Immunologic Research最新文献

Tyro3, Axl, and Mer (TAM) receptors are involved in immunity and affect the progression of several autoimmune diseases. This study investigated the potential role of TAM receptors in individuals diagnosed with idiopathic inflammatory myopathies (IIM). Clinical data and serum samples were obtained from 176 patients with IIM and 50 healthy controls (HCs). The levels of soluble TAM (sTAM) receptors were measured through enzyme-linked immunosorbent assay. Additionally, Tyro3 protein expression in the muscle tissue of both patients and HCs was examined using western blot and immunohistochemistry (IHC) analyses. The levels of sTAM receptors were notably higher in IIM patients than in HCs. Specifically, serum concentrations of soluble Tyro3 (sTyro3) were markedly elevated among patients with dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM). No significant differences were found in sTyro3 levels among IMNM patients with anti-signal recognition particle positive, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase positive, and seronegative subtypes. Further, levels of sTyro3 showed an inverse relationship with the manual muscle testing-8 score, while exhibiting a positive correlation with serum creatine kinase. Following treatment, patients with IMNM and DM exhibited reduced sTyro3 levels. Results from western blotting and IHC revealed a significant expression of Tyro3 in the necrotic muscles of patients with IMNM and DM. This study demonstrated that Tyro3 causes muscle injury in patients with IIM; therefore, it is considered a potential biomarker and therapeutic target for patients with IIM.

Background: Variants of uncertain significance (VUS) represent a major diagnostic challenge in the interpretation of genetic testing results, particularly in the context of inborn errors of immunity such as severe combined immunodeficiency (SCID). The inconsistency among computational prediction tools often necessitates expensive and time-consuming wet-lab analyses.

Objective: This study aimed to develop disease-specific, multi-class machine learning models using in silico scores to classify SCID-associated genetic variants and improve the interpretation of VUS.

Methods: Genes associated with SCID were identified based on the 2024 update of the International Union of Immunological Societies. Missense variants were retrieved from ClinVar and labeled as benign, likely benign, likely pathogenic, or pathogenic. Variants classified as VUS or with conflicting interpretations were excluded. In silico functional prediction scores were collected for each variant. Multi-class classification models were developed using six machine learning algorithms: Random Forest, XGBoost, Gradient Boosting, AdaBoost, Support Vector Machine and Logistic Regression. Performance was evaluated using five-fold cross-validation with five repeats (25 folds).

Results: A total of 537 variants from 71 genes were included in the final dataset. Among the models, Random Forest achieved the best performance with an accuracy of 0.70 ± 0.03 and the highest area under the receiver operating characteristic curve (AUROC: 0.90 ± 0.01). MetaRNN, BayesDel_addAF, and REVEL were the most predictive features.

Conclusion: This study demonstrates that disease-specific, multi-class machine learning models leveraging in silico scores can effectively support the classification of SCID-related variants, offering a promising tool for improving VUS interpretation.

Key messages: Multi-class machine learning models can enhance the interpretation of SCID-related VUS. Random Forest showed the highest diagnostic accuracy and robustness among tested models. Disease-specific modeling improves classification performance despite limited datasets. Capsule Summary This study developed disease-specific multi-class machine learning models to classify SCID-related variants using in silico scores, with Random Forest showing the strongest performance in predicting variant pathogenicity.

The tumor microenvironment (TME) is a complex system composed of the extracellular matrix (ECM) and various cell types, with collagen being one of its core components. Collagen heterogeneity profoundly influences tumor progression and the remodeling of the immune microenvironment by regulating tumor cell behavior, signaling pathways, and immune evasion in TME. Different subtypes of collagen significantly affect tumor growth, metastasis, and therapeutic responses by modulating the infiltration and function of immune cells. In "cold" tumors, the immunosuppressive microenvironment is shaped by collagen deposition, fibroblast activation, and the release of immunosuppressive factors. The excessive accumulation of collagen hinders immune cell infiltration and the efficacy of immunotherapy. Now, therapeutic strategies targeting collagen metabolism have shown promise in converting cold tumors into "hot" tumors by reducing collagen deposition and enhancing tumor immunity. This review systematically explores how different collagen subtypes regulate collagen metabolism offering new perspectives for the treatment of cold tumors and laying the theoretical groundwork for future advances in personalized immunotherapy.

We present six patients with dysautonomia secondary to primary Sjögren's disease (pSjD) and analyze the literature regarding this topic. Case series. Patients were retrospectively recruited from a tertiary center in Mexico from 2001 to 2022 and included if they met 2016 ACR/EULAR criteria for SjD. Dysautonomia was diagnosed by the presence of autonomic symptoms and at least one of Ewin's battery tests. We scored the Composite Autonomic Severity Scale (CASS), and the Composite Autonomic Symptom Score (COMPASS-31). Patients (n = 6) were primarily females (83%), with a range of 23 to 60 years at onset of neurological manifestations. Dysautonomia preceded 2-10 years the diagnosis of pSjD in five patients. The clinical manifestations varied, but all patients had orthostatic hypotension and syncope. Patients had variability regarding non-neurological disease activity (ESSDAI 0-15) at the onset of neurological manifestations. Treatment for dysautonomia included prednisone, hydroxychloroquine, DMARDs, rituximab, or their combinations. Overall, we observed partial improvement in most of the cases and only one patient had remission of her symptoms of dysautonomia. Two patients discontinued treatment and lost follow-up. Few cases of dysautonomia and biopsy proven pSjD were identified in the literature, but they shared clinical features with ours. Dysautonomia is a rare and challenging neurological manifestation attributed with pSjD. The main symptoms in our patients were orthostatic hypotension and syncope; and most of the times preceded SjD diagnosis. Partial improvement was achieved in the majority of patients following treatment.

