Clinical and experimental immunology最新文献

{"title":"Immunomodulatory effects of HYCO-3, a dual action CO-releaser/Nrf2 activator.","authors":"Goran Stegnjaić, Neda Nikolovski, Suzana Stanisavljević, Milica Lazarević, Miljana Momčilović, Roberta Foresti, Roberto Motterlini, Đorđe Miljković","doi":"10.1093/cei/uxae100","DOIUrl":"10.1093/cei/uxae100","url":null,"abstract":"<p><p>HYCOs are hybrid molecules consisting of activators of the transcription factor Nrf2 conjugated to carbon monoxide (CO)-releasing moieties. These 'dual action' compounds (HYCOs) have been designed to mimic the activity of heme oxygenase-1 (HO-1), a stress inducible cytoprotective enzyme that degrades heme to CO which expression is regulated by Nrf2. HYCOs have recently shown efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the mechanism(s) of action of HYCOs still remains to be fully investigated. Here, we assessed the effects of HYCO-3, a prototype of these hybrids, on myeloid-derived cells, microglial cells and T lymphocytes obtained from EAE-immunized mice. HYCO-3 exerted immunomodulatory effects on all the examined cell populations by inhibiting the generation of pro-inflammatory cytokines and nitric oxide, and downregulating antigen-presenting capacity of these cells. The observed effects support the view that HYCOs are promising candidates to be developed for the treatment of autoimmune and chronic inflammatory disorders.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of antibodies to infliximab in routine care: a 4-year French retrospective study.","authors":"Daniel Bertin, Jehanne Aghzadi, Nathalie Balandraud, Céline Roman, Mélanie Serrero, Sophie Desplat-Jégo","doi":"10.1093/cei/uxae122","DOIUrl":"10.1093/cei/uxae122","url":null,"abstract":"<p><p>Despite its wide use to treat various inflammatory diseases, infliximab becomes ineffective in some patients due to inadequate drug levels and production of anti-drug antibodies (ADA). The aim of this study was to compare the prevalence and ADA levels in a large cohort of patients. ADA and infliximab (IFX) through levels measured by enzyme-linked immunosorbent assay were collected from 505 patients within a period of 4 years. The results indicate that (i) 13.5% of patients produce ADA, (ii) male patients were more likely to produce ADA at levels above 10 000 ng/ml than female patients, (iii) ADA levels were lower when associated with immunosuppressant drugs, (iv) there was an inverse relationship between ADA presence and IFX detection, and (v) no correlation was observed between ADA levels and number of injections or brand of IFX administered. This study improves our understanding of the factors promoting IFX immunogenicity and highlights the need to develop personalized treatment strategies.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of whole-exome sequencing to predict inborn errors of immunity in pediatric severe infections and sepsis.","authors":"Abderrahmane Moundir, Ouissal Aissaoui, Nassima Akhrichi, Abire Allaoui, Ibtihal Benhsaien, Emmanuelle Jouanguy, Jean-Laurent Casanova, Jalila El Bakkouri, Fatima Ailal, Ahmed Aziz Bousfiha","doi":"10.1093/cei/uxaf007","DOIUrl":"10.1093/cei/uxaf007","url":null,"abstract":"<p><p>Increasing evidence supports the involvement of inborn errors of immunity in severe infections, but little is known about the prevalence of these genetic defects in children with sepsis. Due to the limited understanding of the molecular and immunological mechanisms driving sepsis, genetic testing is rarely used in routine diagnostics to identify genetic susceptibility to the condition. We performed a prospective observational study on previously healthy children hospitalized for severe infections, including sepsis. Patients underwent immunophenotyping and whole-exome sequencing, followed by in silico analysis to identify potentially causal variants. We assembled a cohort of 194 previously healthy children, including 149 (77%) patients with severe infection and 45 (23%) with sepsis. Our cohort was marked by a high frequency of respiratory tract infections (35%), bloodstream infections (20%), and central nervous system infections (16%). The genetic investigation identified 28 potentially causal variants, 18 (64%) are classified as variants with uncertain significance, and 10 (36%) are likely pathogenic variants. Of 45 patients with sepsis, 6 (13%) had potentially causal genetic variants. Similarly, 22/149 (15%) patients with severe infection presented potentially causal genetic variants. Whole-exome sequencing predicted the impairment of various immune mechanistic pathways such as immune dysregulation defects, antibody deficiencies, and combined immunodeficiencies (18% each). We found no clear association between genetic variants and the studied parameters: organ failure, microbe identification, immunoglobulin levels, and lymphocyte subset numbers. Although whole-exome sequencing is a valuable tool for detecting inborn errors of immunity underlying sepsis and unexplained severe infections, it could be selectively recommended for patients with a strong clinical suspicion of genetic abnormalities, balancing its diagnostic value with its cost and complexity.