (CT). The sensitivity for sIL-2R (76.4%) was higher than for ACE (37.7%), KL-6 (26.3%), and Ca (11.8%), although all showed high specificity: ACE (97.5%), KL-6 (96.2%), sIL-2R (93.8%), and Ca (95.1%). From these results, the Youden index of sIL-2R (0.70) was higher than that of ACE (0.35), KL-6 (0.26), and Ca (0.07). Imaging tests revealed better detection of BHL by contrasting chest CT (82.7%) than by plain chest X-ray (29.5%). The present findings indicate that the systemic parameters, particularly serum sIL-2R levels and BHL on contrasting chest CT, are useful biomarkers for the diagnosis of ocular sarcoidosis.

Autoantibodies, immunoglobulins and cytokine profile in patients with graves' disease and Graves' orbitopathy

Graves' Orbitopathy (GO) - also known as Thyroid Eye Disease (TED) - is an autoimmune condition in the modern sense. It is closely associated with autoimmune thyroid diseases. Cytokine-mediated mechanisms play a critical part in immunopathogenesis of autoimmune thyroid diseases including GO. Investigating cytokine profiles as well as antibodies to tissue-specific antigens is essential for explaining GO pathogenesis and developing future therapeutic strategies. The study examines serum levels of cytokines, autoantibodies and immunoglobulins IgG and IgG4 as mediators of autoimmune inflammation in patients with GO and Graves' Disease (GD). The study included 52 patients (104 orbits) aged 25-70 years (mean age 48,8±12,3) in the active phase of GO and GD verified with the international diagnostic standards. These patients did not get any treatment for GO before. The control group consisted of 14 individuals (28 orbits) aged 30-68 years without known autoimmune disease.Serum levels of IgG, IgG4,TNFα, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-13, sIL-6R, sTNFα- RI и TNFα- R2 IL-2R, TGFβ1, TGF β3, antibodies to TSH-receptor, free T4, free T3 and TSH were measured. A diagnostic ultrasound exam of thyroid gland, multislice computed tomography (MSCT) / magnetic resonance imaging (MRI) of orbits were performed. Mean duration of GO prior to being admitted to the centre was 8,8±1,5 months (range: 1 - 48 months). According to the degree of thyrotoxicosis compensation: 24 patients were clinically euthyroid, TSH 3,3±0,7 mU/L, free T4 11,9±0,59 pmol/L, free T3 3,97±0,1 pmol/L; 28 patients were considered to have subclinical thyrotoxicosis: TSH 0,03±0,01 mU/L, free T4 14,2±1,0 pmol/L, free T3 5,77±0,49 pmol/L. Serum levels of sTNFα-R2 (p=0,041, p≤0,05), sIL-2R (p=0,020, p≤0,05), TGFβ1 (p=0,000, p≤0,001) were significantly higher in patients with GO compared to the control group. Serum levels of sTNFRα2 (p=0,038, p&lt;0,05) and TGFβ1 (P=0,011, p≤0,05) were positively correlated with the duration of GO. The positive correlations between the serum level of sIL-6R (p=0,034, p≤0,05) and the severity of GO as well as between the serum level of sTNFα- R 1 (P=0,012, p≤0,05) and activity of GO were observed. 54% of patients had elevated concentration level of IgG4 in IgG ( &gt;5%). High levels of soluble cytokine receptors sTNFα-R2 and sIL-2R and cytokine TGFβ1 in patients with long-standing untreated GO and GD being euthyroid or having subclinical thyrotoxicosis indicate activation of regulatory T cells aimed at suppressing autoimmune processes. High concentration level of IgG4 in IgG and cytokine TGFβ1 can determine the development of fibrotic changes in the orbital tissues. A decrease in the concentration of cytokine TGFβ1 can indicate an unfavorable course of the disease GO.

Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss−/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.

Disease activity and response to therapy monitored by [18F]FDG PET/CT using volume-based indices in IgG4-related disease

PurposeThe efficiency of [18F]FDG PET/CT using volume-based indices was evaluated to assess the disease activity and response to therapy in patients with immunoglobulin G4-related disease (IgG4-RD).MethodsA total of 17 patients with IgG4-RD were examined with [18F]FDG PET/CT before and during treatment. The lesion boundary was determined using a fixed threshold of standardized uptake value (SUV) ≥ 2.5. The highest maximum SUV (SUVmax) among all affected lesions was calculated for individual patients. We summed metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of each affected lesion to generate a total MTV and total TLG. PET results were compared with those of serum IgG4 and soluble interleukin-2 receptor (sIL-2R) levels.ResultsThe mean number of involved organs per patient was 3.8 as determined by [18F]FDG uptake. The number of involved organs, total MTV and total TLG were significantly correlated with IgG4 (P = 0.046, < 0.001, < 0.001, respectively) and sIL-2R (P < 0.001, = 0.031, 0.031, respectively). According to the clinical assessments for therapy response, all patients were classified as improved. The SUVmax, total MTV, and total TLG during therapy were all significantly lower than those before therapy (all P < 0.001).Conclusion[18F]FDG PET/CT is valuable for assessing the extent of multi-organ involvement before therapy and monitoring subsequent therapy in patients with IgG4-RD. [18F]FDG PET/CT using volumetric indices correlated with serum IgG4 and sIL-2R levels.

