Frontiers in Immunology最新文献

[This corrects the article DOI: 10.3389/fimmu.2024.1465448.].

Background: In recent years, immune checkpoint inhibitors (ICIs) have shown significant efficacy in treating various malignancies and have become a key therapeutic approach in cancer treatment. However, while ICIs activate the immune system, they can also induce immune-related adverse events (irAEs). Due to the variability in the frequency and severity of irAEs, clinical management faces a significant challenge in balancing antitumor efficacy with the risk of irAEs. Predicting and preventing irAEs during the early stages of treatment has become a critical research focus in cancer immunotherapy. This study aims to evaluate the predictive value of peripheral blood cell counts for irAEs.

Methods: Studies meeting the inclusion criteria were identified through database searches. The standardized mean difference (SMD) was used to compare continuous blood cell counts. For studies that did not provide adjusted odds ratios (ORs) and 95% confidence intervals (CIs), crude ORs for categorized blood cell counts were calculated. The study protocol was registered on PROSPERO (CRD42024592126).

Results: The meta-analysis included 60 studies involving 16,736 cancer patients treated with ICIs. Compared to patients without irAEs, those experiencing irAEs had significantly higher baseline continuous ALC (SMD = 0.12, 95% CI = 0.01-0.24), while ANC (SMD = -0.18, 95% CI = -0.28 to -0.07) and PLR (SMD = -0.32, 95% CI = -0.60 to -0.04) were significantly lower. Similarly, categorized blood cell counts indicated that higher baseline ALC (OR = 2.46, 95% CI = 1.69-3.57) and AEC (OR = 2.05, 95% CI = 1.09-3.85), along with lower baseline NLR (OR = 0.64, 95% CI = 0.50-0.81) and PLR (OR = 0.63, 95% CI = 0.48-0.82), were associated with an increased risk of irAEs. Subgroup analysis further identified cutoff values for ALC (2×10^9/L), NLR (5 or 3), and PLR (180) as better predictors of irAEs.

Conclusion: Higher baseline ALC and AEC, along with lower baseline ANC, NLR, and PLR, are associated with an increased risk of irAEs. However, further research is needed to determine the optimal cutoff values and to explore the efficacy of blood cell counts in predicting specific types of irAEs.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024592126.

Background: Tocilizumab (TCZ) is a monoclonal antibody that neutralizes interleukin (IL)-6 and is indicated for diseases characterized by markedly elevated inflammatory markers, such as rheumatoid arthritis (RA). The complement system has been implicated in the etiopathogenesis of RA.

Objective: To evaluate the effect of systemic IL-6 inhibition on complement pathways functional activity in RA patients treated with TCZ.

Desing: Prospective non-interventional study.

Methods: Twenty-seven RA patients included in the TOCRIVAR study who received TCZ (8mg/kg IV/q4w) were evaluated at baseline and at weeks 12, 24 and 52 of treatment. Disease activity, as assessed by composite indices, acute phase reactants, and new-generation functional assays of the three complement pathways, was evaluated at baseline and at each follow-up visit. Multivariable linear mixed models were used to determine changes in the complement system cascades over time.

Results: After adjustment for disease activity, basal levels of the classical and alternative pathways decreased significantly after TCZ treatment. The effect on the classical pathway remained significant after 52 weeks. The decrease in the alternative pathway was significant at weeks 12 and 24, but not at week 52 of TCZ treatment. TCZ had no effect on the lectin cascade throughout the follow-up.

Conclusion: TCZ reduces the activity of the classical and alternative pathways of the complement system in RA patients regardless of the improvement in disease activity. This finding may contribute to a better understanding of the mechanisms by which the IL-6 blockade reduces disease activity in RA patients.

Objective: People with Hashimoto's thyroiditis (HT) often have low vitamin D3 concentrations. Some research has suggested that vitamin D3 supplementation reduces thyroid inflammation, but this remains controversial.

