Pub Date : 2024-03-16DOI: 10.1101/2024.03.09.24304015
Martin Neil, Scott McLachlan, Norman Fenton
It is recognised that many studies reporting high efficacy for Covid-19 vaccines suffer from various selection biases. Systematic review identified thirty-nine studies that suffered from one particular and serious form of bias called miscategorisation bias, whereby study participants who have been vaccinated are categorised as unvaccinated up to and until some arbitrarily defined time after vaccination occurred. Simulation demonstrates that this miscategorisation bias artificially boosts vaccine efficacy and infection rates even when a vaccine has zero or negative efficacy. Furthermore, simulation demonstrates that repeated boosters, given every few months, are needed to maintain this misleading impression of efficacy. Given this, any claims of Covid-19 vaccine efficacy based on these studies are likely to be a statistical illusion.
{"title":"The extent and impact of vaccine status miscategorisation on covid-19 vaccine efficacy studies","authors":"Martin Neil, Scott McLachlan, Norman Fenton","doi":"10.1101/2024.03.09.24304015","DOIUrl":"https://doi.org/10.1101/2024.03.09.24304015","url":null,"abstract":"It is recognised that many studies reporting high efficacy for Covid-19 vaccines suffer from various selection biases. Systematic review identified thirty-nine studies that suffered from one particular and serious form of bias called miscategorisation bias, whereby study participants who have been vaccinated are categorised as unvaccinated up to and until some arbitrarily defined time after vaccination occurred. Simulation demonstrates that this miscategorisation bias artificially boosts vaccine efficacy and infection rates even when a vaccine has zero or negative efficacy. Furthermore, simulation demonstrates that repeated boosters, given every few months, are needed to maintain this misleading impression of efficacy. Given this, any claims of Covid-19 vaccine efficacy based on these studies are likely to be a statistical illusion.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140156005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.10.24303911
Weibo Zhao, Boyang Wang, Lingyao Kong, Qi Wang, Shao Li
Background: Increasing evidence showed that seasonal allergic rhinitis (SAR), as an allergy disease, could be alleviated with traditional Chinese medicine (TCM) formula, one example being Tuomin Zhiti Decoction (TZD). However, as a complex composition of TCM herbs, the mechanism of TZD in the treatment of SAR remain unclear. Purpose: Uncover the mechanism of TZD for treating SAR based on computational analysis and clinical multi-omics experiments. Study design: Integrate computational analysis including network target analysis and machine learning algorithms with clinical multi-omics experiments and public omics data. Methods: By analyzing TZD's composition through a network-based method, we identified the biological effects of each compound, constructing a comprehensive biological network to elucidate TZD's molecular and pathway mechanisms against AR. Single-arm clinical trials on the gut microbiome and serum transcriptomics corroborated our computational insights. Further validation through public omics data highlighted key TZD compounds, paving the way for future research. Results: TZD was discovered to exert a regulatory effect on various modules associated with AR, as demonstrated by the constructed biological network. Insights from gut microbiome and serum transcriptomics in clinical trials, where immune-related microbiomes represented by Prevotella, as well as pathways and biological processes including antigen processing and presentation, activation and regulating immune cell surface receptor, were markedly enriched (P value < 0.05), indicated that TZD played a pivotal role in modulating immune processes and the immune cells against AR. With the verification of multi-omics, it was determined that TZD potentially influences immune responses and downstream immune cells like CD4+ T cells, through both direct mechanisms involving antigen and indirect mechanisms mediated by gut microbiomes in the treatment of AR. Conclusion: Through combination of computational prediction and analysis together with clinical multi-omics, a network target based framework provided a new insight for uncovering the mechanism of TZD for treating AR.
