Pub Date : 2024-05-09DOI: 10.1101/2024.05.06.24306801
Sara M. Tamminga, M. Marlot van der Wal, Elise S. Saager, Lian F. van der Gang, Celeste M. Boesjes, Astrid Hendriks, Yvonne Pannekoek, Marjolein S. de Bruin, Femke van Wijk, Nina M. van Sorge
Atopic dermatitis (AD) is characterized by dysregulated T cell immunity and skin microbiome dysbiosis with predominance of Staphylococcus aureus (S. aureus). Emerging evidence suggests a role for S. aureus in exacerbating AD skin inflammation. We have previously shown that specific glycosylation of S. aureus cell wall structures amplifies skin inflammation through interaction with Langerhans cells (LCs). However, the role of LCs in AD remains poorly characterized. Here, we performed single cell RNA-sequencing of primary epidermal LCs and dermal T cells isolated from skin biopsies of AD patients and healthy controls, alongside specific glycoanalysis of S. aureus strains isolated from the AD lesions. Our findings reveal four LC subpopulations, including two steady-state clusters (LC1 and LC1H) and two pro-inflammatory/matured subsets (LC2 and migratory LCs). The latter two subsets were enriched in AD skin. AD LCs showed enhanced expression of C-type lectin receptors, the high-affinity IgE receptor (FcεR1), and activation of prostaglandin and leukotrienes biosynthesis pathways, as well as upregulated transcriptional signatures related to T cell activation pathways and increased expression of CCL17 (specifically LC2) compared to healthy LCs. Correspondingly, T helper 2 and regulatory T cell populations were increased in AD lesions. Our study provides proof-of-concept for a role of LCs in connecting the S. aureus-T cell axis in the AD inflammatory cycle.
特应性皮炎（AD）的特点是 T 细胞免疫失调和皮肤微生物群失调，其中以金黄色葡萄球菌（S. aureus）为主。新的证据表明，金黄色葡萄球菌在加剧 AD 皮肤炎症中扮演着重要角色。我们之前已经证明，金黄色葡萄球菌细胞壁结构的特异性糖基化会通过与朗格汉斯细胞（Langerhans cells，LCs）的相互作用扩大皮肤炎症。然而，LCs 在 AD 中的作用仍未被充分描述。在这里，我们对从 AD 患者和健康对照组皮肤活检组织中分离出的原发性表皮 LCs 和真皮 T 细胞进行了单细胞 RNA 测序，并对从 AD 病变组织中分离出的金黄色葡萄球菌菌株进行了特异性糖基化分析。我们的发现揭示了四个 LC 亚群，包括两个稳态群（LC1 和 LC1H）和两个促炎/成熟亚群（LC2 和迁移 LCs）。后两个亚群在 AD 皮肤中富集。与健康 LCs 相比，AD LCs 的 C 型凝集素受体、高亲和力 IgE 受体（FcεR1）、前列腺素和白三烯生物合成途径的活化、与 T 细胞活化途径相关的转录特征上调以及 CCL17（特别是 LC2）的表达均有所提高。相应地，AD 病变中的 T 辅助细胞 2 和调节性 T 细胞群也有所增加。我们的研究证明了 LCs 在 AD 炎症循环中连接金黄色葡萄球菌-T 细胞轴的作用。
{"title":"Single Cell Sequencing of Human Langerhans Cells Identifies Altered Gene Expression Profiles in Patients with Atopic Dermatitis","authors":"Sara M. Tamminga, M. Marlot van der Wal, Elise S. Saager, Lian F. van der Gang, Celeste M. Boesjes, Astrid Hendriks, Yvonne Pannekoek, Marjolein S. de Bruin, Femke van Wijk, Nina M. van Sorge","doi":"10.1101/2024.05.06.24306801","DOIUrl":"https://doi.org/10.1101/2024.05.06.24306801","url":null,"abstract":"Atopic dermatitis (AD) is characterized by dysregulated T cell immunity and skin microbiome dysbiosis with predominance of <em>Staphylococcus aureus</em> (<em>S. aureus</em>). Emerging evidence suggests a role for <em>S. aureus</em> in exacerbating AD skin inflammation. We have previously shown that specific glycosylation of <em>S. aureus</em> cell wall structures