Joana Gaifem, Cláudia S. Rodrigues, Francesca Petralia, Inês Alves, Eduarda Leite-Gomes, Bruno Cavadas, Ana M. Dias, Catarina Moreira-Barbosa, Joana Revés, Renee M. Laird, Mislav Novokmet, Jerko Štambuk, Siniša Habazin, Berk Turhan, Zeynep H. Gümüş, Ryan Ungaro, Joana Torres, Gordan Lauc, Jean-Frederic Colombel, Chad K. Porter, Salomé S. Pinho
{"title":"独特的血清 IgG 糖基化特征可预测克罗恩病的发展,并与甘露糖致病抗体有关","authors":"Joana Gaifem, Cláudia S. Rodrigues, Francesca Petralia, Inês Alves, Eduarda Leite-Gomes, Bruno Cavadas, Ana M. Dias, Catarina Moreira-Barbosa, Joana Revés, Renee M. Laird, Mislav Novokmet, Jerko Štambuk, Siniša Habazin, Berk Turhan, Zeynep H. Gümüş, Ryan Ungaro, Joana Torres, Gordan Lauc, Jean-Frederic Colombel, Chad K. Porter, Salomé S. Pinho","doi":"10.1038/s41590-024-01916-8","DOIUrl":null,"url":null,"abstract":"Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention. Here the authors show that there are alterations in the glycome profile of serum IgG Fc regions that precede the diagnosis of Crohn’s disease by many years and are associated with complications during disease. This altered glycome triggers innate immune cell activation at a preclinical phase, which is the basis for the transition from healthy tissue to intestinal inflammation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01916-8.pdf","citationCount":"0","resultStr":"{\"title\":\"A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan\",\"authors\":\"Joana Gaifem, Cláudia S. Rodrigues, Francesca Petralia, Inês Alves, Eduarda Leite-Gomes, Bruno Cavadas, Ana M. Dias, Catarina Moreira-Barbosa, Joana Revés, Renee M. Laird, Mislav Novokmet, Jerko Štambuk, Siniša Habazin, Berk Turhan, Zeynep H. Gümüş, Ryan Ungaro, Joana Torres, Gordan Lauc, Jean-Frederic Colombel, Chad K. Porter, Salomé S. Pinho\",\"doi\":\"10.1038/s41590-024-01916-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention. Here the authors show that there are alterations in the glycome profile of serum IgG Fc regions that precede the diagnosis of Crohn’s disease by many years and are associated with complications during disease. This altered glycome triggers innate immune cell activation at a preclinical phase, which is the basis for the transition from healthy tissue to intestinal inflammation.\",\"PeriodicalId\":19032,\"journal\":{\"name\":\"Nature Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41590-024-01916-8.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41590-024-01916-8\",\"RegionNum\":1,\"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":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-01916-8","RegionNum":1,"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
炎症性肠病(IBD)的特点是肠道慢性炎症。越来越多的证据表明,克罗恩病(CD)存在一个临床前阶段,其特点是症状出现前的免疫学变化,这种变化始于诊断前数年。深入了解这一临床前阶段将有助于疾病的预测和预防。对IBD诊断前6年的临床前血清样本(来自PREDICTS队列)进行分析,发现循环抗体(IgG)上有一个独特的糖基化特征,其特点是IgG片段可结晶(Fc)结构域的半乳糖化水平较低,直到疾病诊断前一直保持稳定。这种特异的 IgG2 Fc 聚糖特征与抗微生物抗体(特别是抗酿酒酵母(ASCA))水平的升高相关,从而确定了在血清中检测到的糖蛋白-ASCA 中枢,而这种糖蛋白-ASCA 中枢的出现要比 CD 的发生早数年。从机理上讲,我们证明了在临床前阶段检测到的这种 ASCA IgG 的琼脂糖基化糖型可通过 FcγR 依赖性机制激活和重编程先天性免疫细胞(如树突状细胞和自然杀伤细胞),触发 NF-κB 和 CARD9 信号转导并导致炎性体激活,从而激发促炎性免疫途径。研究证明,ASCA 的这种促炎作用依赖于甘露糖识别和 IgG Fc 结构域中的半乳糖基化水平。抗甘露糖)ASCA IgG 的致病特性在体内得到了验证。将甘露糖(ASCA)抗体采纳性转移给受体野生型小鼠会导致肠道炎症易感性增加,而受体FcγR缺陷小鼠的易感性可恢复。在这里,我们确定了 CD 发病前循环 IgG 中的糖基化特征,并指出特定的糖蛋白-ASCA 通路是 CD 诊断前多年炎症启动的核心参与者。这种致病性糖基枢纽可能是预测 CD 的一种有希望的新血清生物标记物,也是预防疾病的潜在靶点。
A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention. Here the authors show that there are alterations in the glycome profile of serum IgG Fc regions that precede the diagnosis of Crohn’s disease by many years and are associated with complications during disease. This altered glycome triggers innate immune cell activation at a preclinical phase, which is the basis for the transition from healthy tissue to intestinal inflammation.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.