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and experimental treatment of residual immune activation in people living with HIV.","authors":"Krystelle Nganou-Makamdop","doi":"10.1093/cei/uxaf023","DOIUrl":"10.1093/cei/uxaf023","url":null,"abstract":"<p><p>Potent inflammatory responses stemming from innate and T cell activation are initiated during acute human immunodeficiency virus infection. Suppression of the virus replication by antiretroviral therapy reduces but does not normalize immune activation. By now, it is clear that residual immune activation can persist even after years of antiretroviral therapy and associates with increased risks for co-morbidities, thereby raising interest for strategies that can resolve the residual immune activation in people with human immunodeficiency virus on antiretrovirals. This brief review reports the human studies with various drugs with anti-inflammatory properties and their effects on measures of systemic immune activation on people with human immunodeficiency virus. Along with the possible reasons for conflicting outcomes, considerations for ongoing and future approaches are outlined.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":"219 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human genetics of responses to vaccines.","authors":"Eleanor Karp-Tatham, Julian C Knight, Alexandre Bolze","doi":"10.1093/cei/uxaf034","DOIUrl":"10.1093/cei/uxaf034","url":null,"abstract":"<p><p>The human response to vaccination exhibits considerable variability due to a complex interplay of heritable and environmental factors. This review examines the current understanding of the role of human genetics in vaccine responses, encompassing both rare adverse events following immunization as well as immunogenicity and efficacy. We highlight recent studies including from the coronavirus disease 2019 (COVID-19) pandemic, which provided a unique opportunity to study vaccine genetics at scale for a newly emerging infection and revealed significant associations between HLA alleles and responses to SARS-CoV-2 vaccines. Understanding genetic contributions to vaccine responses holds promise for enhancing vaccine safety and efficacy, and the development of personalized vaccination strategies.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human genetic and immunological determinants of SARS-CoV-2 infection and multisystem inflammatory syndrome in children.","authors":"Halima Kholaiq, Yousra Abdelmoumen, Abderrahmane Moundir, Assiya El Kettani, Fatima Ailal, Ibtihal Benhsaien, Fatima Adnane, Asmaa Drissi Bourhanbour, Naima Amenzoui, Jalila El Bakkouri, Ahmed Aziz Bousfiha","doi":"10.1093/cei/uxae062","DOIUrl":"10.1093/cei/uxae062","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces pneumonia and acute respiratory failure in coronavirus disease 2019 (COVID-19) patients with inborn errors of immunity to type I interferon (IFN-I). The impact of SARS-CoV-2 infection varies widely, ranging from mild respiratory symptoms to life-threatening illness and organ failure, with a higher incidence in men than in women. Approximately 3-5% of critical COVID-19 patients under 60 and a smaller percentage of elderly patients exhibit genetic defects in IFN-I production, including X-chromosome-linked TLR7 and autosomal TLR3 deficiencies. Around 15-20% of cases over 70 years old, and a smaller percentage of younger patients, present with preexisting autoantibodies neutralizing type I interferons. Additionally, innate errors affecting the control of the response to type I interferon have been associated with pediatric multisystem inflammatory syndrome (MIS-C). Several studies have described rare errors of immunity, such as XIAP deficiency, CYBB, SOCS1, OAS1/2, and RNASEL, as underlying factors in MIS-C susceptibility. However, further investigations in expanded patient cohorts are needed to validate these findings and pave the way for new genetic approaches to MIS-C. This review aims to present recent evidence from the scientific literature on genetic and immunological abnormalities predisposing individuals to critical SARS-CoV-2 infection through IFN-I. We will also discuss multisystem inflammatory syndrome in children (MIS-C). Understanding the immunological mechanisms and pathogenesis of severe COVID-19 may inform personalized patient care and population protection strategies against future serious viral infections.