Pub Date : 2024-08-01Epub Date: 2024-05-02DOI: 10.1007/s12026-024-09485-6
Ellen De-Pieri, Rubya Pereira Zaccaron, Camille Generoso Mezzari, Mariana de Melo Cardoso, Laura De Roch Casagrande, Paulo Cesar Lock Silveira, Ricardo Andrez Machado-de-Ávila
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.
{"title":"DAP1-2: a synthetic peptide targeting IL-1R1 receptor effectively suppresses IL-1β in vitro.","authors":"Ellen De-Pieri, Rubya Pereira Zaccaron, Camille Generoso Mezzari, Mariana de Melo Cardoso, Laura De Roch Casagrande, Paulo Cesar Lock Silveira, Ricardo Andrez Machado-de-Ávila","doi":"10.1007/s12026-024-09485-6","DOIUrl":"10.1007/s12026-024-09485-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854924","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}
Pub Date : 2024-08-01Epub Date: 2024-05-07DOI: 10.1007/s12026-024-09488-3
Sylwia Biały, Milena Iwaszko, Jerzy Świerkot, Katarzyna Kolossa, Joanna Wielińska, Sławomir Jeka, Katarzyna Bogunia-Kubik
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.
包括 NK 细胞和 γδ T 细胞在内的各种淋巴细胞亚群被认为是类风湿性关节炎(RA)和强直性脊柱炎(AS)等自身免疫性、炎症性和风湿性疾病发病机制中的一个重要因素。本研究的目的是评估编码三种 NK 和 γδ T 细胞受体基因的多态性变异的潜在作用:NCR3、FCγR3A 和 DNAM-1(分别为 rs1052248、rs396991 和 rs763361)基因的多态性变异在疾病易感性和 TNF 抑制剂疗效中的潜在作用。研究纳入了461名RA患者、168名AS患者和235名自愿献血者作为对照。在缺乏类风湿因子(p = 0.044)的RA患者中,NCR3 rs1052248 AA同源性占多数,在年龄较小(p = 0.005)时发病的患者中,NCR3 rs1052248 AA同源性也占多数,在抗TNF治疗12周后,CRP水平较高(p = 0.021)的患者中,NCR3 rs1052248 AA同源性也占多数。FCγR3A rs396991 多态性与开始抗肿瘤坏死因子治疗前的疼痛视觉模拟量表(VAS)值有关。在GG同源的RA患者(p = 0.024)和TT基因型的AS患者(p = 0.012)中观察到较低的VAS值。此外,在抗肿瘤坏死因子治疗的第 12 周,TG 基因型的 AS 杂合子患者的 CRP 水平更高(p = 0.021)。研究结果表明,NCR3 rs1052248 AA等位基因可能会对RA产生不利影响,而T等位基因则可能对AS的发展起保护作用。此外,rs1052248 T等位基因和TT基因型似乎对RA患者抗TNF治疗的反应有有利影响。
{"title":"Genetic variability of three common NK and γδ T cell receptor genes (FCγ3R, NCR3, and DNAM-1) and their role in Polish patients with rheumatoid arthritis and ankylosing spondylitis.","authors":"Sylwia Biały, Milena Iwaszko, Jerzy Świerkot, Katarzyna Kolossa, Joanna Wielińska, Sławomir Jeka, Katarzyna Bogunia-Kubik","doi":"10.1007/s12026-024-09488-3","DOIUrl":"10.1007/s12026-024-09488-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-04DOI: 10.1007/s12026-024-09494-5
Renan A Pereira, Ellen O Dantas, Jessica Loekmanwidjaja, Juliana T L Mazzucchelli, Carolina S Aranda, Maria E G Serrano, Elisabeth A De La Cruz Córdoba, Liliana Bezrodnik, Ileana Moreira, Janaira F S Ferreira, Vera M Dantas, Valéria S F Sales, Carmen C Fernandez, Maria M S Vilela, Isabela P Motta, Jose Luis Franco, Julio Cesar Orrego Arango, Jesús A Álvarez-Álvarez, Lina Rocío Riaño Cardozo, Julio C Orellana, Antonio Condino-Neto, Cristina M Kokron, Myrthes T Barros, Lorena Regairaz, Diana Cabanillas, Carmen L N Suarez, Nelson A Rosario, Herberto J Chong-Neto, Olga A Takano, Maria I S V Nadaf, Lillian S L Moraes, Fabiola S Tavares, Flaviane Rabelo, Jessica Pino, Wilmer C Calderon, Daniel Mendoza-Quispe, Ekaterini S Goudouris, Virginia Patiño, Cecilia Montenegro, Monica S Souza, Aniela BXCCastelo Branco, Wilma C N Forte, Flavia A A Carvalho, Gesmar Segundo, Marina F A Cheik, Persio Roxo-Junior, Maryanna Peres, Annie M Oliveira, Arnaldo C P Neto, Maria Claudia Ortega-López, Alejandro Lozano, Natalia Andrea Lozano, Leticia H Nieto, Anete S Grumach, Daniele C Costa, Nelma M N Antunes, Victor Nudelman, Camila T M Pereira, Maria D M Martinez, Francisco J R Quiroz, Aristoteles A Cardona, Maria E Nuñez-Nuñez, Jairo A Rodriguez, Célia M Cuellar, Gustavo Vijoditz, Daniélli C Bichuetti-Silva, Carolina C M Prando, Sérgio L Amantéa, Beatriz T Costa-Carvalho
Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.
