sIL-2R Levels Research Articles

Is there an association between serum soluble interleukin-2 receptor levels and syndrome severity in persistent Complex Regional Pain Syndrome?

A potentially useful biomarker for Complex Regional Pain Syndrome (CRPS) is the serum soluble interleukin-2 receptor (sIL-2R) level, which is a marker for T-cell activation. Elevated serum sIL-2R levels have been described in CRPS patients compared to healthy controls. In T-cell mediated inflammatory diseases such as sarcoidosis and rheumatoid arthritis, the serum sIL-2R levels correlate with disease severity. In this study, we investigate whether an association exists between serum sIL-2R levels in CRPS patients and CRPS severity. A cross-sectional cohort study was conducted in a tertiary pain referral center in the Netherlands. Adult CRPS patients diagnosed by the IASP criteria were included between October 2018 until October 2022. The main study parameters were serum sIL-2R levels and the CRPS severity score. Fifty-three CRPS patients were included with a mean syndrome duration of 84 months (Q3 - Q1:180 - 48). The majority had persistent CRPS with a syndrome duration >1 year (n = 52, 98%). The median pain Numerical Rating Score (NRS) was 7 (Q3 - Q1: 8 - 5) and the mean CRPS severity score was 11 (SD ± 2.3). The median serum sIL-2R level was 330 U/mL (Q3 - Q1:451 - 256). No statistically significant correlation was observed between serum sIL-2R levels and the CRPS severity score (rs = 0.15, P = .28). Our findings suggest that serum sIL-2R levels cannot be used as a biomarker for syndrome severity in persistent CRPS (syndrome duration >1 year). Serial measurements of serum sIL-2R from early CRPS to persistent CRPS are needed to investigate whether serum sIL-2R levels can be used to monitor T-cell mediated inflammatory syndrome activity.

Treatments and outcomes of patients with localized extranodal NK/T-cell lymphoma (ENKL) diagnosed between 2014 and 2021: A cooperative study in Japan.

7565 Background: A previous cooperative study of patients (pts) with ENKL who were diagnosed between 2000 and 2013 in 31 institutes in Japan reported that the most common first-line treatment for localized ENKL was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%). The 2-year (yr) overall survival (OS) and progression-free survival (PFS) of pts with localized ENKL were 78% and 68%, respectively (JCO 2017). RT-DeVIC has been included as a preferred regimen of combined modality therapy in the NCCN guidelines. The treatments and outcomes of pts with localized ENKL in recent clinical practice are unknown. Methods: We conducted a cooperative study (NKEA-Next; UMIN000046300) by hemato-oncologists and radiation oncologists of pts with ENKL who were diagnosed between 2014 and 2021 in 45 institutes in Japan. The results were compared with those from the 2000-2013 cohort (JCO 2017). The primary endpoint was OS of pts with ENKL who received next-generation treatment in 2014-2021 at participating institutes. We analyzed the data of localized ENKL. Results: Of 351 pts in the 2014-2021 cohort, 235 (67%) had localized ENKL. First-line therapy was RT-DeVIC in 185 (79%) pts, sequential chemoradiotherapy in 17, RT alone in 15 pts, and chemotherapy alone in 12 pts. Six pts received no treatment due to poor performance status (PS). Only two pts (1%) received anthracycline-containing regimens. With a median follow-up of 3.4 yrs, the 2-yr OS and PFS of localized ENKL were 83% and 75%, respectively. Pts treated with RT-DeVIC showed the following clinical features: median age, 58 yrs (range, 13-82); age > 60 yrs, 45%; stage IIE, 34%; B symptoms present, 27%; elevated serum lactate dehydrogenase, 23%; ECOG PS 2, 4%; and soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN), 31% (57/183). The complete response rate was 88% among the 179 pts who were evaluated for response. The 2-yr OS and PFS of RT-DeVIC were 87% and 79%, respectively. There was no treatment-related death due to RT-DeVIC. G3/4 mucositis was recorded in 32% (G3, n = 59; G4, n = 0). G3/4 febrile neutropenia occurred in 18% (G3, n = 32; G4, n = 2). sIL-2R > ULN was associated with worse OS ( P < 0.01). In comparison with pts with localized disease in the 2000-2013 cohort, pts in the 2014-2021 cohort received RT-DeVIC more frequently ( P < .001). There was no significant difference in OS ( P = 0.24) or PFS ( P = 0.10) between the two cohorts. Conclusions: RT-DeVIC was more frequently used for first-line treatment of localized ENKL, and its efficacy has been maintained, with 87% 2-yr OS in recent clinical practice in Japan, providing further evidence of RT-DeVIC as a preferred first-line regimen for localized ENKL. No obvious improvement in OS and a reduction in G3 mucositis were observed, suggesting that more efficacious and less toxic regimens need to be introduced.

