Anti-GMAbs predict Crohn’s disease years before diagnosis

The presence of autoantibodies against the granulocyte macrophage-colony stimulating factor (aGMAb) appears to precede Crohn’s disease (CD) diagnosis by years, according to a recent study. AGMAbs could be used for the prediction of complicated CD.

“Here, we report the presence of aGMAb in the sera of patients with CD years before diagnosis and propose that these antibodies contribute to the pathophysiology of CD,” the researchers said.

Using enzyme-linked immunosorbent assays, the researchers quantified naturally occurring aGMAbs from serum samples of 220 patients with complicated CD. Longitudinal samples had been collected from these patients even before CD diagnosis. A parallel group of 400 non-CD controls (200 with ulcerative colitis [UC], 200 healthy) underwent the same analysis.

Whereas healthy and UC samples had detection rates of IgG aGMAbs ranging from 5 percent to 10 percent (and nearly no detectable IgA aGMAbs), serum drawn from CD patients had detection rates of 21 percent and 7 percent for the respective immunoglobulins. Of note, these autoantibodies were present as early as 6 years before CD diagnosis. [Gastroenterology 2022;163:659-670]

Moreover, mean IgG and IgA aGMBAb titres increased sharply in CD patients toward the time of their diagnoses. Of note, nearly all patients with detectable aGMABs 6 years before CD either maintained their titres or saw an increase in concentration until the time of their disease diagnoses.

The researchers found the presence of IgA aGMAbs 6 years before diagnosis to be a strong predictor of CD development, with a specificity estimate exceeding 97 percent. Sensitivity, in contrast, was low at 15 percent, but grew slightly to 21 percent as the time of diagnosis approached. The resulting area under the curve value was 0.6.

In turn, the presence of such early aGMAbs correlated with a more complicated CD course, increasing the risk of having penetrating and/or structuring disease or of needing surgery soon after diagnosis by nearly threefold. The researchers could also not find any baseline indicator of early aGMAB detection, with patient age, sex, race, or timing of sample collection showing no significant correlation.

“We demonstrated IgG2- and IgA-skewed aGMAb isotypes in patients with CD, suggesting an origin within the intestinal mucosa,” they said, adding that these autoantibodies “were associated with ileal disease location, were present up to 6 years before diagnosis in asymptomatic subjects developing CD, and predicted complications at disease presentation.”

A putative pathway

According to the researchers, IgA aGMAbs could specifically target granulocyte macrophage-colony stimulating factor (GM-CSF) molecules, thereby interfering with the GM-CSF receptor-associated signaling pathway.

In turn, this disrupted the interactions between innate lymphoid cells (ILC) and myeloid cells in the mucosa of CD patients, resulting in an altered gene expression profile in ILCs. For example, genes involved in retinol metabolism were preferentially turned off in the mucosa of CD patients when IgA aGMAbs were present.

Moreover, the researchers found that GM-CSFs harboured abnormal glycosylation patterns in CD patients, which could be a reflection of the altered expression patterns of the glycosyltransferase gene in ILCs and T cells.

“Together, these results support a novel mechanism of disease pathophysiology that may be exploited for developing personalized CD-preventive and therapeutic strategies,” the researchers said.