Ig Glycosylation in Ulcerative Colitis: It's Time for New Biomarkers.

Riccardo Capecchi,Massimo Bellini,Lorenzo Bertani,Federico Zanzi,Paola Migliorini,Simona Maltinti,Francesco Costa,Ilaria Puxeddu,Santino Marchi,Nicola De Bortoli

doi:10.3389/fphar.2021.654319

Abstract

Background: Ulcerative colitis (UC) is a chronic relapsing disease, which needs a continue monitoring, especially during biological therapies. An increasing number of patients is treated with anti-Tumor Necrosis factor (TNF) drugs, and current research is focalized to identify biomarkers able to monitor the disease and to predict therapeutic outcome. Methods: We enrolled consecutive UC patients treated with anti-TNF, naïve to biologic drugs. Therapeutic outcome was evaluated after 54 weeks of treatment in terms of clinical remission (Partial Mayo Score -PMS- <2) and mucosal healing (Mayo Endoscopic Score <2). On serum samples collected at baseline and after 54 weeks of treatment, a Lectin-based ELISA assay was performed, and specific glycosylation patterns were evaluated by biotin-labelled lectins. We have also collected 21 healthy controls (NHS) samples, age and sex-matched. Results: Out of 44 UC patients enrolled, 22 achieved clinical remission and mucosal healing after 54 weeks. At baseline, when Protein A was used as coating, UC patients non-responders showed a reduced reactivity to Jacalin (JAC) in comparison with NHS (p = 0.04). After one year of treatment, a decrease in JAC binding was seen only in responders, in comparison with baseline (p = 0.04). When JAC binding was tested selecting IgG by means of Fab anti-IgG Fab, UC patients displayed an increased reactivity after anti-TNF therapy (p < 0,0001 vs controls). At baseline, PMS inversely correlates with JAC binding when Fab anti-IgG Fab was used in solid phase (r 2 = 0,2211; p = 0,0033). Patients with higher PMS at baseline (PMS ≥5) presented lower binding capacity for JAC in comparison with NHS and with lower PMS patients (p = 0,0135 and p = 0,0089, respectively). Conclusion: Ig glycosylation was correlated with clinical and endoscopic activity in patients with UC. JAC protein A-selected Ig showed a possible role in predicting therapeutic effectiveness. If these data would be confirmed, Ig glycosylation could be used as biomarker in UC.

Highlights

Ulcerative colitis (UC) is a chronic relapsing disease, characterized by an inflammation affecting the colon and the rectum with superficial mucosal ulceration, rectal bleeding, diarrhea and abdominal pain (Ungaro et al, 2017)
Tumor necrosis factor (TNF) activates a receptor-interacting protein kinase-1 (RIPK1), and when caspase-8 activity is suppressed, RIPK1 could promote necroptosis by interacting with receptor-interacting protein kinase-3, which regulates the phosphorylation of mixed lineage kinase domain-like protein (MLKL) (Zhou et al, 2020)
According to statistical power plan, we chose to enroll 44 consecutive patients with UC treated for the first time with anti-TNF (IFX biosimilars CT-P13 or SB2, or ADA originator), divided in 22 responders and 22 non-responders

Summary

Introduction

Ulcerative colitis (UC) is a chronic relapsing disease, characterized by an inflammation affecting the colon and the rectum with superficial mucosal ulceration, rectal bleeding, diarrhea and abdominal pain (Ungaro et al, 2017). TNF activates a receptor-interacting protein kinase-1 (RIPK1), and when caspase-8 activity is suppressed, RIPK1 could promote necroptosis by interacting with receptor-interacting protein kinase-3, which regulates the phosphorylation of mixed lineage kinase domain-like protein (MLKL) (Zhou et al, 2020). This translocation of MLKL results to membrane perforation, and subsequently releases damage-associated molecular patterns into extracellular environment, triggering necroptosis (Royce et al, 2019). On this basis, the monoclonal antibodies anti-TNF, like infliximab (IFX) and adalimumab (ADA) were developed for treatment of UC. An increasing number of patients is treated with anti-Tumor Necrosis factor (TNF) drugs, and current research is focalized to identify biomarkers able to monitor the disease and to predict therapeutic outcome

Methods

Results

Conclusion