amplifies skin inflammation through interaction with Langerhans cells (LCs). However, the role of LCs in AD remains poorly characterized. Here, we performed single cell RNA-sequencing of primary epidermal LCs and dermal T cells isolated from skin biopsies of AD patients and healthy controls, alongside specific glycoanalysis of <em>S. aureus</em> strains isolated from the AD lesions. Our findings reveal four LC subpopulations, including two steady-state clusters (LC1 and LC1<sub>H</sub>) and two pro-inflammatory/matured subsets (LC2 and migratory LCs). The latter two subsets were enriched in AD skin. AD LCs showed enhanced expression of C-type lectin receptors, the high-affinity IgE receptor (FcεR1), and activation of prostaglandin and leukotrienes biosynthesis pathways, as well as upregulated transcriptional signatures related to T cell activation pathways and increased expression of CCL17 (specifically LC2) compared to healthy LCs. Correspondingly, T helper 2 and regulatory T cell populations were increased in AD lesions. Our study provides proof-of-concept for a role of LCs in connecting the <em>S. aureus</em>-T cell axis in the AD inflammatory cycle.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140929981","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 : 2024-05-04DOI: 10.1101/2024.05.03.24306805
Nicole Unger-Manhart, Martina Morokutti-Kurz, Petra Zieglmayer, Patrick Lemell, Markus Savli, René Zieglmayer, Hanna Dellago, Eva Prieschl-Grassauer
Purpose Carrageenan-containing nasal sprays are known to alleviate symptoms of common cold and allergic symptoms by building a barrier against airborne intruders. The objective of this study was to develop a hyperosmolar nasal spray with barrier-forming properties and to demonstrate its decongestant effect in the context of allergic rhinitis.
{"title":"Demonstration of a Decongestant Effect of “Coldamaris Akut” Compared to Saline Nasal Spray in Participants Suffering from Seasonal Allergic Rhinitis","authors":"Nicole Unger-Manhart, Martina Morokutti-Kurz, Petra Zieglmayer, Patrick Lemell, Markus Savli, René Zieglmayer, Hanna Dellago, Eva Prieschl-Grassauer","doi":"10.1101/2024.05.03.24306805","DOIUrl":"https://doi.org/10.1101/2024.05.03.24306805","url":null,"abstract":"<strong>Purpose</strong> Carrageenan-containing nasal sprays are known to alleviate symptoms of common cold and allergic symptoms by building a barrier against airborne intruders. The objective of this study was to develop a hyperosmolar nasal spray with barrier-forming properties and to demonstrate its decongestant effect in the context of allergic rhinitis.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140881583","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 : 2024-05-01DOI: 10.1101/2024.04.29.24306588
Duan Ni, Ralph Nanan
Objectives Maternal hypertensive disorders (MHD) are widespread globally, modifying maternal and fetal immunity, and have been linked to increased allergic diseases in offsprings. Nevertheless, so far, most studies in this field are small-scale and results remain inconclusive.
