Immunology letters最新文献

{"title":"Inhibition of FOSL1 alleviates inflammatory injury of otitis media by reducing ferroptosis","authors":"Zhuohui Liu ,&nbsp;Fan Zhang ,&nbsp;Fengfeng Jia,&nbsp;Yongmei Yu,&nbsp;Ruiqing Long","doi":"10.1016/j.imlet.2025.107032","DOIUrl":"10.1016/j.imlet.2025.107032","url":null,"abstract":"<div><h3>Objectives</h3><div>Otitis media (OM) is a disease involving inflammation and infection of the middle ear that primarily affects children. Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key regulator in inflammation and various diseases. However, the role of FOSL1 in OM remains largely unknown. Our study aimed to elucidate the function and mechanism of FOSL1 in OM.</div></div><div><h3>Methods</h3><div>The gene expression dataset was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) from OM mice and control mice were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyzes were used to identify potential biological pathways. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to excavate the biological signaling pathways. The OM cell model was induced by <em>Staphylococcus aureus</em> and <em>Bacillus cereus</em> administration<em>.</em> The expression of FOSL1 and ferroptosis-related proteins in OM cell model were determined by western blot. Inflammatory cytokines in cells were detected by qPCR.</div></div><div><h3>Results</h3><div>DEGs was identified from gene set enrichment (GSE) 49128, 441 genes were up-regulated and 180 were down-regulated. FOSL1 was highly expressed in OM mice. Consistent with the bioinformatic analysis, the expression of FOSL1 in bacterial-induced OM cells was upregulated. Inhibition of FOSL1 via siRNA alleviated the inflammatory response and cell ferroptosis in the OM cell model. The reduced level of inflammatory cytokines and cell ferroptosis induced by FOSL1 inhibition could be rescued by ferroptosis activator erastin.</div></div><div><h3>Conclusion</h3><div>FOSL1 inhibition could alleviate release of inflammatory cytokines and ferroptosis in the OM cell model.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107032"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuated notch signaling decreases T-cell factor-1+ Treg subsets in lung adenocarcinoma, assisting early patient screening","authors":"Ayibaota Bahabayi ,&nbsp;Mohan Zheng ,&nbsp;Ainizati Hasimu ,&nbsp;Rui Kang ,&nbsp;Qi Li ,&nbsp;Ziqi Xiong ,&nbsp;Zhao Guan ,&nbsp;Zhonghui Zhang ,&nbsp;Tianci Liu ,&nbsp;Xingyue Zeng ,&nbsp;Chen Liu","doi":"10.1016/j.imlet.2025.107034","DOIUrl":"10.1016/j.imlet.2025.107034","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the role of T-cell factor-1 (TCF1) in early-stage lung adenocarcinoma (LUAD) patients and explore its clinical significance for diagnosing early LUAD.</div></div><div><h3>Methods</h3><div>Blood samples were collected from 34 stage IA LUAD patients and 31 healthy controls. Flow cytometry was used to analyze the levels of TCF1 in circulating T cell subpopulations. Functional characteristics of TCF1-related cells were investigated by staining with CD62L and Ki-67. Changes in TCF1-related proportions in T cell subsets of early LUAD patients were analyzed. The role of Notch signaling was clarified by adding the Notch signal activator Jagged1 (JAG1). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of TCF1-related T cell subsets for screening early LUAD.</div></div><div><h3>Results</h3><div>The expression level of TCF1 in follicular regulatory T(Tfr) and regulatory T(Treg) cells was decreased in early LUAD patients, and TCF1+CD62L+ follicular helper (Tfh) cells were also decreased. TCF1+CD62L+ cells in both Treg and Tfr were decreased in early LUAD patients. Decreased TCF1 in Treg and Tfr recovered in early LUAD after adding JAG1. TCF1-related indicators showed good auxiliary diagnostic significance for early LUAD. TCF1+, TCF1+CD62L+, and TCF1-CD62L+ percentages in Treg and Tfr cells were with areas under the curve (AUCs) between 0.827 and 0.897 to distinguish early LUAD from healthy individuals.</div></div><div><h3>Conclusions</h3><div>Downregulation of Notch signaling contributes to the decrease in TCF1+ Treg subsets in LUAD patients, which is of significant value for screening early-stage lung adenocarcinoma.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107034"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cells and functions in patients with restless legs syndrome","authors":"Aysenur Kokoglu ,&nbsp;Ayse Engin ,&nbsp;Metin Yusuf Gelmez ,&nbsp;Esin Aktas Cetin ,&nbsp;Gulcin Benbir Senel ,&nbsp;Derya Karadeniz ,&nbsp;Gunnur Deniz","doi":"10.1016/j.imlet.2025.107056","DOIUrl":"10.1016/j.imlet.2025.107056","url":null,"abstract":"<div><div>Restless legs syndrome (RLS) is a sleep-related disorder, and some evidence suggests that inflammation contributes to its pathophysiology. This study aimed to investigate the relationship between RLS and immune cells.