背景：越来越多的证据表明，季节性过敏性鼻炎（SAR）作为一种过敏性疾病，可以通过传统中药配方得到缓解，其中一个例子就是土门至瞳煎剂（TZD）。研究目的：基于计算分析和临床多组学实验，揭示涂敏智滴治疗鼻敏感的机制：研究设计：将包括网络靶标分析和机器学习算法在内的计算分析与临床多组学实验和公开的omics数据相结合：通过基于网络的方法分析TZD的组成，我们确定了每个化合物的生物效应，构建了一个全面的生物网络，以阐明TZD抗AR的分子和通路机制。关于肠道微生物组和血清转录组学的单臂临床试验证实了我们的计算见解。通过公开的omics数据进一步验证了关键的TZD化合物，为未来的研究铺平了道路：结果：正如构建的生物网络所示，我们发现TZD对与AR相关的各种模块具有调节作用。临床试验中肠道微生物组和血清转录组学的研究结果表明，以普雷沃特氏菌为代表的免疫相关微生物组，以及包括抗原处理和递呈、激活和调节免疫细胞表面受体在内的通路和生物过程明显富集（P值为0.05），这表明TZD在调节免疫过程和免疫细胞对抗AR方面发挥着关键作用。通过多组学的验证，可以确定 TZD 在治疗 AR 的过程中，通过涉及抗原的直接机制和肠道微生物组介导的间接机制，潜在地影响免疫反应和下游免疫细胞（如 CD4+ T 细胞）。结论通过将计算预测和分析与临床多组学相结合，基于网络靶点的框架为揭示 TZD 治疗 AR 的机制提供了新的视角。
{"title":"Clinical multi-omics reveals the role of Tuomin Zhiti Decoction Intervention in Allergic Rhinitis from the perspective of biological network","authors":"Weibo Zhao, Boyang Wang, Lingyao Kong, Qi Wang, Shao Li","doi":"10.1101/2024.03.10.24303911","DOIUrl":"https://doi.org/10.1101/2024.03.10.24303911","url":null,"abstract":"Background: Increasing evidence showed that seasonal allergic rhinitis (SAR), as an allergy disease, could be alleviated with traditional Chinese medicine (TCM) formula, one example being Tuomin Zhiti Decoction (TZD). However, as a complex composition of TCM herbs, the mechanism of TZD in the treatment of SAR remain unclear.\u0000Purpose: Uncover the mechanism of TZD for treating SAR based on computational analysis and clinical multi-omics experiments.\u0000Study design: Integrate computational analysis including network target analysis and machine learning algorithms with clinical multi-omics experiments and public omics data.\u0000Methods: By analyzing TZD's composition through a network-based method, we identified the biological effects of each compound, constructing a comprehensive biological network to elucidate TZD's molecular and pathway mechanisms against AR. Single-arm clinical trials on the gut microbiome and serum transcriptomics corroborated our computational insights. Further validation through public omics data highlighted key TZD compounds, paving the way for future research.\u0000Results: TZD was discovered to exert a regulatory effect on various modules associated with AR, as demonstrated by the constructed biological network. Insights from gut microbiome and serum transcriptomics in clinical trials, where immune-related microbiomes represented by Prevotella, as well as pathways and biological processes including antigen processing and presentation, activation and regulating immune cell surface receptor, were markedly enriched (P value < 0.05), indicated that TZD played a pivotal role in modulating immune processes and the immune cells against AR. With the verification of multi-omics, it was determined that TZD potentially influences immune responses and downstream immune cells like CD4+ T cells, through both direct mechanisms involving antigen and indirect mechanisms mediated by gut microbiomes in the treatment of AR. Conclusion: Through combination of computational prediction and analysis together with clinical multi-omics, a network target based framework provided a new insight for uncovering the mechanism of TZD for treating AR.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140128402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-06DOI: 10.1101/2024.02.27.24303363
Sonja Fernbach, Nina K. Mair, Irene A. Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W. Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H. Hirsch, Michael Huber, Huldrych F. Günthard, Jacques Fellay, Roger D. Kouyos, Benjamin G. Hale, The Swiss HIV Cohort Study
Pre-existing autoantibodies (autoAbs) neutralizing type I interferons (IFN-Is: IFNα, IFNβ, IFNω) have recently been described as significant contributors to the severity of viral infectious diseases. Here, we explore the development and consequences of anti-IFN-I autoAbs at high-resolution using retrospective samples and data from 1876 well-treated individuals >65 years of age enrolled in the Swiss HIV Cohort Study, a nationwide, longitudinal cohort with up to 35 years of follow-up. Approximately 1.9% of individuals developed anti-IFN-I autoAbs, with a median onset age of ~63 years (range 45-80). Once developed, anti-IFN-I autoAbs persisted for life, and generally increased in titer over years. Most individuals developed distinct neutralizing and non-neutralizing anti-IFN-I autoAb repertoires at discrete times that selectively targeted various combinations of IFNα, IFNβ, and IFNω. Longitudinal analyses further revealed that emergence of neutralizing anti-IFNα autoAbs correlated with reduced IFN-stimulated gene (ISG) levels, indicating impairment of innate immunity. Patient data review suggested that prior recorded viral infections and autoimmune history influence the likelihood of mounting anti-IFN-I autoAbs. Indeed, systematic measurements in biobanked samples revealed significant enrichment of pre-existing autoreactivity against clinically relevant autoantigens in individuals who later developed anti-IFN-I autoAbs. In this context, we describe lifelong neutralizing anti-IFNα autoAbs (and impaired innate immunity), that manifested in an individual following IFNα therapy, and who was retrospectively found to have had pre-existing autoreactivity to β2-glycoprotein-I before IFNα treatment. Our decades-spanning longitudinal analyses illuminate the development and immune implications of anti-IFN-I autoAbs in an aging population, and support a 'two-hit' hypothesis whereby loss of self-tolerance prior to immune-triggering with endogenous or exogenous IFN-I may pose a risk for developing late-onset, lifelong IFN-I functional deficiency.