{"title":"Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study.","authors":"Renan A Pereira, Ellen O Dantas, Jessica Loekmanwidjaja, Juliana T L Mazzucchelli, Carolina S Aranda, Maria E G Serrano, Elisabeth A De La Cruz Córdoba, Liliana Bezrodnik, Ileana Moreira, Janaira F S Ferreira, Vera M Dantas, Valéria S F Sales, Carmen C Fernandez, Maria M S Vilela, Isabela P Motta, Jose Luis Franco, Julio Cesar Orrego Arango, Jesús A Álvarez-Álvarez, Lina Rocío Riaño Cardozo, Julio C Orellana, Antonio Condino-Neto, Cristina M Kokron, Myrthes T Barros, Lorena Regairaz, Diana Cabanillas, Carmen L N Suarez, Nelson A Rosario, Herberto J Chong-Neto, Olga A Takano, Maria I S V Nadaf, Lillian S L Moraes, Fabiola S Tavares, Flaviane Rabelo, Jessica Pino, Wilmer C Calderon, Daniel Mendoza-Quispe, Ekaterini S Goudouris, Virginia Patiño, Cecilia Montenegro, Monica S Souza, Aniela BXCCastelo Branco, Wilma C N Forte, Flavia A A Carvalho, Gesmar Segundo, Marina F A Cheik, Persio Roxo-Junior, Maryanna Peres, Annie M Oliveira, Arnaldo C P Neto, Maria Claudia Ortega-López, Alejandro Lozano, Natalia Andrea Lozano, Leticia H Nieto, Anete S Grumach, Daniele C Costa, Nelma M N Antunes, Victor Nudelman, Camila T M Pereira, Maria D M Martinez, Francisco J R Quiroz, Aristoteles A Cardona, Maria E Nuñez-Nuñez, Jairo A Rodriguez, Célia M Cuellar, Gustavo Vijoditz, Daniélli C Bichuetti-Silva, Carolina C M Prando, Sérgio L Amantéa, Beatriz T Costa-Carvalho","doi":"10.1007/s12026-024-09494-5","DOIUrl":"10.1007/s12026-024-09494-5","url":null,"abstract":"<p><p>Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247761","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}
Pub Date : 2024-08-01Epub Date: 2024-02-08DOI: 10.1007/s12026-024-09459-8
P M Punithavathy, Ramesh Babu Telugu, Vinay Murahari Rao, Savit B Prabhu, Jayakanthan Kabeerdoss, Chanduni Syed, George Joseph, Debashish Danda, Meera Thomas, Ruchika Goel
The relapses and refractory disease are a challenge in the management of patients with Takayasu arteritis (TAK). We quantified pathogenic CD4 + memory T helper cells bearing surface markers CD161 and/or p-glycoprotein (MDR1) in patients with TAK. Peripheral blood mononuclear cells of 21 patients with TAK and 16 age-matched controls were stained with anti-CD3, anti-CD4, anti-CD45RA, anti-CD161 and anti-p-glycoprotein antibodies and subjected to flow cytometry by FACS ARIAIII. Eighteen patients underwent follow-up immunophenotyping. Intracellular staining for interleukin-17 and interferon-γ was performed for 18 patients and 11 controls. Surgical arterial biopsies of 6 TAK and 5 non-inflammatory controls were subjected to immunohistochemistry with anti-CD161 and anti-p-glycoprotein. At baseline the frequency of MDR1 + CD4 + and CD161 + MDR1 + CD4 + memory T cells was higher in TAK than controls (p = 0.002 and 0.01, respectively). After stimulation, the frequency of IFN-y + CD161 + cells was higher in TAK than controls (p = 0.028). Modal fluorescence intensity of CD161 + MDR1 + CD45RA - CD4 + cells was higher in active as compared with stable disease (p = 0.041). At 6 months, MDR1 + and CD161 + MDR1 + memory CD4 + T cells decreased significantly only in patients who had complete/partial response to treatment (p = 0.047 and 0.02, respectively). To conclude, MDR1 + and MDR1 + CD161 + CD4 + memory T-helper cells are increased in patients with TAK. These cells decreased only in patients with response to treatment during subsequent follow-up.
