sTIM-3 Levels Research Articles

Circulating levels of galectin-9 are a potential biomarker of survival in advanced non-small-cell lung cancer.

The immune system is recognized to have therapeutic potential to destroy cancer cells. Soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) and its ligand galectin 9 (Gal-9) cause suppression of cytokine production, cell cycle arrest and cell death. sTIM-3 and Gal-9 levels may have prognostic implications in non-small-cell lung cancer (NSCLC) patients. This prospective cohort study was performed at Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Pernambuco, Brazil. Fifty-eight patients were diagnosed with advanced NSCLC from January 2019 to January 2020. The age median was of 64.0 years. Soluble galectin-9 (sGal-9) levels in the smokers compared to nonsmoker patients (p < 0.0001). By using the receiver operating characteristic curve, we found that a baseline of 1694 pg/mL (cutoff). sGAL9 with specificity (72.2%), sensitivity (83.2%) and area under the curve = 0.8497 (p < 0.0004). Until 18.2 months, 46.8% and 72.9% were alive in the sGAL9low and sGAL9high groups, respectively (log-rank test; p = 0.02). The median survival was 15.9 months for sGAL9low (≤1694 pg/mL). This study indicated an association of tobacco with the release of circulating sGal-9 levels and the accuracy of sGal-9 as a potential biomarker predictive of survival time in advanced NSCLC patients. Furthermore, sGal-9 has may be a potential therapeutic target in the advanced NSCLC.

Evaluation of soluble co‐inhibitors and co‐stimulators levels of the immune response in gastric cancer

AbstractBackgroundCo‐inhibitor and co‐stimulator mediators trigger actions that result in immunological homeostasis and are being evaluated as potential therapeutic targets in gastric cancer (GC).ObjectiveTo evaluate the soluble levels of sPD‐1, sPD‐L1, sPD‐L2, sTIM‐3, sGal9, sGITR, and sGITRL in GC patients.MethodsThe cross‐sectional study was carried out at the Hospital de Cancer de Pernambuco, Brazil between 2017 and 2018. A total of 74 GC patients and 30 healthy controls were included.ResultsLow levels of sPD1 (p = 0.0179), sPDL2 (p = 0.0003), and sGal9 (p &lt; 0.0001), and higher levels of sPDL1 (p = 0.004), sTIM‐3 (p = 0.0072), sGITR (p = 0.0179), and sGITRL (p = 0.0055) compared to the control group. High sPD‐1, sTIM‐3, and sGal9 levels in stage IV compared I/II and III (p &lt; 0.05). High sPDL1, sGal9, and sGITRL levels in esophagogastric junction compared to body and Pylorus/Antrum groups (p &lt; 0.05). No significant differences were observed in sPD1, sPDL1, sPDL2, sTIM3, sGal9, sGITR, and sGITRL levels between the intestinal, diffuse, and mixed GC groups. Low sGITR levels in GC patients who died within the first 24 months compared to the who survived (p = 0.0332).ConclusionsThere is an association of sPD1, sTIM‐3, and sGal9 with disease progression and sGITR with death, these mediators may be potential prognostic biomarkers in GC.

Comprehensive Co-Inhibitory Receptor (Co-IR) Expression on T Cells and Soluble Proteins in Rheumatoid Arthritis.

