Immunologic Research最新文献

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Lysine-specific demethylase 1 (LSD1), an enzyme involved in transcriptional regulation, has an unclear role in synovial inflammation, fibroblast-like synoviocytes migration, and invasion during RA pathogenesis. In this study, we observed increased LSD1 expression in RA synovial tissues and in TNF-α-stimulated MH7A cells. SP2509, an LSD1 antagonist, directly reduced LSD1 expression and reversed the elevated levels of proteins associated with inflammation, apoptosis, proliferation, and autophagy induced by TNF-α. Furthermore, SP2509 inhibited the migratory capacity of MH7A cells, which was enhanced by TNF-α. In CIA models, SP2509 treatment ameliorated RA development, reducing the expression of pro-inflammatory cytokines and alleviating joint pathological symptoms. These findings underscore the significance of LSD1 in RA and propose the therapeutic potential of SP2509.

Multiple sclerosis (MS) is a chronic inflammatory disease that leads to demyelination and damage to the central nervous system. It is well known, the significance of the involvement and influence of the immune system in the development and course of MS. Nowadays, more and more studies are demonstrating that an important factor that affects the action of the immune system is the gut microbiota. Changes in the composition and interrelationships in the gut microbiota have a significant impact on the course of MS. Dysbiosis affects the disease course mainly by influencing the immune system directly but also by modifying the secreted metabolites and increasing mucosal permeability. The essential metabolites affecting the course of MS are short-chain fatty acids, which alter pro- and anti-inflammatory responses in the immune system but also increase the permeability of the intestinal wall and the blood-brain barrier. Dietary modification alone can have a significant impact on MS. Based on these interactions, new treatments for MS are being developed, including probiotics administration, supplementation of bacterial metabolites, fecal microbiota transplantation, and dietary changes. Further studies may serve to develop new drugs and therapeutic approaches for MS.

This study aimed to develop and validate a nomogram based on immune checkpoint genes (ICGs) for predicting prognosis and immune checkpoint blockade (ICB) efficacy in lung adenocarcinoma (LUAD) patients. A total of 385 LUAD patients from the TCGA database and 269 LUAD patients in the combined dataset (GSE41272 + GSE50081) were divided into training and validation cohorts, respectively. Three different machine learning algorithms including random forest (RF), least absolute shrinkage and selection operator (LASSO) logistic regression analysis, and support vector machine (SVM) were employed to select the predictive markers from 82 ICGs to construct the prognostic nomogram. The X-tile software was used to stratify patients into high- and low-risk subgroups based on the nomogram-derived risk scores. Differences in functional enrichment and immune infiltration between the two subgroups were assessed using gene set variation analysis (GSVA) and various algorithms. Additionally, three lung cancer cohorts receiving ICB therapy were utilized to evaluate the ability of the model to predict ICB efficacy in the real world. Five ICGs were identified as predictive markers across all three machine learning algorithms, leading to the construction of a nomogram with strong potential for prognosis prediction in both the training and validation cohorts (all AUC values close to 0.800). The patients were divided into high- (risk score ≥ 185.0) and low-risk subgroups (risk score < 185.0). Compared to the high-risk subgroup, the low-risk subgroup exhibited enrichment in immune activation pathways and increased infiltration of activated immune cells, such as CD8 + T cells and M1 macrophages (P < 0.05). Furthermore, the low-risk subgroup had a greater likelihood of benefiting from ICB therapy and longer progression-free survival (PFS) than did the high-risk subgroup (P < 0.05) in the two cohorts receiving ICB therapy. A nomogram based on ICGs was constructed and validated to aid in predicting prognosis and ICB treatment efficacy in LUAD patients.

Allergic diseases affect nearly 30% of people worldwide. There is a wide range of allergen sources, such as animal dander, food, venom, dust mites, and pollen. The skin prick test is the predominant technique used to identify allergenic sensitivity in vivo; the main problem is that it can be imprecise as many of the allergen extracts are made of mixtures of allergic and nonallergic components, making it difficult to identify the disease-eliciting allergen. An alternative to solve this problem is employing cellular models in vitro that may allow allergen identification, allergy diagnosis, and testing of novel potential compounds that can be used in immunotherapeutics. For example, rat basophilic leukemia (RBL) cells are a well-suited model for studying allergies. Unfortunately, cells generated from RBL cells are not commercially available. Therefore, we developed an RBL model with a degranulation gene reporter capable of recognizing human IgE involved in allergenic sensitivity using commercial plasmids. Employing this model, we successfully evaluated the capacity of union between IgE from allergic patients to allergenic proteins from Oleaceae tree pollen. This RBL cell model can be used as a diagnostic method for sensitivity to any allergens from different sources in vitro.

