Pub Date : 2024-09-15DOI: 10.1101/2024.09.13.24313664
Jacquiline Wangui Mugo, Cascia Day, Ananyo Choudhury, Maria Deetlefs, Robert Freercks, Sian Geraty, Angelica Panieri, Christian Cotchbos, Melissa Ribeiro, Adelein Engelbrecht, Lisa K. Micklesfield, Michèle Ramsay, Sarah Pedretti, Jonny Peter
Background: Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population. Methods: The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls). Results: No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs. Conclusions: Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.
{"title":"A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population.","authors":"Jacquiline Wangui Mugo, Cascia Day, Ananyo Choudhury, Maria Deetlefs, Robert Freercks, Sian Geraty, Angelica Panieri, Christian Cotchbos, Melissa Ribeiro, Adelein Engelbrecht, Lisa K. Micklesfield, Michèle Ramsay, Sarah Pedretti, Jonny Peter","doi":"10.1101/2024.09.13.24313664","DOIUrl":"https://doi.org/10.1101/2024.09.13.24313664","url":null,"abstract":"Background: Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.\u0000Methods: The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls). Results: No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10<sup>-06</sup>). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.\u0000Conclusions: Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262885","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 : 2024-09-13DOI: 10.1101/2024.09.12.24313591
Andrew P Hederman, Hannah M Brookes, Harini Natarajan, Leo Heyndrickx, Kevin K. Arien, Joshua A Weiner, Amihai Rottenstreich, Gila Zarbiv, Dana Wolf, Tessa Goetghebuer, Arnaud Marchant, Margaret E Ackerman
Maternal antibodies serve as a temporary form of inherited immunity, providing humoral protection to vulnerable neonates. Whereas IgG is actively transferred up a concentration gradient via the neonatal Fc Receptor (FcRn), maternal IgA and IgM are typically excluded from fetal circulation. Further, not all IgG molecules exhibit the same transfer efficiency, being influenced by subclass, Fab and Fc domain glycosylation, antigen-specificity, and the temporal dynamics of maternal antibody responses. Here, we investigate the phenotypes and functions of maternal and cord blood antibodies induced by SARS-CoV-2 infection and compare them to those induced by mRNA vaccination, focusing on breadth of antigen recognition and antiviral functions including neutralization and effector function. While cord blood coronavirus-specific antibody functional breadth and potency appeared to be more compromised than binding breadth and potency in both groups, vaccination induced substantially greater function and breadth in cord blood than did natural infection. These functional phenotypes were associated with speciation of the maternal serum repertoires, as some IgG subpopulations were enriched while others were relatively depleted. Relevant to the continued protection of vulnerable populations in the context of a diversifying pathogen, greater breadth was observed for antibody effector functions than for neutralization, and these activities were associated with greater affinity for antigen. This work provides insights into the functional breadth of maternal-fetal antibody responses in the context of novel mRNA vaccines and a recently emerged pathogen that is likely to be a public health burden for the foreseeable future.
母体抗体是一种临时的遗传免疫形式，为脆弱的新生儿提供体液保护。IgG 通过新生儿 Fc 受体（FcRn）积极地沿浓度梯度向上转移，而母体 IgA 和 IgM 通常被排除在胎儿血液循环之外。此外，并非所有的 IgG 分子都表现出相同的转移效率，这受到亚类、Fab 和 Fc 结构域糖基化、抗原特异性以及母体抗体反应的时间动态的影响。在这里，我们研究了 SARS-CoV-2 感染诱导的母体抗体和脐带血抗体的表型和功能，并将它们与 mRNA 疫苗接种诱导的抗体进行了比较，重点是抗原识别的广度和抗病毒功能，包括中和与效应器功能。虽然在两组中，脐带血冠状病毒特异性抗体的功能广度和效力似乎比结合广度和效力受到更大的影响，但疫苗接种在脐带血中诱导的功能和广度远远大于自然感染。这些功能表型与母体血清库的物种分化有关，因为一些 IgG 亚群富集，而另一些则相对减少。在病原体多样化的背景下，抗体的效应功能比中和功能更广泛，而且这些功能与抗原的亲和力更强有关，这与持续保护易感人群有关。在新型 mRNA 疫苗和最近出现的病原体（可能在可预见的未来成为公共卫生负担）的背景下，这项研究为母胎抗体反应的功能广度提供了见解。