{"title":"Study of pathogenic T-helper cell subsets in Asian Indian patients with Takayasu arteritis.","authors":"P M Punithavathy, Ramesh Babu Telugu, Vinay Murahari Rao, Savit B Prabhu, Jayakanthan Kabeerdoss, Chanduni Syed, George Joseph, Debashish Danda, Meera Thomas, Ruchika Goel","doi":"10.1007/s12026-024-09459-8","DOIUrl":"10.1007/s12026-024-09459-8","url":null,"abstract":"<p><p>The relapses and refractory disease are a challenge in the management of patients with Takayasu arteritis (TAK). We quantified pathogenic CD4 + memory T helper cells bearing surface markers CD161 and/or p-glycoprotein (MDR1) in patients with TAK. Peripheral blood mononuclear cells of 21 patients with TAK and 16 age-matched controls were stained with anti-CD3, anti-CD4, anti-CD45RA, anti-CD161 and anti-p-glycoprotein antibodies and subjected to flow cytometry by FACS ARIAIII. Eighteen patients underwent follow-up immunophenotyping. Intracellular staining for interleukin-17 and interferon-γ was performed for 18 patients and 11 controls. Surgical arterial biopsies of 6 TAK and 5 non-inflammatory controls were subjected to immunohistochemistry with anti-CD161 and anti-p-glycoprotein. At baseline the frequency of MDR1 + CD4 + and CD161 + MDR1 + CD4 + memory T cells was higher in TAK than controls (p = 0.002 and 0.01, respectively). After stimulation, the frequency of IFN-y + CD161 + cells was higher in TAK than controls (p = 0.028). Modal fluorescence intensity of CD161 + MDR1 + CD45RA - CD4 + cells was higher in active as compared with stable disease (p = 0.041). At 6 months, MDR1 + and CD161 + MDR1 + memory CD4 + T cells decreased significantly only in patients who had complete/partial response to treatment (p = 0.047 and 0.02, respectively). To conclude, MDR1 + and MDR1 + CD161 + CD4 + memory T-helper cells are increased in patients with TAK. These cells decreased only in patients with response to treatment during subsequent follow-up.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702403","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}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1007/s12026-024-09484-7
Boukje C Eveleens Maarse, Micha N Ronner, Manon A A Jansen, Tessa Niemeyer-van der Kolk, Aliede E In 't Veld, Erica S Klaassen, Saira Ahmad, Andrea Itano, Duncan McHale, Matthijs Moerland
The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod. Capsules with two enteric coating levels (EC1, EC2) were compared. Thirty-six healthy participants were included and received a daily dose of 8 × 1010 cells EDP1815-EC1, EDP1815-EC2 or placebo (randomization 1:1:1) for 60 days. They received KLH vaccinations at days 8, 24 and 36, with intradermal skin challenge at day 57. KLH challenge outcomes were antibody levels, and skin blood flow and erythema after skin challenge, measured by imaging techniques. Imiquimod administration started at day 57, for 72 h. Outcomes consisted of imaging measurements similar to the KLH challenge, and the influx of inflammatory cells and cytokines in blister fluid. There was no effect of EDP1815 treatment on the KLH challenge, neither on the imaging outcomes of the imiquimod challenge. There was a consistently lower influx of inflammatory cells in the blister fluid of EDP1815-treated participants (neutrophils, p = 0.016; granulocytes, p = 0.024), more pronounced in EC1. There was a lower influx of interleukin [IL]-1β, IL-6, IL-8, IL-10, interferon [IFN]-γ and tumour necrosis factor in blister fluid of EDP1815-treated participants. EDP1815 had immunomodulatory effects on the innate immune response driven by imiquimod, but no effect on the KLH challenge was observed. Trial registration number: NCT05682222; date: 22 July 2022.
