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
Abstract
BACKGROUND

Defective neutrophil regulation in inflammatory bowel disease (IBD) is thought to play an important role in the onset or manifestation of IBD, as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens. Like neutrophils in the context of innate immune responses, immunoglobulin A (IgA) as an acquired immune response partakes in the defense of the intestinal epithelium. Under normal conditions, IgA contributes to the elimination of microbes, but in connection with the loss of tolerance to chitinase 3-like 1 (CHI3L1) in IBD, IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms. The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target, the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear.

AIM

To determine the predictive potential of Ig subtypes of a novel serological marker, anti-CHI3L1 autoantibodies (aCHI3L1) in determining the disease phenotype, therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients.

METHODS

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

RESULTS

The IgA type was more prevalent in CD than in UC (29.2% vs 11.1%) or HCONT (2.83%; P < 0.0001 for both). However, sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT (39.3% and 32.8% vs 4.65%, respectively; P < 0.0001). The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement (P < 0.0001 and P = 0.038, respectively) in patients with CD. Complicated disease behavior at sample procurement was associated with aCHI3L1 sIgA positivity (57.1% vs 36.0%, P = 0.009). IgA type aCH3L1 was more prevalent in patients with frequent relapse during the disease course in the CD group (46.9% vs 25.7%, P = 0.005). In a group of patients with concomitant presence of pure inflammatory luminal disease and colon involvement at the time of diagnosis, positivity for IgA or sIgA type aCH3L1 predicted faster progression towards a complicated disease course in time-dependent models. This association disappeared after merging subgroups of different disease locations.

CONCLUSION

CHI3L1 is a novel neutrophil autoantigenic target in IBD. The consideration of antibody classes along with location-based prediction may transform the future of serology in IBD.

Keywords: Chitinase 3-like 1 autoantibodies; Crohn’s disease; Ulcerative colitis; Disease progression; Immunoglobulin subtypes; Enzyme-linked immunosorbent assay

Core Tip: The tolerance brake to chitinase 3-like 1 (CHI3L1), a novel neutrophil autoantigenic target in inflammatory bowel disease (IBD), the presence of immunoglobulin A (IgA) autoantibodies against this specific target, as well as the precise function and underlying processes of CHI3L1 in the development of IBD, continue to be uncertain. In the present prospective observational study, we first reported an enhanced formation of IgA and secretory IgA (sub)type against CHI3L1 in adult patients with Crohn’s disease, which was associated with the clinical phenotype and development of a complicated disease course during follow-up in a tertiary referral IBD center in Hungary. By taking into account the classes of antibodies and utilizing location-based predictions, serology in IBD may undergo a significant transformation in the future.