{"title":"Correction to: Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.","authors":"","doi":"10.1093/cei/uxaf032","DOIUrl":"10.1093/cei/uxaf032","url":null,"abstract":"","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/PMC12139472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233369","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}
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
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.
多血管炎肉芽肿病(GPA)是一种由 B 细胞介导的复发性自身免疫性疾病。目前需要新的治疗方法和复发标志物来实现持久缓解。B 细胞表达的免疫调节分子可调节其活化并维持耐受性。虽然最近的研究显示这些分子在其他自身免疫性疾病中的表达失调,但有关它们在 GPA 中表达的数据却很有限。本研究旨在绘制 GPA 循环 B 细胞亚群表面免疫调节分子的表达图,并将其表达与临床参数相关联。我们使用 35 色 B 细胞特异性光谱流式细胞仪面板,全面检测了活动期 GPA(16 人)、缓解期 GPA(16 人)和健康对照组(16 人)中循环 B 细胞亚群上免疫调节分子的表达。我们的有监督和无监督深入分析显示,GPA 中不同的 B 细胞群中抑制性和刺激性免疫分子的表达存在差异,在活动期 GPA 中观察到的差异最为显著。这些差异包括非成熟 B 细胞上 FcγRIIB 的上调、抗原经验丰富的 B 细胞上 CD21 的下调和 CD86 的上调,以及各种细胞群中 CD22 表达的升高。此外,我们还发现特定 B 细胞群的 FcγRIIB、BTLA 和 CD21 表达与 GPA 的疾病活动性之间存在密切联系。这些发现为了解 GPA 中 B 细胞的免疫调节分子表达谱提供了新的视角,有可能为新的治疗方法和疾病监测标记物奠定基础。
{"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}
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.
{"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}
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
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.
{"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}
Daniel Bertin, Jehanne Aghzadi, Nathalie Balandraud, Céline Roman, Mélanie Serrero, Sophie Desplat-Jégo
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.
{"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":3.8,"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}
Eleanor Karp-Tatham, Julian C Knight, Alexandre Bolze
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.
{"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":3.8,"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}
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.
{"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":3.8,"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}
Felix Werner, Jens Wittner, Christian H K Lehmann, Mandy Wahlbuhl, Ida Allabauer, Adrian Hoffmann, Alexander Schnell, Tobias Krickau, Holger Hackstein, Barbara Dietel-Schor, James S Rush, Catherine H Regnier, Hans-Martin Jäck, Joachim Woelfle, Wolfgang Schuh, André Hoerning
CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B-cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B-cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B-cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN + CD40L, but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B-cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35, and IL-23p19 and TNFα in a B and CD4 + TH-cell co-culture system. Based on these preclinical results, CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells, including hampering the IgG class switch without affecting their viability.
{"title":"CD40 blockade hampers IgG class-switch while enhancing Granzyme B production by transitional B cells.","authors":"Felix Werner, Jens Wittner, Christian H K Lehmann, Mandy Wahlbuhl, Ida Allabauer, Adrian Hoffmann, Alexander Schnell, Tobias Krickau, Holger Hackstein, Barbara Dietel-Schor, James S Rush, Catherine H Regnier, Hans-Martin Jäck, Joachim Woelfle, Wolfgang Schuh, André Hoerning","doi":"10.1093/cei/uxaf044","DOIUrl":"10.1093/cei/uxaf044","url":null,"abstract":"<p><p>CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B-cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B-cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B-cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN + CD40L, but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B-cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35, and IL-23p19 and TNFα in a B and CD4 + TH-cell co-culture system. Based on these preclinical results, CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells, including hampering the IgG class switch without affecting their viability.</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/PMC12658889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728353","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}
Sarah L Moretto, Glauco A F Vitiello, Bruna K Banin-Hirata, Roberta Losi Guembarovski, Maria Angelica E Watanabe, Karen B de Oliveira
The programmed cell death protein 1 (PD-1), expressed mainly by T lymphocytes, is an important checkpoint of the immune response and may contribute to tumorigenesis when associated with its ligands, PD-L1 or PD-L2, expressed by tumor cells. In this context, this study aimed to analyze the allelic variants rs11568821 G > A and rs41386349 C > T of the PDCD1 gene in breast cancer (BC) patients and cancer-free women and correlate them with clinical-pathological parameters. DNA extraction was performed from peripheral blood samples, and the PDCD1 genotyping was carried out by the polymerase chain reaction technique followed by enzymatic restriction. The fragments were separated by acrylamide gel electrophoresis for genotyping. In this case-control association study, it was found that carriers of the A allele of the PDCD1 rs11568821 G > A genetic polymorphism have a higher risk of developing BC (OR = 2.42; CI 95% = 1.59-3.69; P < 0.001). This polymorphism was also correlated with positivity for estrogen (τ = 0.25; P < 0.001) and progesterone receptors (τ = 0.17; P = 0.021). The haplotypic analysis also indicated that AC allele carriers have a higher risk of BC development (OR = 2.41; CI 95% = 1.58-3.69; P < 0.001), specifically luminal A subtype (OR = 3.59; CI 95% = 2.15-5.97; P < 0.001). These results indicate that the PDCD1 rs11568821 G > A polymorphism may contribute as a potential susceptibility and prognosis marker for BC, especially for ER+/PR+ subtypes, considering the importance of PD-1 inhibitor effect over antitumor response.