Comparison of Serum Levels of SIL-2R, IL-6, IL-10, TNF-α, CRP, ESR and Fibrinogen in Patients with Active and Inactive Behçet’s Disease

Behçet's disease (BD) is a chronic inflammatory illness that affects the entire body and is characterized by recurring episodes of oral aphthae, ocular and cutaneous lesions, and scrotal or vaginal ulcerations. The involvement of other organs and systems increases mortality in addition to the significant morbidity. This study involved a total of 40 participants, 20 of whom were healthy controls and 20 of whom were patients (of the 20 Behçet's patients, 12 (60%) were in the active phase and 8 (40%) were in the inactive phase). There was no therapy being given to any of the 20 patients that would have affected their cytokine levels. Only young men made up the patient and control groups because both early onset and male sex are signs of poor prognosis. The ELISA method was used to measure the levels of serum cytokines. The statistical analysis of the derived numerical values employed the Mann-Whitney U Test. We found a significant correlation between serum cytokine levels and classical acute phase markers in active Behçet’s patients. ESR (P < 0,001), CRP (P < 0,001), fibrinogen (P < 0,001), IL-10 (P < 0,001), IL-6 (P < 0,001), SIL-2R (P < 0,001) and TNFα (P < 0,001). There was no statistically significant difference in serum levels of classical acute phase markers ESR (P = 0,746), CRP (P = 0,476) and fibrinogen (P = 0,940) when inactive Behçet’s patients and healthy controls were compared. However, serum levels of IL-10 (P < 0,001), IL-6 (P = 0,001), SIL-2R (P < 0,001) and TNFα (P = 0,001) were statistically different between inactive Behcet's patients and the control group. Our research shows that even in the inactive phase, serum cytokine levels of Behçet’s patients are much higher than the healthy control group. However, the levels of ESR, CRP and fibrinogen, which are classical acute phase markers, were found at normal levels in Behçet’s patients in the inactive phase. These findings show that measurement of serum interleukin levels will enable us to take preventive measures for morbidity and mortality follow-up of Behçet's patients.

The utility of HLA-DR+CD38high expression in quantifying the amplitude of T cell activation in HLH and immune dysregulation disorders

IntroductionIdentifying T-cell activation, the hallmark of multiple hyperinflammatory diseases like HLH and immune dysregulation disorders (IDS) like LRBA deficiency, is critical for diagnosis, management, and monitoring treatment response for patients with immune activation driven disease processes. Soluble Interleukin 2 Receptor (sIL2R) is an established systemic marker for T-cell activation but the clinical availability of sIL2R testing is limited. sIL2R is also not a reliable marker of T-cell activation in patients with eosinophilia or T-cell lymphoma. A recent study by Chaturvedi et.al has demonstrated the utility of flow-based T-cell activation assessment in differentiating HLH from sepsis. However, its utility in defining and quantifying T-cell activation across the hyperinflammatory spectrum and its correlation with sIL2R has not yet been established. MethodsA total of 125 samples were collected either at disease onset (n = 81) or at follow-up (n = 44) from 85 human subjects. Paired plasma sIL2R and T-cell activation markers were prospectively evaluated in patients with suspected HLH (n = 79) or IDS (n = 46). Flow cytometry-based T-cell activation was evaluated in different T-cell sub-compartments by the coexpression of HLA-DR and CD38 surface markers. ResultsEvaluation of T-cell activation measured by HLADR+CD38high in healthy controls (HCs) and different hyperinflammatory/ immune regulatory disorders revealed that HCs have less than 8% of T-cell activation in CD8 + Teffector memory (TEM) and less than 4% for activation in the CD4+ TEM compartments. In patients with suspected hyperinflammatory/ immune regulatory disorders, we identified significant correlation of direct T-cell activation with plasma sIL2R level in different T-cell subsets, CD3 (r = 0.44, p < 0.0001), CD4 (r = 0.41, p < 0.0001), CD8 (r = 0.45, p < 0.001), CD4 TEM (Teffector memory) (r = 0.53, p < 0.001), and CD8 TEM (r = 0.53, p < 0.0001).The strongest correlation between HLADR+CD38high with sIL2R level was noted in CD4+ TEM and CD8+ TEM compartments (Figure 1). [Display omitted] [Display omitted] ConclusionsFlow cytometry-based direct assessment of HLADR+ CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulation disorders.

The use of elevated ferritin levels in neonates and young infants as a screening lab for HLH