{"title":"Patterns and functional consequences of antibody speciation in maternal-fetal transfer of coronavirus-specific humoral immunity","authors":"Andrew P Hederman, Hannah M Brookes, Harini Natarajan, Leo Heyndrickx, Kevin K. Arien, Joshua A Weiner, Amihai Rottenstreich, Gila Zarbiv, Dana Wolf, Tessa Goetghebuer, Arnaud Marchant, Margaret E Ackerman","doi":"10.1101/2024.09.12.24313591","DOIUrl":"https://doi.org/10.1101/2024.09.12.24313591","url":null,"abstract":"Maternal antibodies serve as a temporary form of inherited immunity, providing humoral protection to vulnerable neonates. Whereas IgG is actively transferred up a concentration gradient via the neonatal Fc Receptor (FcRn), maternal IgA and IgM are typically excluded from fetal circulation. Further, not all IgG molecules exhibit the same transfer efficiency, being influenced by subclass, Fab and Fc domain glycosylation, antigen-specificity, and the temporal dynamics of maternal antibody responses. Here, we investigate the phenotypes and functions of maternal and cord blood antibodies induced by SARS-CoV-2 infection and compare them to those induced by mRNA vaccination, focusing on breadth of antigen recognition and antiviral functions including neutralization and effector function. While cord blood coronavirus-specific antibody functional breadth and potency appeared to be more compromised than binding breadth and potency in both groups, vaccination induced substantially greater function and breadth in cord blood than did natural infection. These functional phenotypes were associated with speciation of the maternal serum repertoires, as some IgG subpopulations were enriched while others were relatively depleted. Relevant to the continued protection of vulnerable populations in the context of a diversifying pathogen, greater breadth was observed for antibody effector functions than for neutralization, and these activities were associated with greater affinity for antigen. This work provides insights into the functional breadth of maternal-fetal antibody responses in the context of novel mRNA vaccines and a recently emerged pathogen that is likely to be a public health burden for the foreseeable future.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262886","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}
Dysfunctions in nucleic acid-sensing Toll-like receptors (TLRs) disrupt nucleic acid tolerance, leading to systemic lupus erythematosus (SLE). Here, we report a novel homozygous gain-of-function p.R95L mutation in the TLR chaperone protein UNC93B1 in an SLE patient. Bulk and single-cell transcriptional analysis of the patient's peripheral blood mononuclear cells (PBMCs) revealed significantly elevated inflammation in T cells and myeloid cells due to enhanced dendritic cells function. The UNC93B1 R95L mutation leads to hyperactivation of TLR7/8, but not TLR3/9, upon stimulation with specific agonists in vitro. Transgenic Unc93b1R95L/R95L mice develop inflammatory and autoimmune phenotypes, and the upregulation of inflammatory signaling differs among organs, with a specific contribution of malfunctioned T cells and B cells. In human and mouse cell lines, the UNC93B1 R95L mutation promotes TLR7/8 signaling by enhancing its binding to ssRNA, without affecting TLR7/8 translocation. Overall, our results elucidate the pathology of organs and the immunological profiles of immune cell populations in the development of SLE caused by the UNC93B1 R95L mutation through the TLR7/8 axis.