</div><div>Fourteen RLS patients, and 10 healthy subjects were included in the study. The percentages of T, B, natural killer (NK), natural killer T (NKT) and innate lymphoid cells (ILCs) were analyzed, along with intracellular levels of interferon-gamma (IFN-γ), interleukin (IL)-6, IL-10, and IL-13 in T, B and NK cells. Additionally, CD8⁺ T and NK cell cytotoxic activities were assessed using flow cytometry. Plasma levels of IFN-γ, tumor necrosis factor-alpha (TNF-α), IL-2, IL-4, IL-6, IL-10, and IL-13 were evaluated with bead-based soluble molecule assay.</div><div>Compared to healthy subjects, the ratio of ILC-1 subset and IL-13⁺CD4⁺ T cells were significantly increased in RLS patients, while the levels of ILC-2 subset were significantly decreased. When the NK cell cytotoxic activity of RLS patients was evaluated, it was found that the NK cell perforin levels were lower than healthy subjects. Plasma IL-13 levels were also significantly elevated in RLS patients compared to healthy individuals.</div><div>These findings suggest that both innate and adaptive immune responses may play a role in RLS pathophysiology. Alterations in ILC subsets, along with elevated IL-13, IL-10, and IL-6 levels, as well as NK and CD8⁺ T cell cytotoxic activity, indicate that immune dysregulation might contribute to the disease mechanism. Furthermore, the observed correlation between efficient sleep and immune markers highlights the potential role of immune system modulation in RLS management.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107056"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating challenges of aGvHD predictive biomarkers in αβhaplo-HSCT recipients: Still waiting for MAGIC to happen","authors":"Raul Montiel-Esparza,&nbsp;Isobel Hawes,&nbsp;Rhonda Perriman,&nbsp;Giulia Barbarito,&nbsp;Linda Oppizzi,&nbsp;David Shyr,&nbsp;Laurel Kent,&nbsp;Zhenyu Yao,&nbsp;Alice Bertaina","doi":"10.1016/j.imlet.2025.107062","DOIUrl":"10.1016/j.imlet.2025.107062","url":null,"abstract":"<div><div>The validated Mount Sinai Acute graft-versus-host disease (aGvHD) International Consortium (MAGIC) algorithm and biomarker panels did not predict aGvHD occurrence or severity in pediatric αβT-cell/CD19 B-cell depleted haploidentical hematopoietic stem cell transplant (αβhaplo-HSCT) recipients. These findings suggest distinct aGvHD biology in the αβhaplo-HSCT setting, supporting the need for tailored biomarker studies in this unique transplant platform.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107062"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DUSP14 attenuates airway inflammation and mucus hypersecretion in allergic asthma by regulating TAK1 activity","authors":"Rui Kong ,&nbsp;Jun Bai ,&nbsp;Qing Yao ,&nbsp;Xiaoqing Xu","doi":"10.1016/j.imlet.2025.107047","DOIUrl":"10.1016/j.imlet.2025.107047","url":null,"abstract":"<div><div>Allergic asthma is characterized by persistent chronic airway inflammation, leading to mucus hypersecretion and airway hyperresponsiveness. Dual-specificity phosphatase 14 (DUSP14), a member of the DUSP family, is a key regulator in various biological processes. However, the function of DUSP14 in allergic asthma remains to be elucidated. In this study, we aim to explore the function and mechanism of DUSP14 in asthma-related airway inflammation. In an ovalbumin (OVA) asthma mouse model, DUSP14 was found to be significantly diminished. DUSP14 overexpression relieved airway inflammation and attenuated airway mucus production. <em>In vitro</em>, overexpression of DUSP14 attenuated IL-13-induced cellular inflammation and mucus hypersecretion in bronchial epithelial cells (BEAS-2B). Afterwards, we used the co-immunoprecipitation assay to confirm that DUSP14 interacted with TAK1. DUSP14 overexpression restrained the activation of TAK1 and NF-κB signaling pathway <em>in vitro</em> and <em>in vivo</em>. Taken together, our findings clearly showed that DUSP14 could alleviate airway inflammation by inhibiting TAK1 activity and NF-κB signaling pathway, positioning the DUSP14-TAK1-NF-κB regulatory axis as a potential therapeutic target for allergic asthma.