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory state due to primary genetic defect in T/NK cell cytotoxicity or secondary to infection, rheumatologic process, or malignancy. Activated macrophages/cytotoxic lymphocytes lead to elevated cytokines and T-cell activation. Ferritin is a screening tool, with levels >10,000 mug/L reported to be 90% sensitive and 96% specific for HLH. Its use in neonatal/early infancy hasn’t been specifically evaluated.In our retrospective case review we included patients 3 months or younger, treated in the past 5 years at our institution with an elevated ferritin >5000 mug/L. 20 patients were evaluated, demographic/diagnostic information seen in table 1. Average ferritin was 44 515 IQR (9922–54 853) Four patients, (20%) were diagnosed with primary HLH (pHLH), with non-HLH conditions including: 4 (20%) sepsis/infection, 4 (20%) with acute liver failure/galactosemia, 3 (15%) hematologic complications, and 5 (25%) without definitive diagnosis.All patients with HLH had splenomegaly and thrombocytopenia (< 100); 2 patients with pHLH had anemia (< 9), and 3 with ANC< 1000. Of those without HLH, 1 had splenomegaly, 9 with anemia, 6 with thrombocytopenia, and 1 with neutropenia. Soluble IL-2 receptor (sIL2R), a specific marker for T-cell activation was measured in 12 patients. pHLH patients had sIL2R levels >10 000 U/ml: pHLH average 31 432 (11 000–47 474), without pHLH average 2039 (1123–3161). sIL2R is more specific than ferritin but there are limitations (turn-around-time and locations performing). Figure 1 depicts ferritin/sIL2R levels in these groups.We utilized direct flow-based detection of T-cell activation markers for identification of HLH. As a proof of concept, patient 19 had fulminant HSV and a ferritin >200 000 mug/L. HLH diagnostic criteria were fulfilled, the T-cell activation profile was unremarkable (Figure 2). HLH treatment was not initiated; an unremarkable sIL2R result followed which validated our approach.A broad spectrum of etiologies drives high ferritin in neonatal/early infancy and can cause ferritin of >5000 mug/L. Thus, HLH 2004 criteria can be fulfilled in patients without pHLH resulting in inadvertent use of immune suppression. sIL2R and/or T-cell activation flow should be obtained when evaluating and initiating treatment for HLH. Further, genetic evaluation for other conditions is warranted in this patient population. [Display omitted] [Display omitted] Table 1(abstract: 128) Patient characteristics and information: laboratory values, genetics, and underlying diagnosis included.PatientPeak Ferritin (ng/ml)Large SpleenHgb (g/dL)Platelets (thou/ul)NCFibrinogen (mg/dl)SIL2R (units/ml)CXCL9 (pg/ml)PerforinCD107aGenetic FindingFinal DiagnosisCurrent Status127436+13.45042602761123N/ADecreasedLowNo definitive diagnosisUnknownAlive217491–10.43609700224N/N/AN/AN/ANon-contributoryABO incompatibilityAlive3106635–10809110132N/N/AN/AN/ANon-contributoryUnknownAlive482270–6.511540179N/N/AN/AN/AGALT, compound heterozygoteGalactosemiaDeceased59423N/A9.64010420621665N/AN/AN/AWES without definitive diagnosisUnknownAlive6150000+11.7632143024411,0006603N/ALowSTXBP2(homozygous)pHLHDeceased724304–11.91610480185N/AN/AN/AN/ANot collectedUnknownDeceased87494–8.841960603161N/AN/AN/APendingGalactosemiaAlive911412–9.1408770912144N/AN/AN/AWES without definitive diagnosisAcute liver failureAlive1014175–7.93721575173N/AN/AN/AN/ANo definitive diagnosisFulminant liver failureDeceased1117032–10.9332106023,000N/AAbsentPresentPRF1 (homozygous)pHLHDeceased12140000–5.52211880601644N/AN/AN/ANon-contributoryVitamin-K def hemorrhageDeceased139673–9.96992190216N/AN/AN/AN/ANon-contributoryCOVID-19 infectionAlive1410171–8.52952480N/2297N/AN/AN/ANot collectedViral hepatitisAlive155906–8.6103N/1081791N/AN/AN/ANot collectedCampylobacter bacteremiaAlive1614855+7.2101806844256325N/ALowRAB27A compound heterozygotepHLH, Griscelli SyndromeAlive179615–8.2263N/N/N/AN/AN/ALowIFIH1 heterozygous, pending further evaluationUnknownAlive1818730–7.61851940165N/AN/AN/AN/ANot collectedIntrauterine hydrops, secondary to Rh alloimmunization, liver failureAlive19>200000–6.3411400872493N/AN/AN/ATNFRSF13B HeterozygousHSV2 viremiaAlive2013675+6.8404506047474N/AN/ALowUNC13D, compound heterozygotepHLHDeceased

Successful Recovery from Severe Fever with Thrombocytopenia Syndrome and Hemophagocytic Lymphohistiocytosis with Standard Treatment and a Calcium Channel Blocker of Nicardipine Hydrochloride: A Case Report.

A 67-year-old man was admitted to our hospital with a high fever. Laboratory tests revealed leukopenia, thrombocytopenia, liver dysfunction, rhabdomyolysis, and hyperferritinemia. He was diagnosed with severe fever with thrombocytopenia syndrome (SFTS) complicated by hemophagocytic lymphohistiocytosis and treated with steroid therapy, intravenous calcium channel blocker (CCB), and supportive care, without favipiravir. Serum levels of ferritin and soluble interleukin 2 receptor (sIL2R) were markedly elevated on Day 3 after admission and decreased thereafter, while an SFTS viral load of 6.8×104 copies/μL was detected on Day 2, increasing to 2.9×105 copies/μL on Day 6. Serum ferritin and sIL2R levels may be better indicators of mortality than the SFTS viral load, and CCBs may have a therapeutic effect.

