@article{8a3ab227426541d2a95a524e74f37306,
title = "Neutralizing anti-granulocyte macrophage-colony stimulating factor autoantibodies recognize post-translational glycosylations on granulocyte macrophage-colony stimulating factor years before diagnosis and predict complicated Crohn's disease",
abstract = "Background & Aims: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD. Methods: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis. Results: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa. Conclusions: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis.",
keywords = "Autoantibodies, Crohn's disease, GM-CSF, Innate lymphoid cells, Macrophages",
author = "Arthur Mortha and Romain Remark and {Del Valle}, {Diane Marie} and Chuang, {Ling Shiang} and Zhi Chai and In{\^e}s Alves and Catarina Azevedo and Joana Gaifem and Jerome Martin and Francesca Petralia and Kevin Tuballes and Vanessa Barcessat and Tai, {Siu Ling} and Huang, {Hsin Hui} and Ilaria Laface and Jerez, {Yeray Arteaga} and Gilles Boschetti and Nicole Villaverde and Wang, {Mona D.} and Korie, {Ujunwa M.} and Joseph Murray and Choung, {Rok Seon} and Takahiro Sato and Laird, {Renee M.} and Scott Plevy and Adeeb Rahman and Joana Torres and Chad Porter and Riddle, {Mark S.} and Ephraim Kenigsberg and Pinho, {Salom{\'e} S.} and Cho, {Judy H.} and Miriam Merad and Colombel, {Jean Frederic} and Sacha Gnjatic",
note = "Funding Information: Funding A.M. is supported by a Canadian Institute for Health Research (CIHR) Project Grant (388337), a CIHR Team Grant (8833615), a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (RGPIN-2019-04521), and the Helmsley Foundation and is the Tier 2 Canadian Research Chair in Mucosal Immunology through the Tier 2 Canadian Research Chair (CRC)-CIHR program. S.S.P. acknowledges Portuguese funds through the Portuguese Foundation for Science and Technology ( FCT ) in the framework of the project POCI-01-0145-FEDER-028772 and support by the Broad Medical Research Program at the Crohn{\textquoteright}s and Colitis Foundation of America, the International Organization for the study of Inflammatory Bowel Disease, and the Portuguese Group of Study in IBD (GEDII) for funding. S.S.P. also acknowledges the US Department of Defense , US Army Medical Research Acquisition Activity, FY18 Peer Reviewed Medical Research Program Investigator-Initiated Research Award (award number W81XWH1920053). I.A., C.M.A., and J.G. thank FCT for funding (SFRH/BD/128874/2017, 2021.07357.BD and 2020.00088.CEECIND). S.L.T. acknowledges funding through the Dr. Edward KETCHUM Graduate Student Scholarships at the University of Toronto and the Canada Graduate Scholarships – Master's (CGS-M) award. M.W. is supported by a Undergraduate Research Opportunity Program (UROP) fellowship by the Department of Immunology at the University of Toronto . J.H.C. acknowledges funding from U01 DK062429, U01 DK062422, R01 DK106593, and the Sanford Grossman Charitable Trust. J.F.C and F.P. are supported by the Kenneth Rainin Foundation (grant number 20210021). S.G. and J.F.C. are supported through U01 DK124165 and the Helmsley Foundation. S.G. is additionally supported by grants U24 CA224319 and CA196521. Funding and support of the PREDICTS (PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects) study platform was provided through a Cooperative and Research Development Agreement with direct contributions by Janssen Pharmaceuticals , Prometheus Laboratories, and the Naval Medical Research Center (Naval Cooperative Research And Development Agreement [NCRADA] number NMR-11-3920). The mass cytometry instrumentation at the Human Immune Monitoring Center was obtained with support from S10 OD023547 and P01 CA196521. Funding Information: Conflicts of interest The University of Toronto and the Mount Sinai Hospital have collectively filed a patent application listing S.G., A.M., J.F.C., M.M., and R.R. as inventors, which is related in part to this publication. S.G. reports past consultancy and/or advisory roles for Merck and OncoMed and research funding from Bristol-Myers Squibb, Genentech, Janssen R&D, Pfizer, Takeda, Boehringer-Ingelheim, and Regeneron. J.F.C. reports receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc., Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers-Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, Vifor; and holding stock options in Intestinal Biotech Development. C.K.P. is an employee of the US Government. This work was prepared as part of his official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. This is a US Government work. There are no restrictions on its use.Funding A.M. is supported by a Canadian Institute for Health Research (CIHR) Project Grant (388337), a CIHR Team Grant (8833615), a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (RGPIN-2019-04521), and the Helmsley Foundation and is the Tier 2 Canadian Research Chair in Mucosal Immunology through the Tier 2 Canadian Research Chair (CRC)-CIHR program. S.S.P. acknowledges Portuguese funds through the Portuguese Foundation for Science and Technology (FCT) in the framework of the project POCI-01-0145-FEDER-028772 and support by the Broad Medical Research Program at the Crohn's and Colitis Foundation of America, the International Organization for the study of Inflammatory Bowel Disease, and the Portuguese Group of Study in IBD (GEDII) for funding. S.S.P. also acknowledges the US Department of Defense, US Army Medical Research Acquisition Activity, FY18 Peer Reviewed Medical Research Program Investigator-Initiated Research Award (award number W81XWH1920053). I.A., C.M.A., and J.G. thank FCT for funding (SFRH/BD/128874/2017, 2021.07357.BD and 2020.00088.CEECIND). S.L.T. acknowledges funding through the Dr. Edward KETCHUM Graduate Student Scholarships at the University of Toronto and the Canada Graduate Scholarships – Master's (CGS-M) award. M.W. is supported by a Undergraduate Research Opportunity Program (UROP) fellowship by the Department of Immunology at the University of Toronto. J.H.C. acknowledges funding from U01 DK062429, U01 DK062422, R01 DK106593, and the Sanford Grossman Charitable Trust. J.F.C and F.P. are supported by the Kenneth Rainin Foundation (grant number 20210021). S.G. and J.F.C. are supported through U01 DK124165 and the Helmsley Foundation. S.G. is additionally supported by grants U24 CA224319 and CA196521. Funding and support of the PREDICTS (PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects) study platform was provided through a Cooperative and Research Development Agreement with direct contributions by Janssen Pharmaceuticals, Prometheus Laboratories, and the Naval Medical Research Center (Naval Cooperative Research And Development Agreement [NCRADA] number NMR-11-3920). The mass cytometry instrumentation at the Human Immune Monitoring Center was obtained with support from S10 OD023547 and P01 CA196521. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = sep,
doi = "10.1053/j.gastro.2022.05.029",
language = "English",
volume = "163",
pages = "659--670",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Elsevier",
number = "3",
}