{"title":"Immunomodulating effects of the single bacterial strain therapy EDP1815 on innate and adaptive immune challenge responses - a randomized, placebo-controlled clinical trial.","authors":"Boukje C Eveleens Maarse, Micha N Ronner, Manon A A Jansen, Tessa Niemeyer-van der Kolk, Aliede E In 't Veld, Erica S Klaassen, Saira Ahmad, Andrea Itano, Duncan McHale, Matthijs Moerland","doi":"10.1007/s12026-024-09484-7","DOIUrl":"10.1007/s12026-024-09484-7","url":null,"abstract":"<p><p>The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod. Capsules with two enteric coating levels (EC1, EC2) were compared. Thirty-six healthy participants were included and received a daily dose of 8 × 10<sup>10</sup> cells EDP1815-EC1, EDP1815-EC2 or placebo (randomization 1:1:1) for 60 days. They received KLH vaccinations at days 8, 24 and 36, with intradermal skin challenge at day 57. KLH challenge outcomes were antibody levels, and skin blood flow and erythema after skin challenge, measured by imaging techniques. Imiquimod administration started at day 57, for 72 h. Outcomes consisted of imaging measurements similar to the KLH challenge, and the influx of inflammatory cells and cytokines in blister fluid. There was no effect of EDP1815 treatment on the KLH challenge, neither on the imaging outcomes of the imiquimod challenge. There was a consistently lower influx of inflammatory cells in the blister fluid of EDP1815-treated participants (neutrophils, p = 0.016; granulocytes, p = 0.024), more pronounced in EC1. There was a lower influx of interleukin [IL]-1β, IL-6, IL-8, IL-10, interferon [IFN]-γ and tumour necrosis factor in blister fluid of EDP1815-treated participants. EDP1815 had immunomodulatory effects on the innate immune response driven by imiquimod, but no effect on the KLH challenge was observed. Trial registration number: NCT05682222; date: 22 July 2022.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-21DOI: 10.1007/s12026-024-09487-4
Mingyan Zheng, Feng Zhao
Polycystic ovary syndrome (PCOS) is a diverse endocrine disorder widely recognized as the prevailing metabolic condition among women in their reproductive years. The precise pathophysiological mechanisms underlying PCOS remain incompletely understood. However, existing evidence suggests that the development of PCOS may be linked to factors such as abdominal obesity, hyperandrogenism, and insulin resistance (IR). Excessive central adiposity in women with PCOS may lead to the development of a chronic, low-grade inflammation characterized by the activation of proinflammatory cytokines. The cytokines that belong to the IL-12 family are a collection of distinct heterodimeric cytokines that include IL-12, IL-23, IL-27, and IL-35. Recent research has provided further evidence regarding the significance of IL-12 cytokines in influencing both innate and adaptive immune responses in different diseases. Additionally, these studies have discovered diverse roles for certain members of the IL-12 family, encompassing multiple immunological functions that can either act as effectors or regulators. In this discourse, we examine the distinctive and atypical structural and functional attributes of this particular cytokine family. This study aims to offer a comprehensive overview of the pathophysiological significance of the IL-12 family cytokines in PCOS patients. Additionally, the therapeutic potential of the cytokines as novel approaches for PCOS treatment will be proposed.