Insights Through Detailed Immunophenotyping into The Immune Etiology Of Indeterminate Pediatric Acute Liver Failure (IND-PALF): An Immune Dysregulatory Disease

Approximately one-third of acute pediatric liver failure may be due to indeterminate etiology (IND-PALF). Liver histopathology has shown dense infiltrates of CD8+CD103+ (tissue-resident memory T cell phenotype) Perforin+ T cells in most of these patients suggesting underlying immune dysregulation, which may concurrently evolve to severe aplastic anemia (SAA). A viral etiology has been postulated, and management may require liver transplant and/or HCT. Given the high likelihood of immune dysregulation contributing to the severity of the disease and lack of detailed immunological investigation, we undertook cellular and molecular studies in a small cohort of IND-PALF patients. Four patients (3–8y, 3 males, 1 female) presented with PALF and histopathology consistent with IND-PALF. We performed detailed blood immunophenotyping on 3 of the 4 patients (Table). Key immune anomalies included pan-lymphopenia in 2/3 patients, expansion of activated, exhausted and senescent CD8+ T cells, decreased switched memory B cells and CD19+27+ (total memory + plasmablasts) B cells. To facilitate selection of immunomodulatory therapy best suited for disease control, the ability of FOXP3+Tregs to upregulate CTLA4 on activation was assessed and significantly reduced in 2 of the 3 patients. All patients displayed increased sIL-2R, CXCL9, IL-18 and IL-6 levels compared to healthy controls, with CXCL9 higher than IL-18 indicating T cell activation. Genomic analyses including bulk RNA-seq and pathogen-seeking metagenomics was performed on liver tissue and PBMCs on all 3 patients with appropriate controls. A preliminary analysis of metagenomics data did not reveal evidence of viral RNA in tissue. A monogenic immune etiology was not identified in any of the patients. One patient was initiated on abatacept (P1) and has remained clinically stable without liver transplant or HCT and evidence of normalization of bone marrow cellularity; one patient required a liver transplant (P3) and two patients required allogeneic HCT (P2 and P4). All patients are currently on immunosuppressive therapy. In summary, severe CD8+ T cell dysregulation exemplifies patients diagnosed with IND-PALF, and detailed blood immunophenotyping performed early in the disease course can help identify these patients and enable prompt initiation of targeted immunomodulation, which can mitigate end-stage liver and bone marrow failure.TableImmune Profile of IND-PALF patients at diagnosisP1P2P3Reference Interval/Cut-offAge at Presentation/Dx3 yrs.8 yrs.3 yrs.SexFMMCD45+ALC (cells/µL)23219248191695–5226 cells/µLCD3+Tcell (cells/µL)1281523746969–3471 cells/µLCD4+Tcell (cells/µL)7143121513–2081 cells/µLCD8+Tcell (cells/µL)1071066568336–1355 cells/µLCD19+20+ B cell (cells/µL)487249165–1154 cells/µLCD16/56+ NK cell (cells/µL)632217116–1075 cells/µLT cell Activation MarkersCD4+ HLA DR+ (%CD4)40.1420.676.3610.67%CD8+ HLA DR+ (%CD8)47.4254.5038.3814.60%CD4+CD38+DR+ (%CD4)30.3812.604.245.50%CD8+CD38+DR+ (%CD8)42.9350.3436.347.21%T cell Senescence/Exhaustion MarkersCD4+CD57+ (%CD4)51.3724.054.445.55%CD4+CD28-(%CD4)28.8514.443.402.49%CD8+CD57+ (%CD8)76.6246.4522.9622.43%CD8+CD28-(%CD8)56.1312.4811.7018.53%CD4+PD-1+DR+ (%CD4)24.077.780.651.10%CD8+PD-1+DR+ (%CD8)26.7425.0423.782.28%CTLA4 expression on Activated Tregs (ratio of stimulated/unstimulated)1.111.775.624.22%B cell SubsetsCD19+CD27+ Total memory + plasmablasts (%CD19)6.084.588.356–34%CD19+27+IgM-IgD- (sm B cells) (%CD19)4.120.983.102–18%CD19+CD24++CD38++Transitional B cells (%CD19)39.1937.387.413–23%Cytokines (pg/mL)sIL-2R5987.502986.253741.5144–1329 pg/mLCXCL913926.506224.083582<647 pg/mLIL-181968.041152.733819.5089–540 pg/mLIL-621.03106.7021.8<10 pg/mLFeatures of aplastic anemia were observed in all 4 patients though only 2 required HCT. Abnormal values indicated in red font.

Clinical features and images of malignant lymphoma localized in the pancreatic head to differentiate from pancreatic ductal adenocarcinoma: a case series study

BackgroundPathological examination by endoscopic ultrasonography–guided fine-needle aspiration (EUS-FNA) has been reported to be useful in diagnosing pancreatic malignant lymphoma (ML), but some ML cases are difficult to be differentiated from pancreatic ductal adenocarcinoma (PDAC).MethodsThis retrospective study included 8 patients diagnosed with ML that had a pancreatic-head lesion at initial diagnosis and 46 patients with resected PDAC in the pancreatic head between April 2006 and October 2021 at our institute. ML and PDAC were compared in terms of patients’ clinical features and imaging examinations.ResultsThe median tumor size was larger in ML than in PDAC (45.8 [24–64] vs. 23.9 [8–44] mm), but the median diameter of the caudal main pancreatic duct (MPD) was larger in PDAC (2.5 [1.0–3.5] vs. 7.1 [2.5–11.8] mm), both showing significant differences between these malignancies (both, P < 0.001). In the analysis of covariance, MLs showed a smaller caudal MPD per tumor size than PDACs, with a statistical difference (P = 0.042). Sensitivity and specificity using sIL-2R ≥ 658 U/mL plus CA19-9 < 37 U/mL for the differentiation of ML from PDAC were 80.0% and 95.6%, respectively.ConclusionsDiagnosing pancreatic ML using cytohistological examination through EUS-FNA can be difficult in some cases. Thus, ML should be suspected if a patient with a pancreatic tumor has a small MPD diameter per tumor size, high serum sIL-2R level, normal CA19-9 level. If the abovementioned features are present and still cannot be confirmed as PDAC, re-examination should be considered.

