Anti-EPCR autoantibodies in ulcerative colitis show sex- and lipid-dependent patterns

Autoantibodies targeting the endothelial protein C receptor (EPCR) have been associated with ulcerative colitis (UC). We aimed to assess a potential role of EPCR lipidation on the detection of anti-EPCR antibodies in inflammatory bowel disease (IBD). To this end, serum samples from patients with UC, Crohn’s disease, and healthy controls were analyzed using an in-house ELISA employing either native or delipidated EPCR. Overall, male UC patients showed significantly higher absorbance (mean=1.09) than CD patients (mean=0.50) and controls (mean=0.37). Remarkably, in males, the difference between UC patients and controls was highly significant (p=1.2e-07), as was the difference between UC and CD patients (p=5.7e-05). In women, the difference was less pronounced and only significant when comparing UC to controls (p=0.023). Replacement of native EPCR with delipidated EPCR in the ELISA procedure dropped detection and eliminated the UC-CD discrimination power (p=0.784). These findings indicate a role for the bound lipid as key determinant of male-biased, anti-EPCR reactivity, and support the diagnostic potential of this biomarker when assay conditions preserve the physiological lipid-bound state of EPCR.