Abstract
ObjectiveGlycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.MethodsUsing ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).ResultsMultiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).ConclusionThe IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.
Highlights
Frano Vuckovic,1 Jasminka Kristic,1 Ivan Gudelj,1 Maria Teruel,2 Toma Keser,3 Marija Pezer,1 Maja Pucic-Bakovic,1 Jerko Stambuk,1 Irena Trbojevic-Akmacic,1 Clara Barrios,4 Tamara Pavic,3
The IgG glycome in systemic lupus erythematosus (SLE) patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins
The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE
Summary
IgG are important modulators of IgG effector functions. The views expressed are those of the authors and are not necessarily those of the UK National Health Service (NHS), National Institute for Health Research (NIHR), or Department of Health. Supported by the European Union Seventh Framework Programme (projects IBD-BIOM [contract 305479], HighGlycan [contract 278535], MIMOmics [contract 305280], HTP-GlycoMet [contract 324400], and IntegraLife [contract 315997]), the Instituto de Carlos III (ISCIII contract 02558), European Union FEDER funding, the Andalusian Government (Proyecto de Excelencia grant), the National Natural Science Foundation of China (grants 81370083 and 81273170), the National 12th Five-Year Plan for Science and Technology Support, China (grant 2012BAI37B03), the Edith Cowan University–Industry Collaboration Scheme (grant 2013-1011358), and the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust, King’s College London. The Trinidad systemic lupus erythematosus studies were supported by Arthritis Research UK (grants M0600 and M0651). Pons-Estel, MD: Sanatorio Parque, Rosario, Argentina; 11Paul McKeigue, PhD: University of Edinburgh, Edinburgh, UK; 12Alan Leslie Patrick, MD(Lond), FRCP: Kavanagh Street Medical Centre, Port of Spain, Trinidad, West Indies; 13Miroslav Harjacek, MD, PhD: Clinical Hospital Center Sestre Milosrdnice, Zagreb, Croatia; 14Marta AlarconRiquelme, MD, PhD: Pfizer–University of Granada–Junta de Andalucia Centre for Genomics and Oncological Research (GENYO), Granada, Spain, and Oklahoma Medical Research Foundation, Oklahoma City; 15Wei Wang, MD, PhD: Capital Medical University, Beijing, China, and Edith Cowan University, Perth, Western Australia, Australia; 16Gordan Lauc, PhD: Genos Ltd., Glycoscience Research Laboratory, and University of Zagreb, Zagreb, Croatia
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