The Impact of IgG Fc-Glycosylation on Disease Dynamics in Primary Sjögren's Disease- Insights from the Belgian Sjögren's Syndrome Transition Trial.

in Arthritis & rheumatology (Hoboken, N.J.) by Helena Achten, Leander Meuris, Liselotte Deroo, Matthias Jarlborg, Tine Decruy, Joke Deprez, Emilie Dumas, Kristel De Boeck, Eva Genbrugge, Wouter Bauters, Frederick Dochy, David Creytens, Dimitri Roels, Nico Callewaert, Dirk Elewaut, Isabelle Peene

TLDR

  • The study found that the way proteins called glycans are attached to a specific part of an antibody called IgG Fc affects how the antibody works in people with Sjögren's Disease (SjD). The study found that people with SjD had lower levels of these glycans attached to their IgG Fc compared to people without SjD. The study also found that these lower levels of glycans were associated with an increased risk of developing non Hodgkin lymphoma (NHL) in people with SjD. The study suggests that targeting these glycans could be a new way to treat SjD and reduce the risk of NHL.

Abstract

Glycans attached to the fragment crystallizable region (Fc) of IgG antibodies influence their pro- or anti-inflammatory effector function. We aimed to explore the interrelation between the Fc-glycosylation profile and disease transition, disease activity and outcome in patients with suspected and confirmed primary Sjögren's Disease (SjD). IgG Fc-sialylation and IgG Fc-galactosylation serum levels were determined in 300 patients from the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). This cohort includes both suspected and confirmed SjD patients meeting the 2016 ACR/EULAR criteria. Salivary gland involvement was evaluated through ultrasonography (Hocevar score 0-48) and histopathology (focus score). The relative amount of sialylated and galactosylated IgG was determined by capillary electrophoresis after using the endoS endoglycosidase based assay. SjD patients exhibited significantly lower sialylation and galactosylation levels versus asymptomatic anti-SSA carriers and sicca patients. Lower sialylation and galactosylation levels were significantly associated with an increase in B-cell activation markers and distinct autoantibody profiles, particularly with multiple autoantibody reactivities. They were also linked to histopathological salivary gland alterations, higher Hocevar scores and importantly with risk factors for non Hodgkin lymphoma (NHL) development. In contrast, mono-anti-Ro60 positive and anti-SSA negative SjD patients had normal IgG Fc-glycosylation. This study points to a novel role of IgG Fc-glycosylation in SjD in predicting disease transition, monitoring disease activity, and risk stratification for NHL development.

Overview

  • The study explores the relationship between the Fc-glycosylation profile and disease transition, disease activity, and outcome in patients with suspected and confirmed primary Sjögren's Disease (SjD).
  • IgG Fc-sialylation and IgG Fc-galactosylation serum levels were determined in 300 patients from the Belgian Sjögren's Syndrome Transition Trial (BeSSTT).
  • The study aims to answer the question: How does the Fc-glycosylation profile influence disease transition, disease activity, and outcome in patients with suspected and confirmed primary SjD?

Comparative Analysis & Findings

  • SjD patients exhibited significantly lower sialylation and galactosylation levels versus asymptomatic anti-SSA carriers and sicca patients. Lower sialylation and galactosylation levels were significantly associated with an increase in B-cell activation markers and distinct autoantibody profiles, particularly with multiple autoantibody reactivities. They were also linked to histopathological salivary gland alterations, higher Hocevar scores, and importantly with risk factors for non Hodgkin lymphoma (NHL) development. In contrast, mono-anti-Ro60 positive and anti-SSA negative SjD patients had normal IgG Fc-glycosylation.

Implications and Future Directions

  • The study highlights the importance of IgG Fc-glycosylation in SjD in predicting disease transition, monitoring disease activity, and risk stratification for NHL development. Future research should focus on the development of targeted therapies that modulate IgG Fc-glycosylation to improve disease outcomes in SjD patients. Additionally, further studies are needed to validate the findings in larger cohorts and to explore the role of IgG Fc-glycosylation in other autoimmune diseases.
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