{"title":"Global associations of maternal hypertensive disorders and offspring allergic disease burden","authors":"Duan Ni, Ralph Nanan","doi":"10.1101/2024.04.29.24306588","DOIUrl":"https://doi.org/10.1101/2024.04.29.24306588","url":null,"abstract":"<strong>Objectives</strong> Maternal hypertensive disorders (MHD) are widespread globally, modifying maternal and fetal immunity, and have been linked to increased allergic diseases in offsprings. Nevertheless, so far, most studies in this field are small-scale and results remain inconclusive.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140887844","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 : 2024-04-30DOI: 10.1101/2024.04.29.24306533
LM Roesner, KM Gupta, V Kopfnagel, N van Unen, X Jiang, Y Kemmling, J Heise, L Riemann, S Traidl, B Lange, S Castell, KW Sühs, T Illig, T Strowig, Y Li, R Förster, J Huehn, TF Schulz, T Werfel, the RESIST SI Cohort Investigators
The number of older adults worldwide is growing exponentially. However, while living longer, older individuals are more susceptible to both non-infectious and infectious diseases, at least in part due to alterations of the immune system. Here, we report on a prospective cohort study investigating the influence of age on immune responses and susceptibility to infection. The RESIST Senior Individuals (SI) cohort was established as a general population cohort with a focus on the elderly, enrolling an age- and sex-stratified sample of 650 individuals (n=100 20-39y, n=550 61-94y, 2019-2023, Hannover, Germany). It includes clinical, demographic, and lifestyle data and also extensive biomaterial sampling. Initial insights indicate that the SI cohort exhibits characteristics of the aging immune system and the associated susceptibility to infection, thereby providing a suitable platform for the decoding of age-related alterations of the immune system and unraveling the molecular mechanisms underlying the impaired immune responsiveness in aging populations by exploring comprehensive, unbiased multi-omics datasets.
{"title":"The RESIST Senior Individuals Cohort: Design, participant characteristics and aims","authors":"LM Roesner, KM Gupta, V Kopfnagel, N van Unen, X Jiang, Y Kemmling, J Heise, L Riemann, S Traidl, B Lange, S Castell, KW Sühs, T Illig, T Strowig, Y Li, R Förster, J Huehn, TF Schulz, T Werfel, the RESIST SI Cohort Investigators","doi":"10.1101/2024.04.29.24306533","DOIUrl":"https://doi.org/10.1101/2024.04.29.24306533","url":null,"abstract":"The number of older adults worldwide is growing exponentially. However, while living longer, older individuals are more susceptible to both non-infectious and infectious diseases, at least in part due to alterations of the immune system. Here, we report on a prospective cohort study investigating the influence of age on immune responses and susceptibility to infection. The RESIST Senior Individuals (SI) cohort was established as a general population cohort with a focus on the elderly, enrolling an age- and sex-stratified sample of 650 individuals (n=100 20-39y, n=550 61-94y, 2019-2023, Hannover, Germany). It includes clinical, demographic, and lifestyle data and also extensive biomaterial sampling. Initial insights indicate that the SI cohort exhibits characteristics of the aging immune system and the associated susceptibility to infection, thereby providing a suitable platform for the decoding of age-related alterations of the immune system and unraveling the molecular mechanisms underlying the impaired immune responsiveness in aging populations by exploring comprehensive, unbiased multi-omics datasets.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831718","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 : 2024-04-12DOI: 10.1101/2024.04.09.24305582
Pendo M Ibrahim, Felix Anthony, Happiness Mshana, Kevin Rwegoshola, Hadija Semvua, Jaffu Chilongola
Background Health Care Workers (HCWs) have been playing crucial role in treating patient with COVID-19. They have a higher occupational risk of contracting the disease than the general population, and a greater chance of them transmitting the disease to vulnerable patients under their care. Given their scarcity and low COVID-19 vaccine acceptance in Africa, it is essential that HCWs are seroprotected and their exposure to COVID-19 minimized. This study was therefore designed to determine IgG antibody response to SARS-CoV-2 among HCWs in North Eastern, Tanzania.