主要由T淋巴细胞表达的程序性细胞死亡蛋白1 (programmed cell death protein 1, PD-1)是免疫应答的重要检查点,当其与肿瘤细胞表达的配体PD-L1或PD-L2相关时,可能有助于肿瘤的发生。在此背景下,本研究旨在分析乳腺癌患者和无癌女性PDCD1基因的等位基因变异rs11568821 G b> A和rs41386349 C b> T,并将其与临床病理参数进行关联。材料与方法:外周血标本DNA提取,采用聚合酶链反应-酶切法(PCR-RFLP)进行PDCD1基因分型,丙烯酰胺凝胶电泳分离片段进行基因分型。结果:在本病例对照关联研究中,发现PDCD1 rs11568821 G>A基因多态性A等位基因携带者发生乳腺癌的风险较高(OR = 2.42; CI 95% = 1.59 ~ 3.69; p)结论:考虑到PD-1抑制剂作用对抗肿瘤反应的重要性,PDCD1 rs11568821 G>A基因多态性可能作为乳腺癌的潜在易感性和预后标志物,特别是对于ER+/PR+亚型。
{"title":"PDCD1 gene single nucleotide polymorphisms and haplotypes are associated with higher risk of breast cancer development.","authors":"Sarah L Moretto, Glauco A F Vitiello, Bruna K Banin-Hirata, Roberta Losi Guembarovski, Maria Angelica E Watanabe, Karen B de Oliveira","doi":"10.1093/cei/uxaf071","DOIUrl":"10.1093/cei/uxaf071","url":null,"abstract":"<p><p>The programmed cell death protein 1 (PD-1), expressed mainly by T lymphocytes, is an important checkpoint of the immune response and may contribute to tumorigenesis when associated with its ligands, PD-L1 or PD-L2, expressed by tumor cells. In this context, this study aimed to analyze the allelic variants rs11568821 G > A and rs41386349 C > T of the PDCD1 gene in breast cancer (BC) patients and cancer-free women and correlate them with clinical-pathological parameters. DNA extraction was performed from peripheral blood samples, and the PDCD1 genotyping was carried out by the polymerase chain reaction technique followed by enzymatic restriction. The fragments were separated by acrylamide gel electrophoresis for genotyping. In this case-control association study, it was found that carriers of the A allele of the PDCD1 rs11568821 G > A genetic polymorphism have a higher risk of developing BC (OR = 2.42; CI 95% = 1.59-3.69; P < 0.001). This polymorphism was also correlated with positivity for estrogen (τ = 0.25; P < 0.001) and progesterone receptors (τ = 0.17; P = 0.021). The haplotypic analysis also indicated that AC allele carriers have a higher risk of BC development (OR = 2.41; CI 95% = 1.58-3.69; P < 0.001), specifically luminal A subtype (OR = 3.59; CI 95% = 2.15-5.97; P < 0.001). These results indicate that the PDCD1 rs11568821 G > A polymorphism may contribute as a potential susceptibility and prognosis marker for BC, especially for ER+/PR+ subtypes, considering the importance of PD-1 inhibitor effect over antitumor response.</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/PMC12712379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630838","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}
Diana C Yanez, Jasmine Rowell, Maximillian Woodall, Stuart Adams, Lauran O'Neill, Konstantinos Mengrelis, Ching-In Lau, Susan Ross, Sarah Benkenstein, Kate Plant, Claire M Smith, Benny Chain, Mark J Peters, Tessa Crompton
During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which correlated with previous or recent SARS-CoV-2 infection. PIMS-TS led to severe multiorgan inflammation, suggestive of disruption of central tolerance and thymus function. Here we investigated the possible role of the thymus in paediatric PIMS-TS. We confirmed that human thymus explants can be infected with SARS-CoV-2 in vitro. Comparison of T-cell populations in blood from PIMS-TS patients and age-matched healthy control children showed that although the overall proportions of CD4 and CD8 T-cell populations were decreased in PIMS-TS patients, the proportion of naïve cells in the CD4 population was higher in the PIMS-TS group. In PIMS-TS patients, the number of TREC in Peripheral blood