{"title":"A novel UNC93B1 gain-of-function mutation leads to TLR7 and TLR8 hyperactivation and systemic lupus erythematosus","authors":"Xu Han, RuoRan Wang, Seza Ozen, Qintao Wang, Wei Dong, Yi Zeng, Ouyuan Xu, Seher Şenar, Li Guo, Ying Gu, Huanming Yang, Xiaomin Yu, Panfeng Tao, Qing Zhou","doi":"10.1101/2024.09.11.24313360","DOIUrl":"https://doi.org/10.1101/2024.09.11.24313360","url":null,"abstract":"Dysfunctions in nucleic acid-sensing Toll-like receptors (TLRs) disrupt nucleic acid tolerance, leading to systemic lupus erythematosus (SLE). Here, we report a novel homozygous gain-of-function p.R95L mutation in the TLR chaperone protein UNC93B1 in an SLE patient. Bulk and single-cell transcriptional analysis of the patient's peripheral blood mononuclear cells (PBMCs) revealed significantly elevated inflammation in T cells and myeloid cells due to enhanced dendritic cells function. The UNC93B1 R95L mutation leads to hyperactivation of TLR7/8, but not TLR3/9, upon stimulation with specific agonists in vitro. Transgenic Unc93b1R95L/R95L mice develop inflammatory and autoimmune phenotypes, and the upregulation of inflammatory signaling differs among organs, with a specific contribution of malfunctioned T cells and B cells. In human and mouse cell lines, the UNC93B1 R95L mutation promotes TLR7/8 signaling by enhancing its binding to ssRNA, without affecting TLR7/8 translocation. Overall, our results elucidate the pathology of organs and the immunological profiles of immune cell populations in the development of SLE caused by the UNC93B1 R95L mutation through the TLR7/8 axis.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142262887","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 : 2024-09-12DOI: 10.1101/2024.09.12.24313504
Rex L Hung, Wilson W Ng, Peter K Chung, Ashley B S Li, Theodora H Y Luk, Rosanna Fong, Anna Lee, Raina Mok, Hebronson Yung, Vera Tse, Raven Cheng, Amandine Schneider, Rachel L Telford, Florian Dubois, Elsa Bourayou, Milieu Interieur, Rafael De Andrade Moral, Jean Marc Doisne, Milena Hasan, Gabriel M Leung, Michael Y Ni, Michael Tse, Malik Peiris, James Di Santo, Roberto Bruzzone, Vincent Rouilly, Darragh Duffy
Immune responses are highly variable from one individual to another, with this variability determined by factors such as age, sex, genetics and environment, which also affect physical and mental well-being. Systems immunology studies have been applied to human cohort studies to better understand these effects, but most are performed in Western populations of mostly European ancestry, neglecting the vast majority of human global diversity. To overcome this limitation, we established the Healthy Human Global Project Hong Kong (HHGP-HK) cohort to allow the study of immune variability in a healthy Asian population. Taking inspiration from the established French Milieu Interieur study we adapted inclusion and exclusion criteria to identify healthy donors, and to facilitate cross comparison between the two cohorts we collected similar demographic, medical and lifestyle information. To study the effects of age and sex, donors were stratified for both ranging from 20-79 years. We report here significant age and sex effects on multiple clinical laboratory measures, many of which were consistently observed in the Milieu Interieur cohort. C-reactive protein and liver enzymes were two exceptions perhaps reflecting different environmental effects between the two cohorts. We applied biological aging, physiological, and mental health scores to our cohort which highlights the need to develop and adapt such scores for application to populations of non-European descent. We also included wearable fitness trackers from which we observed significant age and sex differences for sleep, physical activity, and heart rate variability. This unique cohort will enable the better understanding of factors that determine immune variability within Asian populations.
不同个体的免疫反应差异很大，这种差异由年龄、性别、遗传和环境等因素决定，这些因素也会影响身心健康。系统免疫学研究已被应用于人类队列研究，以更好地了解这些影响，但大多数研究都是在以欧洲血统为主的西方人群中进行的，忽略了全球绝大多数人类的多样性。为了克服这一局限性，我们建立了香港健康人类全球项目（HHGP-HK）队列，以研究亚洲健康人群的免疫变异性。为了便于对两个队列进行交叉比较，我们收集了类似的人口、医疗和生活方式信息。为了研究年龄和性别的影响，我们对年龄在 20-79 岁之间的捐献者进行了分层。我们在此报告了年龄和性别对多项临床实验室指标的明显影响，其中许多指标在 Milieu Interieur 队列中也得到了一致观察。C 反应蛋白和肝酶是两个例外，这可能反映了两个队列之间不同的环境影响。我们在队列中应用了生物老化、生理和心理健康评分，这突出表明有必要开发和调整此类评分，以便应用于非欧洲后裔人群。我们还加入了可穿戴健身追踪器，从中观察到睡眠、体力活动和心率变异性方面存在显著的年龄和性别差异。这一独特的队列将有助于更好地了解决定亚洲人群免疫变异性的因素。