Co-IRs T cells were immunophenotyped employing multicolor flow cytometry, and ELISA was utilized for measuring soluble PD-1, PDL-2, and TIM3. Correlations have been detected across the percentage of T cells expressing Co-IRs (MFI) and different indicators in the blood, including ESR, high-sensitivity CRP (hsCRP), 28 joint disease activity scores (DAS28), and soluble PD-1/PDL-2/TIM3. In RA patients, we recognized elevated levels of PD-1 (CD279), CTLA-4, and TIGIT in CD4+ T cells; TIGIT, HLA-DR, TIM3, and LAG3 in CD8+ T cells; and CD8+CD279+TIM3+, CD8+HLA-DR+CD38+ T cells. The following tests were revealed to be correlated with hsCRP: CD4/CD279 MFI, CD4/CD279%, CD4/TIM3%, CD8/TIM3%, CD8/TIM3 MFI, CD8/LAG3%, and CD8+HLA-DR+CD38+%. CD8/LAG3 and CD8/TIM3 MFIs are linked to ESR. DAS28-ESR and DAS28-CRP exhibited relationships with CD4/CD127 MFI, CD8/CD279%, and CD8/CD127 MFI, respectively. CD4+CD279+TIM3+% was correlated with DAS28-ESR (p = 0.0084, N = 46), DAS28-CRP (p = 0.007, N = 47), and hsCRP (p = 0.002, N = 56), respectively. In the serum of patients with RA, levels of soluble PD-1, PDL-2, and Tim3 were extremely elevated. CD4+ TIM3+% (p = 0.0089, N = 46) and CD8+ TIM3+% (p = 0.0305, N = 46) were correlated with sTIM3 levels; sPD1 levels were correlated with CD4+CD279+% (p < 0.0001, N = 31) and CD3+CD279+% (p = 0.0084, N = 30). Co-IR expressions on CD4+ and CD8+ T cells, as well as soluble PD-1, PDL-2, and TIM3 levels, could function as indicators of disease activity and potentially play crucial roles in the pathogenesis of RA.

Soluble immune checkpoints are elevated in patients with primary biliary cholangitis

BackgroundPrimary biliary cholangitis (PBC) is a chronically progressive liver disease mediated by an autoimmune response. The aetiology and pathogenesis of PBC are not fully understood and may be related to immune disorders caused by genetic factors and their interaction with environmental factors. Immune checkpoints play an important role in preventing the occurrence of autoimmunity. However, the level of immune checkpoints in PBC has not been reported. Here, we aimed to identify the serum levels of soluble checkpoints in patients with PBC.MethodsSoluble checkpoint levels were evaluated using enzyme-linked immunosorbent assay in 60 patients with PBC and 20 healthy controls (HCs). The expression of immune checkpoints was compared in liver biopsy tissue samples using immunohistochemistry. Receiver operating characteristic (ROC) curves and area under the curve (AUCs) were used to determine the diagnostic performance of soluble checkpoints and laboratory indexes between patients with PBC and HCs and patients with mild and advanced PBC. A logistic regression was performed for advanced PBC.ResultssCD134, sLAG-3, sPD-1, sPD-L1, and sTIM-3 levels were significantly increased in patients with PBC compared with those in healthy controls. Additionally, the levels of sCD134, sPD-1, sPD-L1, and sTIM-3 were positively associated with disease progression. Moreover, soluble checkpoints were correlated with immunoglobulin and liver functions. ROC analyses between patients with PBC and HCs showed that the AUCs of sOX40, sPD-1, and sPD-L1 were 0.967, 0.922, and 0.971, respectively. The optimal cut-off values of sOX40, sPD-1, and sPD-L1 for PBC diagnosis were 89.15, 213.4, and 68, respectively. ROC analyses between mild and advanced patients with PBC revealed that the AUCs of sOX40 and sTIM-3 were 0.767 and 0.765, respectively. The optimal cut-off values for predicting PBC stage ≥ III were 199.45 and 361.5, respectively. In univariate analysis, age, ALB, and sOX40 were associated with advanced PBC. Further, the expression of CD134 and TIM-3 was upregulated in the liver of patients with PBC.ConclusionsOur study results indicate that the serum titer of soluble checkpoints is increased in Chinese patients with PBC.

T-Cell Exhaustion in HIV-1/Hepatitis C Virus Coinfection Is Reduced After Successful Treatment of Chronic Hepatitis C.