{"title":"The IL-12 family of heterodimeric cytokines in polycystic ovarian syndrome: biological role in induction, regulation, and treatment.","authors":"Mingyan Zheng, Feng Zhao","doi":"10.1007/s12026-024-09487-4","DOIUrl":"10.1007/s12026-024-09487-4","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is a diverse endocrine disorder widely recognized as the prevailing metabolic condition among women in their reproductive years. The precise pathophysiological mechanisms underlying PCOS remain incompletely understood. However, existing evidence suggests that the development of PCOS may be linked to factors such as abdominal obesity, hyperandrogenism, and insulin resistance (IR). Excessive central adiposity in women with PCOS may lead to the development of a chronic, low-grade inflammation characterized by the activation of proinflammatory cytokines. The cytokines that belong to the IL-12 family are a collection of distinct heterodimeric cytokines that include IL-12, IL-23, IL-27, and IL-35. Recent research has provided further evidence regarding the significance of IL-12 cytokines in influencing both innate and adaptive immune responses in different diseases. Additionally, these studies have discovered diverse roles for certain members of the IL-12 family, encompassing multiple immunological functions that can either act as effectors or regulators. In this discourse, we examine the distinctive and atypical structural and functional attributes of this particular cytokine family. This study aims to offer a comprehensive overview of the pathophysiological significance of the IL-12 family cytokines in PCOS patients. Additionally, the therapeutic potential of the cytokines as novel approaches for PCOS treatment will be proposed.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070912","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}
Pub Date : 2024-08-01Epub Date: 2024-05-23DOI: 10.1007/s12026-024-09490-9
Man Lun Hsu, Kai Fu Jhuang, Moncef Zouali
Studies in animal models and human subjects have shown that, in addition to their implication in innate immunity, inflammasomes also can play a role in adaptive immunity. However, the contribution of the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway to adaptive immunity remains incompletely explored. Here, we show that NLRP3 plays an important role in different facets of B cell functions, including proliferation, antibody production, and secretion of inflammatory and anti-inflammatory cytokines. When exposed to B cell receptor engagement, Toll-like receptor activation, stimulation in conditions that mimic T cell-dependent responses, or NLRP3 activation, B cells manifest disparate responses and produce different cytokine patterns critical for modulating innate and adaptive immunity, indicating that the cytokines produced serve a critical link between the early innate immune response and the delayed adaptive immunity. Importantly, genetic ablation of nlrp3 reduced the inflammasome-mediated functions of B cells. We propose that, in the absence of other cell types, the potential of B lymphocytes to respond to NLRP3 engagement enables them to initiate inflammatory cascades through recruitment of other cell subsets, such as macrophages and neutrophils. Since NLRP3 activation of B cells is not followed by pyroptosis, even in the presence of a basal caspase-1 activity, this pathway acts as a bridge that optimizes interactions between the innate and adoptive branches of the immune response.
对动物模型和人体的研究表明,炎性体除了参与先天性免疫外,还能在适应性免疫中发挥作用。然而,核苷酸结合低聚物结构域、富亮氨酸重复序列和含吡啶结构域的蛋白 3(NLRP3)炎性体通路对适应性免疫的贡献仍未完全探明。在这里,我们发现 NLRP3 在 B 细胞功能的不同方面发挥着重要作用,包括增殖、抗体产生以及炎症和抗炎细胞因子的分泌。当暴露于 B 细胞受体接合、Toll 样受体激活、模拟 T 细胞依赖性反应的条件刺激或 NLRP3 激活时,B 细胞会表现出不同的反应,并产生对调节先天性免疫和适应性免疫至关重要的不同细胞因子模式,这表明所产生的细胞因子是早期先天性免疫反应和延迟适应性免疫之间的关键环节。重要的是,基因消减 nlrp3 会降低 B 细胞炎性体介导的功能。我们认为,在缺乏其他细胞类型的情况下,B 淋巴细胞对 NLRP3 参与做出反应的潜力使它们能够通过招募其他细胞亚群(如巨噬细胞和中性粒细胞)启动炎症级联。由于 B 细胞的 NLRP3 激活后不会发生热凋亡,即使存在基本的 caspase-1 活性也是如此,因此这种途径就像一座桥梁,优化了免疫反应的先天分支和后天分支之间的相互作用。