{"title":"The Healthy Human Global Project - Hong Kong : a community-based cross-sectional study of a healthy Asian population","authors":"Rex L Hung, Wilson W Ng, Peter K Chung, Ashley B S Li, Theodora H Y Luk, Rosanna Fong, Anna Lee, Raina Mok, Hebronson Yung, Vera Tse, Raven Cheng, Amandine Schneider, Rachel L Telford, Florian Dubois, Elsa Bourayou, Milieu Interieur, Rafael De Andrade Moral, Jean Marc Doisne, Milena Hasan, Gabriel M Leung, Michael Y Ni, Michael Tse, Malik Peiris, James Di Santo, Roberto Bruzzone, Vincent Rouilly, Darragh Duffy","doi":"10.1101/2024.09.12.24313504","DOIUrl":"https://doi.org/10.1101/2024.09.12.24313504","url":null,"abstract":"Immune responses are highly variable from one individual to another, with this variability determined by factors such as age, sex, genetics and environment, which also affect physical and mental well-being. Systems immunology studies have been applied to human cohort studies to better understand these effects, but most are performed in Western populations of mostly European ancestry, neglecting the vast majority of human global diversity. To overcome this limitation, we established the Healthy Human Global Project Hong Kong (HHGP-HK) cohort to allow the study of immune variability in a healthy Asian population. Taking inspiration from the established French Milieu Interieur study we adapted inclusion and exclusion criteria to identify healthy donors, and to facilitate cross comparison between the two cohorts we collected similar demographic, medical and lifestyle information. To study the effects of age and sex, donors were stratified for both ranging from 20-79 years. We report here significant age and sex effects on multiple clinical laboratory measures, many of which were consistently observed in the Milieu Interieur cohort. C-reactive protein and liver enzymes were two exceptions perhaps reflecting different environmental effects between the two cohorts. We applied biological aging, physiological, and mental health scores to our cohort which highlights the need to develop and adapt such scores for application to populations of non-European descent. We also included wearable fitness trackers from which we observed significant age and sex differences for sleep, physical activity, and heart rate variability. This unique cohort will enable the better understanding of factors that determine immune variability within Asian populations.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212224","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 : 2024-09-08DOI: 10.1101/2024.09.07.24313230
Ifrah Siddiqui, Nabeel Ahmad Khan, Fatima Ahmad, Maham Nawaz, Almas Naeem, Muhammad Usaid Khalid, Usman Haroon Mirza, Hamza Ali Danish, Syed Saqib Khalid
Objective: To investigate the roles of chemokines in activating the NF-κB signaling pathway in retinal pigment epithelium (RPE) and photoreceptor cells, and their contribution to the pathogenesis of age-related macular degeneration (AMD). Background: AMD is a leading cause of vision loss in older adults, driven by chronic inflammation and oxidative stress. The NF-κB transcription factor plays a key role in regulating these processes, with various chemokines, such as CCL2 and CX3CL1, influencing NF-κB activation. Despite advances in treatment, a deeper understanding of how chemokines affect NF-κB activation in RPE and photoreceptor cells remains critical for developing effective therapies. This study seeks to address this gap and improve AMD management. Methods: A comprehensive search of databases, including PubMed, MEDLINE, and Google Scholar, was conducted to identify relevant studies on the roles of chemokines in activating NF-κB signaling in RPE and photoreceptor cells. The search covered chemokines such as CCL2 (MCP-1), CX3CL1 (Fractalkine), CCL3 (MIP-1α), CCL5 (RANTES), CXCL8 (IL-8), CXCL10 (IP-10), CXCL1 (GRO-α), CXCL12 (SDF-1), CCL11 (Eotaxin), CXCL16, CXCL9 (MIG), and CXCL11 (I-TAC). Studies were systematically reviewed following PRISMA guidelines to assess the involvement of these chemokines in NF-κB activation. Results: The analysis revealed that chemokines, including CCL2, CX3CL1, CCL3, and CCL5, significantly activated NF-κB in RPE and photoreceptor cells, leading to increased inflammation and apoptosis through enhanced cytokine production and reactive oxygen species (ROS) generation. Additionally, CXCL8, CXCL10, CXCL1, and CXCL12 triggered NF-κB activation, contributing to oxidative stress and extracellular matrix (ECM) remodeling, which disrupts retinal structure and function. Other chemokines, such as CCL11, CXCL16, CXCL9, and CXCL11, sustained chronic inflammation and modulated matrix metalloproteinases (MMPs), further implicating them in AMD progression. Conclusion: Chemokines, including CCL2, CX3CL1, CCL3, CCL5, CXCL8, CXCL10, CXCL1, CXCL12, CCL11, CXCL16, CXCL9, and CXCL11, activate the NF-κB pathway in RPE and photoreceptor cells, driving chronic inflammation, oxidative stress, and ECM remodeling in AMD. These findings highlight potential therapeutic targets to mitigate disease progression.