T-cell responses during chronic viral infections become exhausted, which is reflected by upregulation of inhibitory receptors (iRs) and increased interleukin 10 (IL-10). We assessed 2 iRs-PD-1 (programmed cell death protein 1) and Tim-3 (T-cell immunoglobulin and mucin domain-containing protein 3)-and IL-10 mRNAs in peripheral blood mononuclear cells (PBMCs) and their soluble analogs (sPD-1, sTim-3, and IL-10) in plasma in chronic HIV-1/hepatitis C virus (HCV) coinfection and explored the effect of HCV treatment on these markers. We also aimed to establish whether iR expression may be determined by the HCV CD8+ T-cell immunodominant epitope sequence. Plasma and PBMCs from 31 persons with chronic HIV-1/HCV coinfection from the Swiss HIV Cohort Study were collected before and after HCV treatment. As controls, 45 persons who were HIV-1 negative with chronic HCV infection were recruited. Exhaustion markers were assessed by enzyme-linked immunosorbent assay in plasma and by quantitative reverse transcription polymerase chain reaction in PBMCs. Analysis of an HCV epitope sequence was conducted by next-generation sequencing: HLA-A*02-restricted NS31073-1081 and NS31406-1415 and HLA-A*01-restricted NS31436-1444. The study revealed higher plasma sPD-1 (P = .0235) and IL-10 (P = .002) levels and higher IL-10 mRNA in PBMCs (P = .0149) in HIV-1/HCV coinfection. A decrease in plasma sPD-1 (P = .0006), sTim-3 (P = .0136), and IL-10 (P = .0003) and Tim-3 mRNA in PBMCs (P = .0210) was observed following successful HCV treatment. Infection with the HLA-A*01-restricted NS31436-1444 ATDALMTGY prototype variant was related to higher sTim-3 levels than infection with the ATDALMTGF escape variant (P = .0326). The results underscore the synergistic effect of coinfection on expression of exhaustion markers, their reduction following successful HCV treatment and imply that iR levels may operate on an epitope-specific manner.

Serum soluble immune checkpoint levels predict cervical lymph node metastasis of differentiated thyroid carcinoma patients.

Cervical lymph node metastasis (CLNM) is common in patients with differentiated thyroid carcinoma (DTC); however, the efficiency to distinguish CLNM before surgery is limited. T cell exhaustion, characterized by the overexpression of immune checkpoints, plays a critical role in the immune evasion of tumors. The aim of this study is to analyze the association between serum levels of soluble immune checkpoints (sICs) and CLNM in DTC patients. Levels of sICs in serum of 71 DTC patients and 56 healthy volunteers were analyzed by ELISA. Peripheral blood mononuclear cells and cervical lymph nodes of DTC patients were isolated and their expression of sICs were analyzed. Lymphocytes in cervical lymph nodes were analyzed for immune checkpoints expression and transcription of exhaustion-associated factors. 30 out of 71 DTC patients were followed up from 3 to 9 months after the operation, and postoperative sTIM-3 were analyzed. Four sICs, including LAG-3, PD-1, PD-L1, and TIM-3, were increased in DTC patients. All four sICs exhibited higher sensitivity at discriminating CLNM than cervical ultrasound. In the patient-matched comparison, higher sTIM-3 levels were observed in tumor-involved lymph nodes (TILNs) than in normal lymph nodes (nLNs). T lymphocytes in TILNs had higher TIM-3 surface expression and increased secretion of sTIM-3 than those in patient-matched nLNs. Finally, postoperative serum sTIM-3 levels were decreased in DTC patients with CLNM compared to their preoperative levels. Serum levels of sICs, especially sTIM-3, could help to predict CLNM and provide evidence for surgical decision-making in DTC.

Prognostic Role of Serum Soluble Tim-3 in Severe Traumatic Brain Injury: A Prospective Observational Study

T cell immunoglobulin and mucin domain-3 (Tim-3) may be implicated in neuroinflammation. Herein, we attempted to discern the role of serum soluble (s) Tim-3 as an inflammatory prognostic biomarker of severe traumatic brain injury (sTBI). In this prospective observational study of 112 sTBI patients and 112 controls, serum sTim-3 levels were determined, Rotterdam computed tomography (CT) classification and Glasgow coma scale (GCS) were selected as the two severity indicators, serum C-reactive protein (CRP) was regarded as an inflammatory biomarker, and poor prognosis was referred to as extended Glasgow outcome scale (GOSE) scores 1-4 at 180 days after trauma. Serum sTim-3 levels were markedly higher in patients than in controls (median, 4.2 ng/mL versus 0.7 ng/mL; P<0.001). Serum sTim-3 levels of patients were independently related to Rotterdam CT scores (β=1.126), GCS scores (β=-0.589), serum CRP levels (β=0.155) and GOSE scores (β=-0.211). Serum sTim-3 appeared as an independent predictor of post-traumatic 180-day mortality (odds ratio=1.289), overall survival (hazard ratio=1.208) and poor prognosis (odds ratio=1.293). Serum sTim-3 levels discriminated patients at risk of post-injury 180-day mortality and poor prognosis with areas under curve (AUCs) at 0.753 and 0.782, respectively. Serum sTim-3 levels combined with GCS scores and Rotterdam CT scores (AUC=0.869) exhibited significantly higher AUC than Rotterdam CT scores (P=0.026), but not than GCS scores (P=0.181) for death prediction and their combination (AUC=0.895) had significantly higher AUC than GCS scores (P=0.036) or Rotterdam CT scores (P=0.005) for outcome prediction. Elevated serum sTim-3 levels, in close correlation with traumatic severity and inflammation, are substantially associated with long-term death and poor outcome, indicating that serum sTim-3, as an inflammatory biomarker, may be of clinical significance in severity assessment and prediction of prognosis following sTBI.

