A Circulating Antibody Enables Prediction of Crohn’s Disease Long Before Symptoms Appear

The appearance of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in the blood predict the development of complicated Crohn’s disease long before the diagnosis of the disorder.

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, and weight loss. While the precise causes of CD are unknown, it is believed to be caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals. CD causes a chronic inflammatory disorder, in which the body's immune system defends the gastrointestinal tract, possibly targeting microbial antigens. Although Crohn's is an immune-related disease, it does not appear to be an autoimmune disease.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a monomeric glycoprotein secreted by macrophages, T-cells, mast cells, natural killer cells, endothelial cells, and fibroblasts that functions as a cytokine. Autoantibodies to multiple cytokines have been identified and some, including antibodies against GM-CSF (aGMAb), have been associated with increased susceptibility to infection.

Investigators at the University of Toronto (Canada) and their colleagues studied the underlying mechanisms associated with induction of aGMAbs and evaluated the use of these antibodies as a predictive biomarker for CD. For this study, they worked with 220 blood samples from the U.S. Department of Defense Serum Repository, which had been collected annually over a 10-year period from military personnel who developed CD and compared them to samples from patients with ulcerative colitis and 400 healthy controls.

The investigators used an ELISA procedure to characterize naturally occurring aGMab in longitudinal serum samples from patients archived before the diagnosis of CD as well as from the healthy individuals. In addition, they employed biochemical, cellular, and transcriptional analysis to uncover a mechanism that governed the impaired immune balance in CD mucosa after diagnosis.

Neutralizing aGMAbs, which were found in about a quarter of the CD patients, were found to be specific for posttranslational glycosylation on GM-CSF, detectable years prior to diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in CD patients, and aGMAb affected myeloid homeostasis and promoted innate lymphoid cells.

"Our team identified a serological biomarker for Crohn's disease that also participates in its pathogenesis and occurs years before the disease shows its full clinical spectrum," said first author Dr. Arthur Mortha, assistant professor of immunology at the University of Toronto. "The current arsenal of therapeutics that causes relieving remission in Crohn's patients is good but suffers limitations. A biomarker or predictive indicators to guide interventions are a clinical need. In addition, our characterization of this biomarker suggests it is a suitable therapeutic target for intervention and maybe even prevention."

The study was published in the May 25, 2022, online edition of the journal Gastroenterology.

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