Frontiers in Immunology最新文献

Introduction: Acute rejection is a significant risk factor for developing chronic lung allograft dysfunction. Current monitoring tools, transbronchial biopsies and HLA antibody determination, have limitations in detecting acute rejection. This study aims to explore the potential utility of donor-derived cell-free DNA (ddcfDNA) as a non-invasive biomarker for detecting acute rejection in lung transplant recipients (LTR).

Methods: We developed a molecular method based on digital droplet PCR to determine the total amount and the proportion of ddcfDNA. Using blood samples collected sequentially post-transplant from a cohort of 81 LTR, we compared median levels of %ddcfDNA in patients with acute cellular rejection (ACR), antibody-mediated rejection (AMR), infection, or decline in pulmonary function (FEV₁).

Results: Median %ddcfDNA levels were significantly higher in groups with ACR (1.92% [0.70%, 2.30%], p=0.0006), AMR (1.27% [0.34%, 2.29%], p=0.0009), isolated lymphocytic bronchiolitis (0.54% [0.23%, 2.18%], p=0.03), and infection or prolonged ventilation over 30 days (0.50% [0.22%, 2.35%], p=0.005) versus stable allograft function group (0.26% [0.09%, 0.60%]). %ddcfDNA levels were also elevated in patients with FEV1 loss compared to those with stable or improving FEV1 after 12 months (1.98% vs. 1.36%, p=0.04). An optimal cut-off of 0.73% for %ddcfDNA was calculated to detect ACR and AMR with 80% specificity and 68% sensitivity.

Discussion: %ddcfDNA is a promising biomarker for identifying allograft injury due to acute rejection in LTR and could be a valuable tool for monitoring allograft health.

The immunopeptidome, a diverse set of peptides presented by Major Histocompatibility Complex (MHC) molecules, is a critical component of immune recognition and response. This review article delves into the mechanisms of peptide presentation by MHC molecules, particularly emphasizing the roles of ncRNA-derived peptides and extracellular vesicles (EVs) in shaping the immunopeptidome landscape. We explore established and emerging insights into MHC molecule interactions with peptides, including the dynamics of peptide loading, transport, and the influence of cellular and genetic variations. The article highlights novel research on non-coding RNA (ncRNA)-derived peptides, which challenge conventional views of antigen processing and presentation and the role of EVs in transporting these peptides, thereby modulating immune responses at remote body sites. This novel research not only challenges conventional views but also opens up new avenues for understanding immune responses. Furthermore, we discuss the implications of these mechanisms in developing therapeutic strategies, particularly for cancer immunotherapy. By conducting a comprehensive analysis of current literature and advanced methodologies in immunopeptidomics, this review aims to deepen the understanding of the complex interplay between MHC peptide presentation and the immune system, offering new perspectives on potential diagnostic and therapeutic applications. Additionally, the interactions between ncRNA-derived peptides and EVs provide a mechanism for the enhanced surface presentation of these peptides and highlight a novel pathway for their systemic distribution, potentially altering immune surveillance and therapeutic landscapes.

Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer of a negatively charged four-carbon succinyl group to the ϵ-amino group of lysine residues, mediated by succinyl-coenzyme A. Recent studies have highlighted the involvement of succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), a member of the sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside its deacetylase function. To date, only a limited number of SIRT5 substrates have been identified. These substrates mediate diverse physiological processes such as glucose oxidation, fatty acid oxidation, ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation of these activities can occur through either the same enzymatic activity acting on different substrates or distinct enzymatic activities targeting the same substrate. Aberrant expression of SIRT5 has been closely linked to tumorigenesis and disease progression; however, its role remains controversial. SIRT5 exhibits dual functionalities: it can promote tumor proliferation, metastasis, drug resistance, and metabolic reprogramming, thereby acting as an oncogene; conversely, it can also inhibit tumor cell growth and induce apoptosis, functioning as a tumor suppressor gene. This review aims to provide a comprehensive overview of the current research status of SIRT5. We discuss its structural characteristics and regulatory mechanisms, compare its functions with other sirtuin family members, and elucidate the mechanisms regulating SIRT5 activity. Specifically, we focus on the role of succinylation modification mediated by SIRT5 in tumor progression, highlighting how desuccinylation by SIRT5 modulates tumor development and delineating the underlying mechanisms involved.