Soluble immune checkpoint molecules in patients with antineutrophil cytoplasmic antibody-associated vasculitis

Immune checkpoint molecules balance immune effector responses with regulatory reactions. We speculated that soluble immune checkpoint molecules are involved in dysregulation of the immune response and autoimmunity. We evaluated the association between soluble immune checkpoint molecules and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).A total of 56 patients with AAV from a prospective observational cohort and 40 healthy controls (HCs) were analyzed. Soluble PD-1, PD-L1, PD-L2, CTLA-4, CD28, CD80, CD86, ICOS, TIM-3, BTLA, CD40, LAG-3, TLR-2, and CD27 were measured in stored sera using the Milliplex MAP assay. Paired analyses were performed before and after the treatment. AAV-specific indices, including Birmingham vasculitis activity score, five factor score , vasculitis damage index, and blood samples, were collected.Patients with AAV had higher levels of sPD-L1, sCD28, sCD80, sCD86, sICOS, sTIM-3, sLAG-3, sTLR-2, and sCD27 and lower level of sCTLA-4 than HCs (p < 0.05). Patients with AAV had higher serum sCD28, sCD80, sTIM-3, and sCD27 levels than HCs at baseline and decreased after treatment. Furthermore, the serum levels of sCD28 and sTIM-3 were significantly correlated with disease activity.This study demonstrated altered concentrations of serum soluble immune checkpoint molecules in patients with AAV. In particular, sCD28 and sTIM-3 may act as surrogate markers of AAV disease activity.

Elevated serum levels of soluble T cell immunoglobulin and mucin-containing-molecule-3 in patients with idiopathic inflammatory myopathy.

Dear Editor, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), an important immune-checkpoint molecule, is a transmembrane glycoprotein expressed by T lymphocytes that functions in immune response and tolerance in autoimmune diseases [1]. Soluble TIM-3 (sTIM-3) is produced by alternative splicing and cleavage, and may negatively regulate T cell-mediated immune responses [2, 3]. Myositis is a common rheumatic immune-related adverse event that can occur during treatment with immune-checkpoint inhibitors [4]. However, whether immune-checkpoint proteins, including TIM-3, exert opposite effects in autoimmune diseases and cancers remains debatable. This cross-sectional study assessed serum sTIM-3 levels in patients with idiopathic inflammatory myopathy (IIM), which is characterized by muscle fibre necrosis and infiltration of inflammatory cells, particularly activated T cells and phagocytes. Seventy adult patients with IIM and 29 healthy age- and sex-matched controls were recruited at the Department of Rheumatology and Immunology, West China Hospital, Sichuan University, from May 2021 to July 2022. All patients met the Bohan and Peter criteria and the EULAR/ACR criteria (2017), and those with immune-mediated necrotizing myopathy (IMNM) met the European Neuromuscular Centre criteria (2017). Participants <18 years of age; patients with other autoimmune diseases, tumours, HIV infection, chronic liver disease, or other muscle diseases; pregnant or lactating women; and patients who had undertaken strenuous exercise within 1 week prior to recruitment were excluded from the study. Sera samples from four patients with lipid storage myopathy (LSM) were used as the non-IIM group. Disease activity was determined using the myositis activity visual analogue score (VAS), interstitial lung disease (ILD) was confirmed by high-resolution CT, and serum sTIM-3 levels were measured by ELISA (RX105593H; Ruixinbio, Quanzhou, China). Spearman correlations between serum sTIM-3 levels, clinical indicators, and disease activity were determined. This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the hospital (No. 521, 2021).