{"title":"Inflammasome functional activities in B lymphocytes.","authors":"Man Lun Hsu, Kai Fu Jhuang, Moncef Zouali","doi":"10.1007/s12026-024-09490-9","DOIUrl":"10.1007/s12026-024-09490-9","url":null,"abstract":"<p><p>Studies in animal models and human subjects have shown that, in addition to their implication in innate immunity, inflammasomes also can play a role in adaptive immunity. However, the contribution of the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway to adaptive immunity remains incompletely explored. Here, we show that NLRP3 plays an important role in different facets of B cell functions, including proliferation, antibody production, and secretion of inflammatory and anti-inflammatory cytokines. When exposed to B cell receptor engagement, Toll-like receptor activation, stimulation in conditions that mimic T cell-dependent responses, or NLRP3 activation, B cells manifest disparate responses and produce different cytokine patterns critical for modulating innate and adaptive immunity, indicating that the cytokines produced serve a critical link between the early innate immune response and the delayed adaptive immunity. Importantly, genetic ablation of nlrp3 reduced the inflammasome-mediated functions of B cells. We propose that, in the absence of other cell types, the potential of B lymphocytes to respond to NLRP3 engagement enables them to initiate inflammatory cascades through recruitment of other cell subsets, such as macrophages and neutrophils. Since NLRP3 activation of B cells is not followed by pyroptosis, even in the presence of a basal caspase-1 activity, this pathway acts as a bridge that optimizes interactions between the innate and adoptive branches of the immune response.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081286","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}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1007/s12026-024-09491-8
Xiaoyu Liu, Yan Li, Weijian Zhang, Nan Gao, Jie Chen, Cheng Xiao, Guoqiang Zhang
Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination. Additionally, cIAP1/2 inhibition led to the up-regulation of programmed cell death, including apoptosis, necroptosis, and pyroptosis, and inhibiting these three cell death pathways can further reduce the inflammatory response, which is similar to the recently discovered programmed cell death pathway PANoptosis. Our findings suggest that cIAP1/2 and PANoptosis inhibition may be a new strategy for treating sepsis-induced lung injury and provide important references for further exploring the mechanism of sepsis-induced lung injury and identifying new therapeutic targets.
{"title":"Inhibition of cIAP1/2 reduces RIPK1 phosphorylation in pulmonary endothelial cells and alleviate sepsis-induced lung injury and inflammatory response.","authors":"Xiaoyu Liu, Yan Li, Weijian Zhang, Nan Gao, Jie Chen, Cheng Xiao, Guoqiang Zhang","doi":"10.1007/s12026-024-09491-8","DOIUrl":"10.1007/s12026-024-09491-8","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination. Additionally, cIAP1/2 inhibition led to the up-regulation of programmed cell death, including apoptosis, necroptosis, and pyroptosis, and inhibiting these three cell death pathways can further reduce the inflammatory response, which is similar to the recently discovered programmed cell death pathway PANoptosis. Our findings suggest that cIAP1/2 and PANoptosis inhibition may be a new strategy for treating sepsis-induced lung injury and provide important references for further exploring the mechanism of sepsis-induced lung injury and identifying new therapeutic targets.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921822","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}
Pub Date : 2024-08-01Epub Date: 2024-01-26DOI: 10.1007/s12026-024-09460-1
Camilla Mattiuzzi, Giuseppe Lippi
{"title":"Evidence of concerning decline of COVID-19 vaccination in older persons.","authors":"Camilla Mattiuzzi, Giuseppe Lippi","doi":"10.1007/s12026-024-09460-1","DOIUrl":"10.1007/s12026-024-09460-1","url":null,"abstract":"","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139564100","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}
Pub Date : 2024-08-01Epub Date: 2024-01-31DOI: 10.1007/s12026-024-09457-w
Joana Lopes, Maria João Malaquias, Joana Freitas, Rodrigo Valido, Paula Carneiro, Esmeralda Neves, Ana Maria Moreira, Raquel Samões, Ernestina Santos, Ana Paula Correia
