Poster Session II – Poster of Distinction II - A207 EXPANSION OF PERIPHERAL RORγT+ POLYMORPHONUCLEAR MYELOID-DERIVED SUPPRESSOR CELLS (PMN-MDSCS) SIGNALS EARLY IMMUNE DYSREGULATION LINKED TO CROHN’S DISEASE RISK

TL;DR

This study identifies early immune changes, including the expansion of RORγt+ PMN-MDSCs, that signal future Crohn’s disease risk years before symptoms appear.

Contribution

The study reveals a novel immune signature, specifically the early expansion of RORγt+ PMN-MDSCs, as a potential marker for Crohn’s disease risk.

Findings

Early expansion of RORγt+ PMN-MDSCs and CCR9+ dendritic cells occurs more than 2.5 years before Crohn’s disease onset.

RORγt+ PMN-MDSCs correlate with elevated antimicrobial antibodies and show high potential for CD risk stratification (AUC=0.821).

Proteomic analysis shows a shift from regulatory to proinflammatory phenotypes as Crohn’s disease approaches onset.

Abstract

Crohn’s disease (CD) is a chronic inflammatory bowel disease thought to be driven, in part, by an exaggerated immune response to intestinal microbes. While impaired epithelial barrier function, and anti-microbial antibodies can be detected years before CD onset; the immunological changes preceding CD onset remains unexplored

To identify immune signatures associated with CD risk by phenotyping the peripheral immune landscape during the preclinical phase of CD

In a nested case-control cohort of the CCC-GEM Project, which prospectively follows healthy first-degree relatives (FDRs) of CD patients, 80 FDRs who developed CD (pre-CD) were matched by age, sex, follow-up duration, and location with FDRs who remained healthy (HMC, n = 310). PBMCs collected at recruitment were analyzed by single-cell mass cytometry using 40 phenotypic and functional markers. Immune subsets were identified by automated unbiased clustering, and their associations with future CD, faecal calprotectin (FCP), serum proteomics (Olink®), and antimicrobial antibodies (Prometheus®) were assessed using conditional logistic regression, generalized estimating equations, or partial Spearman correlation as appropriate. ROC analyses evaluated performance of immune subsets to stratify future CD cases from controls

A distinct peripheral immune landscape, characterized by increased myeloid and reduced lymphoid subsets, was associated with FCP and future CD (p = 0.00003-0.05). Subgroup analysis based on median follow-up time to diagnosis revealed temporal immune alterations during the preclinical phase, with early expansion of RORγt+ PMN-MDSCs and CCR9+ dendritic cells occurring more than 2.5 years prior to CD onset, preceding the peripheral loss of α4β7+ activated naïve-like T and B cells observed within 2.5 years before diagnosis. Early expansion of these myeloid subsets correlated with elevated serum ASCA- or ompc-IgA levels. Although RORγt+ PMN-MDSCs remained elevated until CD onset, proteomic analysis revealed a shift from regulatory to proinflammatory phenotypes approaching CD onset. Finally, ROC analysis identified RORγt+ PMN-MDSCs as having the highest potential for CD risk stratification (AUC=0.821).

This study delineates the immune cell alterations associated with future CD and identifies RORγt+ PMN-MDSCs as a potential early immune marker for CD risk stratification and target for preventive intervention.

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