Clinical value of the sTim‑3 level in chronic kidney disease.

Chronic kidney disease (CKD) is a global disease that is harder to treat at a later stage. Therefore, early diagnosis and monitoring of CKD are crucial. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) is a negative regulator of the T cell responses and it is involved in the immunomodulation of kidney disease. To date, only a small number of reports regarding serum soluble Tim-3 (sTim-3) in CKD are available. In the present study, the serum levels of sTim-3 in patients with CKD at different stages and the levels of sTim-3 in the early diagnosis and monitoring of CKD were analyzed. A highly sensitive time-resolved fluorescence immunoassay was performed to quantify sTim-3 levels in 318 patients with CKD and 114 healthy individuals. The serum levels of sTim-3 in patients with CKD (33.47±20.77 ng/ml) were significantly higher than those in the healthy individuals group (8.32±3.23 ng/ml; P<0.0001). As CKD progressed from stage G1 to G5, the serum sTim-3 level gradually increased (P<0.0001). A cut-off value of 13.63 ng/ml for the sTim-3 concentration was effective in diagnosing patients with CKD (area under the receiver operating characteristic curve, 0.9176; sensitivity, 79.87%; specificity, 96.49%). At this critical value, the positive detection rate of CKD in the early stages (G1 + G2), G3, G4 and G5 was 55.70, 77.78, 84.44 and 92.86%, respectively. In conclusion, the serum sTim-3 levels in patients with CKD were significantly higher than those in the healthy individuals group. As CKD progressed from G1 to G5, the serum sTim-3 concentration gradually increased, facilitating the monitoring of the progression of CKD. In addition, serum sTim-3 had an auxiliary effect that was useful in the early diagnosis of CKD. The positive detection rate of CKD in the early stages was 55.70%, which can assist other clinically common kidney disease indicators.

Circulating T Cell Activation and Exhaustion Markers Are Associated With Radiation Pneumonitis and Poor Survival in Non-Small-Cell Lung Cancer.

IntroductionPersistent inflammation and immune activation in the lungs are associated with adverse outcomes such as radiation pneumonitis (RP) and poor survival in non-small-cell lung cancer (NSCLC) patients. However, it is unknown how this is reflected by leukocyte activation markers in serum.ObjectiveThe aim was to evaluate the serum levels of activation of different leukocyte subsets and to examine those in relation to the pathogenesis of RP and survival in NSCLC.MethodsWe analyzed the serum levels of MPO, sCD25, sTIM-3, sPD-L1, sCD14, sCD163, CCL19 and CCL21 in 66 inoperable NSCLC patients with stage IA-IIIA disease. The patients were treated with stereotactic body radiation therapy (SBRT) or concurrent chemoradiation therapy (CCRT), followed by regular blood sampling for 12 months after treatment and for 5 years for survival.ResultsNineteen (29%) patients developed RP, which occurred more frequently and earlier in patients receiving CCRT than in those receiving SBRT. Increases in sCD25, sTIM-3 and CCL21 levels were observed at the last 6 months of follow-up in patients who had RP after SBRT. Patients who had RP after CCRT had higher sTIM-3 levels during the first 3 months of follow-up. Baseline sCD25 was independently associated with both 2- and 5-year mortality outcomes, while baseline sTIM-3 was independently associated with 2-year mortality.ConclusionWe showed that T cell activation and exhaustion markers such as sCD25 and sTIM-3 are enhanced in patients developing RP and are associated with poor survival in NSCLC.