{"title":"Antibody Responses to SARS-Cov-2 among Health Care Workers of a Tertiary Hospital in North-Eastern, Tanzania","authors":"Pendo M Ibrahim, Felix Anthony, Happiness Mshana, Kevin Rwegoshola, Hadija Semvua, Jaffu Chilongola","doi":"10.1101/2024.04.09.24305582","DOIUrl":"https://doi.org/10.1101/2024.04.09.24305582","url":null,"abstract":"<strong>Background</strong> Health Care Workers (HCWs) have been playing crucial role in treating patient with COVID-19. They have a higher occupational risk of contracting the disease than the general population, and a greater chance of them transmitting the disease to vulnerable patients under their care. Given their scarcity and low COVID-19 vaccine acceptance in Africa, it is essential that HCWs are seroprotected and their exposure to COVID-19 minimized. This study was therefore designed to determine IgG antibody response to SARS-CoV-2 among HCWs in North Eastern, Tanzania.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581521","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 : 2024-04-10DOI: 10.1101/2024.04.09.24305559
Catherine Inizan, Adrien Courtot, Chloé Sturmach, Anne-Fleur Griffon, Antoine Biron, Timothée Bruel, Vincent Enouf, Thibaut Demaneuf, Sandie Munier, Olivier Schwartz, Ann-Claire Gourinat, Georges Médevielle, Marc Jouan, Sylvie van der Werf, Yoann Madec, Valérie Albert-Dunais, Myrielle Dupont-Rouzeyrol
Background Pacific Islanders are underrepresented in vaccine efficacy trials. Few studies describe their immune response to COVID-19 vaccination. Yet, this characterization is crucial to re-enforce vaccination strategies adapted to Pacific Islanders singularities.
{"title":"Hybrid humoral immune response of Pacific Islanders to BNT162b2 vaccination and Delta/Omicron infection: a cohort study","authors":"Catherine Inizan, Adrien Courtot, Chloé Sturmach, Anne-Fleur Griffon, Antoine Biron, Timothée Bruel, Vincent Enouf, Thibaut Demaneuf, Sandie Munier, Olivier Schwartz, Ann-Claire Gourinat, Georges Médevielle, Marc Jouan, Sylvie van der Werf, Yoann Madec, Valérie Albert-Dunais, Myrielle Dupont-Rouzeyrol","doi":"10.1101/2024.04.09.24305559","DOIUrl":"https://doi.org/10.1101/2024.04.09.24305559","url":null,"abstract":"<strong>Background</strong> Pacific Islanders are underrepresented in vaccine efficacy trials. Few studies describe their immune response to COVID-19 vaccination. Yet, this characterization is crucial to re-enforce vaccination strategies adapted to Pacific Islanders singularities.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581518","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 : 2024-04-08DOI: 10.1101/2024.04.06.24305435
Duan Ni, Alistair Senior, Jian Tan, Laurence Macia, Ralph Nanan
Diets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management.
{"title":"How dietary landscapes impact food allergy","authors":"Duan Ni, Alistair Senior, Jian Tan, Laurence Macia, Ralph Nanan","doi":"10.1101/2024.04.06.24305435","DOIUrl":"https://doi.org/10.1101/2024.04.06.24305435","url":null,"abstract":"Diets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581519","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 : 2024-04-06DOI: 10.1101/2024.04.05.24305357
Nicolas Gemander, Julika Neumann, Rafael Veiga, Isabelle Etienne, Teresa Prezzemolo, Delphine Kemlin, Pieter Pannus, Stéphanie Depickère, Véronique Olislagers, Inès Vu Duc, Alexandra Waegemans, Margaux Gerbaux, Leoni Bücken, Hafid Dahma, Charlotte Martin, Nicolas Dauby, Maria E Goossens, Isabelle Desombere, Carlos P Roca, Mathijs Willemsen, Stanislas Goriely, Alain Le Moine, Arnaud Marchant, Adrian Liston, Stephanie Humblet-Baron
Solid organ transplant (SOT) recipients are at enhanced risk of adverse outcomes following infectious challenges due to immunosuppressive treatment and additional comorbidities. Unfortunately, SOT recipients are also poor responders to the key medical intervention to preventing infection: vaccines. Here we performed a systems vaccinology study on a cohort of 59 kidney transplant recipients and 31 lung transplant recipients who received the mRNA Pfizer-BioNTech COVID-19 vaccine. Analyzing the immunological status of the patients prior to vaccination, we were able to identify multiple immunological associates of relatively improved vaccine responses following two or three doses of mRNA-based SARS-CoV-2 vaccine. These immunological associates predicted, with 95.0% and 93.3% accuracy, vaccine response after the second and third dose, respectively. Comparison of the immunological associates with vaccine response in SOT recipients revealed two distinct immune configurations: a non-classical configuration, distinct from the immune state of healthy subjects, associated with responses to two doses of mRNA vaccine and that could be mediated partly by the presence of double negative B cell subsets which are more prominently represented in responsive SOT recipients, and a “normalized” configuration, closer to the immune state of healthy subjects, associated with potent antibody responses to three doses of mRNA vaccine. These results suggest that immunosuppression in SOT recipients can result in distinct immune states associated with different trade-offs in vaccine responsiveness. Immune phenotyping of SOT recipients for immune constellation may be an effective approach for identifying patients most at risk of poor vaccine responses and susceptibility to vaccine-preventable diseases.