{"title":"Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population","authors":"Sonja Fernbach, Nina K. Mair, Irene A. Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W. Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H. Hirsch, Michael Huber, Huldrych F. Günthard, Jacques Fellay, Roger D. Kouyos, Benjamin G. Hale, The Swiss HIV Cohort Study","doi":"10.1101/2024.02.27.24303363","DOIUrl":"https://doi.org/10.1101/2024.02.27.24303363","url":null,"abstract":"Pre-existing autoantibodies (autoAbs) neutralizing type I interferons (IFN-Is: IFNα, IFNβ, IFNω) have recently been described as significant contributors to the severity of viral infectious diseases. Here, we explore the development and consequences of anti-IFN-I autoAbs at high-resolution using retrospective samples and data from 1876 well-treated individuals >65 years of age enrolled in the Swiss HIV Cohort Study, a nationwide, longitudinal cohort with up to 35 years of follow-up. Approximately 1.9% of individuals developed anti-IFN-I autoAbs, with a median onset age of ~63 years (range 45-80). Once developed, anti-IFN-I autoAbs persisted for life, and generally increased in titer over years. Most individuals developed distinct neutralizing and non-neutralizing anti-IFN-I autoAb repertoires at discrete times that selectively targeted various combinations of IFNα, IFNβ, and IFNω. Longitudinal analyses further revealed that emergence of neutralizing anti-IFNα autoAbs correlated with reduced IFN-stimulated gene (ISG) levels, indicating impairment of innate immunity. Patient data review suggested that prior recorded viral infections and autoimmune history influence the likelihood of mounting anti-IFN-I autoAbs. Indeed, systematic measurements in biobanked samples revealed significant enrichment of pre-existing autoreactivity against clinically relevant autoantigens in individuals who later developed anti-IFN-I autoAbs. In this context, we describe lifelong neutralizing anti-IFNα autoAbs (and impaired innate immunity), that manifested in an individual following IFNα therapy, and who was retrospectively found to have had pre-existing autoreactivity to β2-glycoprotein-I before IFNα treatment. Our decades-spanning longitudinal analyses illuminate the development and immune implications of anti-IFN-I autoAbs in an aging population, and support a 'two-hit' hypothesis whereby loss of self-tolerance prior to immune-triggering with endogenous or exogenous IFN-I may pose a risk for developing late-onset, lifelong IFN-I functional deficiency.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140045998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-05DOI: 10.1101/2024.03.02.24303242
Doan C Nguyen, Ian T Hentenaar, Andrea Morrison-Porter, David Solano, Natalie S. Haddad, Carlos Castrillon, Pedro A Lamothe, Joel Andrews, Danielle Roberts, Sagar Lonial, Ignacio Sanz, Frances Eun-Hyung Lee
The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19-) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.
{"title":"The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination","authors":"Doan C Nguyen, Ian T Hentenaar, Andrea Morrison-Porter, David Solano, Natalie S. Haddad, Carlos Castrillon, Pedro A Lamothe, Joel Andrews, Danielle Roberts, Sagar Lonial, Ignacio Sanz, Frances Eun-Hyung Lee","doi":"10.1101/2024.03.02.24303242","DOIUrl":"https://doi.org/10.1101/2024.03.02.24303242","url":null,"abstract":"The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19-) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-02DOI: 10.1101/2024.02.29.24303561
Andreza Gomes Pascoal, Paula de Souza Mendes, Luiz Eduardo Rodrigues Lima, Bruno Mori
Background Obesity is a global health problem that affects millions of people around the world, especially children and adolescents. The main causes of obesity are a sedentary lifestyle, unhealthy diet, and lack of reduction in the level of physical activity with negative consequences for physical and mental health, such as increased risk of cardiovascular diseases, diabetes, hypertension, dyslipidemia, and inflammation. Therefore, we will carry out a perform a systematic review to evaluate the effectiveness of physical activity in obese children and adolescents and serum interleukin-10 levels.