Evaluation of systemic IL-6 trans-signalling in patients with primary open-angle glaucoma

To evaluate systemic trans-signalling of interleukin (IL)-6 in patients with primary open-angle glaucoma (POAG). Fifty-one POAG patients and 47 matched healthy controls were enrolled. Serum concentrations of IL-6, sIL-6R, and sgp130 were quantified. Serum levels of IL-6, sIL-6R, and IL-6/sIL-6R ratios in the POAG group were significantly higher than those in control group, while only the sgp130/sIL-6R/IL-6 ratio was decreased. Among POAG subjects, advanced-stage patients exhibited significantly higher intraocular pressure (IOP), serum IL-6 and sgp130 levels, and IL-6/sIL-6R ratio than those in the early to moderate stage. The ROC curve analysis revealed that the IL-6 level and IL-6/sIL-6R ratio performed better than other parameters in diagnosing POAG and discriminating POAG severity. Serum IL-6 level was moderately correlated with IOP and C/D ratio, while a weak correlation was observed between sIL-6R levels with C/D ratio. IL-6 and sIL-6R levels were correlated with each other in POAG patients but not in healthy controls. Overstimulation of systemic IL-6 trans-signalling has been implicated in POAG.

Soluble interleukin-2 receptor combined with interleukin-8 is a powerful predictor of future adverse cardiovascular events in patients with acute myocardial infarction.

Little is known about the role of interleukin (IL) in patients with acute myocardial infarction (MI), especially soluble IL-2 receptor (sIL-2R) and IL-8. We aim to evaluate, in MI patients, the predictive value of serum sIL-2R and IL-8 for future major adverse cardiovascular events (MACEs), and compare them with current biomarkers reflecting myocardial inflammation and injury. This was a prospective, single-center cohort study. We measured serum concentrations of IL-1β, sIL-2R, IL-6, IL-8 and IL-10. Levels of current biomarkers for predicting MACEs were measured, including high-sensitivity C reactive protein, cardiac troponin T and N-terminal pro-brain natriuretic peptide. Clinical events were collected during 1-year and a median of 2.2 years (long-term) follow-up. Twenty-four patients (13.8%, 24/173) experienced MACEs during 1-year follow-up and 40 patients (23.1%, 40/173) during long-term follow-up. Of the five interleukins studied, only sIL-2R and IL-8 were independently associated with endpoints during 1-year or long-term follow-up. Patients with high sIL-2R or IL-8 levels (higher than the cutoff value) had a significantly higher risk of MACEs during 1-year (sIL-2R: HR 7.7, 3.3-18.0, p < 0.001; IL-8: HR 4.8, 2.1-10.7, p < 0.001) and long-term (sIL-2R: HR 7.7, 3.3-18.0, p < 0.001; IL-8: HR 4.8, 2.1-10.7, p < 0.001) follow-up. Receiver operator characteristic curve analysis regarding predictive accuracy for MACEs during 1-year follow-up showed that the area under the curve for sIL-2R, IL-8, sIL-2R combined with IL-8 was 0.66 (0.54-0.79, p = 0.011), 0.69 (0.56-0.82, p < 0.001) and 0.720 (0.59-0.85, p < 0.001), whose predictive value were superior to that of current biomarkers. The addition of sIL-2R combined with IL-8 to the existing prediction model resulted in a significant improvement in predictive power (p = 0.029), prompting a 20.8% increase in the proportion of correct classifications. High serum sIL-2R combined with IL-8 levels was significantly associated with MACEs during follow-up in patients with MI, suggesting that sIL-2R combined with IL-8 may be a helpful biomarker for identifying the increased risk of new cardiovascular events. IL-2 and IL-8 would be promising therapeutic targets for anti-inflammatory therapy.

Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients.

Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

Role of Serum Soluble Interleukin-2 Receptor Level in the Diagnosis of Sarcoidosis: A Systematic Review and Meta-Analysis.