A Consensus of Psychoimmunology Experts (Pollak et al., 2019) established a set of red flags and proposed diagnostic criteria for psychosis of autoimmune origin (AIP). Previous studies on AIP are limited by the scarcity of CSF analysis, preventing the valorization of blood anti-neuronal antibodies (Ab). The aims of this study are to determine the relative frequency and characterize AIP in a cohort of psychotic patients that underwent CSF workup. This work is a retrospective study in a tertiary psychiatric hospital. Clinical and paraclinical data were collected from medical records, and patients were classified according to Pollak et al. (2019) criteria. From 68 patients, ten (14.7%) had positive anti-neuronal antibodies (Ab): n = 5 in CSF and blood (n = 4 anti-NMDAr, n = 1 -GAD65), and n = 5 in blood only (n = 1 anti-GABAb, n = 1 -GAD65, n = 1 -SOX1, n = 1 -NMDAr, n = 1 -zic4). After 5- (2-10)-year follow-up, n = 6/68 (8.8%) had AIP diagnosis in context of autoimmune encephalitis (AE), and the remaining (n = 4/10, blood-only Ab) alternative diagnoses (n = 2 dementia, n = 1 schizophrenia, n = 1 intellectual disability). Ten of the 13 patients that fulfilled criteria for possible AIP were mimics, and only three AE had criteria for probable AIP. All AIP developed neurological manifestations (mostly cognitive dysfunction); EEG was usually abnormal (66.7%), and all had normal MRI. We found statistically significant associations between AIP/AE and systemic autoimmune disease, presentation with seizures and EEG abnormalities. All AE developed neurological symptoms alongside psychosis. Ab positivity occurred predominantly in AE but also in other neuropsychiatric disorders. Clinical suspicion based on the knowledge of the described presentations of established Ab is crucial in the psychotic patient approach.
{"title":"Blood and CSF anti-neuronal antibodies testing in psychotic syndromes: a retrospective analysis from a tertiary psychiatric hospital.","authors":"Joana Lopes, Maria João Malaquias, Joana Freitas, Rodrigo Valido, Paula Carneiro, Esmeralda Neves, Ana Maria Moreira, Raquel Samões, Ernestina Santos, Ana Paula Correia","doi":"10.1007/s12026-024-09457-w","DOIUrl":"10.1007/s12026-024-09457-w","url":null,"abstract":"<p><p>A Consensus of Psychoimmunology Experts (Pollak et al., 2019) established a set of red flags and proposed diagnostic criteria for psychosis of autoimmune origin (AIP). Previous studies on AIP are limited by the scarcity of CSF analysis, preventing the valorization of blood anti-neuronal antibodies (Ab). The aims of this study are to determine the relative frequency and characterize AIP in a cohort of psychotic patients that underwent CSF workup. This work is a retrospective study in a tertiary psychiatric hospital. Clinical and paraclinical data were collected from medical records, and patients were classified according to Pollak et al. (2019) criteria. From 68 patients, ten (14.7%) had positive anti-neuronal antibodies (Ab): n = 5 in CSF and blood (n = 4 anti-NMDAr, n = 1 -GAD65), and n = 5 in blood only (n = 1 anti-GABAb, n = 1 -GAD65, n = 1 -SOX1, n = 1 -NMDAr, n = 1 -zic4). After 5- (2-10)-year follow-up, n = 6/68 (8.8%) had AIP diagnosis in context of autoimmune encephalitis (AE), and the remaining (n = 4/10, blood-only Ab) alternative diagnoses (n = 2 dementia, n = 1 schizophrenia, n = 1 intellectual disability). Ten of the 13 patients that fulfilled criteria for possible AIP were mimics, and only three AE had criteria for probable AIP. All AIP developed neurological manifestations (mostly cognitive dysfunction); EEG was usually abnormal (66.7%), and all had normal MRI. We found statistically significant associations between AIP/AE and systemic autoimmune disease, presentation with seizures and EEG abnormalities. All AE developed neurological symptoms alongside psychosis. Ab positivity occurred predominantly in AE but also in other neuropsychiatric disorders. Clinical suspicion based on the knowledge of the described presentations of established Ab is crucial in the psychotic patient approach.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642000","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}