{"title":"Investigating Chemokine-Induced NF-κB Activation in Retinal Cells and Its Contribution to Age-Related Macular Degeneration Pathogenesis: A Systematic Review","authors":"Ifrah Siddiqui, Nabeel Ahmad Khan, Fatima Ahmad, Maham Nawaz, Almas Naeem, Muhammad Usaid Khalid, Usman Haroon Mirza, Hamza Ali Danish, Syed Saqib Khalid","doi":"10.1101/2024.09.07.24313230","DOIUrl":"https://doi.org/10.1101/2024.09.07.24313230","url":null,"abstract":"Objective:\u0000To investigate the roles of chemokines in activating the NF-κB signaling pathway in retinal pigment epithelium (RPE) and photoreceptor cells, and their contribution to the pathogenesis of age-related macular degeneration (AMD).\u0000Background:\u0000AMD is a leading cause of vision loss in older adults, driven by chronic inflammation and oxidative stress. The NF-κB transcription factor plays a key role in regulating these processes, with various chemokines, such as CCL2 and CX3CL1, influencing NF-κB activation. Despite advances in treatment, a deeper understanding of how chemokines affect NF-κB activation in RPE and photoreceptor cells remains critical for developing effective therapies. This study seeks to address this gap and improve AMD management.\u0000Methods:\u0000A comprehensive search of databases, including PubMed, MEDLINE, and Google Scholar, was conducted to identify relevant studies on the roles of chemokines in activating NF-κB signaling in RPE and photoreceptor cells. The search covered chemokines such as CCL2 (MCP-1), CX3CL1 (Fractalkine), CCL3 (MIP-1α), CCL5 (RANTES), CXCL8 (IL-8), CXCL10 (IP-10), CXCL1 (GRO-α), CXCL12 (SDF-1), CCL11 (Eotaxin), CXCL16, CXCL9 (MIG), and CXCL11 (I-TAC). Studies were systematically reviewed following PRISMA guidelines to assess the involvement of these chemokines in NF-κB activation.\u0000Results:\u0000The analysis revealed that chemokines, including CCL2, CX3CL1, CCL3, and CCL5, significantly activated NF-κB in RPE and photoreceptor cells, leading to increased inflammation and apoptosis through enhanced cytokine production and reactive oxygen species (ROS) generation. Additionally, CXCL8, CXCL10, CXCL1, and CXCL12 triggered NF-κB activation, contributing to oxidative stress and extracellular matrix (ECM) remodeling, which disrupts retinal structure and function. Other chemokines, such as CCL11, CXCL16, CXCL9, and CXCL11, sustained chronic inflammation and modulated matrix metalloproteinases (MMPs), further implicating them in AMD progression.\u0000Conclusion:\u0000Chemokines, including CCL2, CX3CL1, CCL3, CCL5, CXCL8, CXCL10, CXCL1, CXCL12, CCL11, CXCL16, CXCL9, and CXCL11, activate the NF-κB pathway in RPE and photoreceptor cells, driving chronic inflammation, oxidative stress, and ECM remodeling in AMD. These findings highlight potential therapeutic targets to mitigate disease progression.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212233","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 : 2024-09-06DOI: 10.1101/2024.09.06.24313180
Moustafa Sherif, Aya Darwish, Balazs Adam
Background Pesticides, commonly employed in both agricultural and domestic environments, have been associated with disturbing the balance of the immune system during prenatal and early childhood phases of development. This disturbance has the potential to result in various outcomes such as autoimmunity, immunosuppression, inflammation, hypersensitivity, tissue damage, and overall alterations in immune modulation. The escalating concern regarding the immunotoxic effects of pesticides necessitates a systematic review and potential meta-analysis to consolidate empirical evidence and address the knowledge gaps. This systematic review aims to comprehensively assess the immunotoxic impact of pesticide exposure on children, considering alterations in immune system function induced by specific types of pesticides. Methods Through a meticulous search of the literature and synthesis of findings, the review will scrutinize prevalence, effect size, mechanisms, vulnerable periods, and the role of pre-existing conditions. The submitted protocol to PROSPERO aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, ensuring methodological rigor. A preliminary exploration involved a systematic search in electronic databases based on a pre-defined Population, Exposure, Comparator, and Outcome (PECO) statement. Data extraction sheets and risk of bias assessment tools were piloted on eight eligible articles to ensure reliability and efficiency. Subsequently, a rerun of the search will be executed, and two independent reviewers will employ the systematic review tool Covidence for article screening and data extraction, and Excel for risk of bias assessment. The results will be synthetized narratively in summary tables, and, if findings allow, meta-analysis including subgroup and sensitivity analysis will be conducted. Discussion By elucidating the intricate relationship between pesticide exposure and immunotoxicity during prenatal and early childhood, this review will provide insights into immune response that can contribute to public health awareness and guide interventions. PROSPERO Registration number: [CRD42024510916].