Serum Soluble Interleukin-2 Receptor (sIL-2R) levels are used clinically as a disease activity marker for systemic sarcoidosis. Studies have investigated the diagnostic role of serum soluble interleukin-2 receptor (sIL-2R) level for sarcoidosis relative to biopsy. We performed a systematic review and meta-analysis of studies evaluating the diagnostic utility of sIL-2R. We carried out an electronic search in Medline, Embase, Google Scholar, and Cochrane databases using keyword and Medical Subject Heading (MeSH) terms: sarcoidosis and sIL-2R. Studies evaluating the sIL-2R levels as a diagnostic tool in clinically diagnosed or biopsy-proven sarcoidosis patients compared to control groups with non-sarcoidosis patients were included. Forest plots were constructed using a random effect model depicting pooled sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy. We selected ten studies comprising 1477 patients, with 592 in the sarcoidosis group and 885 in the non- sarcoidosis group. Pooled sensitivity and specificity of sIL-2R levels were 0.88 (95% CI: 0.75-0.95) and 0.87 (95% CI 0.73-0.94) respectively. Pooled negative predictive value and positive predictive value were 0.91 (95% CI 0.77-0.97) and 0.85 (95% CI 0.59-0.96) respectively with diagnostic accuracy of 0.86 (95% CI 0.71- 0.93). In addition to its utility as a marker of sarcoidosis disease activity, sIL-2R has high diagnostic accuracy. Despite the limitations of the heterogenous sarcoidosis population and different sIL-2R cutoffs, our results suggest that sIL-2R is an important biomarker that can be used to confirm sarcoidosis diagnosis in unconfirmed or unclear cases.

Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction.

Neurosarcodosis is one of the most frequent differential diagnoses of multiple sclerosis (MS) and requires central nervous system (CNS) biopsy to establish definite diagnosis according to the latest consensus diagnostic criteria. We here analyzed diagnostic values of basic cerebrospinal fluid (CSF) parameters to distinguish neurosarcoidosis from MS without CNS biopsy. We retrospectively assessed clinical, radiological and laboratory data of 27 patients with neurosarcoidosis treated at our center and compared following CSF parameters with those of 138 patients with relapsing-remitting MS: CSF white cell count (WCC), CSF/serum albumin quotient (Qalb), intrathecal production of immunoglobulins including oligoclonal bands (OCB), MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of 3 the viruses measles (M), rubella (R), and zoster (Z) virus, and CSF lactate levels. Additional inflammatory biomarkers in serum and/or CSF such as neopterin, soluble interleukin-2 receptor (sIL-2R) and C-reactive protein (CRP) were assessed. There was no significant difference in the frequency of CSF pleocytosis, but a CSF WCC > 30/μl was more frequent in patients with neurosarcoidosis. Compared to MS, patients with neurosarcoidosis showed more frequently an increased Qalb and CSF lactate levels as well as increased serum and CSF levels of sIL-2R, but a lower frequency of intrathecal IgG synthesis and positive MRZ reaction. Positive likelihood ratio (PLR) of single CSF parameters indicating neurosarcoidosis was highest, if (a) CSF WCC was >30/μl (PLR 7.2), (b) Qalb was >10 × 10-3 (PLR 66.4), (c) CSF-specific OCB were absent (PLR 11.5), (d) CSF lactate was elevated (PLR 23.0) or (e) sIL-2R was elevated (PLR>8.0). The combination of (a) one of three following basic CSF parameters, i.e., (a.1.) CSF WCC >30/ul, or (a.2.) QAlb >10 × 10-3, or (a.3.) absence of CSF-specific OCB, and (b) absence of positive MRZ reaction showed the best diagnostic accuracy (sensitivity and specificity each >92%; PLR 12.8 and NLR 0.08). Combined evaluation of basic CSF parameters and MRZ reaction is powerful in differentiating neurosarcoidosis from MS, with moderate to severe pleocytosis and QAlb elevation and absence of intrathecal IgG synthesis as useful rule-in parameters and positive MRZ reaction as a rule-out parameter for neurosarcoidosis.

Usefulness of Serum Soluble Interleukin-2 Receptor Levels for Differentiating between PCNSL and SCNSL.

Serum soluble interleukin-2 receptor (sIL-2R) is a practical tumor marker that is elevated in hematogenous tumors. The purpose of this study was to determine the usefulness of serum sIL-2R for differentiating among malignant brain tumors, including primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). This study retrospectively investigated the sIL-2R levels in 130 patients with various types of malignant brain tumors, including PCNSL patients (n = 48) and SCNSL (n = 8); metastatic brain tumors (MTs, n = 16); and glioblastoma (GBM, n = 58). The median sIL-2R level (U/mL) of the PCNSL, SCNSL, MTs, and GBM groups were 489.7, 1024.8, 413.3, and 332.7 respectively. The sIL-2R level was significantly higher in the SCNSL group than in the PCNSL or other groups. The area under the ROC curve generated from the sIL-2R level was 0.826 (sensitivity: 0.875, specificity: 0.667, cutoff value: 521 U/mL) for differentiating SCNSL from PCNSL and 0.685 (sensitivity: 0.667, specificity: 0.707, cutoff value: 342 U/mL) for differentiating PCNSL from GBM. Measurement of sIL-2R level was convenient and useful to differentiate between SCNSL and PCSNL, both of which demand different treatment strategies.

Levels of Soluble Interleukin 6 Receptor and Asp358Ala Are Associated With Cognitive Performance and Alzheimer Disease Biomarkers.