We present a series of preclinical studies focused on developing in vitro 2D and 3D models for assessing immunogenic factors in preventing infectious diseases. Human peripheral blood mononuclear cells (PBMC) and Calu-3 cell lines (bronchial epithelial cells) were used to develop 2D and 3D models. Peptides: Spike-S1-His (S-His), nucleocapsid-His and adjuvants: human adenovirus five serotype-based viral vector (AdV-D24-ICOSL-CD40L), armed with inducible co-stimulator (ICOSL) and CD40 ligand (CD40L), and a vector lacking these transgenes (AdV5/3) were used due to their effective initial interaction with antigen-presenting cells (APC). Studying the potency of biologics in vitro revealed a significant increase in the percentage of CD4⁺ TCM, CD4⁺ TEMRA, and CD4⁺ TEM lymphocyte subpopulations involved in memory cell generation after 24 h of treatment. Prolonging the exposure for 7 days, a significant increase in CD4⁺ cells was observed when PBMCs were treated with AdV1 (56.00 ± 0.26% vs. 48.17 ± 1.10%). In contrast, a decrease in CD8⁺ cells was observed in those treated with AdV1 (37.93 ± 0.35%) compared to AdV1 + S-His + N-His (38.47 ± 0.38%) versus the untreated group (44.63 ± 1.07%). A decrease in EMRA was noted when PBMCs were treated with AdV1 + S-His + N-His (2.97 ± 0.23% vs. 4.50 ± 0.35%). Moreover, it was pointed out that PBMCs treated with AdV1 alone or in combination with S-His and N-His showed an elevated number of naïve CD4⁺/CD8⁺ and SCM CD4⁺/CD8⁺ cells. No changes in the number of EMRA CD4⁺ subpopulations were detected when PBMCs were treated with AdV2 compared with untreated ones (4.27 ± 0.06% vs. 4.50 ± 0.35%). Analysis of the humoral response induced by AdV1, AdV2, S-His, N-His, AdV1 + S-His + N-His, and AdV2 + S-His + N-His showed that AdV1 alone (4.17 ± 0.25% vs. 3.17 ± 0.06%) and in combination with S-His and N-His (3.87 ± 0.25 vs. 3.17 ± 0.06%) slightly increased the number of CD19⁺ cells. RNA-Seq analysis of PBMC cells in the 3D model revealed gene overexpression, including FGFR4, associated with the Rap1 pathway in samples exposed to AdV1 + S-His + N-His. Thus, the proposed platform's impact on lymphocyte differentiation was confirmed, and cytokine profile analysis in this sample revealed elevated levels of IL-10, IL-12p70, and IL-8. All samples exposed to AdV showed increased levels of IFN-γ. The safety and biodistribution studies of the vaccine platform demonstrated that a 30-day exposure did not impact mice's survival or organ morphology. Exploring the CD40 pathway notably reveals its significant impact on immune cell populations, suggesting potential therapeutic avenues.

Since the beginning of the COVID-19 pandemic, various groups around the world have intensively worked in the development of vaccine candidates against SARS-CoV-2. Several vaccines have been approved in the past years; the majority is based on the Spike or RBD proteins and employs parenteral administration routes. Considering the recent history of coronavirus zoonotic events, which are known to have caused serious human health problems, the development of vaccines with a broad scope of protection and the potential to cut/reduce the transmission remains in the spotlight. The current global pandemic preparedness initiatives have also promoted the preclinical evaluation of a new group of coronavirus vaccines. In line with current needs, the goal of the present work is the preclinical evaluation, in two different mice strains, of a novel nasal vaccine candidate based on two highly conserved sarbecovirus proteins, S2 and nucleocapsid (N). The vaccine preparation, containing a CpG ODN as adjuvant, was able to generate high antibody titers against both antigens, in sera and bronchoalveolar lavages. This humoral response results cross-reactive to SARS-CoV-1 and MERS-CoV. In addition, the preparation induces IFNγ secretion, and a marked IgG2a response, against both proteins at the systemic compartment, consistent with the development of a Th1 pattern. Although further evaluations should be done, the level of cross-reactivity and the mucosal response obtained constitute promising features of this vaccine candidate.

