P0118Plasma proteomic signatures relate to disease course and intestinal immune responses, uncovering immunotypes among Crohn’s Disease and Ulcerative Colitis patients

Abstract Background Plasma immune proteomics is a potent tool to identify patient-specific immunotypes needed for tailored treatment of inflammatory bowel disease. Implementation requires in-depth understanding of how plasma immune profiles differ between Crohn’s disease (CD) and ulcerative colitis (UC), and relate to underlying intestinal and systemic memory T helper cell (ThM) responses, intestinal permeability, and severity of clinical and histological disease. Methods We performed deep immune characterization of therapy naïve paediatric CD (n = 85) and UC (n = 34) patients from the PIBD-SetQ cohort and age-matched controls (HC; n = 55) by measuring 92 plasma immune proteins (Olink), circulating ThM subpopulations, intestinal permeability (plasma lipopolysaccharide binding protein; LBP), histological damage (GHAS), and immunohistochemistry. Results Abundance of 27 proteins discriminated CD from HC, and derivative immune profiles identified CD-hi (n = 41), CD-inter (n = 18), and CD-low (n = 26) patient clusters. Clusters had significant differences in plasma protein profile composition, disease activity, disease behaviour and biochemical parameters, with highest values in CD-hi, but no differences in disease location. CD-high patients had highest abundance of HGF, TNFSF14, OSM and interferon-g-related proteins and higher frequencies of pathogenic circulating gut-homing ex-Th17/ThM1* known to associate with a worse disease course. These systemic immune features in CD-hi patients related to increased number of Tbet+ cells in ileum and increased intestinal permeability, but not histological or endoscopic severity, demonstrating that plasma proteomics discerns CD patients with qualitatively distinctive immune responses in blood and intestine. In UC, 23 protein concentrations, belonging to IL-17/neutrophil pathways, differed from HC. Their derivative profiles clustered patients into UC-hi (n = 23) and UC-low (n = 11). UC-hi had higher clinical parameters, increased intestinal disease extent, higher intestinal permeability and histological disease severity. In line, UC-hi patients required earlier anti-TNF treatment during 2 years follow-up compared to UC-low. UC-hi patients had higher numbers of infiltrating IL-17A+ ThM and neutrophils in their intestine, but no systemic changes in gut-homing ThM populations. As such, in contrast to the qualitative differences in CD, UC plasma proteomics relates to quantitative differences in disease extent and degree of intestinal immune infiltration. Conclusion In CD and UC, plasma protein profiles capture severity of ongoing intestinal immune responses. In UC, they have a linear relationship with extent and degree of intestinal immune infiltration, while they capture qualitative intestinal tissue- and blood- ThM responses in CD. Conflict of interest: Ms. Calado, Beatriz: No conflict of interest Heredia, Maud: No conflict of interest Charrout, Mohammed: No conflict of interest Klomberg, Renz: No conflict of interest Barendregt, Danielle: No conflict of interest Hulleman-van Haaften, Danielle H.: No conflict of interest Tuk, Bastiaan: No conflict of interest van Berkel, Lisette A.: No conflict of interest Bley Folly, Brenda: No conflict of interest Escher, Johanna Caroline Hankje: Grant: MSD Other: Janssen, Abbvie de Ridder, Lissy: No conflict of interest Samsom, Janneke N.: No conflict of interest