Alzheimer disease (AD) is a neurodegenerative disease process manifesting clinically with cognitive impairment and dementia. AD pathology is complex, and in addition to plaques and tangles, neuroinflammation is a consistent feature. Interleukin (IL) 6 is a multifaceted cytokine involved in a plethora of cellular mechanisms including both anti-inflammatory and inflammatory processes. IL6 can signal classically through the membrane-bound receptor or by IL6 trans-signaling forming a complex with the soluble IL6 receptor (sIL6R) and activating membrane-bound glycoprotein 130 on cells not expressing IL6R. IL6 trans-signaling has been demonstrated as the primary mechanism of IL6-mediated events in neurodegenerative processes. In this study, we performed a cross-sectional analysis to investigate whether inheritance of a genetic variation in the IL6R gene and associated elevated sIL6R levels in plasma and CSF were associated with cognitive performance. We genotyped the IL6R rs2228145 nonsynonymous variant (Asp358Ala) and assayed IL6 and sIL6R concentrations in paired samples of plasma and CSF obtained from 120 participants with normal cognition, mild cognitive impairment, or probable AD enrolled in the Wake Forest Alzheimer's Disease Research Center's Clinical Core. IL6 rs2228145 genotype and measures of plasma IL6 and sIL6R were assessed for relationships with cognitive status and clinical data, including the Montreal Cognitive Assessment (MoCA), modified Preclinical Alzheimer's Cognitive Composite (mPACC), cognitive domain scores obtained from the Uniform Data Set, and CSF concentrations of phosphoTauT181 (pTau181), β-amyloid (Aβ) Aβ40 and Aβ42 concentrations. We found that inheritance of the IL6R Ala358 variant and elevated sIL6R levels in plasma and CSF were correlated with lower mPACC, MoCA and memory domain scores, increases in CSF pTau181, and decreases in the CSF Aβ42/40 ratio in both unadjusted and covariate-adjusted statistical models. These data suggest that IL6 trans-signaling and the inheritance of the IL6R Ala358 variant are related to reduced cognition and greater levels of biomarkers for AD disease pathology. Follow-up prospective studies are necessary, as patients who inherit IL6R Ala358 may be identified as ideally responsive to IL6 receptor-blocking therapies.

M1-Like Macrophages Modulate Fibrosis and Inflammation of Orbital Fibroblasts in Graves' Orbitopathy: Potential Relevance to Soluble Interleukin-6 Receptor.

Background: Graves' orbitopathy (GO) is a disfiguring and sight-threatening autoimmune disease. Previous studies have shown the infiltration of macrophages in GO orbital connective tissues. However, the immunophenotypes of macrophages and their modulatory effects on orbital fibroblasts (OFs) have not been examined so far. In this study, we sought to determine the pathophysiology of macrophages in GO. Methods: In this case-control study, orbital connective tissues collected from 40 GO patients and 20 healthy controls were immunohistochemically stained for cytokines and macrophage cell surface antigens. The polarization of orbital-infiltrating macrophages was investigated by flow cytometry and immunofluorescence. Effects of interleukin (IL)-6 combined with soluble IL-6 receptor (sIL-6R) on the proliferation, differentiation, and inflammation of different OF subsets were examined by CCK-8, Western blotting, and Luminex assays, respectively. The antigen-presenting abilities of different OF subsets under IL-6/sIL-6R signaling were studied by proteomics. Finally, the differentiation of CD8+ IL-17A-producing T cells by sIL-6R was tested. Results: GO orbital connective tissues displayed increased IL-6, sIL-6R, STAT3, and IL-17A levels. CD86+ M1-like macrophages were predominant in active GO patients, while stable GO patients tended to have more CD163+ M2-like macrophages. The expression of IL-6 was higher in M1-like macrophages, and the expression of transforming growth factor-β was higher in M2-like macrophages both in GO orbital connective tissues in situ in vivo and in cell culture system in vitro. The IL-6/sIL-6R stimulation promoted the fibrosis of both CD34+ and CD34- OFs. Monocyte chemoattractant protein-1 expression was also induced by IL-6/sIL-6R stimulation in both OF subsets. IL-6/sIL-6R stimulation enhanced the antigen processing of CD34+ OFs through upregulating the intact major histocompatibility complex I and antigen transporters. However, the protein expressions of the thyrotropin receptor and insulin-like growth factor 1 receptor could not be directly increased by IL-6/sIL-6R stimulation in CD34+ OFs. Furthermore, sIL-6R was conducive to the differentiation of CD8+ IL-17A-producing T cells. Conclusions: Our study demonstrated the immunophenotypes of orbital-infiltrating macrophages that may activate OFs depending on the IL-6/sIL-6R signaling in GO. Our preclinical findings implicate, at least in part, the molecular rationale for blocking sIL-6R as a promising therapeutic agent for GO.

Analysis of the value and safety of thyroid-stimulating hormone in the clinical efficacy of patients with thyroid cancer.