Soluble T Cell Immunoglobulin and Mucin Domain-3 (sTIM-3) Predicts Graft-Versus-Host Disease (GVHD) in Iranian Allogeneic Hematopoietic Stem Cell Transplantation

Background: T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune-checkpoint molecule that is upregulated following allogeneic immune responses and could play an important role in the development and pathogenesis of graft-versus-host disease (GVHD). The soluble form of TIM-3 (sTIM-3) is increased following the upregulation of membranous TIM-3. Objectives: The aim of this study was to evaluate the association between plasma level of sTIM-3 and acute GVHD (aGVHD) incidence in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Blood samples were collected from 42 allo-HSCT patients and 20 healthy individuals 2 weeks after allo-HSCT. The plasma level of sTIM-3 was measured using enzyme-linked immunosorbent assay (ELISA). The clinical and demographic data of patients were collected from the clinical documents. Data analysis was evaluated using student t-test and one-way ANOVA tests. P-values less than 0.05 were assumed statistically significant. Results: Among 18 (42.8%) patients with aGVHD symptoms, 10 (23.8%) had severe GVHD and 8 (19%) experienced mild GVHD. Plasma sTIM-3 levels at day +14 were significantly higher in patients who developed aGVHD compared to allo-HSCT patients without GVHD and also the healthy control individuals (P-value = 0.015 and &lt; 0.001). Among the aGVHD patients, the sTIM-3 levels in those with severe GVHD were approximately 2.5 times higher than those with mild GVHD (P-value &lt; 0.001). Conclusions: We have identified a high plasma level of sTIM-3 as a valuable biomarker in predicting the development of acute GVHD, especially severe aGVHD in allo-HSCT patients.

Increase in Serum Soluble Tim-3 Level Is Related to the Progression of Diseases After Hepatitis Virus Infection.

BackgroundViral hepatitis is a widespread and serious infectious disease, and most patients with liver cirrhosis and hepatocellular carcinoma are prone to viral infections. T cell immunoglobulin-and mucin-domain-containing molecule-3 (Tim-3) is an immune checkpoint molecule that negatively regulates T cell responses, playing an extremely important role in controlling infectious diseases. However, reports about the role of serum soluble Tim-3 (sTim-3) in hepatitis virus infection are limited. Therefore, this study explored changes in sTim-3 levels in patients infected with hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV).MethodsThis study applied high-sensitivity time-resolved fluorescence immunoassay for the detection of sTim-3 levels. A total of 205 cases of viral hepatitis infection (68 cases of HBV infection, 60 cases of HCV infection, and 77 cases of HEV virus infection) and 88 healthy controls were quantitatively determined. The changes in serum sTim-3 level and its clinical value in hepatitis virus infection were analyzed.ResultsPatients with HBV infection (14.00, 10.78–20.45 ng/mL), HCV infection (15.99, 11.83–27.00 ng/mL), or HEV infection (19.09, 10.85–33.93 ng/mL) had significantly higher sTim-3 levels than that in the healthy control group (7.69, 6.14–10.22 ng/mL, P < 0.0001). Patients with hepatitis and fibrosis infected with HBV (22.76, 12.82–37.53 ng/mL), HCV (33.06, 16.36–39.30 ng/mL), and HEV (28.90, 17.95–35.94 ng/mL) had significantly higher sTim-3 levels than patients with hepatitis without fibrosis (13.29, 7.75–17.28; 13.86, 11.48–18.64; 14.77, 9.79–29.79 ng/mL; P < 0.05).ConclusionsTim-3 level was elevated in patients infected with HBV, HCV, or HEV and gradually increased in patients with either hepatitis or hepatitis with hepatic fibrosis. It has a certain role in the evaluation of the course of a disease after hepatitis virus infection.

The diagnostic value of soluble TIM-3 in oral squamous cell carcinoma.

Objective: To evaluate the soluble TIM-3 (sTIM-3) expression level in oral squamous cell carcinoma (OSCC) and determine its clinical diagnostic potential. Methods: The sTIM-3 and squamous cell carcinoma antigen (SCCAg) levels of 199 OSCC patients and 107 healthy individuals were assessed using an enzyme-linked immunosorbent assay and their individual and combined efficiency rates were compared. Results: The results showed higher sTIM-3 and SCCAg levels in the OSCC patients and better diagnostic potential for a combination of these markers than for their individual assessments, as well as positive correlation of sTIM-3 levels with clinicopathological factors. Conclusion: sTIM-3 is a potential novel and readily accessible OSCC biomarker, which in combination with SCCAg expression level might better diagnose OSCC patients.