The brain and spinal cord, collectively known as the central nervous system, are encapsulated by an overlapping series of membranes known as the meninges. Once considered primarily a physical barrier for central nervous system protection, the bordering meninges are now recognized as highly immunologically active. The meninges host diverse resident immune cells and serve as a critical interface with peripheral immunity, playing multifaceted roles in maintaining central nervous system homeostasis, responding to pathogenic threats, and neurological disorders. This review summarizes recent advancements in our understanding of meningeal immunity including its structural composition, physiological functions, and role in health and disease.

Esophageal squamous cell carcinoma (ESCC) is the most prevalent primary malignant esophageal tumor in China and has a poor prognosis, but lacks effective diagnostic and prognostic biomarkers. Through single-sample gene set enrichment analysis (ssGSEA), we conducted immune genomic analysis based on 28 immune features using transcriptomic data from 155 ESCC cases. We established of two ESCC subtypes characterized by high and low immune profiles, and 352 differentially expressed immune genes were identified between the two subtypes. Performed with univariate and multivariate Cox regression, a novel prognostic prediction model was developed based on three immune-related genes (MAP3K8, SECTM1, IGLV7-43), which has been identified as a relatively accurate, independent, and specific prognostic risk model for ESCC patients in different ESCC cohorts. Furthermore, SECTM1 was upregulated in ESCC tissues and associated with adverse clinical outcomes. In cell experiments, overexpression of SECTM1 effectively promoted the proliferation, migration, and invasion of ESCC cells, while SECTM1 knockdown significantly inhibited these cellular processes. Furthermore, its overexpression promoted macrophage polarization towards the M2-like phenotype and promoted the migration of M2-like macrophage cells and C-C Motif Chemokine Ligand 5 (CCL5) was the key mediator in the pro-cancer effect of SECTM1. In a Conclusion, our study established a prognostic prediction model based on immune-related gene signature, which provided a reliable prognostic tool for ESCC and identified SECTM1 as a potential biomarker in ESCC.

Background: Type 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune response in disease development. Previously, we discovered that β-cell autophagy is impaired prior to the onset of T1D, implicating this pathway in T1D pathogenesis.

Aims: To assess the role of autophagy in β-cell health and survival, and whether defects in autophagy render islets more immunogenic.

Methods: We knocked out the critical autophagy enzyme, ATG7, in the β-cells of mice (ATG7^Δβ-cell) then monitored blood glucose, performed glucose tolerance tests, and evaluated bulk islet mRNA and protein. We also assessed MHC-I expression and presence of CD45+ immune cells in ATG7^Δβ-cell islets and evaluated how impaired autophagy affects EndoC-βH1 HLA-I expression under basal and IFNα stimulated conditions. Lastly, we co-cultured ATG7^Δβ-cell islet cells with diabetogenic BDC2.5 helper T cells and evaluated T cell activation.

Results: We found that all ATG7^Δβ-cell mice developed diabetes between 11-15 weeks of age. Gene ontology analysis revealed a significant upregulation of pathways involved in inflammatory processes, response to ER stress, and the ER-associated degradation pathway. Interestingly, we also observed upregulation of proteins involved in MHC-I presentation, suggesting that defective β-cell autophagy may alter the immunopeptidome, or antigen repertoire, and enhance β-cell immune visibility. In support of this hypothesis, we observed increased MHC-I expression and CD45+ immune cells in ATG7^Δβ-cell islets. We also demonstrate that HLA-I is upregulated in EndoC β-cells when autophagic degradation is inhibited. This effect was observed under both basal and IFNα stimulated conditions. Conversely, a stimulator of lysosome acidification/function, C381, decreased HLA-I expression. Lastly, we showed that in the presence of islet cells with defective autophagy, there is enhanced BDC2.5 T cell activation.

Conclusions: Our findings demonstrate that β-cell autophagy is critical to cell survival/function. Defective β-cell autophagy induces ER stress, alters pathways of antigen production, and enhances MHC-I/HLA-I presentation to surveilling immune cells. Overall, our results suggest that defects in autophagy make β-cells more susceptible to immune attack and destruction.

Sinonasal small-cell neuroendocrine carcinoma (SCNEC) is an uncommon malignant epithelial neuroendocrine tumor in the sinonasal cavity that often presents in isolation and rarely occurs in synchronous fashion with small-cell lung carcinoma (SCLC). Here, we present a case of a 65-year-old man diagnosed with SCNEC concurrently combined with SCLC. He received first-line platinum-doublet chemotherapy combined with durvalumab, followed by radiotherapy to thoracic as well as head and neck regions. The follow-up computed tomography and magnetic resonance imaging showed a complete response according to Response Evaluation Criteria in Solid Tumors criteria until 9 June 2024. This case highlights the need for accurate diagnostic characterization of primary lesions and the need to formalize treatment paradigms using chemotherapy, radiation therapy, immunotherapy with immune checkpoint inhibitors, and targeted prophylactic cranial irradiation.

Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is associated with the development of hundreds of adenomas in the small and large intestines of individuals starting in the teenage years with a near 100% risk of developing colorectal cancer by adulthood. Eventually polyps develop throughout the gastrointestinal tract. Chemoprevention approaches have been somewhat successful in reducing polyp burden, but have not reduced the risk of the development of colorectal cancer or other cancers. The lack of efficacy of more standard drug approaches may be due to limited exposure to the agent only to specific periods while the drug is being metabolized, limited drug penetrance in the colon, and patient adherence to daily dosing and drug side effects. The success of immune therapy for the treatment of invasive cancer has led to research focused on the use of immune based approaches for polyp control in FAP, specifically polyp directed vaccines. Vaccines targeting antigens expressed in FAP lesions may be a superior method to control polyp burden and prevent disease progression as compared to classic chemoprevention drugs. A limited number of vaccines can be administered over a short period of time to generate a lasting immune response. Appropriately primed antigen specific T-cells can traffic to any site in the body where antigen is expressed, recognize, and eliminate the antigen expressing cell. Immunologic memory will allow the immune response to persist and the specificity of the immune response will limit toxicity to the targeted polyp. This review will examine the current state of vaccines directed against FAP lesions and highlight the challenges and opportunities of translating vaccines for cancer interception in FAP to the clinic.

Introduction: Donor lymphocyte infusion (DLI) is a therapeutic approach for relapse after hematopoietic stem cell transplantation (HSCT). Despite their reported efficacy, the evolution of DLI practices over time remains underexplored.

Methods: This study provided a comprehensive analysis of DLI strategies and outcomes over 30 years at a single institution. A retrospective analysis was conducted on 75 patients who underwent DLI for disease relapse between April 1994 and March 2024. The primary endpoint was the 3-year overall survival (OS) rate after DLI. Secondary endpoints included the 100-day complete remission (CR) rate and incidence of acute graft-versus-host disease (GVHD).

Results: The median age at the first DLI was 49 years (range, 20-69 years). The most common underlying diseases in all 75 cases were acute myeloid leukemia (AML, n = 46) and myelodysplastic syndromes (MDS, n = 12). Until 2014, DLI was only performed in patients with AML (n = 14), MDS (n = 2), or chronic myeloid leukemia (n = 5). However, since 2015, patients with various diseases, including lymphoid malignancies, have also undergone DLI. Azacitidine was the most frequently used combination therapy with DLI (n = 34). Regimens including venetoclax and FLT3 inhibitors have been commonly used since 2019 (n = 18). The 3-year OS rate was 29.1% (95% CI, 18.8-40.2%). Factors negatively influencing OS included age ≥50 years and a high or very high refined disease risk index. The 100-day CR rate was 52.1%, and acute GVHD occurred in 25.3% of the patients, with no strong correlation between GVHD incidence and CR achievement. Among 18 patients who underwent three or more DLIs since 2018, 88.9% achieved remission following DLI or second HSCT, with a median follow-up of 949.5 days for survivors.

Conclusion: This study highlighted the evolving trends in DLI practices and the diversification of combination therapies. Future research should focus on further validating these findings and optimizing DLI protocols to improve patient outcomes.

Immunoglobulin M (IgM) and IgM⁺ B cells are key components of the humoral immune system, providing defense against pathogen invasion. While the role of IgM in the systemic and mucosal immune responses of fish to parasites and bacteria has been partially investigated, its function in viral infections remains underexplored. This study successfully developed a largemouth bass (Micropterus salmoides) model for ranavirus immersion infection. Our findings revealed that viral infection caused significant pathological changes in the gill and head kidney tissues, along with a marked upregulation of adaptive immune gene expression. Interestingly, fish that survived an initial viral infection exhibited minimal mortality and low viral loads in the gill and head kidney tissues when exposed to a higher viral concentration. Notably, in these fish with secondary infections, there was a significant increase in IgM protein levels in both the blood and gill mucus, as well as a pronounced accumulation of IgM⁺ B cells in the gill and head kidney tissues. Additionally, the serum contained high levels of virus-specific IgM, which demonstrated the ability to neutralize the virus. These findings highlight the crucial role of IgM in the immune response to viral infections in largemouth bass and suggest its potential as a target for enhancing viral resistance in aquaculture.