由于免疫抑制治疗和额外的合并症，实体器官移植（SOT）受者在面临感染挑战后出现不良后果的风险更高。不幸的是，SOT 受者对预防感染的关键医疗干预措施--疫苗的反应也很差。在此，我们对接受了辉瑞-生物技术公司 COVID-19 mRNA 疫苗的 59 例肾移植受者和 31 例肺移植受者进行了系统疫苗学研究。通过分析接种疫苗前患者的免疫状态，我们发现了接种两到三剂基于 mRNA 的 SARS-CoV-2 疫苗后疫苗应答相对改善的多种免疫学关联。这些免疫相关因子预测第二剂和第三剂疫苗反应的准确率分别为 95.0% 和 93.3%。将这些免疫学相关因素与 SOT 受试者的疫苗反应进行比较，发现了两种不同的免疫结构：一种是非经典结构，与健康受试者的免疫状态不同，与对两剂 mRNA 疫苗的反应有关，部分原因可能是双阴性 B 细胞亚群的存在，这种亚群在有反应的 SOT 受试者中表现得更为突出；另一种是 "正常化 "结构，更接近健康受试者的免疫状态，与对三剂 mRNA 疫苗的强效抗体反应有关。这些结果表明，SOT 受体的免疫抑制可导致不同的免疫状态，与疫苗应答性的不同权衡有关。对 SOT 受试者的免疫表型进行分析以确定其免疫状态，可能是一种有效的方法，可用于识别疫苗应答不良和易患疫苗可预防疾病的高危患者。
{"title":"Systems vaccinology identifies clinical and immunological correlates of SARS-CoV-2 vaccine response in solid-organ transplant recipients","authors":"Nicolas Gemander, Julika Neumann, Rafael Veiga, Isabelle Etienne, Teresa Prezzemolo, Delphine Kemlin, Pieter Pannus, Stéphanie Depickère, Véronique Olislagers, Inès Vu Duc, Alexandra Waegemans, Margaux Gerbaux, Leoni Bücken, Hafid Dahma, Charlotte Martin, Nicolas Dauby, Maria E Goossens, Isabelle Desombere, Carlos P Roca, Mathijs Willemsen, Stanislas Goriely, Alain Le Moine, Arnaud Marchant, Adrian Liston, Stephanie Humblet-Baron","doi":"10.1101/2024.04.05.24305357","DOIUrl":"https://doi.org/10.1101/2024.04.05.24305357","url":null,"abstract":"Solid organ transplant (SOT) recipients are at enhanced risk of adverse outcomes following infectious challenges due to immunosuppressive treatment and additional comorbidities. Unfortunately, SOT recipients are also poor responders to the key medical intervention to preventing infection: vaccines. Here we performed a systems vaccinology study on a cohort of 59 kidney transplant recipients and 31 lung transplant recipients who received the mRNA Pfizer-BioNTech COVID-19 vaccine. Analyzing the immunological status of the patients prior to vaccination, we were able to identify multiple immunological associates of relatively improved vaccine responses following two or three doses of mRNA-based SARS-CoV-2 vaccine. These immunological associates predicted, with 95.0% and 93.3% accuracy, vaccine response after the second and third dose, respectively. Comparison of the immunological associates with vaccine response in SOT recipients revealed two distinct immune configurations: a non-classical configuration, distinct from the immune state of healthy subjects, associated with responses to two doses of mRNA vaccine and that could be mediated partly by the presence of double negative B cell subsets which are more prominently represented in responsive SOT recipients, and a “normalized” configuration, closer to the immune state of healthy subjects, associated with potent antibody responses to three doses of mRNA vaccine. These results suggest that immunosuppression in SOT recipients can result in distinct immune states associated with different trade-offs in vaccine responsiveness. Immune phenotyping of SOT recipients for immune constellation may be an effective approach for identifying patients most at risk of poor vaccine responses and susceptibility to vaccine-preventable diseases.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140581610","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 : 2024-03-19DOI: 10.1101/2024.03.16.24304180
Sophia Renee Chou, Alexis Christine Bailey, Kathleen Christine Baysac, Andrew Oler, Joshua D. Milner, Michael Joseph Ombrello