{"title":"Effectiveness of physical activity in obese children and adolescents and serum interleukin-10 levels: A protocol for systematic review","authors":"Andreza Gomes Pascoal, Paula de Souza Mendes, Luiz Eduardo Rodrigues Lima, Bruno Mori","doi":"10.1101/2024.02.29.24303561","DOIUrl":"https://doi.org/10.1101/2024.02.29.24303561","url":null,"abstract":"<strong>Background</strong> Obesity is a global health problem that affects millions of people around the world, especially children and adolescents. The main causes of obesity are a sedentary lifestyle, unhealthy diet, and lack of reduction in the level of physical activity with negative consequences for physical and mental health, such as increased risk of cardiovascular diseases, diabetes, hypertension, dyslipidemia, and inflammation. Therefore, we will carry out a perform a systematic review to evaluate the effectiveness of physical activity in obese children and adolescents and serum interleukin-10 levels.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-29DOI: 10.1101/2024.02.28.24302787
Maonezi Abas Hamisi, Nur Ain Mohd Asri, Aini Syahida Mat Yassim, Rapeah Suppian
Objective For more than a century, developing novel and effective vaccines against malaria and tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials.
{"title":"A Systematic Review on Malaria and Tuberculosis (TB) Vaccine Challenges in Sub-Saharan African Clinical Trials","authors":"Maonezi Abas Hamisi, Nur Ain Mohd Asri, Aini Syahida Mat Yassim, Rapeah Suppian","doi":"10.1101/2024.02.28.24302787","DOIUrl":"https://doi.org/10.1101/2024.02.28.24302787","url":null,"abstract":"<strong>Objective</strong> For more than a century, developing novel and effective vaccines against malaria and tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-27DOI: 10.1101/2024.02.25.24303331
Emily M. Harris, Sarah Chamseddine, Anne Chu, Leetah Senkpeil, Matthew Nikiciuk, Amer Al-Musa, Brian Woods, Elif Ozdogan, Sarife Saker, David P Hoytema van Konijnenburg, Christina S.K. Yee, Ryan Nelson, Pui Y Lee, Olha Halyabar, Rebecca C Hale, Megan Day-Lewis, Lauren A Henderson, Alan A Nguyen, Megan Elkins, Toshiro K. Ohsumi, Maria Gutierrez-Arcelus, Janique M. Peyper, Craig D. Platt, Rachael F. Grace, Brenna LaBere, Janet Chou
Introduction. Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods. The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3-CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results. This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass early progenitors of cTfh or Tfh cells as well as effector memory T cells that eventually lose CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions. This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are ofte