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107047"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and transcriptional dysregulation of innate antiviral immune pathways in type 1 diabetes","authors":"Mia Ø Mønsted ,&nbsp;Kristina Pedersen ,&nbsp;Mathias H. Jensen ,&nbsp;Simranjeet Kaur ,&nbsp;Sofía C. Sustacha ,&nbsp;Laurits J. Holm ,&nbsp;Karsten Buschard ,&nbsp;Flemming Pociot ,&nbsp;Martin Haupt-Jorgensen","doi":"10.1016/j.imlet.2025.107060","DOIUrl":"10.1016/j.imlet.2025.107060","url":null,"abstract":"<div><div>Innate antiviral immune pathways (InAIPs) are dysregulated in islets of type 1 diabetes (T1D) patients, implying how enterovirus might contribute to beta-cell autoimmunity. However, it is unclear whether similar dysregulation occurs in the intestine, contributing to pathologies like barrier dysfunction. Thus, we used a published genome-wide association study to identify polymorphisms in intestinal permeability and InAIP genes. We compared female prediabetic non-obese diabetic (NOD) and C57BL/6 mice and their jejunal epithelial RNA profile by GeneChip analysis. The potential link between dysregulation of InAIP genes and increased intestinal permeability was assessed by measuring trans-epithelial electrical resistance in intestinal Caco-2 cells upon R837 toll-like receptor 7 stimulation. There was genetic predisposition to T1D among intestinal permeability genes. However, InAIP genes contained more promising T1D-associated polymorphisms, especially for <em>TNFA, OAS3, PIGR, CD55, NOD2</em>, and <em>IFIH1</em>. Comparing prediabetic NOD with C57BL/6 mice revealed age-dependent dysregulation of several InAIP genes (<em>Ifih1, Rnase1 etc.</em>) in jejunum. Lastly, mimicking an enterovirus infection with R837 stimulation of Caco-2 cells increased intestinal permeability. We demonstrate genetic and transcriptional dysregulation of InAIPs in T1D and their potential involvement in intestinal barrier dysfunction, providing new clues to the disease-manifesting mechanisms of enterovirus infection.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107060"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated ascitic interleukin-36 receptor antagonist mediates CD8+ T cell exhaustion in vitro in liver cirrhotic patients with spontaneous bacterial peritonitis","authors":"Lanlan Yang,&nbsp;Siqi Liu,&nbsp;Chen Qiu,&nbsp;Qian Zhang,&nbsp;Chuanhui Zhang,&nbsp;Zhenjing Jin","doi":"10.1016/j.imlet.2025.107061","DOIUrl":"10.1016/j.imlet.2025.107061","url":null,"abstract":"<div><div>Interleukin-36 (IL-36) signaling pathway plays an important regulatory role in inflammatory and infectious diseases. However, the modulatory function of IL-36 in CD8⁺ <em>T</em> cells that are involved in liver cirrhosis with spontaneous bacterial peritonitis (SBP) has not been understood. Sixty-five liver cirrhotic patients (42 untainted ascites and 23 SBP patients) and 20 controls were included. IL-36 levels were measured by ELISA. CD8⁺ <em>T</em> cells were purified from ascites, and were stimulated with IL-36 receptor antagonist (IL-36RA). CD8⁺ <em>T</em> cells were co-cultured with HepG2 cells in direct contact and indirect contact manners. Target cell death and cytotoxic molecules levels were investigated to assess CD8⁺ <em>T</em> cell cytotoxicity. The immune-checkpoint molecules expressions on CD8⁺ <em>T</em> cells were measured by flow cytometry. There were no significant differences in IL-36alpha, IL-36beta, or IL-36gamma levels between untainted ascites and SBP patients. SBP patients had increased ascitic IL-36RA, which positively correlated with alanine aminotransferase and ascitic neutrophil count. IL-36RA stimulation did not affect CD8⁺ <em>T</em> cell proliferation, but dampened CD8⁺ <em>T</em> cell-induced cell death and proinflammatory cytokine secretions. Perforin and granzyme B productions were down-regulated in direct contact manner. IL-36RA stimulation promoted immune-checkpoint molecules expressions on CD8⁺ <em>T</em> cells. The present findings revealed that elevated ascitic IL-36RA might inhibit ascitic CD8⁺ <em>T</em> cell cytotoxicty in liver cirrhotic patients with SBP.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107061"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate lymphoid cells: Dual roles and therapeutic opportunities in breast cancer","authors":"Marija Mojić ,&nbsp;Nataša Radulović ,&nbsp;Simonida Bobić ,&nbsp;Sandra Radenković ,&nbsp;Aránzazu Cruz-Adalia ,&nbsp;Ivana Stojanović","doi":"10.1016/j.imlet.2025.107051","DOIUrl":"10.1016/j.imlet.2025.107051","url":null,"abstract":"<div><div>Innate lymphoid cells (ILC) play a crucial role in shaping immune responses and maintaining tissue homeostasis. Recent research has identified their involvement in breast cancer pathogenesis, mainly through shaping the tumor microenvironment, where they can exert dual roles, either promoting tumor eradication by enhancing anti-tumor immunity, or facilitating tumor progression through mechanisms of immune evasion. This functional plasticity makes ILC attractive targets for immunotherapy. Furthermore, their slow proliferation enables them to survive anti-proliferative radiation therapy and chemotherapy, which may support continuous immune surveillance of breast cancer tissue. However, this same resilience poses a significant challenge, as surviving ILC could contribute to tumor persistence or recurrence. Additionally, anti-estrogen therapy, chemotherapy and immune checkpoint inhibitors, commonly used in breast cancer treatment, may interfere with ILC function, either dampening their anti-tumor potential or enhancing their pro-tumor activities. Understanding the complex interactions between ILC and conventional therapies is critical for designing effective immunotherapeutic approaches that include ILC targeting, potentially overcoming resistance and improving patient outcomes in breast cancer therapy.