Soluble T cell immunoglobulin and mucin-domain containing protein 3 in children hospitalized with pneumonia in resource-limited settings

In a prospective cohort study of 77 children with severe pneumonia from two hospitals in Uganda, we assessed soluble T cell immunoglobulin and mucin-domain containing protein 3 (sTIM-3) levels at hospital admission and their association with pneumonia severity and subsequent mortality. sTIM-3 levels were positively correlated with the Respiratory Index of Severity in Children (RISC) (ρ = 0.35, p = 0.0017), sTIM-3 levels were higher in children who required transfer to a tertiary hospital (p = 0.014) and in fatal cases (p = 0.011). In summary, sTIM-3 is associated with disease severity and predictive of mortality in childhood pneumonia in resource-limited settings.

Clinical Value of Combined Detection of Serum sTim-3 and Pepsinogen for Gastric Cancer Diagnosis.

PurposeThe present study aimed to evaluate the clinical value of the combined detection of soluble T cell immunoglobulinand mucin domain molecule 3 (sTim-3) and pepsinogen (PG) in sera for gastric cancer (GC) diagnosis.Patients and MethodsThe double antibody sandwich method was used to establish a highly sensitive time-resolved fluorescence immunoassay for the detection of sTim-3. Serum sTim-3, PGI, and PGII levels in 149 GC patients (123 first-diagnosis GC patients and 26 post-GC patients), 81 patients with benign gastric disease (BGD), and 73 healthy controls were quantitatively detected. The clinical diagnostic value of the combined detection of sTim-3 and PG in GC was analyzed.ResultsSerum sTim-3 levels in GC (20.41 ± 9.55 ng/mL) and BGD (16.50 ± 9.76 ng/mL) patients were significantly higher (P < 0.001) than those in healthy controls (9.22 ± 3.40 ng/mL). Combined detection of sTim-3 and PGI/PGII (AUC: 0.9330, sensitivity: 86.44%, and specificity: 91.78%) showed a high diagnostic value for GC. When the level of PGI/PGII was less than 12.11 and that of sTim-3 was greater than 14.30 ng/mL, the positive rate of the control group was reduced to 0%, and the positive detection rate of GC was 54.47%. In addition, in post-operative patients, serum sTim-3 levels in the recurrence group (33.56 ± 4.91 ng/mL) were significantly higher than those in the no recurrence group (11.95 ± 5.16 ng/mL).ConclusionsTim-3 levels in BGD and GC sera were significantly higher than those in the control group sera. Additionally, sTim-3 serum levels can predict recurrence in post-operative patients. Compared with PG alone, the combined detection of serum PG and sTim-3 can significantly improve the detection sensitivity and specificity of BGD and GC.

Role of Soluble T-Cell Immunoglobulin Mucin Domain-3 in Differentiating Nontuberculous Mycobacterial Lung Disease from Pulmonary Colonization

BackgroundDifferentiating between nontuberculous mycobacterial lung disease (NTM-LD) and pulmonary NTM colonization (NTM-Col) is difficult. Compared with healthy controls, patients with NTM-LD generally present immune tolerance along with increased expressions of T-cell immunoglobulin mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) on T lymphocytes. However, the role of soluble TIM-3 (sTIM-3) and soluble PD-1 (sPD-1) in differentiating NTM-LD from NTM colonization (NTM-Col) remains unclear. MethodsPatients with NTM-positive respiratory samples and controls were enrolled from 2016 to 2019. Patients were classified into NTM-Col and NTM-LD groups. Levels of sTIM-3, sPD-1, soluble PD-ligand-1 (sPD-L1), and TIM-3 expression were measured. Factors associated with NTM-LD were analyzed by logistical regression. ResultsTIM-3 expression on CD4+ and CD8+ T lymphocytes were highest in NTM-LD group, followed by NTM-Col, and control (P=.017 and P=.011 for trend). sTIM-3 elevated in the NTM-Col group compared with the NTM-LD and control groups (856.3±518.7 vs. 595.3±352.6pg/mL, P=.009; vs. 437.0±267.4pg/mL, P<.001). Levels of soluble PD-1 and its ligand were similar among groups. Among the 79 NTM-positive patients, sTIM-3 was associated with NTM-LD (100-pg/mL increase, adjusted odds ratio (aOR) 0.658 [95% CI, 0.502–0.864], P=.003). Patients with ≥2 risk factors (sTIM-3≤530pg/mL, BMI≤22.5, and radiographic score ≥5) were 13 times more likely to exhibit NTM-LD than those without (aOR 13.234 [2.983–58.709], P=.001). ConclusionssTIM-3 was an independent factor for differentiating NTM-LD from NTM-Col, suggesting the immunologic role of sTIM-3 in NTM-LD pathogenesis. By assessing sTIM-3 levels and other risk factors, physicians may be able to identify NTM-LD cases in a simplified manner.

