Observational Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2023; 29(42): 5728-5750
Published online Nov 14, 2023. doi: 10.3748/wjg.v29.i42.5728
Location-based prediction model for Crohn’s disease regarding a novel serological marker, anti-chitinase 3-like 1 autoantibodies
Nora Sipeki, Patricia Julianna Kovats, Claudia Deutschmann, Peter Schierack, Dirk Roggenbuck, Maria Papp
Nora Sipeki, Patricia Julianna Kovats, Maria Papp, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
Patricia Julianna Kovats, Kálmán Laki Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
Claudia Deutschmann, Peter Schierack, Dirk Roggenbuck, Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
Peter Schierack, Dirk Roggenbuck, Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
Dirk Roggenbuck, Medipan GmbH & GA Generic Assays GmbH, Dahlewitz-Berlin 15827, Germany
Author contributions: Sipeki N, Roggenbuck D, and Papp M made the concept and designed the present study; Sipeki N and Kovats PJ were responsible for clinical data acquisition; Deutschmann C, Schierack P, and Roggenbuck D made the experimental work and were responsible for laboratory data acquisition; Sipeki N, Kovats PJ, and Papp M made the analysis and interpretation of the data, and wrote paper; Deutschmann C, Schierack P, and Roggenbuck D supervised the work, provided expert insights and made critical revisions related to important intellectual content of the manuscript; all authors have read and approved the final manuscript.
Supported by the German Federal Ministry of Education and Research (BMBF- Wachstumskern- PRAEMED.BIO), 03WKDB2C. Papp M was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, BO/00232/17/5; Research Grants of National Research Development and Innovation Office, K115818/2015/1; and New National Excellence Program of the Ministry of Human Capacities, ÚNKP-18-4 Bolyai Plus. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Institutional review board statement: The study was reviewed and approved by the Hungarian National Review Board and the Institutional Review Board of the University of Debrecen (DE RKEB/IKEB: 4773-2017; DE OEC RKEB/IKEB: 3515-2011; TUKEB: ad.3880/2012-EKU).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Nora Sipeki, MD, PhD, Assistant Lecturer, Attending Doctor, Doctor, Postdoc, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei blv 98, Debrecen H-4032, Hungary. sipeki.nora@med.unideb.hu
Received: June 28, 2023
Peer-review started: June 28, 2023
First decision: September 1, 2023
Revised: October 3, 2023
Accepted: November 2, 2023
Article in press: November 2, 2023
Published online: November 14, 2023
Processing time: 137 Days and 21.4 Hours
ARTICLE HIGHLIGHTS
Research background

Chitinase 3-like 1 (CHI3L1) is a 40 kDa heparin-, chitin-, hyaluronan-, and collagen-binding glycoprotein expressed by various cell types, including fibroblast-like cells, macrophages, neutrophils, and colonic epithelial cells (CEC). Under normal conditions, CHI3L1 levels are extremely low; however, under inflammatory conditions, they are also expressed at elevated levels in CEC and macrophages. Upregulated expression of CHI3L1 in the lamina propria and CECs has been described in patients with inflammatory bowel disease (IBD). This upregulation, along with the loss of tolerance to CHI3L1, can enhance the adhesion and invasion of certain commensal and/or pathogenic bacteria via carbohydrate binding (chitin binding protein 21) or homologous motifs (for example, ChiA). Microbial overload, along with mechanical and/or functional derangement of the gut barrier, can lead to the uncontrolled uptake of various luminal bacteria and/or bacterial products. As a result, enhanced bacterial translocation exacerbates local and systemic proinflammatory processes already underway, thereby contributing to disease exacerbation and complications.

Research motivation

Given the current state of knowledge, the precise function and mechanism of CHI3L1 in the development of IBD, loss of tolerance to this antigen, formation of immunoglobulin A (IgA) autoantibodies against it, and their role in the pathogenesis of IBD remain elusive. Concomitantly, there is an unmet need to identify new biomarkers to identify patients with IBD with a complicated disease course.

Research objectives

To evaluate the predictive value of different immunoglobulin subtypes of the novel serological marker, anti-CHI3L autoantibodies (aCHI3L1), in terms of their ability to define the disease phenotype, therapeutic strategy, and long-term disease course in a group of adult IBD patients with prospective follow-up.

Research methods

A total of 257 patients with Crohn’s disease (CD) and 180 patients with ulcerative colitis (UC) from a tertiary IBD referral center in Hungary (Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen) were tested for IgG, IgA, and secretory IgA (sIgA) type aCHI3L1 using enzyme-linked immunosorbent assay with recombinant CHI3L1, along with 86 healthy controls.

Research results

Enhanced formation of IgA and sIgA (sub)-type against CHI3L1 was first detected in adult patients with CD, which was associated with the clinical phenotype in a tertiary referral IBD center in Hungary. This observational study presents, for the first time, longitudinal and prospective results on the predictive ability of aCHI3L1 antibodies to identify disease-specific complications and surgical requirements, which are critical for patient care. The presence of IgA or sIgA aCH3L1 antibodies in CD patients with both inflammatory luminal disease and colon involvement at the time of diagnosis indicates a faster progression towards a complicated disease course in time-dependent models.

Research conclusions

CHI3L1 is a newly discovered neutrophil autoantigenic target in IBD. By taking into account the classes of antibodies and utilizing location-based predictions, serology in IBD may undergo a significant transformation in the future.

Research perspectives

Based on both the pathogenic and clinical heterogeneity of IBD, instead of the “the one size fits all” model, an increasing amount of data points towards the need for the development and application of prognostic matrix models. Therefore, identifying new biomarkers for this purpose is of utmost importance. A significantly higher prevalence of IgA and sIgA (sub)type antibodies against CHI3L1 in patients with colonic involvement, along with a positive predictive value for complicated disease course in only this subgroup of CD patients, could be considered as an indirect confirmation of colonic origin of these antibodies. Further studies to assess the presence of aCHI3L1 antibodies in different parts of the gut mucosa of IBD patients are needed to confirm this hypothesis. Unravelling the role of CHI3L1 and aCHI3L1 autoantibodies in IBD pathogenesis can help identify new potential therapeutic targets for IBD.