{"title":"Immunotoxic Effects in Children Resulting from Prenatal and Early Childhood Exposure to Pesticides: Protocol of a Systematic Review and Meta-Analysis","authors":"Moustafa Sherif, Aya Darwish, Balazs Adam","doi":"10.1101/2024.09.06.24313180","DOIUrl":"https://doi.org/10.1101/2024.09.06.24313180","url":null,"abstract":"Background Pesticides, commonly employed in both agricultural and domestic environments, have been associated with disturbing the balance of the immune system during prenatal and early childhood phases of development. This disturbance has the potential to result in various outcomes such as autoimmunity, immunosuppression, inflammation, hypersensitivity, tissue damage, and overall alterations in immune modulation. The escalating concern regarding the immunotoxic effects of pesticides necessitates a systematic review and potential meta-analysis to consolidate empirical evidence and address the knowledge gaps. This systematic review aims to comprehensively assess the immunotoxic impact of pesticide exposure on children, considering alterations in immune system function induced by specific types of pesticides. Methods Through a meticulous search of the literature and synthesis of findings, the review will scrutinize prevalence, effect size, mechanisms, vulnerable periods, and the role of pre-existing conditions. The submitted protocol to PROSPERO aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, ensuring methodological rigor. A preliminary exploration involved a systematic search in electronic databases based on a pre-defined Population, Exposure, Comparator, and Outcome (PECO) statement. Data extraction sheets and risk of bias assessment tools were piloted on eight eligible articles to ensure reliability and efficiency. Subsequently, a rerun of the search will be executed, and two independent reviewers will employ the systematic review tool Covidence for article screening and data extraction, and Excel for risk of bias assessment. The results will be synthetized narratively in summary tables, and, if findings allow, meta-analysis including subgroup and sensitivity analysis will be conducted. Discussion By elucidating the intricate relationship between pesticide exposure and immunotoxicity during prenatal and early childhood, this review will provide insights into immune response that can contribute to public health awareness and guide interventions.\u0000PROSPERO Registration number: [CRD42024510916].","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212227","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 : 2024-09-04DOI: 10.1101/2024.09.04.24312986
M Rosenzwajg, A Gherasim, F Dietsch, M. Beck, N Domis, R Lorenzon, Yannick Chantran, B Bellier, E Vicaut, A Soria, F De Blay, D Klatzmann
Background Regulatory T cells (Tregs) are pivotal in immune tolerance to allergens. Low-dose IL-2 (IL-2LD) expands and activates Tregs. We assessed IL-2LD efficacy for controlling clinical responses to allergen exposures.
