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Dermatomyositis (DM) represents a multifaceted chronic inflammatory myopathy, primarily manifesting as progressive deterioration of muscular and cutaneous tissues. Despite an incomplete comprehension of DM's etiology and pathogenesis, current evidence implicates the involvement of T lymphocyte infiltration, extensive cytokine release, myositis-specific antibodies, and myositis-associated antibodies in disease development. Serum soluble interleukin-2 receptor (sIL-2R) frequently serves as a marker for T cell activation; however, its role remains elusive. Consequently, this investigation sought to elucidate the association between sIL-2R levels, peripheral blood lymphocyte subset counts, and related cytokines in DM patients, with the aim of uncovering the intricate mechanisms underlying DM and establishing a theoretical foundation for the implementation of precise, targeted, individualized immunomodulatory therapy. In this study, a cohort of 60 dermatomyositis (DM) patients, comprising 32 with inactive DM and 28 with active DM, was enrolled and stratified into inactive and active groups based on the Myositis Disease Activity Visual Analogue Scale (MYOACT). Flow cytometry was employed to quantify the absolute counts of peripheral lymphocyte subsets and CD4+T cell subsets in each group, while a flow cytometry bead array was utilized to measure serum cytokine levels. In a comparative analysis between healthy individuals and patients diagnosed with DM, we observed a marked elevation in serum sIL-2R concentrations (P < 0.001) and T-helper 17 cell/regulatory T cell (Th17/Treg) ratios (P < 0.01) within the latter group. A positive correlation was identified between serum sIL-2R levels and various parameters, including ESR, CRP, VAS, AST, CKMB, LDH, HBDH, PT, APTT, DDi, IL-6, IL-10, and IFN-γlevels (P < 0.05). In contrast, serum sIL-2R levels demonstrated a negative correlation with LY, HGB, ALB, Th17 cell populations, and Th17/Treg cell ratios (P < 0.05). Employing multivariate logistic regression, we identified serum sIL-2R concentrations as an independent risk factor for both disease activity and hepatic involvement in DM patients. Moreover, receiver operating characteristic (ROC) curve analyses revealed that serum sIL-2R levels significantly contributed to the differentiation of disease activity and the detection of liver involvement in DM patients, with areas under the ROC curve (AUC) of 0.757 (95% CI 0.630-0.884, P = 0.001) and 0.826 (95% CI 0.717-0.935, P < 0.001), respectively. This study highlights the potential utility of serum sIL-2R levels as a valuable biomarker for assessing disease activity and liver involvement in dermatomyositis. Elevated serum concentrations of sIL-2R were observed in patients with DM, exhibiting significant associations with Th17 cell populations and Th17/ Treg ratios. These findings indicate that sIL-2R may be implicated in the immunopathogenesis of DM, thereby warranting further investigation to elucidate its role in the disease process., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Sarcoidosis is a multisystem granulomatous disease of unknown origin. Ninety percent of patients with sarcoidosis have lung involvement. The onset can be acute or non-acute and the severity of sarcoidosis ranges widely from asymptomatic patients with accidental radiographic findings to patients with severe organ involvement. This case control analytic prospective study was conducted at the Chest Clinic, Al Zahraa hospital, to assess the diagnostic value of serum soluble interleukin 2 receptor (sIL-2R), cluster of differentiation 4 (CD4)/CD8 ratio and CD103 in sarcoidosis. We investigated the value of serum sIL-2R using ELISA and blood CD103, blood CD4/CD8 ratio using flow cytometry for 30 cases of sarcoidosis in different stages and 30 control persons to detect their use as a marker for diagnosis. We found a significant increase in sIL-2R in the sarcoidosis group as compared to the control group (p˂0.0001), while there was a significant decrease in CD103/CD4 in sarcoidosis group as compared to the control group (p < 0.001). In conclusion, sIL-2R and CD103 can be used as diagnostic markers for sarcoidosis., (Copyright© by the Egyptian Association of Immunologists.)

Background: Serum soluble interleukin-2 receptor (sIL-2R) is recognized as a marker of T-cell activation and is abnormally elevated in sarcoidosis. However, its value for stage I sarcoidosis in benign granulomatous diseases is unclear., Methods: We enrolled 33 stage I sarcoidosis patients, 17 lymph node tuberculosis patients, 15 reactive lymphadenopathy patients, and 11 healthy controls. Serum biomarkers concentrations were collected and collated., Results: Serum sIL-2R concentrations were the highest in stage I sarcoidosis. The AUC of serum sIL-2R for stage I sarcoidosis was 0.7452 in all subjects and 0.6861 in granulomatous diseases. The AUCs of two combined diagnostic forms, sIL-2R with angiotensin-converting enzyme (ACE) and sIL-2R with ACE, erythrocyte sedimentation rate (ESR), and lactate dehydrogenase (LDH) were 0.7994 and 0.891 in all subjects, respectively. In granulomatous disease groups for ROC analysis, the best cut-off value of sIL-2R was 745.00 U/ml with 48.50% sensitivity and 84.40% specificity. The combination of four parameters increased the diagnostic accuracy for stage I sarcoidosis in granulomatous diseases (74.10% sensitivity and 100% specificity). Serum sIL-2R concentrations were positively correlated with serum ACE (r = 0.4652, P = 0.0126)., Conclusion: Serum sIL-2R appeared to be valuable in identifying stage I sarcoidosis in a group of benign granulomatous disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 ( χ 2 = 4.97, P = 0.026) and lymphatic metastasis ( χ 2 = 4.154, P = 0.042), while serum sIL-2R was remarkably related to gender ( χ 2 = 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., Competing Interests: The authors declare that no potential conflicts of interest were disclosed in this research., (Copyright © 2022 Xiaoqin Xu et al.)