Background: Phospholipase Cγ2 (PLCγ2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants of PLCG2 cause PLCγ2-associated immune dysregulation (PLAID), a family of conditions that are classified by mutational effect. PLAID with cold urticaria (CU-PLAID) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at sub-physiologic temperatures. Objective: To identify genetic lesions causing PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing. Methods: We studied nine probands with antibody deficiency and a positive evaporative cooling test, together with two known CU-PLAID patients and three healthy subjects. Illumina sequencing was performed on full-length PLCG2 cDNA synthesized from peripheral blood mononuclear cell RNA and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in the Plcg2-deficient DT40 cell overexpression system. ERK phosphorylation was quantified by flow cytometry with and without BCR crosslinking. Results: Two probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. The first, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. The second, expressing PLCG2 without exons 19-22, carried a 14kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to BCR crosslinking. Conclusion: In addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause CU-PLAID. All of these can be identified by cDNA-based sequencing.
{"title":"Splice site and de novo mutations can cause mixed gain of function/dominant negative PLCG2-associated immune dysregulation with cold urticaria (CU-PLAID)","authors":"Sophia Renee Chou, Alexis Christine Bailey, Kathleen Christine Baysac, Andrew Oler, Joshua D. Milner, Michael Joseph Ombrello","doi":"10.1101/2024.03.16.24304180","DOIUrl":"https://doi.org/10.1101/2024.03.16.24304180","url":null,"abstract":"Background: Phospholipase Cγ2 (PLCγ2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants of PLCG2 cause PLCγ2-associated immune dysregulation (PLAID), a family of conditions that are classified by mutational effect. PLAID with cold urticaria (CU-PLAID) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at sub-physiologic temperatures.\u0000Objective: To identify genetic lesions causing PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing. Methods: We studied nine probands with antibody deficiency and a positive evaporative cooling test, together with two known CU-PLAID patients and three healthy subjects. Illumina sequencing was performed on full-length PLCG2 cDNA synthesized from peripheral blood mononuclear cell RNA and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in the Plcg2-deficient DT40 cell overexpression system. ERK phosphorylation was quantified by flow cytometry with and without BCR crosslinking.\u0000Results: Two probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. The first, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. The second, expressing PLCG2 without exons 19-22, carried a 14kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to BCR crosslinking.\u0000Conclusion: In addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause CU-PLAID. All of these can be identified by cDNA-based sequencing.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140171500","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 : 2024-03-18DOI: 10.1101/2024.03.17.24304320