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107051"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splenomegaly in CVID patients associates with CMV replication and alterations of immune cells and functions","authors":"Luca Marri ,&nbsp;Paola Contini ,&nbsp;Federico Ivaldi ,&nbsp;Chiara Schiavi ,&nbsp;Ottavia Magnani ,&nbsp;Chiara Vassallo ,&nbsp;Andrea Guastalla ,&nbsp;Noemi Traversone ,&nbsp;Davide Deraco ,&nbsp;Claudia Angelini ,&nbsp;Genny Del Zotto ,&nbsp;Raffaele De Palma ,&nbsp;Andrea De Maria","doi":"10.1016/j.imlet.2025.107058","DOIUrl":"10.1016/j.imlet.2025.107058","url":null,"abstract":"<div><h3>Background</h3><div>Splenomegaly represents a frequent non-infectious manifestation in Common Variable Immunodeficiency (CVID) and associates with specific clinical and immunophenotypic characteristics.</div></div><div><h3>Objective</h3><div>To investigate the association between splenomegaly, infections, and immunophenotype in CVID patients.</div></div><div><h3>Methods</h3><div>A cohort of 32 CVID patients (13 with splenomegaly) was enrolled. Infectious workup encompassed a detailed medical history and data derived from routine diagnostic assessments including specific virological analysis of blood and stool samples, and QuantiFERON assay for tuberculosis. Immunophenotype was assessed by multiparametric flow cytometry. Statistical analyses were performed using Prism and Jamovi software.</div></div><div><h3>Results</h3><div>CMV viraemia was detected in 40 % of splenomegalic CVID (sCVID) and was absent in non-sCVID patients. Of all infectious agents, CMV was the only one associated with splenomegaly (<em>p</em> = 0.009). The inclusion of CMV replication as a causative factor for splenomegaly in CVID is in line with the knowledge that splenomegaly is a hallmark of acute CMV infection and could help explain in the present CVID cohort 75 % of otherwise unexplained splenomegalies. Flow cytometric analysis in sCVID vs. non-sCVID confirmed decreases in NK cell numbers and activation, in circulating inflammatory precursors (Lin⁻CD16⁺), and increased T cell activation as defined by HLA-DR/CD69/CD38 expression.</div></div><div><h3>Conclusion</h3><div>Splenomegaly in CVID patients may associate also with CMV replication. The combined identification in CMV⁺ sCVID of NK cell, inflammatory precursor and T cell imbalances suggests a possible combined cellular defect at precursor level in a subset of sCVID patients. When integrated into everyday clinical management, CMV viraemia could become a useful additional parameter for patient characterization and stratification.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107058"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrostatic potential is the dominant force in antigenic selection of naïve T-cells and B-cells for activation and maturation","authors":"Kripa N. Nand,&nbsp;Christopher Bystroff","doi":"10.1016/j.imlet.2025.107037","DOIUrl":"10.1016/j.imlet.2025.107037","url":null,"abstract":"<div><div>Peptide antigenicity can be predicted from sequence using a simple method invented by Hopp and Woods in the early 1980′s. Since then, a much clearer understanding of T-cell/B-cell signaling and maturation calls for a new understanding of the amino acid determinants of antigenicity. We show that short peptides with more charged side chains generate significantly higher titers of peptide specific antibodies in co-immunized mice. Peptide docking simulations using linearized Poisson-Boltzmann calculations of electrostatic potential show that immunoglobulins distinguish the cognate peptide sequence from randomly selected sequences at \"arms length\" (10–20 Å) with &gt;70 % of alternative sequences having higher energy at this distance, consistent with the weak specificity observed for naive T-cell and B-cell receptor interactions with MHC-bound antigen. Orders of magnitude lower complexity of the state space of charged surfaces as compared to the state space of surface shapes suggests a dominant role of electrostatics in selecting naive immune cells from the population of circulating cell lines. We propose a two-stage antigen recognition process, first electrostatic and then shape-based, that explains the dominant contribution of charged residues to peptide immunogenicity.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"276 ","pages":"Article 107037"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}