Purpose: Epithelial ovarian cancer (EOC) is regarded as the deadliest gynecological cancer, and the demand for novel noninvasive prognostic biomarkers remains significant. This study aimed to investigate the prognostic value of preoperative blood biomarkers in EOC patients., Methods: In total, 73 patients who had undergone ovarian mass resection were enrolled. Serum concentration of biomarkers, including soluble interleukin 2 receptor α (sIL-2R), was measured 1-2 weeks before surgery. Independent prognostic factors for progression-free survival (PFS) were investigated with multivariate Cox regression analysis. A prognostic model was subsequently developed and evaluated by discrimination, calibration and clinical net benefit. Furthermore, transcriptome data of 376 EOC cases from The Cancer Genome Atlas (TCGA) were analyzed with ESTIMATE, CIBERSORT and Maftools algorithm to evaluate the correlation of IL2RA expression with tumor immune microenvironment and immunotherapeutic response., Results: High sIL-2R concentration was found to be the only significant prognostic blood biomarker for PFS by multivariate Cox regression analysis in our center. A prognostic nomogram was developed with satisfactory discrimination, calibration and clinical net benefit. In addition, higher IL2RA expression was significantly associated with higher immune scores, activated CD4 + T cells, M2 macrophages and resting dendritic cells in TCGA data. Furthermore, IL2RA expression was closely related to TMB scores., Conclusions: sIL-2R is a potential prognostic immune biomarker for EOC patients, and a comprehensive prognostic model comprising sIL-2R with satisfactory discrimination and clinical appliance was developed. Therefore, we recommend routine sIL-2R testing in EOC patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The aim of this study is to explore the clinical application value of high-frequency ultrasound combined with detection of serum high mobility group box (HMGB-1), soluble IL-2 receptor (SIL-2R), and thyroglobulin antibody (TgAb) in diagnosing thyroid cancer., Methods: By means of retrospective study, 50 thyroid cancer patients treated in our hospital from January 2019 to January 2021 were selected as the thyroid cancer group, 50 patients with benign thyroid lesions were included in the benign lesion group, and 50 healthy individuals examined in our hospital in the same period were included in the control group. All study objects received high-frequency ultrasound examination, and at the same time, their serum HMGB-1, SIL-2R, and TgAb levels were measured. After that, the results of high-frequency ultrasound examination were analyzed, the diagnostic efficacy of different diagnosis methods was explored, and receiver operating characteristic (ROC) curves were plotted., Results: According to the results of high-frequency ultrasound examination, there were significant differences in echogenicity surrounding and inside the lesion, calcification, blood flow distribution, and blood flow parameters between the thyroid cancer group and the benign lesion group ( P  < 0.001); the HMGB-1, SIL-2R, and TgAb levels were statistically different among the three groups ( P  < 0.001), and the level values of HMGB-1, SIL-2R, and TgAb of the thyroid cancer group were, respectively, (12.26 ± 1.32) ng/ml, (108.65 ± 9.75) pmol/L, and (690.65 ± 34.47) IU/mL; the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of high-frequency ultrasound combined with detection of serum HMGB-1, SIL-2R, and TgAb were, respectively, 98.0%, 95.0%, 90.7%, and 99.0%, and AUC (95%CI) = 0.965 (0.931-0.999)., Conclusion: High-frequency ultrasound combined with detection of serum HMGB-1, SIL-2R, and TgAb has a good value in diagnosing thyroid cancer, which should be promoted in practice., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Ning Li et al.)

Objectives: Early and simple detection of high-risk groups is crucial for minimizing severe coronavirus disease 2019 (COVID-19)-related deaths. Soluble interleukin 2 receptors (sIL2R) have been suspected as being prognostic markers for infectious diseases. This study validated the usefulness of sIL2R as a marker for deaths related to COVID-19., Methods: This retrospective observational study enrolled participants who showed positive results for severe acute respiratory syndrome coronavirus 2 RNA admitted to the current hospital between 01 April and 30 September 2020. Of the 102 patients enrolled in this study, sIL2R levels were measured in 87 patients. For comparisons between survival and non-survival groups, potential confounding variables were entered into univariate models, and variables showing significant correlations (p < 0.05) in those models were added to a multivariate model., Results: Being aged ≥60 years and sIL2R levels ≥1060 U/ml were significantly associated with mortality on univariate analyses; only sIL2R levels significantly correlated with mortality on multivariate logistic regression analysis. Further, sequential sIL2R levels in three patients were increased at progression or death., Conclusion: SIL2R on admission and sequential monitoring of sIL2R might reflect disease severity., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Our previous study demonstrated that the soluble interleukin-2 receptor (sIL-2R) index, defined as the ratio of serum sIL-2R levels at neutrophil engraftment to that before conditioning, is a biomarker that can predict acute graft-vs-host disease (GVHD) after unrelated bone marrow transplantation. In the present study, we evaluated the significance of the sIL-2R index among patients who underwent cord blood transplantation (CBT)., Methods: We retrospectively analyzed 31 patients who underwent single-unit CBT as their first transplantation for hematologic malignancies., Results: The median sIL-2R index was 4.2. The cumulative incidence of grade II to IV acute GVHD was not associated with the sIL-2R index. However, the cumulative incidence of relapse at 3 years after transplantation was significantly lower, with an sIL-2R index ≥ 3.7 than with an index < 3.7 (12.8% vs 50.0%; P = .04). As a result, the probability of overall survival at 3 years after transplantation was significantly higher in the former group than in the latter (79.8% vs 20.0%; P < .01). Only the dose of corticosteroid administered in the pre-engraftment period influenced the sIL-2 index., Conclusion: The sIL-2R index can predict the incidence of relapse and probability of survival after CBT, possibly reflecting a graft-vs-leukemia effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A soluble form of the interleukin-2 receptor (sIL-2R) is secreted upon T-cell activation. Increased blood levels of sIL-2R occur in a variety of immunological diseases. Although the biological function of sIL-2R is incompletely understood, both in health and disease, sIL-2R serum measurements are commonly conducted in clinical practice as it may help to facilitate diagnosis of specific immune-mediated diseases, such as haemophagocytic lymphohistiocytosis and sarcoidosis. In these, and in other immune-diseases, sIL-2R levels may be used as a biomarker to monitor/predict disease activity and treatment response. In this review, we will give a brief overview of the biology of the IL-2/IL-2R system and will subsequently discuss the clinical utility of sIL-2R measurement, especially in the context of haemophagocytic lymphohistiocytosis, sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis, adult-onset Still's disease, ANCA-associated vasculitis, and IgG4-related disease.

Tumor biopsy is essential for the definitive diagnosis of central nervous system (CNS) lymphoma. However, the biopsy procedure carries the risk of complications such as bleeding, convulsions, and infection. Cerebrospinal fluid (CSF) β2-microglobulin (β2-MG), soluble IL-2 receptor (sIL-2R), and interleukin-10 (IL-10) are known to be useful diagnostic biomarkers for CNS lymphoma. The C-X-C motif chemokine ligand 13 (CXCL13) was recently reported to be another useful biomarker for CNS lymphoma. The purpose of this study is to establish a diagnostic algorithm that can avoid biopsy by combining these diagnostic biomarkers. In the first, we conducted a case-control study (n = 248) demonstrating that the CSF CXCL13 concentration was significantly increased in CNS lymphoma patients compared with various other brain diseases (AUC = 0.981). We established a multi-marker diagnostic model using CSF CXCL13, IL-10, β2-MG, and sIL-2R from the results of the case-control study and then applied the model to a prospective study (n = 104) to evaluate its utility. The multi-marker diagnostic algorithms had excellent diagnostic performance: the sensitivity, specificity, positive predictive value, and negative predictive value were 97%, 97%, 94%, and 99%, respectively. In addition, CSF CXCL13 was a prognostic biomarker for CNS lymphoma patients. Our study suggests that multi-marker algorithms are important diagnostic tools for patients with CNS lymphoma., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: It is often difficult to diagnose central nervous system (CNS) inflammatory demyelinating diseases (IDDs) because they are similar to CNS lymphoma and glioma., Objective: To evaluate whether cerebrospinal fluid (CSF) analysis can differentiate CNS IDDs from CNS lymphoma and glioma., Methods: We measured CSF cell counts; concentrations of proteins, glucose, interleukin (IL)-6, IL-10, soluble IL-2 receptor (sIL-2R), and myelin basic protein; and IgG index in patients with multiple sclerosis (MS, n = 64), neuromyelitis optica spectrum disorder (NMOSD, n = 35), tumefactive demyelinating lesion (TDL, n = 17), CNS lymphoma ( n = 12), or glioma ( n = 10). We detected diagnostic markers using logistic regression and receiver operating characteristic (ROC) analyses., Results: Median CSF IL-10 and sIL-2R levels were higher in CNS lymphoma patients than in MS, NMOSD, or TDL patients. Logistic regression revealed that CSF sIL-2R levels predicted CNS lymphoma. In the ROC analysis of CSF sIL-2R levels, the area under the curve was 0.867, and the sensitivity and specificity were 83.3% and 90.0%, respectively., Conclusion: CSF sIL-2R levels can be used to differentiate CNS lymphoma from CNS IDDs. Further studies may identify other applications of CSF as a diagnostic biomarker.