Elevated soluble Tim-3 correlates with disease activity of systemic lupus erythematosus

T cell immunoglobulin and mucin domain-containing molecule-3(Tim-3) has been found to play important roles in systemic lupus erythematosus (SLE), but whether sTim-3 is involved in the development of SLE remains unknown. In this study, we firstly observed an increased expression of plasma sTim-3 in SLE patients, especially active SLE patients. The plasma sTim-3 levels were positively correlated with anti-dsDNA, SLEDAI score, ESR, and urine albumin. The plasma sTim-3 levels were negatively correlated with C3 and C4. The area under the ROC curve (AUC) values indicated that the plasma sTim-3 level was significantly discriminative of early active SLE from stable SLE and HC with high sensitivity and specificity. The present results suggest that sTim-3 might serve as a potential biomarker for promising the disease activity of SLE.

Association of soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis.

BackgroundAutoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH.MethodsWe enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization–AIH-liver–network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA.ResultsSerum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122–7471]) compared to those in CHC (1026 pg/ml [IQR: 806–1283] p<0.001), PBC (2395 pg/ml [IQR: 2012–3422] p<0.001) or healthy controls (1285 pg/ml [IQR: 1098–1812] p<0.001). In AIH group, serum sTIM-3 were correlated with alanine aminotransferase (ALT), or total bilirubin (TB) and negatively correlated with serum levels of albumin (Alb). Serum levels of sTIM-3 were also strongly correlated with Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum sTIM-3 levels (2147±623pg/ml versus 1321±378pg/ml, p<0.001).ConclusionsCirculating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted.

Serum Levels of T Cell Immunoglobulin and Mucin-Domain Containing Molecule 3 in Patients with Systemic Lupus Erythematosus.

Objective: T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) is implicated in the development of various autoimmune diseases. We aimed to investigate the levels of soluble TIM-3 (sTIM-3) and their associations between clinical parameters in patients with systemic lupus erythematosus (SLE). Methods: Serum samples were collected from 65 patients with SLE and 35 age-matched healthy controls (HCs). The SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) were used to assess SLE disease activity and SLE-related organ damage. British Isles Lupus Assessment Group (BILAG)-2004 index was also used to assess SLE disease activity. Soluble TIM-3 (sTIM-3) in sera from patients with SLE and HCs were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical parameters of SLE including SLE disease activity. Results: Serum sTIM-3 levels in patients with SLE (median 2123 pg/mL (interquartile range (IQR), 229–7235)) were significantly higher than those in HCs (1363 pg/mL; IQR, 1097–1673; p = 0.0015). Serum levels of sTIM-3 were correlated with disease activity of SLE using the SLEDAI-2K score (p < 0.001, r = 0.53). The serum sTIM-3 levels in SLE patients with active renal disease (BILAG renal index A-B) were significantly higher than those without the active renal disease (BILAG renal index C–E). However, no significant difference was observed in serum sTIM-3 levels between SLE patients with and without active involvement in other organs (BILAG index). Serum sTIM-3 levels were significantly elevated in SLE patients with organ damage (2710 pg/mL; IQR, 256–7235) compared to those without organ damage (1532 pg/mL; IQR, 228–5274), as assessed by the SDI (p = 0.0102). Conclusions: Circulating sTIM-3 levels are elevated in SLE patients, and serum sTIM-3 levels are associated with SLE disease activity and SLE-related organ damage. The data indicate a possible link between the TIM-3/Gal-9 pathway and SLE clinical phenotypes, and further investigation of the TIM-3 pathway in SLE pathophysiology is warranted.