Mandeep Singh, Raymond HY Louie, Jerome Samir, Matthew Field, Claire Milthorpe Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine JL Jackson, Andrew Calcino, Melinda Y Hardy, Piers Blombery, Timothy G Amos, Ira W Deveson, Scott A Read, Dmitry Shek, Antoine Guerin, Cindy S Ma, Stuart G Tangye, Antonio Di Sabatino, Marco Lenti, Alessandra Pasini, Rachele Ciccocioppo, Golo Ahlenstiel, Dan Suan, Jason A Tye-Din, Christopher C Goodnow, Fabio Luciani
Intestinal inflammation continues in a subset of celiac disease (CD) patients despite a gluten-free diet. Here, by applying multiomic single cell analysis to duodenal biopsies, we find low-grade malignancies with lymphoma driver mutations in refractory CD type 2 (RCD2) patients comprise surface CD3 negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC) - progenitor T cell stage undergoing extensive TCR recombination. In people with refractory CD type 1 (RCD1), who currently lack explanation, we discover sCD3+ T cells with lymphoma driver mutations forming large clones displaying inflammatory and cytotoxic molecular profiles in 6 of 10 individuals, and a single small clone in 1 of 4 active recently diagnosed CD cases. Accumulation of driver-mutated T cells and their sCD3- progenitors may explain chronic, non-responsive autoimmunity.
尽管采用了无麸质饮食，但一部分乳糜泻（CD）患者的肠道炎症仍在持续。在这里，通过对十二指肠活检组织进行多组学单细胞分析，我们发现难治性 CD 2 型（RCD2）患者体内存在淋巴瘤驱动基因突变的低度恶性肿瘤，其中包括表面 CD3 阴性（sCD3-）淋巴细胞，它们停滞在先天性淋巴细胞（ILC）-祖先 T 细胞阶段，正在经历广泛的 TCR 重组。在目前无法解释的难治性 CD 1 型（RCD1）患者中，我们发现在 10 个个体中的 6 个中，有淋巴瘤驱动突变的 sCD3+ T 细胞形成了显示炎症和细胞毒性分子特征的大型克隆，而在 4 个近期诊断的活跃 CD 病例中，有 1 个是单一的小型克隆。驱动基因突变的T细胞及其sCD3-祖细胞的积累可以解释慢性、非反应性自身免疫。
{"title":"Expanded T cell clones with lymphoma driver somatic mutations in refractory celiac disease","authors":"Mandeep Singh, Raymond HY Louie, Jerome Samir, Matthew Field, Claire Milthorpe Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine JL Jackson, Andrew Calcino, Melinda Y Hardy, Piers Blombery, Timothy G Amos, Ira W Deveson, Scott A Read, Dmitry Shek, Antoine Guerin, Cindy S Ma, Stuart G Tangye, Antonio Di Sabatino, Marco Lenti, Alessandra Pasini, Rachele Ciccocioppo, Golo Ahlenstiel, Dan Suan, Jason A Tye-Din, Christopher C Goodnow, Fabio Luciani","doi":"10.1101/2024.03.17.24304320","DOIUrl":"https://doi.org/10.1101/2024.03.17.24304320","url":null,"abstract":"Intestinal inflammation continues in a subset of celiac disease (CD) patients despite a gluten-free diet. Here, by applying multiomic single cell analysis to duodenal biopsies, we find low-grade malignancies with lymphoma driver mutations in refractory CD type 2 (RCD2) patients comprise surface CD3 negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC) - progenitor T cell stage undergoing extensive TCR recombination. In people with refractory CD type 1 (RCD1), who currently lack explanation, we discover sCD3+ T cells with lymphoma driver mutations forming large clones displaying inflammatory and cytotoxic molecular profiles in 6 of 10 individuals, and a single small clone in 1 of 4 active recently diagnosed CD cases. Accumulation of driver-mutated T cells and their sCD3- progenitors may explain chronic, non-responsive autoimmunity.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140171503","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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