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

A smouldering adult T-cell leukaemia/lymphoma (ATLL) patient was admitted because of multiple erosions in the colon, which were infiltrated by a mixed population of lymphocytes. PET/CT demonstrated diffuse 18 F-Fluorodeoxyglucose accumulation in the whole colon accompanied by multiple lymph node swelling. Histological examinations of lymph node suggested aggressive transformation to lymphoma type of ATLL. However, the general condition worsened with extremely elevated LDH, cytomegalovirus pp65 and sIL-2R after the administration of prednisolone. By contrast, subsequent administration of ganciclovir with tapered prednisolone ameliorated the laboratory findings. Differential diagnosis for aggressive ATLL and serious cytomegalovirus infection is needed.

Objectives: The magnitude and role of the cellular immune response following pediatric traumatic brain injury remains unknown. We tested the hypothesis that macrophage/microglia and T-cell activation occurs following pediatric traumatic brain injury by measuring cerebrospinal fluid levels of soluble cluster of differentiation 163 and ferritin and soluble interleukin-2 receptor α, respectively, and determined whether these biomarkers were associated with relevant clinical variables and outcome., Design: Retrospective analysis of samples from an established, single-center cerebrospinal fluid bank., Setting: PICU in a tertiary children's hospital., Patients: Sixty-six pediatric patients after severe traumatic brain injury (Glasgow Coma Scale score < 8) who were 1 month to 16 years old and 17 control patients who were 1 month to 14 years old., Interventions: None., Measurements and Main Results: Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α were determined by enzyme-linked immunosorbent assay at two time points (t1 = 17 ± 10 hr; t2 = 72 ± 15 hr) for each traumatic brain injury patient. Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α after traumatic brain injury were compared with controls and analyzed for associations with age, patient sex, initial Glasgow Coma Scale score, diagnosis of abusive head trauma, the presence of hemorrhage on CT scan, and Glasgow Outcome Scale score. Cerebrospinal fluid level of soluble cluster of differentiation 163 was increased in traumatic brain injury patients at t2 versus t1 and controls (median, 95.4 ng/mL [interquartile range, 21.8-134.0 ng/mL] vs 31.0 ng/mL [5.7-77.7 ng/mL] and 27.8 ng/mL [19.1-43.1 ng/mL], respectively; p < 0.05). Cerebrospinal fluid level of ferritin was increased in traumatic brain injury patients at t2 and t1 versus controls (8.3 ng/mL [<7.5-19.8 ng/mL] and 8.9 ng/mL [<7.5-26.7 ng/mL] vs <7.5 ng/mL below lower limit of detection, respectively; p < 0.05). Cerebrospinal fluid levels of soluble interleukin-2 receptor α in traumatic brain injury patients at t2 and t1 were not different versus controls. Multivariate regression revealed associations between high ferritin and age 4 years or younger, lower Glasgow Coma Scale score, abusive head trauma, and unfavorable Glasgow Outcome Scale score., Conclusions: Children with traumatic brain injury demonstrate evidence for macrophage activation after traumatic brain injury, and in terms of cerebrospinal fluid ferritin, this appears more prominent with young age, initial injury severity, abusive head trauma, and unfavorable outcome. Further study is needed to determine whether biomarkers of macrophage activation may be used to discriminate between aberrant and adaptive immune responses and whether inflammation represents a therapeutic target after traumatic brain injury.