Methods: EAT was induced in female NOD/ShiLtJ mice by giving them water containing 0.05% sodium iodide, and 1μg/kg of 1α,25-(OH)₂D₃ was injected intraperitoneally every other day. After 8 weeks, the morphological architecture of the mouse thyroid follicles was examined by histological sections, thyroid autoantibodies and thyroid hormone concentrations were determined by enzyme-linked immunosorbent assays (ELISAs), and the major functions and subsets of B- and T-lymphocytes in the mouse thyroid were determined by tissue multiple immunofluorescence technology and ELISA.

Results: EAT caused thyroiditis follicle destruction and interfollicular lymphocyte infiltration in mice, increased concentrations of circulating thyroid autoimmune antibodies TG-Ab and TPO-Ab, and abnormal thyroid hormone levels. EAT also increased the number and functionality of CD4+ Tfh, Th17,Th1 and Th2 cells in the thyroid, while decreasing the number and functionality of CD4+ Treg cells and CD19⁺B10 cells. Treatment with VD3 reversed these changes.

Conclusion: Vitamin D3 supplementation can effectively treat autoimmune thyroiditis in mice. VD3 reduces autoimmune thyroid damage and decreases serum thyroid antibody levels in mice by inhibiting the differentiation and functionality of pro-inflammatory Tfh, Th17, Th1 and Th2 cells and by facilitating the differentiation and functionality of anti-inflammatory B10 cells and Treg.

[This corrects the article DOI: 10.3389/fimmu.2024.1533740.].

Introduction: Ulcerative colitis (UC) is a global gastrointestinal disease, which is mainly caused by both dysfunctional epithelial barrier and inflammation response. Iron is a critical fundamental element for both the maintenance of homeostasis and the mediation of inflammation in many tissues. However, the role and mechanism of iron in the phase of enteritis and the subsequent repairing phase of intestinal stem cells has not been elucidated. In this study, we aimed to explore whether and how iron depletion would affect the occurrence and outcome of experimental colitis.

Methods: Iron depletion was realized by deferoxamine (DFO) at either the early stage or late stage of dextran sulfate sodium (DSS) induced experimental colitis in mice. The gross images of colons, general health, histology, barrier integrity, and qRT-PCR were performed. Meanwhile, cell culture and colonic organoids were used to examine the influence of iron depletion in vitro. Signaling pathway and inflammatory infiltration were investigated by immunostaining.

Results: Iron depletion within the early stage of DSS treatment significantly inhibited the onset of the inflammatory response, maintained the integrity of the colonic epithelium, and preserved the activity of intestinal stem cells (ISCs) both in vivo and in vitro. However, both continuous iron depletion by DFO and late DFO treatment aggravated colonic injury and postponed the recovery from colitis. Early DFO-induced iron depletion was able to maintain the p-STAT3 and p-ERK1/2 signaling pathways within the colonic epithelium at the early phase of colitis, but late DFO treatment inhibited the activity of these two pathways.

Discussion: Our study demonstrated that the manipulation of iron depletion by DFO might greatly affect the outcomes of experimental colitis in a phase-dependent manner, which suggests that the balance of iron metabolism might be an effective therapeutic target for the clinical treatment of IBD patients.

Introduction: The large yellow croaker iridovirus (LYCIV) poses a significant threat to the aquaculture industry of Larimichthys crocea. Understanding the host defense response to LYCIV infection is crucial for developing effective strategies to mitigate its impact.

Methods: In this study, an epigenetic approach was employed to investigate dynamic changes in chromatin accessibility using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Additionally, RNA sequencing (RNA-seq) was used to analyze the expression pattern of immune response genes upon LYCIV infection.

Results: Substantial alterations in chromatin accessibility were observed, particularly in the regulatory regions of key immune-related genes. Significant changes in the expression of AP-1 transcription factors, including the Batf gene, were noted. CUT&Tag results revealed that AP-1 was significantly enriched in the open chromatin regions of cytokine genes, with Batf potentially regulating the cytokine genes LIF and CLCF1.

Discussion: These findings suggest that AP-1 may play a crucial role in the defense response against viral infection by modulating inflammatory cytokines and contributing to cellular inflammatory responses. This study provides a comprehensive analysis of the epigenomic landscape and gene expression regulation during iridovirus infection in L. crocea, offering valuable insights for breeding programs aimed at combating iridovirus infections.