mononuclear cells (PBMC) correlated strongly with the proportion of naïve CD4 and CD8 T cells, whereas this correlation was not present in healthy children. Sequencing rearranged TCRβ and TCRɑ transcripts from FACS-sorted CD4+CD8-CD3+ and CD4-CD8+CD3+ from blood from PIMS-TS, healthy children, and additionally paediatric severe COVID-19 patients showed that while all three groups showed similar diversity and distribution, the repertoire of the PIMS-TS and COVID-19 groups had distinctive patterns of TCR gene segment usage and VJ combinatorial usage compared to healthy controls (TRBV11-2 × TRBJ2-7, TRBV11-2 × TRBJ1-1, TRBV11-2 × TRBJ2-5, TRBV11-2 × TRBJ2-1; TRBV29-1 × TRBJ2-7, TRBV29-1 × TRBJ1-1 enriched in PIMS-TS; TRBV7-9 × TRBJ1-2, TRAV9-2 × TRAJ30, and TRAV26-1 × TRAJ39 enriched in COVID-19). The non-productive TCR rearrangements in the PIMS-TS group were also enriched for TRBV11-2, and showed bias towards distal (5'TRAV to 3'TRAJ) TCRɑ gene segment usage, suggesting involvement of the thymus in PIMS-TS.
{"title":"Distinctive T-cell receptor repertoire in paediatric inflammatory multisystem syndrome temporally associated with coronavirus disease 2019/multisystem inflammatory syndrome in children patients: possible thymus involvement.","authors":"Diana C Yanez, Jasmine Rowell, Maximillian Woodall, Stuart Adams, Lauran O'Neill, Konstantinos Mengrelis, Ching-In Lau, Susan Ross, Sarah Benkenstein, Kate Plant, Claire M Smith, Benny Chain, Mark J Peters, Tessa Crompton","doi":"10.1093/cei/uxaf027","DOIUrl":"10.1093/cei/uxaf027","url":null,"abstract":"<p><p>During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which correlated with previous or recent SARS-CoV-2 infection. PIMS-TS led to severe multiorgan inflammation, suggestive of disruption of central tolerance and thymus function. Here we investigated the possible role of the thymus in paediatric PIMS-TS. We confirmed that human thymus explants can be infected with SARS-CoV-2 in vitro. Comparison of T-cell populations in blood from PIMS-TS patients and age-matched healthy control children showed that although the overall proportions of CD4 and CD8 T-cell populations were decreased in PIMS-TS patients, the proportion of naïve cells in the CD4 population was higher in the PIMS-TS group. In PIMS-TS patients, the number of TREC in Peripheral blood mononuclear cells (PBMC) correlated strongly with the proportion of naïve CD4 and CD8 T cells, whereas this correlation was not present in healthy children. Sequencing rearranged TCRβ and TCRɑ transcripts from FACS-sorted CD4+CD8-CD3+ and CD4-CD8+CD3+ from blood from PIMS-TS, healthy children, and additionally paediatric severe COVID-19 patients showed that while all three groups showed similar diversity and distribution, the repertoire of the PIMS-TS and COVID-19 groups had distinctive patterns of TCR gene segment usage and VJ combinatorial usage compared to healthy controls (TRBV11-2 × TRBJ2-7, TRBV11-2 × TRBJ1-1, TRBV11-2 × TRBJ2-5, TRBV11-2 × TRBJ2-1; TRBV29-1 × TRBJ2-7, TRBV29-1 × TRBJ1-1 enriched in PIMS-TS; TRBV7-9 × TRBJ1-2, TRAV9-2 × TRAJ30, and TRAV26-1 × TRAJ39 enriched in COVID-19). The non-productive TCR rearrangements in the PIMS-TS group were also enriched for TRBV11-2, and showed bias towards distal (5'TRAV to 3'TRAJ) TCRɑ gene segment usage, suggesting involvement of the thymus in PIMS-TS.</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/PMC12202041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975540","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}