The interleukin-9 receptor (IL-9R) consists of an α subunit and a γ(c) chain that are shared with other cytokine receptors, including interleukin-2 receptor (IL-2R), an important regulator of T cells. We previously showed that IL-2R is expressed in common clusters with major histocompatibility complex (MHC) glycoproteins in lipid rafts of human T lymphoma cells, which raised the question about what the relationship between clusters of IL-2R/MHC and IL-9R is. Confocal microscopy colocalization and fluorescence resonance energy transfer experiments capable of detecting membrane protein organization at different size scales revealed nonrandom association of IL-9R with IL-2R/MHC clusters at the surface of human T lymphoma cells. Accommodation of IL-9Rα in membrane areas segregated from the IL-2R/MHC domains was also detected. The bipartite nature of IL-9R distribution was mirrored by signal transducer and activator of transcription (STAT) activation results. Our data indicate that co-compartmentalization with MHC glycoproteins is a general property of γ(c) receptors. Distribution of receptor chains between different membrane domains may regulate their function., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Immunotoxicity studies of nanoparticles on T cells addressed their effects on activation by T antigen receptor, but have neglected the regulation of proliferation by IL-2. In this study, the IL-2-dependent T lymphoblastoid WE17/10 cell line was used to compare silver (Ag-NPs) and fullerene (C60-NPs) nanoparticles' toxicity and evaluate whether these NPs could interfere with IL-2-dependent proliferation. Results have shown that Ag-NPs are more toxic, as they reduced cell viability at the highest concentration tested (100 μg/ml), while C60-NPs have shown good biocompatibility. Characterization of NP suspensions by dynamic light scattering measured large aggregates for C60-NPs, whereas Ag-NPs were relatively stable and well dispersed. This translated into a much larger uptake of Ag-NPs compared to C60-NPs, as measured by flow cytometry. Proliferation measurements by CFSE following 72 h incubation have shown that Ag-NPs decrease cell proliferation and C60-NPs slightly increase proliferation. CD25 expression was unchanged following exposure to C60-NPs, but was significantly increased by Ag-NPs' presence for short and long-term incubations. Analyses of three key signaling proteins activated by IL-2 receptor (Stat5, JNK and ERK1/2) by western immunoblotting have shown no effects from either NPs on Stat5 and JNK phosphorylation. ERK1/2 was slightly activated following a short exposure to Ag-NPs, while C60-NPs had no effect. Our results show that C60-NPs have good biocompatibility and do not interfere with IL-2-dependent proliferation. A deeper investigation would be needed for the case of Ag-NPs, since the mechanism of their action is still unclear., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the postmortem distributions of procalcitonin (PCT), C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and soluble interleukin-2 receptor (sIL-2R) levels in postmortem serum from femoral blood, pericardial fluid and pleural fluid in a series of sepsis-related fatalities (12 subjects) and control cases (20 subjects) that underwent medico-legal investigations. Our aim was to assess the diagnostic potential of the results obtained from pericardial and pleural fluid analysis in identifying sepsis-related deaths. All sepsis-related cases had a documented, clinical diagnosis that was established in vivo during hospitalization. Pneumonia was the main infectious focus identified during autopsy and histology. Pseudomonas aeruginosa, Klebsiella pnemoniae and Escherichia coli were the most commonly identified bacteria in blood and lung tissue cultures. The preliminary results corroborate the usefulness of PCT, CRP, sTREM-1 and sIL-2R determination in postmortem serum for the identification of sepsis-related deaths. Moreover, the data suggest that, as far as PCT, CRP, sTREM-1 and sIL-2R measurements are concerned, pericardial and pleural fluids can be considered suitable alternatives to postmortem serum should femoral blood prove unavailable at autopsy., (Copyright © 2014 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: More than two-thirds of depressed patients complain of somatic and pain symptoms, which are frequently regarded as a psychological reaction. Although there is a growing body of evidence showing that depression is related to immune abnormalities, few studies have investigated the association between inflammatory cytokines and somatic/pain symptoms., Method: Patients with depressive disorder but without any medical disorders, and age/gender/body mass index (BMI)-matched healthy subjects were enrolled. All the subjects completed the self-rating scales of the Beck Depression Inventory-II and the Depression and Somatic Symptoms Scale, which was comprised of depressive, somatic, and pain subscales. Pro-inflammatory cytokines, including C-reactive protein (CRP), interleukin-2 receptor (sIL-2R), soluble interleukin 6 receptor (sIL-6R), soluble TNF-receptors (sTNF-R), soluble P-selectin (sP-selectin), monocyte chemotactic protein-1 (MCP-1), and adiponectin, were assessed by enzyme-linked immunosorbent assays., Results: In all, 109 patients with depressive disorder and 126 normal controls were enrolled. The patients with depressive disorder had significantly more severe depression, somatic and pain symptoms (all p<0.001), and higher levels of sIL-2R (p<0.0001), sTNF-R (p<0.001), and sP-selectin (p=0.005) than the normal control group. Using multivariate regression analysis with controlling of age, gender, BMI, and other pro-inflammatory cytokines, sIL-2R was the most significant predictor for depressive symptoms (p<0.0001); with further controlling of severity of depressive symptom, sP-selectin was the only predictor for somatic (p=0.002) and pain (p=0.059) symptoms., Conclusion: The elevated sP-selectin associated with somatic symptoms in depression, may indicate early micro-vascular changes occur subtly, and provide neurobiological evidence for somatic and pain symptom in depression., (© 2013 Published by Elsevier B.V.)

Cutaneous mast cell tumours (MCTs) are among the most important skin tumours in dogs. Apart from c-KIT mutations, which are present in <18% of MCTs, little is known of the mechanisms of MCT development and independent growth of tumour cells. Recently, the α-subunit (CD25) of the interleukin (IL)-2 receptor (IL-2R) has been found to be expressed by canine cutaneous MCTs and this expression is negatively correlated with tumour grade. We thus hypothesized that the other two subunits of the IL-2R and the ligand IL-2 are also expressed and that IL-2-dependent pathways may have an impact on MCT development and independent tumour cell growth. Messenger RNA and protein expression levels of the IL-2R β-subunit (CD122), the IL-2R γ-subunit (CD132) and IL-2 were analyzed in canine cutaneous MCTs and compared with tumour grade and c-KIT mutation status. Eighty-six percent of the tumours expressed both subunits of the IL-2R and 64% expressed IL-2. In addition, neoplastic mast cells seem able to bind IL-2. IL-2Rγ and IL-2 protein expression levels were significantly decreased in higher grade tumours and IL-2 expression was significantly decreased in c-KIT mutated tumours. Thus, expression of the complete IL-2R and its ligand by canine cutaneous MCTs indicates a potential impact of IL-2R signalling in MCT development and tumour cell proliferation. The decrease in IL-2R expression with increasing histological evidence of malignancy suggests that the IL-2R may be more relevant for early MCT development and well-differentiated tumours., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The clinical significance of serum soluble interleukin-2 receptor (sIL2R) levels was retrospectively assessed in patients with advanced diffuse large B-cell lymphoma (DLBCL). Twenty-one patients, who were newly-diagnosed with advanced DLBCL (stage III and IV) between 2006 and 2009, were evaluated. The median follow-up period was 37 months. All patients received 6-8 cycles of chemotherapy with rituximab in combination with doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP)-like regimens and attained complete remission. Although all patients reached complete remission, six patients experienced disease relapse within 1 year after treatment completion. The overall survival was significantly poorer in patients with relapse than in patients with durable remission. The sIL2R levels after the sixth cycle of treatment were significantly higher in the relapse group than in the non-relapse group. Thus, the present study suggests sIL2R levels to be a valuable predictor for the prognosis of patients with advanced DLBCL.

Background: Many studies have explored the association between soluble interleukin-2 receptor (sIL-2R), cytokines and major depressive disorder (MDD). However, the results of these studies were not consistent. The aim of our study is to compare the levels of sIL-2R and cytokines in the blood between MDD patients and controls by a meta-analysis and to identify moderators accounting for potential heterogeneity in the levels of sIL-2R and cytokines in MDD patients versus controls by meta-regression analyses., Methods: A comprehensive literature search was performed to identify studies comparing the levels of sIL-2R and cytokines between MDD patients and controls. We pooled the effect sizes for standardized mean differences (SMD) of the levels of sIL-2R and cytokines. We also performed meta-regression and sensitivity analyses to investigate the roles of age, gender, sample type, ethnic origin and selected studies' quality in explaining potential heterogeneity and differences in results respectively., Results: Twenty-nine studies were selected for this analysis. The levels of sIL-2R, TNF-α and IL-6 in MDD patients were significantly higher than those of healthy controls (SMD=0.555, p<0.001, SMD=0.567, p=0.010; SMD=0.680, p<0.001). Mean age of all subjects was a significant moderator to explain the high heterogeneity of IL-6. Sensitivity analysis found that European but not non-European subjects have higher levels difference of sIL-2R, TNF-α and IL-1β between MDD patients and controls., Limitation: The severity of MDD was not considered., Conclusion: The blood levels of sIL-2R, TNF-α and IL-6 were significantly higher in MDD patients than controls. Age, samples source and ethnic origins may play a potential role in heterogeneity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Neurosarcoidosis (NS) represents an important differential diagnosis of multiple sclerosis (MS). However, thus far no reliable laboratory marker of neurosarcoidosis exists. The objective of this study was to evaluate whether cerebrospinal fluid (CSF) levels of soluble interleukin 2 receptor (sIL2-R) distinguish NS and other inflammatory disorders of the central nervous system. For this purpose, 139 paired CSF and serum samples from 11 patients with NS, 21 with MS, 10 with CNS vasculitis, 22 with bacterial meningitis, 17 with viral meningitis/encephalitis, seven with neurotuberculosis, and 18 healthy donors were assessed for sIL2-R using an enzyme-linked immunosorbent assay. We found that sIL2-R CSF levels above 150 pg/ml identified untreated NS patients with an overall accuracy of 93% against a group of non-infectious CNS-diseases. Furthermore, an increase in sIL2-R in the CSF was associated with and preceded the outbreak of new neurological symptoms. In conclusion, these findings suggest that sIL2-R measurement in the CSF may be a valuable tool in the diagnosis and follow-up of patients with suspected and proven neurosarcoidosis.