简介自身免疫性疾病具有异质性，通常缺乏特异或敏感的诊断测试。CD4+CXCR5+PD1+ 循环 T 滤泡辅助细胞（cTfh）百分比升高和 cTfh 亚型分布不均与自身免疫有关。然而，尽管疾病活动持续存在，但在接受免疫调节治疗后，cTfh 细胞百分比可恢复正常，这表明有必要确定与自身免疫相关的其他细胞和/或血清学特征。研究方法研究对象包括50名对照组和56名自身免疫性细胞减少症、胃肠道、肺和/或神经系统自身免疫性疾病患者。流式细胞术用于测量表达趋化因子受体 CXCR3 和/或 CCR6 的 CD4+CXCR5+ T 细胞亚群：CXCR3+CCR6- 1 型、CXCR3-CCR6- 2 型、CXCR3+CCR6+ 1/17 型和 CXCR3-CCR6+ 17 型 T 细胞。IgG和IgA自身抗体的量化采用了一个具有1616个全长、构象完整的蛋白质抗原的芯片。对照组的 97.5 百分位数定义了 T 细胞亚群百分比和自身抗体总数（负担）的正常范围。研究结果这项研究的重点是 CD4+CXCR5+ T 细胞，因为在自身免疫性疾病特有的同源 T-B 细胞相互作用后会出现 CXCR5 上调。我们将这些细胞称为循环 T 滤泡记忆（cTfm）细胞，以确认抗原体验 CXCR5+ T 细胞的动态性质，其中包括 cTfh 或 Tfh 细胞的早期祖细胞以及最终失去 CXCR5 的效应记忆 T 细胞。与对照组相比，57.1%的患者CXCR5+CXCR3+CCR6+ cTfm1/17细胞百分比增加，25%的患者CXCR5+CXCR3-CCR6+ cTfm17细胞百分比增加。与对照组相比，患者的IgG和IgA自身抗体种类明显增多，44.6%的患者自身抗体负担加重。无监督自身抗体聚类发现了三个患者群，其IgG自身抗体谱与对照组不同，富集于活动性自身免疫和单基因疾病患者。cTfm17细胞百分比的增加与高滴度IgG和IgA自身抗体负担的增加关系最为密切。综合测量 cTfm1/17、cTfm17 和高滴度 IgG 和/或 IgA 自身抗体的增加，对识别自身免疫患者的灵敏度为 91.1%，特异度为 90.9%。在接受免疫调节治疗的患者中，cTfm1/17 和 cTfm17 的百分比以及高滴度自身抗体的数量与未接受治疗的患者没有差异，这表明 cTfm 的测量可以补充受治疗影响的其他细胞标记物的测量。结论。本研究强调了评估自身免疫的两种新方法：测量 CD4+CXCR5+ cTfm 亚群和自身抗体总负荷。我们的研究结果表明，这些方法尤其适用于罕见自身免疫性疾病患者，因为这些患者的目标抗原和预后往往是未知的。
{"title":"Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders","authors":"Emily M. Harris, Sarah Chamseddine, Anne Chu, Leetah Senkpeil, Matthew Nikiciuk, Amer Al-Musa, Brian Woods, Elif Ozdogan, Sarife Saker, David P Hoytema van Konijnenburg, Christina S.K. Yee, Ryan Nelson, Pui Y Lee, Olha Halyabar, Rebecca C Hale, Megan Day-Lewis, Lauren A Henderson, Alan A Nguyen, Megan Elkins, Toshiro K. Ohsumi, Maria Gutierrez-Arcelus, Janique M. Peyper, Craig D. Platt, Rachael F. Grace, Brenna LaBere, Janet Chou","doi":"10.1101/2024.02.25.24303331","DOIUrl":"https://doi.org/10.1101/2024.02.25.24303331","url":null,"abstract":"Introduction. Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods. The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3-CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results. This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass early progenitors of cTfh or Tfh cells as well as effector memory T cells that eventually lose CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions. This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are ofte","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139981196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-24DOI: 10.1101/2024.02.23.24303270
Liting Jiang, Linhui Shen, Yuan Zong, Jiawen Zhao, Yi Yang, Lei Li, Ning Li, Yiming Gao, Xianfei Xie, Qiyuan Bao, Weiguo Hu
Sarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. To gain insights into the immune cell composition and interactions, we combined single-nuclei RNA sequencing data, bulk RNA sequencing datasets, and comprehensive bioinformatic analyses on skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Overall, we analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Among the immune cells, macrophages constituted the largest immune fraction. A specific marker gene LYVE1 for skeletal muscle macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play a different role in physiological or non-physiological conditions. Using bulk RNA sequencing data, we identified strong enrichment for a macrophage- rich inflammation in sarcopenia. Our findings demonstrate age-related changes in the composition and cross-talk of immune cells, which contribute to chronic inflammation. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.