Prompt disease control of flares in patients with systemic lupus erythematosus (SLE) is a priority in treatment strategy planning. However, the long-term dosage-related collateral effects of glucocorticoids (GCs) have pushed researchers towards the identification and utilization of novel biological agents that could both induce and maintain low disease activity and remission, especially in the context of lupus nephritis (LN). This scoping review aims at assessing the current evidence of the potential steroid-sparing effect of biologic therapies by reviewing phase II and phase III randomized, placebo-controlled trials involving SLE/LN patients. A scoping review of the literature was carried out in accordance with PRISMA-ScR recommendations. Risk of bias was assessed through the utilization of the Cochrane Collaboration's tool for randomized controlled trials (RCTs). Eight RCTs met the inclusion criteria and were included in this analysis (treatment drug, 7 belimumab; 1 anifrolumab). Four studies showed a definite steroid-sparing effect (treatment drug, 3 belimumab; 1 anifrolumab), while in the remaining four RCTs, the steroid-sparing effect was not observed. When focusing on phase III trials, the overall quality of the studies resulted fair or good considering the risk of bias. However, a degree of heterogeneity of steroid regimen protocol (considering initial dosage, tapering and rescue treatment allowance) was observed. While a growing body of evidence is supporting the safety and efficacy of biological treatment in SLE, the evidence on their steroid-sparing effect remains scattered. Future research needs to pursue the identification of precise SLE clusters of patients who would benefit most from a specific treatment protocol with a definite steroid-sparing effect.

The pathological manifestation of the inflammatory process primarily stems from the heightened release of pro-inflammatory cytokines, with IL-1β standing out as a pivotal cytokine. The excessive presence of IL-1β disrupts immune signaling, thereby assuming a pathogenic and exacerbating role in the pathophysiology of numerous inflammatory diseases. Regulating IL-1β levels becomes crucial, and the IL-1Ra molecule serves this purpose by binding to the IL-1R1 receptor, thereby impeding the binding of IL-1β. Several pharmaceuticals have entered the market, aiming to neutralize IL-1β's biological function through diverse mechanisms. However, the existing IL-1β inhibitors are recombinant proteins, characterized by a high production cost and limited stability. Therefore, this study aimed to predict a peptide, named DAP1-2, based on the IL-1Ra molecule. DAP1-2 was designed to attenuate responses triggered by IL-1β by blocking the IL-1R1 receptor. The selection of amino acids from the IL-1Ra molecule (PDB: I1RA) that interact with the three domains of the IL-1R1 receptor was performed using Swiss PDB Viewer. After prediction, chemical synthesis was made using the Fmoc-Synthesis technique. The efficacy of DAP1-2 was assessed using RAW 264.7 cells, which were exposed to LPS (5 μg/mL) for 24 h to induce IL-1β expression and treated with the peptides in different concentrations. IL-1β levels were assessed using ELISA, and the gene expression of IL-1β was measured by RT-qPCR, additionally to the viability test. Results revealed a significant reduction in IL-1β levels and gene expression in cells stimulated by LPS and treated with DAP1-2 in different concentrations. Furthermore, the MTT assay confirmed the nontoxic nature of the peptides on the cell lineage. This alternative approach shows promise as an IL-1 inhibitor, due to the stability, ease of production, and cost-effectiveness provided by the use of synthetic peptides.

Various lymphocyte subpopulations, including NK cells as well as γδ T cells, have been considered an important element in the pathogenesis of autoimmune, inflammatory, rheumatic diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). The aim of this study was to assess the potential role of polymorphic variations in the genes coding for three NK and γδ T cell receptors: NCR3, FCγR3A, and DNAM-1 (rs1052248, rs396991, and rs763361, respectively) in the disease susceptibility and the efficacy of treatment with TNF inhibitors. The study included 461 patients with RA, 168 patients with AS, and 235 voluntary blood donors as controls. The NCR3 rs1052248 AA homozygosity prevailed in RA in patients lacking rheumatoid factor (p = 0.044) as well as in those who manifested the disease at a younger age (p = 0.005) and had higher CRP levels after 12 weeks of anti-TNF therapy (p = 0.021). The FCγR3A rs396991 polymorphism was associated with pain visual analogue scale (VAS) values before the initiation of anti-TNF treatment. Lower VAS values were observed in the GG homozygous RA patients (p = 0.024) and in AS patients with the TT genotype (p = 0.012). Moreover, AS heterozygous patients with the TG genotype presented higher CRP levels in the 12th week of anti-TNF treatment (p = 0.021). The findings suggest that the NCR3 rs1052248 AA homozygosity may have an adverse effect on RA, while the T allele potentially plays a protective role in the development of AS. Moreover, the rs1052248 T allele and TT genotype appear to have a favorable impact on the response to anti-TNF therapy in RA patients.