Objectives: To explore whether T1 mapping parameters and the functional liver imaging score (FLIS) based on Gd-EOB-DTPA MRI could evaluate liver regeneration after hepatectomy for HCC patient.

Methods: This retrospective study finally included 60 HCC patients (48 men and 12 women, with a median age of 53 years). T1 relaxation time of liver before gadoxetic acid injection (T1_pre) and during the hepatobiliary phase (T1_HBP), reduction rate (Δ%) and FLIS were calculated, their correlations with liver fibrosis stage, hepatic steatosis, and liver regeneration, quantified as regeneration index (RI), were assessed by Kendall's tau-b correlation test or Spearman's correlation test. Multivariate linear regression analyses were used to explore the indicator of RI.

Results: T1_pre, T1_HBP, Δ%, and FLIS manifested significant correlation with fibrosis stage (r = 0.434, P =0.001; r = 0.546, P < 0.001; r = -0.356, P =0.005; r = -0.653, P <0.001, respectively). T1_pre showed significant correction with steatosis grade (r = 0.415, P =0.001). Fibrosis stage and steatosis grade were associated with RI (r = -0.436, P<0.001; r = -0.338, P =0.008). Accordingly, T1_pre, T1_HBP and FLIS were the significant predictors (P<0.05) of RI in multivariate analysis. Similarly, in the patients undergoing minor hepatectomy (n=35), T1_HBP, Δ% and FLIS were related to RI (P<0.05) in multivariate analysis. Nevertheless, in the patients undergoing major hepatectomy (n=25), no T1 mapping parameter and FLIS was the independent predictor of RI.

Conclusions: T1 mapping parameters and FLIS were the potential noninvasive indicators of liver regeneration, except for HCC patients undergoing major hepatectomy.

Clinical relevance statement: The value of T1 mapping and FLIS with Gd-EOB-DTPA MRI for accurate preoperative evaluation of liver regeneration is critical to prevent liver failure and improve prognosis of HCC patients.

Introduction: New biomarkers are urgently needed to detect pancreatic ductal adenocarcinoma (PDAC) at an earlier stage for individualized treatment strategies and to improve outcomes. Autoantibodies (AAbs) in principle make attractive biomarkers as they arise early in disease, report on disease-associated perturbations in cellular proteomes, and are static in response to other common stimuli, yet are measurable in the periphery, potentially well in advance of the onset of clinical symptoms.

Methods: Here, we used high-throughput, custom cancer antigen microarrays to identify a clinically relevant autoantibody biomarker combination able to differentially detect PDAC. Specifically, we quantified the serological AAb profiles of 94 PDAC, chronic pancreatitis (CP), other pancreatic- (PC) and prostate cancers (PRC), non-ulcer dyspepsia patients (DYS), and healthy controls (HC).

Results: Combinatorial ROC curve analysis on the training cohort data from the cancer antigen microarrays identified the most effective biomarker combination as CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Additionally, differential expression analysis on the samples run on the iOme™ array identified 4 biomarkers (ALX1-GPA33-LIP1-SUB1) upregulated in PDAC against diseased and healthy controls. Identified AAbs were validated in silico using public immunohistochemistry datasets and experimentally using a custom PDAC protein microarray comprising the 11 optimal AAb biomarker panel. The clinical utility of the biomarker panel was tested in an independent cohort comprising 223 PDAC, PC, PRC, colorectal cancer (CRC), and HC samples. Combinatorial ROC curve analysis on the validation data identified the most effective biomarker combination to be CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Subsequently, the specificity of the 11-biomarker panel was validated against other cancers (PDAC vs PC: AUC = 70·3%; PDAC vs CRC: AUC = 84·3%; PDAC vs PRC: AUC = 80·2%) and healthy controls (PDAC vs HC: AUC = 80·9%), confirming that this novel AAb biomarker panel is able to selectively detect PDAC amongst other confounding diseases.

Conclusion: This AAb panel may therefore have the potential to form the basis of a novel diagnostic test for PDAC.

[This corrects the article DOI: 10.3389/fimmu.2024.1371620.].