Prognostic factors in IgG4-related disease: a long-term monocentric Chinese cohort study.

Patients with IgG4-related disease (IgG4-RD) suffer high relapse rates during long-term treatment, but factors that predict relapse outcomes are not well established. In the present study, we aimed to identify predictive factors for treatment resistance and disease relapse in a Chinese IgG4-RD cohort. This study enrolled 102 patients newly diagnosed with IgG4-RD. Disease prognosis was determined by evaluating disease activity and dosage of glucocorticoids. Predictive factors for refractory and relapsed disease were identified by univariate analysis and Cox regression. Among the 102 patients, 78 cases received medical treatment with regular follow-up (21 [6-111] months). During the follow-up period, 55 (70.5%) patients sustained clinical remission, and 23 (29.5%) patients suffered refractory or relapsed disease. The relapse rate of the patients with IgG4-RD was significantly higher among patients who stopped taking medicine than among those who continued treatment with glucocorticoids (GC) + immunosuppressor (IM). Serum TNF-α ≥ 13 pg/mL, sIL-2R ≥ 1010 U/mL, total cholesterol < 3.55 mmol/L, low-density lipoprotein < 2.0 mmol/L, IgG ≥ 20.2 g/L, and drug withdrawal were predictive factors for refractory and relapsed IgG4-RD. Multivariate Cox regression revealed that both sIL-2R and TNF-α were independent risk factors for refractory and relapsed disease. The combination of GC and IM treatment was an independent protective factor against refractory and relapsed IgG4-RD. High serum levels of sIL-2R and TNF-α may be informative risk factors for refractory and relapsed IgG4-RD. Our data suggest that a combination treatment of GC along with IM may be protective against refractory and relapsed IgG4-RD. Key Points • High sIL-2R and TNF-α levels are informative risk factors for refractory and relapsed IgG4-related disease. • Combination treatment of GC with IM protects against refractory and relapsed IgG4-related disease.

IL-2 and IL-2R gene polymorphisms and immune function in people residing in areas with high background radiation, Yangjiang, China

Purpose Long-term exposure to low dose radiation may trigger immune response and stimulate hormesis. Interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) play a crucial role in immune function. We aimed to explore the possible association of IL-2 and IL-2R gene polymorphisms with low dose radiation exposure, as well as the relationship with IL-2 gene expression in people residing in areas with a high background radiation in Yangjiang, China. Materials and methods We recruited and assigned 54 native men residing in Yangxi County, Yangjiang city to the high natural background radiation (HNBR) group, and 53 native men residing in Hengpi County, Enping city to the control area (CA) group. All the participants wore a thermoluminescent dosimeter (TLD) for 90 days, and answered questionnaires. The serum levels of IL2, IL4, IL5, sIL2R, and tumor growth factor (TGF), and expression levels of IL2RA, IL2RB, IL2RG, and IL2 were also analyzed. Additionally, we tested 10 polymorphic loci associated with the IL-2 gene. Results The annual effective radiation doses in the HNBR and CA groups were 6.24 mSv y–1 and 1.95 mSv y–1, respectively. After adjusting for potential confounding factors, the serum levels of IL-2 and IL-5 were higher in the HNBR group than the CA group (p < .05), while the serum level of TGFβ was lower in the HNBR group (p < .05). The IL-2 gene mRNA expression level was higher in the HNBR group than the CA group (p < .05). The IL-2RB rs76206423 AA allele showed significant variations in the HNBR group (p = .0381). Conclusions Long-term exposure to low dose radiation may enhance immune function, and IL-2RB rs76206423 may be related to the expression of IL-2 by other coding variants. Moreover, our data provide a better understanding of the molecular mechanism of the immune response to low dose radiation.

Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting.

Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001; no CRPS vs. controls, p < 0.001. Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score (rs = −0.468, p = 0.024). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.

Clinical Features and Dynamics of T Cells-Related Markers in Immunocompetent Patients with Cytomegalovirus Hepatitis.

Aim Cytomegalovirus (CMV) can cause hepatitis, encephalomyelitis, and pneumonitis in immunocompromised patients. In contrast, CMV infection of immunocompetent patients can lead to the development of infectious mononucleosis and is typically self-limiting; severe complications are rare. We evaluated the pathophysiology and immunological aspects of CMV hepatitis in recently immunocompetent adult patients. Methods We examined the clinical features and outcomes of 47 adult immunocompetent patients with CMV hepatitis (29 men, 18 women; mean age, 34 ± 11 years) from January 2005 to August 2019 treated in our hospital. We also assayed T-cell activation to evaluate the immune responses in these patients. Results Fever (74.5%), hepatosplenomegaly (74.5%), sore throat (36.2%), headache (31.9%), abdominal pain (27.7%), lymphadenopathy (23.4%), and skin rash (6.4%) were present at admission. Complications included gastrointestinal injury (25.5%), neuropathy (4.3%), thrombocytopenia (2.1%), and splenic infarction (2.1%). All patients had a good clinical course without liver failure or transition to chronic liver injury. The time to recover from liver injury ranged from 12 to 142 days (mean, 43.4 ± 28.7 days). The serum sIL-2R level, which reflects T-cell activation, was transiently elevated and correlated with the extent of hepatic inflammation. Conclusions CMV hepatitis in immunocompetent individuals has a satisfactory outcome, but occasionally results in complications in other organs. The sIL-2R level has potential as a surrogate marker of hepatic inflammation in immunocompetent patients with CMV hepatitis.