We describe for the first time fluorescent virus-like particles decorated with biologically active mono- and multisubunit immune receptors of choice and the basic application of such fluorosomes (FSs) to visualize and target immune receptor-ligand interactions. For that purpose, human embryonic kidney (HEK)-293 cells were stably transfected with Moloney murine leukemia virus (MoMLV) matrix protein (MA) GFP fusion constructs. To produce FSs, interleukins (ILs), IL-receptors (IL-Rs), and costimulatory molecules were fused to the glycosyl phosphatidyl inositol anchor acceptor sequence of CD16b and coexpressed along with MoMLV group-specific antigen-polymerase (gag-pol) in MA::GFP(+) HEK-293 cells. We show that IL-2 decorated but not control-decorated FSs specifically identify normal and malignant IL-2 receptor-positive (IL-2R(+)) lymphocytes by flow cytometry. In addition to cytokines and costimulatory molecules, FSs were also successfully decorated with the heterotrimeric IL-2Rs, allowing identification of IL-2(+) target cells. Specificity of binding was proven by complete inhibition with nonlabeled, soluble ligands. Moreover, IL-2R FSs efficiently neutralized soluble IL-2 and thus induced unresponsiveness of T cells receiving full activation stimuli via T-cell antigen receptor and CD28. FSs are technically simple, multivalent tools for assessing and blocking mono- and multisubunit immune receptor-ligand interactions with natural constituents in a plasma membrane context.

Cushing's syndrome is characterized by excessive elevation of glucocorticoid concentrations. In rare cases, the treatment of Cushing's syndrome may result in unmasking or aggravation of diseases responsive to glucocorticoid medication. We report two cases of sarcoidosis following Cushing's syndrome. A 43 year-old male developed cutaneous sarcoidosis and mediastinal lymphadenopathy after resection of an ACTH-secreting pituitary microadenoma. A 32 year-old female showed cutaneous sarcoidosis, arthralgia, mediastinal lymphadenopathy and elevation of angiotensin-converting enzyme and interleukin 2-receptor concentrations after traumatic adrenal bleeding, which ceased formerly undiagnosed hypercortisolism caused by an adrenal adenoma. Sarcoidosis seems to be a rare sequel following the treatment of hypercortisolism. Skin affections were present and suggestive for the diagnosis in all reported cases. As some cases are probably missed when skin affections are lacking, a more frequent evaluation of patients after Cushing's syndrome for the possible diagnosis of sarcoidosis might be necessary., (J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart * New York.)

Objective: To investigate the association between high-risk human papillomavirus (HPV) types and soluble interleukin-2 receptor (sIL-2R) levels in female sex workers with a negative cervical smear result, and to determine the effectiveness of using sIL-2R levels to screen for high-risk strains of HPV., Method: A negative cervical smear result and a blood sample were obtained from 68 women: 43 female sex workers and 25 women acting as controls. HPV DNA genotyping was performed and sIL-2R levels were assessed., Results: Female sex workers had significantly higher sIL-2R levels than women in the control group (318.37+/-239.7 vs 114.4+/-56.5 U/mL, respectively P<0.001). In addition, female sex workers with high-risk strains of HPV had significantly higher sIL-2R levels than those who did not have high-risk strains of HPV (736.7+/-251.5 vs 250.5+/-156.1 U/mL, respectively; P=0.001)., Conclusion: High sIL-2R levels may be useful in screening for high-risk strains of HPV in female sex workers who have a negative cervical smear result.

Previously we have demonstrated that in-vivo growth of a murine T-cell lymphoma of spontaneous origin designated as Dalton's lymphoma (DL) shows sex dimorphism (J Rep Immunol 2005; 65:17-32). It remained unclear, however, if DL growth in female and male tumor-bearing hosts also shows a sex-dependent differential susceptibility to the antitumor action of cancer chemotherapeutic drugs. In this study we have demonstrated that in-vivo administration of anticancer drugs: cisplatin or doxorubicin to the DL-bearing host results in a sex-dependent different antitumor activity of the drugs, causing a sex dimorphism in the antitumor response of the drugs with respect to tumor growth inhibition. The antitumor effect of both drugs was found to be better in male tumor-bearing hosts compared with female tumor-bearing hosts. The study also shows that DL cells obtained from male and female tumor-bearing hosts display a differential growth response to following treatment with cisplatin in vitro. Cell growth regulatory proteins: interleukin-2, interferon-gamma, tumor growth factor-beta, p53, caspase-activated DNase, vascular endothelial growth factor, and interleukin-2 receptor were found to be involved in the observed sex-specific response of DL cells to the antitumor action of cisplatin. Moreover, gonadal hormones: androgen, estrogen, and their specific antagonists flutamide and tamoxifen were found to directly modulate the cytotoxicity of cisplatin against DL cells in vitro. This study, therefore, suggests for the first time that the efficacy of cancer chemotherapeutic may vary in a sex-specific manner in a host-bearing a T-cell lymphoma.

We report a 62-year-old woman with intravascular lymphomatosis (IVL) which presented as subacute encephalopathy. She was admitted to our hospital because of loss of consciousness in the middle of February, 2006. Laboratory tests indicated elevated serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and cerebrospinal fluid protein. Magnetic resonance imaging (MRI) of the brain revealed multiple infarct-like lesions mainly in the white matter. After admission, her consciousness was soon improved, but the inflammatory response did not disappear with any antibiotics or virucides. Her consciousness was not exacerbated, and she was discharged in the middle of March, although the reason for loss of consciousness remained unknown. After discharge she developed an abnormal behavior and mental deterioration, and therefore she was readmitted late in March. On second admission, her consciousness was drowsy. Neurological examinations revealed conjugate deviation of her eyes to the left, left hemiparesis, and generalized hyporeflexia. Laboratory tests showed more elevated CRP than that of the last time, and raised soluble IL-2 receptor (sIL-2R). The repeated MRI of the brain disclosed that initial lesions of the white matter progressively enlarged and increased in number. To make an appropriate diagnosis of the lesions on the brain MRI, the open brain biopsy was performed. Microscopic examination showed that many small vessels were occluded by lymphoma cells (B-lymphocytes) with hemorrhage, and IVL was diagnosed. She was treated with regimens of combined chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). After chemotherapy her consciousness and left hemiparesis were gradually improved and the levels of CRP were normalized. The infarcts-like lesions detected on the brain MRI became reduced and decreased. IVL is a rare disease, and the prognosis is generally poor, with a rapidly fatal outcome, leading to a postmortem diagnosis. In the present report, we successfully treated the patient by rituximab in addition to standard CHOP therapy. Rituximab may play an important role in the treatment of IVL.

