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.
Arthur Mortha, Romain Remark, Diane Marie Del Valle, Ling-Shiang Chuang, Zhi Chai, Inês Alves, Catarina Azevedo, Joana Gaifem, Jerome Martin, Francesca Petralia, Kevin Tuballes, Vanessa Barcessat, Siu Ling Tai, Hsin-Hui Huang, Ilaria Laface, Yeray Arteaga Jerez, Gilles Boschetti, Nicole Villaverde, Mona D Wang, Ujunwa M Korie, Joseph Murray, Rok-Seon Choung, Takahiro Sato, Renee M Laird, Scott Plevy, Adeeb Rahman, Joana Torres, Chad Porter, Mark S Riddle, Ephraim Kenigsberg, Salomé S Pinho, Judy H Cho, Miriam Merad, Jean-Frederic Colombel, Sacha Gnjatic
Published in May 2022, Gastroenterology
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.