Cell-free DNA (cfDNA) is emerging as a promising biomarker in liquid biopsy applications for cancer, with growing interest in its potential utility also for the diagnosis, monitoring of treatment response, and detection of relapse in hematologic malignancies. However, the precise origin and clinical relevance of cfDNA in these disorders remain to be fully clarified. In this study, we analyzed plasma samples from 98 patients with hematologic malignancies and 80 healthy donors using quantitative PCR (qPCR) to quantify cfDNA concentrations. We further examined associations between cfDNA levels and clinical parameters, including sex and measurable residual disease (MRD). Our results demonstrated significantly elevated cfDNA levels in patients compared to healthy individuals, with a strong correlation between cfDNA concentration and presence/MRD of the disease. We also identified sex-specific differences in cfDNA levels. Notably, our findings suggest that neutrophils, through the release and degradation of neutrophil extracellular traps (NETs), may constitute a relevant source of circulating cfDNA. In addition, cfDNA concentrations were significantly associated with MRD status, supporting the potential role of cfDNA as a non-invasive biomarker for disease monitoring. Overall, our data highlight the clinical relevance of cfDNA in hematologic malignancies, both as a surrogate for disease burden and as a possible player in disease pathophysiology, thus offering a promising avenue for improved diagnostic and therapeutic strategies.

Psoriasis is one of the most common chronic inflammatory skin diseases and is characterised by the uncontrolled proliferation of keratinocytes and their abnormal differentiation. Sirtuins are a group of enzymes that play an important role in post-translational modifications of proteins, such as deacetylation, poly-ADP-ribosylation, demalonylation and lipoamidation. They are found in various cell types and are involved in ribosomal DNA recombination, gene silencing and DNA repair. This study aimed to examine the plasma levels of sirtuin 3, 4 and 5 in patients with psoriasis and correlate these levels with clinical parameters. The study included 43 patients with plaque-type psoriasis and 28 healthy controls. The plasma concentrations of sirtuin 3 were statistically significantly increased in patients with psoriasis compared to the control subjects. The plasma concentrations of sirtuin 4 and 5 were statistically significantly lower in patients with psoriasis than in the control group. No statistically significant correlations were found between the plasma levels of sirtuin 3 and 4 and the psoriasis activity tools of PASI, DLQI and the BSA index or the selected clinical parameters in patients with psoriasis. Plasma concentrations of sirtuin 5 correlated statistically significantly with the BSA index, haemoglobin and leukocytes. The results of this study suggest the involvement of sirtuin 3, 4 and 5 in the pathogenesis of psoriasis. However, an explanation of the role of sirtuins in psoriasis requires further research.

Single-cell transcriptome analysis has made outstanding contributions to the identification of new cell lineages and the study of cancer immune microenvironment. Yet, the characterization of human liver type 1 innate lymphoid cells (ILC1s) and their dynamic changes in the tumor microenvironment have not been thoroughly studied at this detailed level. Here, we performed an integrated analysis of mouse and human liver immune cells to identify human liver ILC1s based on identified mouse liver ILC1s and to verify its functional similarity. Additionally, our findings highlighted the different expression patterns of the transcription factor EOMES in human versus mouse liver ILC1s, suggesting its reduced regulatory significance in human liver nature killer (NK) cells and ILC1s compared to murine models. A unique subset of intermediate innate lymphoid cells (intILCs) was identified, exhibiting traits of both human liver NK cells and ILC1s. Single-cell RNA sequencing (scRNA-seq) data analysis and TCGA dataset were utilized to characterize the distinct alterations in the genes and functions of NK cells, ILC1s, and intILCs in human hepatocellular carcinoma (HCC). It was found that the dynamic changes of liver ILC1s and intILCs, along with some of their subpopulations, may be key factors in tumor progression. This study provided new insights into the identification of ILC1s in human liver and the immunologic changes and mechanism of innate lymphoid cells (ILCs) in the tumor microenvironment, and these findings may be applicable to improving the diagnosis and treatment of hepatocellular carcinoma.

The field of epigenetics has significantly advanced our understanding of gene regulation in cancer, revealing dynamic modifications that do not alter the DNA sequence yet profoundly influence gene expression. These include DNA methylation, histone modifications, non-coding RNAs, chromatin remodeling, and RNA modifications. In malignancies such as colorectal, breast, lung, glioblastoma, and hematologic cancers, these epigenetic alterations contribute to tumor initiation, progression, and immune evasion. Emerging evidence reveals that such modifications shape the tumor-immune interface by influencing antigen presentation, immune cell infiltration, and cytokine signaling. This review explores the interplay between key epigenetic modifications and cancer immunity, emphasizing how these mechanisms contribute to immune escape and therapeutic resistance. We also examine the emergence of epigenetic therapies-particularly DNMT inhibitors, HDAC inhibitors, and BET inhibitors-as promising tools to reprogram immune responses and restore anti-tumor immunity. Furthermore, we discuss combinatorial approaches integrating epigenetic modulators with immune checkpoint inhibitors, underscoring their potential to enhance treatment efficacy. By outlining current challenges and emerging strategies, this review underscores the need for personalized epigenetic interventions and biomarker-driven approaches to improve outcomes in cancer immunotherapy. These insights establish epigenetic regulation as a critical frontier in next-generation cancer immunotherapy.