Rationale: Sarcoidosis is known as a disease with high heterogeneity in clinical severity and inflammatory activity. On the basis of radiologic criteria, John Guyette Scadding developed a classification system, which is widely used, but is insufficient for clinical decision making. Therefore, biomarkers and genetic markers that predict outcome are urgently needed., Objectives: To obtain a classification system based on clinical criteria to evaluate biomarker and genetic markers., Methods: We developed a protocol for classification of various disease courses (sarcoid clinical activity classification [SCAC]) based on clinical criteria with three categories: (1) whether the disease was acute or nonacute in onset, (2) whether treatment was required, and (3) whether there was need for long-term treatment., Measurements and Main Results: In total, we evaluated 225 patients with sarcoidosis, applying both classification protocols retrospectively. The described SCAC protocol based on clinical criteria was retrospectively able to stratify patients according to disease outcome. The classes of patients with chronic disease differed significantly regarding pulmonary function test parameters and bronchoalveolar lavage fluid cell composition. Most interestingly, concentrations of soluble IL-2 receptor and neopterin were particularly increased in patients with acute disease who required long-term treatment. A moderate but significant increase in soluble IL-2 receptor and neopterin was also observed in patients with nonacute disease who needed long-term treatment. In contrast to the clinical classification system, the system based on radiologic criteria separated the patients with the need for long-term therapy insufficiently, but identified patients with advanced fibrotic remodeling., Conclusions: The described SCAC protocol is practicable and gives additional information not yet acquired by radiologic typing and seems suitable for studies evaluating genetic influence and biomarkers.

This study evaluated the levels of soluble interleukin-2 receptor (sIL-2R) and soluble intercellular adhesion molecule-1 (sICAM-1) in patients with dengue. Sera from 17 patients with dengue fever (DF), 15 with dengue hemorrhagic fever (DHF) and 12 healthy individuals were obtained. Increased levels of sIL-2R and sICAM-1 were found in patients with DF and DHF when compared to normal; those were not correlated with leukocytes, hepatic serum enzyme levels or haemostatic parameters. Levels of sIL-2R were related to the different grades of DHF. These results suggest that increased levels of sIL-2R and sICAM-1 are a common feature of dengue.

Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with B-cell non-Hodgkin lymphoma (NHL). This phase II trial evaluated response rate (RR) and tolerability of DD in this population. Patients were stratified into two arms: those with NHL expressing > or =20% IL-2R (IL-2R+) or <20% IL-2R (IL-2R-). DD was dosed at 18 microg/kg/day for 5 days every 21 days. Corticosteroid pre-medication was not allowed. Thirty-five patients of a planned 77 accrued due to closure for slow accrual. This report is on 29 patients (18 males) with indolent B-cell NHL (11 IL-2R+ and 18 IL-2R-). Histologic subtypes included small lymphocytic (SLL) (8 patients) and follicular grade I/II lymphoma (21 patients). Patients received a median of three prior regimens, including rituximab in 76%. Three partial responses were observed (RR 10%). The RR for the IL-2R- and IL-2R+ patients was 11% and 9%, respectively. Of 8 patients with SLL, 2 responded. Toxicities were generally grade I - II and transient but 1 patient experienced a fatal thrombo-embolism. Therapy with DD is tolerable and modest efficacy was observed in SLL subtype. Measured IL-2R status did not correlate with efficacy.

Results of studies of immune response during hepatitis C virus (HCV) infection were reviewed in order to reveal immunologic markers of the disease progression. Genetic heterogeneity of HCV and immunogenetic features of the host determine heterogeneity of immune response to the virus and differences in the course of the disease and outcomes. Spontaneous elimination of HCV-infection in acute phase occurs due to vigorous and sustained multispecific Th1-response toviral antigens. During such response proliferation of virus-specific CD4+ T-cells and secretion of IFN-gamma by them are observed, otherwise chronic hepatitis develops. Great importance in persistence of HCV as well as in quantitative and functional suppression of HCV-specific CD8+ T-cells has increased number of CD4+ CD25+ regulatory T-cells. Cellular immune response plays a key role not only in the elimination of HCV, but also in liver pathology associated with HCV-infection. Progression of the process and shift to its chronic form are also associated with decrease of production of IFN-gamma, alpha, IL-2 by peripheral blood mononuclear cells and increase of TNF-alpha, IFN-gamma, IL-4, IL-2r levels in blood serum.

The interleukin-2 is a cytokine that is essential for lymphocytic survival and function. Ectopic expression of the IL-2 receptor in epithelial tissues has been reported previously, although the functional significance of this expression is still being investigated. We provided novel structural and functional information on the expression of the IL-2 receptor in kidney cancer cells and in other normal and neoplastic human epithelial tissues. In A-498 kidney cancer cells, we showed that IL-2 binding to its own receptor triggers a signal transduction pathway leading to the inhibition of proliferation and apoptosis. We found that the inhibition of proliferation is associated with Erk1/2 dephosphorylation, whereas the survival signals appear to be mediated by Sgk1 activation. This investigation focuses on the IL-2 induced regulation of Sgk1 and describes a role of the IL-2 receptor and Sgk1 in the regulation of epithelial tumor cell death and survival.

The study was purposed to investigate the effects of humanized recombined CD25 monoclonal antibody (rhCD25MAb) on activation and proliferation of T lymphocytes in vitro. Peripheral blood mononuclear cells (PBMNC) were incubated with phytohemagglutinin (PHA). Before or after T cell activation, the cells were cultured with or without rhCD25MAb or cyclosporine A (CsA) in vitro. After 72 hours incubation, the proliferation of lymphocytes was analyzed by MTT assay. The expression of CD3 and CD25 antigens on T lymphocytes were detected by flow cytometry. The levels of sIL-2R in the supernatants were determined with ELISA. The results showed that both rhCD25MAb and CsA could inhibit the proliferation of T lymphocytes significantly in concentration-dependent manner and CsA was more efficient than rhCD25MAb. Both rhCD25MAb and CsA could also decrease the levels of sIL-2R in the supernatant and inhibit the expression of CD25 antigen on T lymphocytes. The level of sIL-2R and the expression of CD25 on T lymphocytes decreases more profoundly in rhCD25MAb group. It is concluded that rhCD25MAb shows strong immunosuppressive activity both before and after T cell activation, suggesting that this agent may be useful in not only prophylaxis but also the treatment of acute graft-versus-host disease.