背景调节性 T 细胞（Tregs）在对过敏原的免疫耐受中起着关键作用。低剂量 IL-2（IL-2LD）可扩增和激活 Tregs。我们评估了 IL-2LD 对控制过敏原暴露临床反应的功效。
{"title":"Low-dose interleukin-2 in birch pollen allergy: a phase-2 randomized double-blind placebo-controlled trial","authors":"M Rosenzwajg, A Gherasim, F Dietsch, M. Beck, N Domis, R Lorenzon, Yannick Chantran, B Bellier, E Vicaut, A Soria, F De Blay, D Klatzmann","doi":"10.1101/2024.09.04.24312986","DOIUrl":"https://doi.org/10.1101/2024.09.04.24312986","url":null,"abstract":"<strong>Background</strong> Regulatory T cells (Tregs) are pivotal in immune tolerance to allergens. Low-dose IL-2 (IL-2<sub>LD</sub>) expands and activates Tregs. We assessed IL-2<sub>LD</sub> efficacy for controlling clinical responses to allergen exposures.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"264 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212228","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 : 2024-08-26DOI: 10.1101/2024.08.25.24312379
Joanne Topping, Samuel Lara-Reyna, Alice I Ibbotson, Heledd Jarosz-Griffiths, Leon Chang, James A Poulter, Daniel G Peckham, Michael F Mcdermott, Sinisa Savic, ImmunAID Consortium
The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear. This study aimed to develop a method to detect ASC aggregates originating from NLRP3 inflammasomes. Initially, human monocytes, macrophages, and THP-1 ASC reporter cells were employed to validate the detection of ASC/NLRP3-positive events through flow cytometry. The presence of ASC/NLRP3 specks was confirmed in cell supernatants from monocytes and macrophages treated with LPS and nigericin or ATP. Flow cytometry analysis identified double-positive specks in patient sera from inflammatory conditions when compared to healthy controls. Elevated ASC/NLRP3 specks were observed in conditions such as CAPS and Schnitzler's syndrome. We validated FACS as a reliable method for detecting ASC/NLRP3 specks in human sera, with potential diagnostic and monitoring applications in certain systemic autoinflammatory diseases.
{"title":"FACS-based detection of extracellular ASC specks from NLRP3 inflammasomes in inflammatory diseases","authors":"Joanne Topping, Samuel Lara-Reyna, Alice I Ibbotson, Heledd Jarosz-Griffiths, Leon Chang, James A Poulter, Daniel G Peckham, Michael F Mcdermott, Sinisa Savic, ImmunAID Consortium","doi":"10.1101/2024.08.25.24312379","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312379","url":null,"abstract":"The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear. This study aimed to develop a method to detect ASC aggregates originating from NLRP3 inflammasomes. Initially, human monocytes, macrophages, and THP-1 ASC reporter cells were employed to validate the detection of ASC/NLRP3-positive events through flow cytometry. The presence of ASC/NLRP3 specks was confirmed in cell supernatants from monocytes and macrophages treated with LPS and nigericin or ATP. Flow cytometry analysis identified double-positive specks in patient sera from inflammatory conditions when compared to healthy controls. Elevated ASC/NLRP3 specks were observed in conditions such as CAPS and Schnitzler's syndrome. We validated FACS as a reliable method for detecting ASC/NLRP3 specks in human sera, with potential diagnostic and monitoring applications in certain systemic autoinflammatory diseases.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212169","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 : 2024-08-20DOI: 10.1101/2024.08.14.24311337
Elien Beyls, Evi Duthoo, Lynn Backers, Karlien Claes, RAPID clinicians, Marieke De Bruyne, Lore Pottie, Victoria Bordon, Carolien Bonroy, Simon J Tavernier, Kathleen BM Claes, Anne Vral, Ans Baeyens, Filomeen Haerynck
Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.