Usefulness of Combined Measurement of Serum Soluble IL-2R and Angiotensin-Converting Enzyme in the Detection of Uveitis Associated with Japanese Sarcoidosis.

PurposeAngiotensin-converting enzyme (ACE) is conventionally used as a biomarker in the diagnosis of uveitis associated with sarcoidosis, but its sensitivity is relatively low. In this study, we investigated whether serum soluble interleukin-2 receptor (sIL-2R) is also useful as a diagnostic marker, in addition to ACE, in the detection of uveitis associated with sarcoidosis.Patients and MethodsData were analyzed from 126 patients with uveitis (52 sarcoidosis and 74 non-sarcoid uveitis) and 12 with primary intraocular lymphoma (PIOL) who had their serum sIL-2R and ACE levels measured.ResultsSerum sIL-2R level was elevated in 69.2% of patients with sarcoid uveitis, 5.4% of those with non-sarcoid uveitis, and 16.7% of those with PIOL. The sensitivity and specificity of an elevated sIL-2R level for the detection of sarcoidosis were 69.2% and 93.0%, respectively. In contrast, serum ACE levels were elevated only in patients with sarcoid uveitis, with a sensitivity of 44.2% and specificity of 100%. Furthermore, serum sIL-2R and/or ACE level was elevated in 75.0% of patients with sarcoid uveitis, which is higher than those who had elevated serum ACE level only (44.2%, P = 0.0025). The sensitivity and specificity of elevated sIL-2R and/or ACE in detecting sarcoid uveitis were 75.0% and 93.0%, respectively. The PPV was 0.87, and the NPV was 0.86.ConclusionCompared with the sensitivity of serum ACE levels alone, combined measurement of both serum sIL-2R and ACE levels improves sensitivity in the detection of uveitis associated with sarcoidosis. Nevertheless, serum ACE alone remains useful thanks to its high specificity in the differentiation of uveitis patients, with sarcoidosis from those without sarcoidosis.

Soluble IL-2 Receptor in Dermatomyositis: Its Associations with Skin Ulcers and Disease Activity.

Objective To investigate the role of soluble interleukin-2R (sIL-2R) in idiopathic inflammatory myopathies (IIM). Methods Serum sIL-2R levels were measured in 74 dermatomyositis (DM), 16 immune-mediated necrotizing myopathy (IMNM), 24 rheumatoid arthritis (RA), 20 systemic lupus erythematosus (SLE), and 20 healthy controls (HCs) by chemiluminescent immunometric assay. Clinical features and laboratory data were collected from electronic medical record. Disease activity was evaluated by using physician global disease activity and myositis disease activity assessment visual analog scale (MYOACT) on admission. 20 DM patients were followed. Serum sIL-2R levels were analyzed and compared with clinical features, laboratory data, and measures of disease activity. Results Serum sIL-2R levels were significantly higher in DM patients than in IMNM patients and HCs (648.8 ± 433.1 U/ml vs. 352.3 ± 126.0 U/ml and 648.8 ± 433.1 U/ml vs. 285.8 ± 101.9 U/ml, respectively; all P < 0.001), while there was no significant difference between IMNM and HCs. There were also no significant differences of sIL-2R levels in DM, SLE, and RA. Importantly, serum sIL-2R levels were significantly higher in treatment-naïve or active DM patients than those that are not (1100.9 ± 550.4 U/ml vs. 615.6 ± 330.4 U/ml, P = 0.006; 808.8 ± 421.6 U/ml vs. 339.8 ± 103.4 U/ml, P < 0.001). DM patients with skin ulcers had significantly higher sIL-2R levels than those without (889.3 ± 509.9 U/ml vs. 640.0 ± 368.7 U/ml, P = 0.023). Cross-sectional analysis in DM showed that sIL-2R levels positively correlated with CK, ESR, CRP, ferritin, physician VAS, and MYOACT scores (rho = 0.278, rho = 0.474, rho = 0.469, rho = 0.454, r = 0.646, and r = 0.600, respectively; all P < 0.05), negatively correlated with T cell counts and MMT8 scores (r = −0.380, P = 0.002; rho = −0.394, P = 0.001). Follow-up study showed that changes in sIL-2R levels after treatment correlated with changes in physician VAS and MYOACT scores (r = 0.823 and r = 0.695, respectively; all P < 0.01). Conclusion Serum sIL-2R levels were elevated in DM but not in IMNM. Serum sIL-2R could act as a disease activity marker and be associated with ulcerative skin lesions in DM.