{"title":"Characterizing the skeletal muscle immune microenvironment for sarcopenia using transcriptome analysis and histological validation","authors":"Liting Jiang, Linhui Shen, Yuan Zong, Jiawen Zhao, Yi Yang, Lei Li, Ning Li, Yiming Gao, Xianfei Xie, Qiyuan Bao, Weiguo Hu","doi":"10.1101/2024.02.23.24303270","DOIUrl":"https://doi.org/10.1101/2024.02.23.24303270","url":null,"abstract":"Sarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. To gain insights into the immune cell composition and interactions, we combined single-nuclei RNA sequencing data, bulk RNA sequencing datasets, and comprehensive bioinformatic analyses on skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Overall, we analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Among the immune cells, macrophages constituted the largest immune fraction. A specific marker gene LYVE1 for skeletal muscle macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play a different role in physiological or non-physiological conditions. Using bulk RNA sequencing data, we identified strong enrichment for a macrophage- rich inflammation in sarcopenia. Our findings demonstrate age-related changes in the composition and cross-talk of immune cells, which contribute to chronic inflammation. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139948389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-23DOI: 10.1101/2024.02.20.24303049
Mingce Zhang, Remy R Cron, Niansheng Chu, Junior Nguyen, Scott M Gordon, Esraa M Eloseily, Thomas Prescott Atkinson, Peter Weiser, Mark R Walter, Portia A Kreiger, Scott W Canna, Edward M Behrens, Randy Q Cron
Background: Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyper-inflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients. Objective: We explore the role of CSS patient derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of Dock8-/- in murine models of CSS. Methods: DOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNlower case Greek gamma) production were explored by flow cytometry (FCM). A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNlower case Greek gamma levels) upon challenge with lymphochoriomeningitic virus (LCMV) and excess IL-18. Results: Both patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. Dock8-/- mice tolerated excess IL-18 but developed features of CSS upon LCMV infection. Conclusion: Mutations in DOCK8 may contribute to CSS-like hyper-inflammatory states by altering cytolytic function in a threshold model of disease.
{"title":"Role of DOCK8 in Hyper-inflammatory Syndromes","authors":"Mingce Zhang, Remy R Cron, Niansheng Chu, Junior Nguyen, Scott M Gordon, Esraa M Eloseily, Thomas Prescott Atkinson, Peter Weiser, Mark R Walter, Portia A Kreiger, Scott W Canna, Edward M Behrens, Randy Q Cron","doi":"10.1101/2024.02.20.24303049","DOIUrl":"https://doi.org/10.1101/2024.02.20.24303049","url":null,"abstract":"Background: Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyper-inflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare <em>DOCK8</em> variants in CSS patients. Objective: We explore the role of CSS patient derived <em>DOCK8</em> mutations on cytolytic activity in NK cells. We further study effects of <em>Dock8<sup>-/-</sup></em> in murine models of CSS. Methods: <em>DOCK8</em> cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNlower case Greek gamma) production were explored by flow cytometry (FCM). A third CSS patient <em>DOCK8</em> mRNA splice acceptor site variant was explored by exon trapping. <em>Dock8<sup>-/-</sup></em> mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNlower case Greek gamma levels) upon challenge with lymphochoriomeningitic virus (LCMV) and excess IL-18. Results: Both patient <em>DOCK8</em> missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion <em>in vitro</em>. The patient <em>DOCK8</em> splice variant disrupted mRNA splicing <em>in vitro</em>. <em>Dock8<sup>-/-</sup></em> mice tolerated excess IL-18 but developed features of CSS upon LCMV infection. Conclusion: Mutations in <em>DOCK8</em> may contribute to CSS-like hyper-inflammatory states by altering cytolytic function in a threshold model of disease.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"284 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139956529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-19DOI: 10.1101/2024.02.15.24302255
Stephanie Guillet, Tomi Lazarov, Natasha Jordan, Bertrand Boisson, Maria Tello, Barbara Craddock, Ting Zhou, Chihiro Nishi, Rohan Bareja, Hairu Yang, Frederic Rieux-Laucat, Rosa Irene Fregel Lorenzo, Sabrina D. Dyall, David Isenberg, David D'Cruz, Nico Lachmann, Olivier Elemento, Agnes Viale, Nicholas D. Socci, Laurent Abel, Shigekazu Nagata, Morgan Huse, W Todd Miller, Jean-Laurent Casanova, Frédéric Geissmann
Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an in vivo SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.
{"title":"ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis","authors":"Stephanie Guillet, Tomi Lazarov, Natasha Jordan, Bertrand Boisson, Maria Tello, Barbara Craddock, Ting Zhou, Chihiro Nishi, Rohan Bareja, Hairu Yang, Frederic Rieux-Laucat, Rosa Irene Fregel Lorenzo, Sabrina D. Dyall, David Isenberg, David D'Cruz, Nico Lachmann, Olivier Elemento, Agnes Viale, Nicholas D. Socci, Laurent Abel, Shigekazu Nagata, Morgan Huse, W Todd Miller, Jean-Laurent Casanova, Frédéric Geissmann","doi":"10.1101/2024.02.15.24302255","DOIUrl":"https://doi.org/10.1101/2024.02.15.24302255","url":null,"abstract":"Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an <em>in vivo</em> SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"254 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139902703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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