{"title":"Investigating chromosomal radiosensitivity in inborn errors of immunity: insights from DNA repair disorders and beyond.","authors":"Elien Beyls, Evi Duthoo, Lynn Backers, Karlien Claes, RAPID clinicians, Marieke De Bruyne, Lore Pottie, Victoria Bordon, Carolien Bonroy, Simon J Tavernier, Kathleen BM Claes, Anne Vral, Ans Baeyens, Filomeen Haerynck","doi":"10.1101/2024.08.14.24311337","DOIUrl":"https://doi.org/10.1101/2024.08.14.24311337","url":null,"abstract":"Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212234","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 : 2024-08-07DOI: 10.1101/2024.08.07.24311531
Jaewoo Park, Jung Yeon Jang, Jeong Heon Kim, Se Eun Yi, Yeong Ju Lee, Myeong Sang Yu, Yoo-Sam Chung, Yong Ju Jang, Ji Heui Kim, Kyuho Kang
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease characterized by multiple inflammatory endotypes. Although recent progress has been made in endotype-based classification, developing tailored therapeutic strategies for CRSwNP remains challenging. This study aimed to optimize therapeutic outcomes in CRSwNP by identifying potential molecular markers. Methods: We utilized an integrated approach that combined bulk and single-cell RNA sequencing (scRNA-seq) to delineate the molecular signatures inherent to the cellular components of nasal polyp (NP) tissue. The levels of C11-BODIPY (as a marker of lipid peroxidation) and SLC27A2/FATP2 were assessed using quantitative PCR and immunofluorescence (IF) staining. The effects of lipofermata, a FATP2 inhibitor, were examined in air-liquid interface (ALI) cultured epithelial cells derived from CRSwNP patients and healthy controls. Results: Deconvolution analysis of NP tissue revealed an upregulation of genes associated with lipid metabolism in the NP epithelium. In CRSwNP patients, we observed a significant increase in lipid peroxidation and SLC27A2/FATP2 expression in the NP epithelium. A marked expression of genes critical to metabolic pathways involved in lipid peroxidation was identified in SLC27A2-positive epithelial cells. Additionally, FATP2 and lipid peroxidation staining patterns exhibited a positive correlation in their respective % Area levels. Elevated SLC27A2 expression was associated with disease pathogenesis and correlated with disease severity. Treatment with lipofermata resulted in decreased mRNA levels of ALOX15, a key mediator of inflammation and lipid peroxidation, and FOXJ1, a marker of abnormal ciliogenesis. Conclusion: Elevated SLC27A2 expression in the NP epithelium correlates with the severity of CRSwNP, highlighting its potential as a therapeutic target for managing advanced CRSwNP cases.
{"title":"SLC27A2 as a molecular marker of impaired epithelium in chronic rhinosinusitis with nasal polyps","authors":"Jaewoo Park, Jung Yeon Jang, Jeong Heon Kim, Se Eun Yi, Yeong Ju Lee, Myeong Sang Yu, Yoo-Sam Chung, Yong Ju Jang, Ji Heui Kim, Kyuho Kang","doi":"10.1101/2024.08.07.24311531","DOIUrl":"https://doi.org/10.1101/2024.08.07.24311531","url":null,"abstract":"<strong>Background:</strong> Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease characterized by multiple inflammatory endotypes. Although recent progress has been made in endotype-based classification, developing tailored therapeutic strategies for CRSwNP remains challenging. This study aimed to optimize therapeutic outcomes in CRSwNP by identifying potential molecular markers. <strong>Methods:</strong> We utilized an integrated approach that combined bulk and single-cell RNA sequencing (scRNA-seq) to delineate the molecular signatures inherent to the cellular components of nasal polyp (NP) tissue. The levels of C11-BODIPY (as a marker of lipid peroxidation) and <em>SLC27A2</em>/FATP2 were assessed using quantitative PCR and immunofluorescence (IF) staining. The effects of lipofermata, a FATP2 inhibitor, were examined in air-liquid interface (ALI) cultured epithelial cells derived from CRSwNP patients and healthy controls. <strong>Results:</strong> Deconvolution analysis of NP tissue revealed an upregulation of genes associated with lipid metabolism in the NP epithelium. In CRSwNP patients, we observed a significant increase in lipid peroxidation and <em>SLC27A2</em>/FATP2 expression in the NP epithelium. A marked expression of genes critical to metabolic pathways involved in lipid peroxidation was identified in <em>SLC27A2</em>-positive epithelial cells. Additionally, FATP2 and lipid peroxidation staining patterns exhibited a positive correlation in their respective % Area levels. Elevated <em>SLC27A2</em> expression was associated with disease pathogenesis and correlated with disease severity. Treatment with lipofermata resulted in decreased mRNA levels of <em>ALOX15</em>, a key mediator of inflammation and lipid peroxidation, and <em>FOXJ1</em>, a marker of abnormal ciliogenesis. <strong>Conclusion:</strong> Elevated <em>SLC27A2</em> expression in the NP epithelium correlates with the severity of CRSwNP, highlighting its potential as a therapeutic target for managing advanced CRSwNP cases.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934915","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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