Thyroid cancer (TC) is a common malignant tumor in the endocrine system. In recent years, the incidence and recurrence rates of TC have been raising due to increasing work pressure and irregular lifestyles. Thyroid-stimulating hormone (TSH) is a specific parameter for thyroid function screening. This study aims to explore the clinical value of TSH in regulating the progression of TC, so as to find a breakthrough for the early diagnosis and treatment of TC. To explore the value and safety of TSH in the clinical efficacy of patients with TC. 75 patients with TC admitted to the Department of Thyroid and Breast Surgery of our hospital from September 2019 to September 2021 were selected as the observation group, and 50 healthy subjects were selected as the control group during the same period. The control group was treated with conventional thyroid replacement therapy, and the observation group was treated with TSH suppression therapy. The soluble interleukin (IL)-2 receptor (sIL-2R), IL-17, IL-35 levels, free triiodothyronine (FT3), free tetraiodothyronine (FT4), CD3+, CD4+, CD8+, CD44V6, and tumor supplied group of factor (TSGF) levels were observed in the two groups. The occurrence of adverse reactions was compared between the two groups. After treatment with different therapies, the levels of FT3, FT4, CD3+, and CD4+ in the observation group and the control group were higher than those before treatment, while the levels of CD8+, CD44V6, and TSGF were lower than those before treatment, and the differences were statistically significant (P < 0.05). More importantly, the levels of sIL-2R and IL-17 in the observation group were lower than those in the control group after 4 wk of treatment, while the levels of IL-35 were higher than those in the control group, and the differences were statistically significant (P < 0.05). The levels of FT3, FT4, CD3 +, and CD4 + in the observation group were higher than those in the control group, and the levels of CD8+, CD44V6, and TSGF were lower than those in the control group. There was no significant difference in the overall incidence rate of adverse reactions between the two groups (P > 0.05). TSH suppression therapy can improve the immune function of patients with TC, lower the CD44V6 and TSGF levels, and improve serum FT3 and FT4 levels. It demonstrated excellent clinical efficacy and a good safety profile.

Plasma N-Cleaved Galectin-9 Is a Surrogate Marker for Determining the Severity of COVID-19 and Monitoring the Therapeutic Effects of Tocilizumab.

Galectin-9 (Gal-9) is known to contribute to antiviral responses in coronavirus disease 2019 (COVID-19). Increased circulating Gal-9 in COVID-19 is associated with COVID-19 severity. In a while, the linker-peptide of Gal-9 is susceptible to proteolysis that can cause the change or loss of Gal-9 activity. Here, we measured plasma levels of N-cleaved-Gal9, which is Gal9 carbohydrate-recognition domain at the N-terminus (NCRD) with attached truncated linker peptide that differs in length depending on the type of proteases, in COVID-19. We also investigated the time course of plasma N-cleaved-Gal9 levels in severe COVID-19 treated with tocilizumab (TCZ). As a result, we observed an increase in plasma N-cleaved-Gal9 levels in COVID-19 and its higher levels in COVID-19 with pneumonia compared to the mild cases (healthy: 326.1 pg/mL, mild: 698.0 pg/mL, and with pneumonia: 1570 pg/mL). N-cleaved-Gal9 levels were associated with lymphocyte counts, C-reactive protein (CRP), soluble interleukin-2 receptor (sIL-2R), D-dimer, and ferritin levels, and ratio of percutaneous oxygen saturation to fraction of inspiratory oxygen (S/F ratio) in COVID-19 with pneumonia and discriminated different severity groups with high accuracy (area under the curve (AUC): 0.9076). Both N-cleaved-Gal9 and sIL-2R levels were associated with plasma matrix metalloprotease (MMP)-9 levels in COVID-19 with pneumonia. Furthermore, a decrease in N-cleaved-Gal9 levels was associated with a decrease of sIL-2R levels during TCZ treatment. N-cleaved-Gal9 levels showed a moderate accuracy (AUC: 0.8438) for discriminating the period before TCZ from the recovery phase. These data illustrate that plasma N-cleaved-Gal9 is a potential surrogate marker for assessing COVID-19 severity and the therapeutic effects of TCZ.

Effects of Candidalysin Derived from Candida albicans on the Expression of Pro-Inflammatory Mediators in Human Gingival Fibroblasts.

Candida albicans (Ca) is frequently detected in the peri-implant sulcus with peri-implantitis, a major postoperative complication after oral implant therapy. However, the involvement of Ca in the pathogenesis of peri-implantitis remains unclear. In this study, we aimed to clarify Ca prevalence in the peri-implant sulcus and investigated the effects of candidalysin (Clys), a toxin produced by Ca, on human gingival fibroblasts (HGFs). Peri-implant crevicular fluid (PICF) was cultured using CHROMagar and Ca colonization rate and colony numbers were calculated. The levels of interleukin (IL)-1β and soluble IL-6 receptor (sIL-6R) in PICF were quantified by enzyme-linked immunosorbent assay (ELISA). Pro-inflammatory mediator production and intracellular signaling pathway (MAPK) activation in HGFs were measured by ELISA and Western blotting, respectively. The Ca colonization rate and the average number of colonies in the peri-implantitis group tended to be higher than those in the healthy group. IL-1β and sIL-6R levels in the PICF were significantly higher in the peri-implantitis group than in the healthy group. Clys significantly induced IL-6 and pro-matrix metalloproteinase (MMP)-1 productions in HGFs, and co-stimulation with Clys and sIL-6R increased IL-6, pro-MMP-1, and IL-8 production levels in HGFs compared with Clys stimulation alone. These findings suggest that Clys from Ca plays a role in the pathogenesis of peri-implantitis by inducing pro-inflammatory mediators.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.