Objective and Background: Interferon gamma-inducible protein (IP)-10 and epithelial neutrophil-activating peptide (ENA)-78 belong to the CXC chemokine family and are important factors in inflammatory lung diseases. In sarcoidosis, the potential role of IP-10 to regulate the migration and activation of T-cells towards sites of sarcoid activity has been suggested., Methods: In this study, the concentrations of IP-10 and ENA-78 in the serum and BAL fluid of patients with different stages of active pulmonary sarcoidosis (n=41) and healthy subjects (n=12) were measured by enzyme-linked immunosorbent assay to evaluate the contribution of these CXC chemokines to this disease., Results: Serum and BAL fluid concentrations of IP-10 and BAL fluid levels of ENA-78 in patients with sarcoidosis were significantly higher than those in control subjects. The serum levels of IP-10 were significantly increased only in patients with stages I and II sarcoidosis, while BAL fluid levels of ENA-78 were increased only in stage III sarcoidosis. In addition, serum concentrations of IP-10 were elevated in patients with extrapulmonary lesions compared with those without such lesions. In patients with sarcoidosis, IP-10 concentrations in BAL fluid correlated with lymphocyte proportions in BAL fluid., Conclusion: IP-10 may play an important role in regulating lymphocytes into the lung and that ENA-78 may be associated with lung parenchymal disease in pulmonary sarcoidosis.

We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+) T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.

Cryptococcus neoformans is a frequent cause of meningoencephalitis in immunosuppressed individuals. To better understand the mechanisms of a protective immune response to C. neoformans, a long-term in vitro model of human immune control of cryptococcal infection was developed. Peripheral blood mononuclear cells (PBMC) prestimulated with heat-killed C. neoformans significantly restricted the growth of C. neoformans after a subsequent live infection compared to that with unstimulated PBMC. Live infection with encapsulated C. neoformans was controlled for as long as 10 days, while infection with acapsular organisms could sometimes be eradicated. During immune control, fungal cells were both intracellular and extracellular within aggregates of mononuclear phagocytes and lymphocytes. Optimal immune control depended on the presence of both CD4+ and CD8+ T cells. Immune control of cryptococcal growth was more effective following prestimulation with acapsular compared with encapsulated organisms. Prestimulation with acapsular organisms was associated with a significant and prolonged increase in interleukin-6 (IL-6) production compared with prestimulation with encapsulated C. neoformans. Addition of IL-6 and depletion of CD25+ T cells prior to prestimulation and infection with encapsulated organisms resulted in reductions in cryptococcal growth that reached borderline statistical significance. Depletion of CD25+ T cells significantly reduced cryptococcal growth in wells with unstimulated PBMC. The results demonstrate an association between high levels of IL-6 and resistance to infection and, through suppression of IL-6 release, an additional mechanism whereby the cryptococcal capsule subverts a protective immune response. Further work is required to clarify the mechanism of action of IL-6 in this setting and any interaction with regulatory T cells.

Objective: MHC class II molecules play central roles in immune recognition and rejection. As statins have been shown to inhibit the production of these molecules, we analyzed the possible immunosuppressive effect of pravastatin, using our rat model of orthotopic lung transplantation., Methods: Single orthotopic lung transplantation was performed in a Fischer 344-to-Wistar Kyoto strain combination. One group received pravastatin i.p. after transplantation, controls NaCl. Statin serum levels were analyzed by high performance liquid chromatography (HPLC). Animals were sacrificed on postoperative day (POD) 14 and 21. At sacrifice, samples were obtained for histology, immunhistochemistry, flow cytometry and real-time RT-PCR analysis of CD25, TNF-alpha, and MHC class II expression. Rejection was graded via histochemistry, using a system based on the working formulation of The International Society of Heart and Lung Transplantation. Immunohistochemistry was performed for expression of MHC class II, T-cell receptor, CD25, CD4/8 cell, NK cells, granulocytes and monocytes in naïve lungs and grafts from donor and recipient animals. Flow cytometric analysis of recipient peripheral blood mononuclear cells (PBMC) was used to analyze expression of CD3, CD4, CD8, and RT1B in both groups. In vitro analyses of MHC class II expression were performed in parallel., Results: HPLC confirmed effective delivery of pravastatin. Recipients treated with pravastatin showed significantly less rejection on POD 14 and on POD 21, when compared to controls. Immunohistochemistry showed specific differences, suggesting a delay in rejection in the pravastatin group. Flow cytometric analyses showed a higher expression of CD4 in the control group on POD 21. Results of real-time RT-PCR analyses for MHC class II expression showed a significant decrease in expression in the statin-treated group. Flow cytometric analysis of gamma-IFN stimulated rat PBMC showed an inhibition of upregulation of MHC class II expression by pravastatin in vitro., Conclusions: Pravastatin prolongs graft survival in our allogeneic rat model of orthotopic lung transplantation. We assume that the underlying mechanism for this effect is the inhibition of upregulation of MHC class II molecule synthesis, thus blocking downstream effector mechanisms of the immune system.

To determine the mechanisms by which dietary fish oil (FO) affects antigen-stimulated Th1 cell development, DO11.10 Rag 2(-/-) T cell receptor transgenic mice were fed a control diet (5% corn oil (CO) or a FO diet (1% CO + 4% FO, (n-3) PUFA) for 2 wk. CD4(+) T cells were cultured under neutral or Th1 polarizing conditions. FO feeding suppressed (P < 0.05) ovalbumin peptide-induced proliferation of nonpolarized CD4(+) T cells. Differentiation in vitro to Th1 cells was not affected by dietary FO, as evidenced by similar percentages of KJ1-26(+), IFN-gamma(+), IL-4(-) Th1 cells in cultures from CO-fed (99%) and FO-fed (97%) mice. However, the absolute number of viable Th1 cells in polarized cultures from FO-fed mice was less than half that observed in CO-fed mice (P < 0.05), indicating that FO inhibits in vitro Th1 clonal expansion. The reduced number of Th1 cells in FO cultures was not a result of increased apoptosis, because similar percentages of apoptotic Th1 cells were observed in cultures from FO- and CO-fed mice. IL-2-induced cell proliferation was significantly decreased in polarized Th1 cells from the FO group; however, the suppressed proliferation was not linked to reduced CD25 surface expression on antigen-stimulated CD4(+) T cells. Adoptively transferred CFSE-labeled DO11.10 CD4(+) cells into immunized mice (Th1 polarizing agents) showed that dietary FO reduced (P < 0.05) the number of cell divisions in vivo. These studies suggest that the attenuated inflammatory response which accompanies FO feeding may be explained, at least in part, by suppression of Th1 clonal expansion.