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating B cells display differential immune regulatory molecule expression in granulomatosis with polyangiitis.","authors":"Carlo G Bonasia, Nanthicha Inrueangsri, Theo Bijma, Malte Borggrewe, Aline I Post, Kevin P Mennega, Wayel H Abdulahad, Abraham Rutgers, Nicolaas A Bos, Peter Heeringa","doi":"10.1093/cei/uxae096","DOIUrl":"10.1093/cei/uxae096","url":null,"abstract":"<p><p>Granulomatosis with polyangiitis (GPA) is a B-cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B-cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B-cell subsets was comprehensively examined in active GPA (n = 16), GPA in remission (n = 16), and healthy controls (n = 16) cross-sectionally using a 35-color B-cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B-cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on nonmature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B-cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA and could potentially form the foundation for new therapeutic approaches and disease monitoring markers.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-phenotype correlations in specific granule deficiency: loss of DNA-binding ability and impaired nuclear localization cause severe manifestations due to the c.655_665del CEBPE variant.","authors":"Tomoya Tamaru, Rina Katayama, Juna Momokino, Yume Maruoka, Atsushi Ueda, Hirokazu Kanegane, Taizo Wada, Syed Tariq Ahmad Bukhari, Aaqib Zaffar Banday, Tadayuki Akagi","doi":"10.1093/cei/uxaf045","DOIUrl":"10.1093/cei/uxaf045","url":null,"abstract":"<p><strong>Introduction: </strong>Specific granule deficiency (SGD)-a rare innate immune disorder-is classified into types 1 and 2 (SGD-1 and -2). SGD-1 is caused by variants of the CCAAT/enhancer-binding protein epsilon (C/EBPε) gene.</p><p><strong>Methods: </strong>We assessed the molecular mechanisms underlying C/EBPε dysfunction in SGD-1, caused by the frameshift variant (c.655_665del; del11) that we previously reported. We compared the functions of del11 with those of the previously reported p.Arg247_Ser248del (ΔRS) variant and wild-type (WT) C/EBPε.</p><p><strong>Results: </strong>Forced expression in embryonic stem cells revealed that both the del11 and ΔRS variants inhibited C/EBPε-mediated target gene induction, indicating a loss of transcriptional activity. In NIH3T3 cells, WT and ΔRS C/EBPε were localized to the nucleus, whereas del11 C/EBPε showed cytoplasmic retention and induced morphological changes in expressing cells. Protein-protein interaction analyses demonstrated that both mutants failed to interact with the transcription factors GATA-binding protein 1 and purine-rich box-1. DNA-binding assays revealed that del11 C/EBPε completely lost its ability to bind to target DNA sequences, whereas WT and ΔRS C/EBPε retained binding capacity. Thus, del11 disrupts multiple C/EBPε functions, including nuclear localization, DNA-binding, and protein interactions.</p><p><strong>Conclusion: </strong>Based on these functional differences, we propose a novel classification of SGD-1 into types 1a and 1b (SGD-1a and -1b). Patients with SGD-1b,-associated with nonsense and frameshift variants, such as del11,-exhibit more severe clinical phenotypes than those with SGD-1a,-associated with missense variants and in-frame deletions. This study offers novel insights into the pathogenesis of SGD and genotype-phenotype correlations, potentially informing the development of future therapeutic strategies.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects.","authors":"Joseph Mackie, Daniel Suan, Peter McNaughton, Filomeen Haerynck, Michael O'Sullivan, Antoine Guerin, Cindy S Ma, Stuart G Tangye","doi":"10.1093/cei/uxaf005","DOIUrl":"10.1093/cei/uxaf005","url":null,"abstract":"<p><strong>Introduction: </strong>Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA-binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema, and enteropathy over a 35-year period.</p><p><strong>Methods: </strong>In vitro demonstration of prolonged STAT3 activation due to delayed dephosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis.</p><p><strong>Results: </strong>B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery.</p><p><strong>Conclusion: </strong>This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in the peripheral blood of patients with STAT3 gain-of-function syndrome. Identifying cellular biomarkers of disease provides a flow cytometric-based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescence in diffuse systemic sclerosis is elevated and may play a role in fibrosis.","authors":"Steven O'Reilly","doi":"10.1093/cei/uxad077","DOIUrl":"10.1093/cei/uxad077","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9817209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}