Иммунные изменения при воспалительных заболеваниях кишечника фиксируются за 10 лет до появления симптомов

Variation in antibody response evident ‘long before symptoms’ of IBD develop Key takeaways: - Researchers observed disease-specific changes in immune response years before diagnosis of ulcerative colitis or Crohn’s. - These findings could inform preventive intervention strategies for at-risk patients. Serological profiling detected distinct immune-response changes long before symptoms emerged among patients who developed inflammatory bowel disease compared with healthy controls, according to a case-control study published in Gut. Differences in antibody response were identified up to 10 years before diagnosis, notably to Epstein-Barr virus and bacterial flagellins. “It has become evident that by the time we diagnose Crohn’s disease or ulcerative colitis, the disease process has usually been underway for years,” study author Saurabh Mehandru, MD, professor of gastroenterology and director of the IBD Research Center at Icahn School of Medicine at Mount Sinai, told Healio. “Patients often arrive with established bowel damage, and we are left managing consequences rather than preventing them.” Prior research indicates these chronic immune-mediated diseases develop during a prolonged prodromal phase, in which changes in immune response appear years before clinical IBD onset. “The biology is clearly in motion long before symptoms,” Mehandru said. To better understand immune changes during this preclinical phase, Mehandru, Colombel, Bourgonje and colleagues used a new technology — phage-display immunoprecipitation sequencing (PhIP- Seq) — that could aid in defining antibody responses. They collaborated with the laboratory of Thomas Vogl, PhD, MSc, at the University of Vienna. Unlike conventional assays — which only detect a small fraction of antibody reactivities against prespecified antigens — PhIP-Seq “allows us to profile antibody reactivity against thousands of peptides at once,” Mehandru said. The researchers applied PhIP-Seq to 2,000 longitudinal serum samples from the Proteomic Evaluation and Discovery in an IBD Cohort of Tri- service Subjects (PREDICTS) cohort, which includes active-duty U.S. service members diagnosed with new-onset CD or UC between 1998 and 2013. Samples were obtained from individuals with CD (n = 200; mean age, 33.8 years, 87.5% men; 82.5% white) or UC (n = 200; mean age, 33.5 years; 92% men; 83% white), as well as healthy controls without IBD (n = 100; mean age, 33.5 years; 92% men; 83% white). The CD and UC groups contributed 800 samples each, and the control group submitted 400. The researchers profiled antibody responses against 357,000 peptide antigens in samples taken approximately 10, 4 and 2 years before IBD diagnosis, as well as a postdiagnosis sample. Differences were observed in antibody responses between the control group and the CD and UC groups up to 4 years prior to diagnosis. “We found that antibody repertoires are remarkably stable through most of the prodrome of IBD, with variability increasing only around 4 years before diagnosis,” Mehandru said. “Additionally, we noted that disease-specific differences were already detectable at our earliest time point, roughly 10 years out.” Among individuals who would develop CD, disease-specific differences included elevated reactivity to herpesviruses, especially Epstein-Barr virus, as well as an increase in anti-flagellin antibodies. This association was more pronounced among individuals who were diagnosed with complicated CD or ileal disease. “Our data suggest that panels combining anti-flagellin, anti-EBV and selected antibacterial reactivities could enrich detection for high-risk individuals; for instance, among first-degree relatives,” Mehandru said. “These findings may add to existing data that is building prediction models for early diagnosis of IBD aiming for disease prevention.” As patients approached CD diagnosis, their immune response to encapsulated bacteria — like Streptococcus pneumoniae and Haemophilus — progressively declined. “Loss of humoral reactivity may be as informative as gain, and it hints at a broader compromise in immune competence developing well before diagnosis,” Mehandru said. Among those diagnosed with UC, the researchers noted a distinct combination of antimicrobial, antiviral and autoantibody signatures, including progressive elevations in MAP kinase-activating death domain (MADD) protein autoantibodies nearing diagnosis. “MADD regulates inflammatory signaling through the [mitogen-activated protein kinase] pathway, and its complete deficiency causes impaired lymphocyte cytotoxicity, a plausible and previously unrecognized finding in UC,” Mehandru said. The researchers acknowledged that demographics of the PREDICTS cohort — predominantly male active-duty members of the military — are a notable limitation of the study, and may limit generalizability of findings. Mehandru and colleagues also noted that while PhIP-Seq has more bandwidth than any other comparable tool, it can only detect around 10% of antigens. Further research is needed before these findings could be applied to clinical practice. “We have shown that prediagnostic serum contains a discriminative signal, that the signal is disease-specific, and that it is detectable with archived samples using a novel and scalable platform,” Mehandru said. External validation is the next top priority, according to Mehandru. “A decade-long window exists in which the immune system is measurably abnormal but the patient may appear to be well,” he said. “That window is where preventive intervention could happen, and our data suggest that this time period may be long enough to be clinically usable.” For more information: Saurabh Mehandru, MD, can be reached at [email protected].