Object: Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS)., Methods: The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors. Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells., Conclusions: The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

Flow cytometry is useful to study lymphoid malignancies since it allows both immunophenotyping of neoplastic cells and quantification of antigen expression. CD18 and CD45 are commonly exposed membrane antigens with different levels of expression on blood leukocyte and neoplastic cells. The aim of this retrospective study was to semi-quantitatively evaluate the expression of CD18 and CD45 in dogs with different lymphoid malignancies with blood involvement and to compare results with those from healthy dogs and dogs with reactive diseases. Blood samples from 13 dogs with precursor lymphoid malignancies, 20 with mature neoplasms (either chronic lymphocytic leukaemia or lymphoma), of different immunophenotypes, were compared with 24 healthy dogs and 12 dogs with different reactive diseases. The median fluorescence intensity (MFI) for CD18 and CD45 was recorded on lymphoid and granulocytic populations using dual colour flow cytometry, and the ratio between MFI for lymphoid and granulocytic populations (L/N ratio) was calculated to compare the results obtained in different sessions using an internal control (granulocyte fluorescence intensity). Significant decreases in the L/N ratio were detected in neoplastic samples for both CD18 (either precursors or mature versus controls) and CD45 (either precursors or mature versus control), while using MFI only slight differences were detectable in CD45 between precursors and controls. Neoplastic cells often exhibited lower expression of the L/N ratio for CD18, and mainly for CD45, most likely due to a less mature pattern than normal cells and/or to an aberrant quantitative expression of surface antigen. Moreover, more than 50% of neoplastic lymphoid cells exhibited L/N ratios that were not within the values observed in controls for at least one antigen. Altered L/N ratios, in particular decreases of CD45, were mainly observed in precursor neoplasms and in T-cell neoplasms. Detection of altered expression of common antigens, and in particular a L/N ratio for CD45 lower than a value of 103% may be useful as a confirmation of pseudo-clonality thus helping in differentiating reactive and neoplastic lymphocyte expansions.

Background: The interleukin-7 (IL-7)/IL-7 receptor alpha (IL-7Ralpha) system is an important regulator of T-cell homeostasis. We evaluated the IL-7/IL-7Ralpha system in a large cohort of HIV-infected patients, including a subset treated with intermittent IL-2., Methods: IL-7 serum levels and CD127 (IL-7Ralpha) expression on T cells were evaluated in a cross-sectional study of 36 healthy volunteers, 151 HIV-infected patients, and 83 HIV-infected patients who had received IL-2 therapy. Multivariate regression models were used to determine predictors of CD127 expression., Results: HIV-infected patients had higher IL-7 levels compared with healthy volunteers (P = 0.022) and IL-2-treated patients (P = 0.012). CD127 expression was significantly lower on CD4 and CD8 T cells of HIV-infected patients compared with healthy volunteers (P = 0.008 and P < 0.001, respectively), and CD127 median fluorescence intensity was lowest on CD4 T cells in IL-2-treated patients (P < 0.001 compared with HIV-infected patients). The proportion of naive and effector memory/effector T cells were significant predictors of CD127 expression on T cells. IL-2 immunotherapy led to the expansion of a CD25/CD127-low subset of CD4 T cells., Conclusions: CD127 expression on T cells remains low in HIV-infected patients despite antiretroviral therapy, reflecting persistent aberration in the subset composition of the T-cell pool.

Background: The coexistence of endometrial and immune cells during decidualization is preserved by the ability of endometrial cells to regulate the cytotoxic immune activity and their capability to be resistant to immune-mediated apoptosis. These phenomena enable the survival of endometrial ectopic cells. RCAS1 is responsible for regulation of cytotoxic activity. Metallothionein expression seems to protect endometrial cells against apoptosis. The aim of the present study was to evaluate RCAS1 and metallothionein expression in human ovarian and scar endometriomas in relation to the presence of immune cells and their activity., Methods: Metallothionein, RCAS1, CD25, CD69, CD56, CD16, CD68 antigen expression was assessed by immunohistochemistry in ovarian and scar endometriomas tissue samples which were obtained from 33 patients. The secretory endometrium was used as a control group (15 patients)., Results: The lowest metallothionein expression was revealed in ovarian endometriomas in comparison to scar endometriomas and to the control group. RCAS1 expression was at the highest level in the secretory endometrium and it was at comparable levels in ovarian and scar endometriomas. Similarly, the number of CD56-positive cells was lower in scar and ovarian endometriomas than in the secretory endometrium. The highest number of macrophages was found in ovarian endometriomas. RCAS1-positive macrophages were observed only in ovarian endometriomas. CD25 and CD69 antigen expression was higher in scar and ovarian endometriomas than in the control group., Conclusion: The expression of RCAS1 and metallothionein by endometrial cells may favor the persistence of these cells in ectopic localization both in scar following cesarean section and in ovarian endometriosis.

Thymic derived naturally occurring CD25+ CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we discuss the capacity of dendritic cells (DCs) to expand antigen-specific Tregs, particularly polyclonal Tregs directed to alloantigens. Initial studies have shown that mature DCs are specialized antigen-presenting cells (APCs) for expanding antigen-specific CD25+ CD4+ Tregs from TCR transgenic mice. When triggered by specific antigen, these Tregs act back on immature DCs to block the upregulation of CD80 and CD86 costimulatory molecules. More recently, DCs have been used to expand alloantigen-specific CD25+ CD4+ Tregs from the polyclonal repertoire in the presence of interleukin-2 (IL-2). Allogeneic DCs are much more effective than allogeneic spleen cells for expanding CD25+ CD4+ Tregs. The DC-expanded Tregs continue to express high levels of Foxp3, even without supplemental IL-2, whereas spleen cells poorly sustain Foxp3 expression. When suppressive activity is tested, relatively small numbers of DC-expanded CD25+ CD4+ Tregs exert antigen-specific suppression in the mixed leukocyte reaction (MLR), blocking immune responses to the original stimulating strain 10 times more effectively than to third party stimulating cells. DC-expanded Tregs also retard graft versus host disease (GVHD) across full major histocompatibility complex (MHC) barriers. In vitro and in vivo, the alloantigen-specific CD25+ CD4+ Tregs are much more effective suppressors of transplantation reactions than polyclonal populations. We suggest that the expansion of Tregs from a polyclonal repertoire via antigen-presenting DCs will provide a means for antigen-specific control of unwanted immune reactions.

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

As self-recognition is fundamental to the efficient operation of the immune system, a number of mechanisms have evolved to keep this potential pathologic self-reactivity in check. Thus, even though the majority of strongly self-reactive T cells are deleted in the thymus during T-cell maturation, a number of mature T cells that recognize self-antigens can be found in the peripheral circulation in healthy individuals as well as in patients with autoimmune disease. These self-reactive cells are kept in a non-responsive state in healthy individuals while they appear to be involved in the etiology of a number of autoimmune diseases in patients. The primary role of a relatively recently identified T-cell population, referred to as natural CD4+ CD25+ regulatory T cells, is to modulate the activity of these self-reactive cells. Although it is still unclear how these regulatory cells function, they can inhibit the activation of other potentially pathologic T cells in in vitro assays. Using such assays, regulatory T cells isolated from patients with a number of autoimmune diseases have been shown to exhibit reduced inhibitory function as compared with those isolated from healthy individuals. In this review, we discuss human natural regulatory T cells, what is known about their function, and their associations with specific autoimmune diseases.