Francesco Saettini, Fabiola Guerra, Mario Mauri, Claire G Salter, Margaret P Adam, David Adams, Emma L Baple, Estibaliz Barredo, Sanil Bhatia, Arndt Borkhardt, Alfredo Brusco, Cristina Bugarin, Clizia Chinello, Andrew H Crosby, Precilla D'Souza, Vanna Denti, Grazia Fazio, Silvia Giuliani, Hye Sun Kuehn, Hassan Amel, Asha Elmi, Bernice Lo, Federica Malighetti, Giorgia Mandrile, Andrea Martín-Nalda, Heather C Mefford, Daniele Moratto, Fatemeh Emam Mousavi, Zoe Nelson, Luis González Gutiérrez-Solana, Ellen Macnamara, Vincent Michaud, Melanie O'Leary, Lisa Pagani, Lisa Pavinato, Patricia VVelez Santamaria, Laura Planas-Serra, Manuel Quadri, Miquel Raspall-Chaure, Stefano Rebellato, Sergio D Rosenzweig, Agathe Roubertie, Dirk Holzinger, Christin Deal, Catherine Walsh Vockley, Angela Maria Savino, Jennifer L Stoddard, Holm H Uhlig, Aurora Pujol, Fulvio Magni, Giuseppe Paglia, Gianni Cazzaniga, Rocco Piazza, Matteo Barberis, Andrea Biondi
{"title":"双叶 PI4KA 基因突变会破坏 B 细胞代谢,导致 B 细胞淋巴细胞减少症和低丙种球蛋白血症。","authors":"Francesco Saettini, Fabiola Guerra, Mario Mauri, Claire G Salter, Margaret P Adam, David Adams, Emma L Baple, Estibaliz Barredo, Sanil Bhatia, Arndt Borkhardt, Alfredo Brusco, Cristina Bugarin, Clizia Chinello, Andrew H Crosby, Precilla D'Souza, Vanna Denti, Grazia Fazio, Silvia Giuliani, Hye Sun Kuehn, Hassan Amel, Asha Elmi, Bernice Lo, Federica Malighetti, Giorgia Mandrile, Andrea Martín-Nalda, Heather C Mefford, Daniele Moratto, Fatemeh Emam Mousavi, Zoe Nelson, Luis González Gutiérrez-Solana, Ellen Macnamara, Vincent Michaud, Melanie O'Leary, Lisa Pagani, Lisa Pavinato, Patricia VVelez Santamaria, Laura Planas-Serra, Manuel Quadri, Miquel Raspall-Chaure, Stefano Rebellato, Sergio D Rosenzweig, Agathe Roubertie, Dirk Holzinger, Christin Deal, Catherine Walsh Vockley, Angela Maria Savino, Jennifer L Stoddard, Holm H Uhlig, Aurora Pujol, Fulvio Magni, Giuseppe Paglia, Gianni Cazzaniga, Rocco Piazza, Matteo Barberis, Andrea Biondi","doi":"10.1007/s10875-024-01793-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells.</p><p><strong>Methods: </strong>Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells.</p><p><strong>Results: </strong>Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization.</p><p><strong>Conclusion: </strong>By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"15"},"PeriodicalIF":7.2000,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.\",\"authors\":\"Francesco Saettini, Fabiola Guerra, Mario Mauri, Claire G Salter, Margaret P Adam, David Adams, Emma L Baple, Estibaliz Barredo, Sanil Bhatia, Arndt Borkhardt, Alfredo Brusco, Cristina Bugarin, Clizia Chinello, Andrew H Crosby, Precilla D'Souza, Vanna Denti, Grazia Fazio, Silvia Giuliani, Hye Sun Kuehn, Hassan Amel, Asha Elmi, Bernice Lo, Federica Malighetti, Giorgia Mandrile, Andrea Martín-Nalda, Heather C Mefford, Daniele Moratto, Fatemeh Emam Mousavi, Zoe Nelson, Luis González Gutiérrez-Solana, Ellen Macnamara, Vincent Michaud, Melanie O'Leary, Lisa Pagani, Lisa Pavinato, Patricia VVelez Santamaria, Laura Planas-Serra, Manuel Quadri, Miquel Raspall-Chaure, Stefano Rebellato, Sergio D Rosenzweig, Agathe Roubertie, Dirk Holzinger, Christin Deal, Catherine Walsh Vockley, Angela Maria Savino, Jennifer L Stoddard, Holm H Uhlig, Aurora Pujol, Fulvio Magni, Giuseppe Paglia, Gianni Cazzaniga, Rocco Piazza, Matteo Barberis, Andrea Biondi\",\"doi\":\"10.1007/s10875-024-01793-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells.</p><p><strong>Methods: </strong>Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells.</p><p><strong>Results: </strong>Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization.</p><p><strong>Conclusion: </strong>By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.</p>\",\"PeriodicalId\":15531,\"journal\":{\"name\":\"Journal of Clinical Immunology\",\"volume\":\"45 1\",\"pages\":\"15\"},\"PeriodicalIF\":7.2000,\"publicationDate\":\"2024-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10875-024-01793-8\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10875-024-01793-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的:PI4KA 相关疾病是一种临床表现多变的疾病,以神经系统(肢体痉挛、发育迟缓、智力障碍、癫痫发作、共济失调、眼球震颤)和胃肠道(炎症性肠病和多发性肠闭锁)表现为特征。虽然有报道称一部分患者具有与免疫缺陷相一致的特征(自身免疫/自身炎症和反复感染),但对 B 细胞缺乏和低丙种球蛋白血症的负担尚未进行广泛研究。我们试图描述 PI4KA 相关疾病患者的临床表现和表现,并研究 B 细胞中双拷贝 PI4KA 变异的代谢后果:方法:获取了PI4KA变异体患者的临床数据。在 EBV 转化的 B 细胞中结合转录组、蛋白质组、脂质组和代谢组分析以及功能测定进行多组学分析:收集了 13 名患者的临床和实验室数据。结果:共收集了 13 名患者的临床和实验室数据,他们经常出现反复感染(7/13)、自身免疫/自身炎症表现(5/13)、B 细胞缺乏(8/13)和低丙种球蛋白血症(8/13)。患者的 B 细胞经常出现过渡性 B 细胞亚群增多、转换记忆性 B 细胞亚群减少的现象。基于差异表达转录本和蛋白质的通路分析证实,PI4KA 在 B 细胞分化中起着核心作用,并改变了 B 细胞受体(BCR)复合物和信号传导。通过改变脂质的产生和三羧酸循环调节,并导致内质网应激增加,双侧PI4KA突变破坏了B细胞的新陈代谢,诱发线粒体功能障碍。因此,B细胞表现出PI3K/mTOR通路亢进、自噬增加和细胞骨架组织失调:结论:通过改变脂质代谢和 TCA 循环、损害线粒体活性、过度激活 mTOR 通路和增加自噬,PI4KA 相关疾病会导致出现 B 细胞缺乏和低丙种球蛋白血症的先天性免疫综合症。
Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.
Purpose: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells.
Methods: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells.
Results: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization.
Conclusion: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.
期刊介绍:
The Journal of Clinical Immunology publishes impactful papers in the realm of human immunology, delving into the diagnosis, pathogenesis, prognosis, or treatment of human diseases. The journal places particular emphasis on primary immunodeficiencies and related diseases, encompassing inborn errors of immunity in a broad sense, their underlying genotypes, and diverse phenotypes. These phenotypes include infection, malignancy, allergy, auto-inflammation, and autoimmunity. We welcome a broad spectrum of studies in this domain, spanning genetic discovery, clinical description, immunologic assessment, diagnostic approaches, prognosis evaluation, and treatment interventions. Case reports are considered if they are genuinely original and accompanied by a concise review of the relevant medical literature, illustrating how the novel case study advances the field. The instructions to authors provide detailed guidance on the four categories of papers accepted by the journal.