Antibodies recognising sulfated carbohydrates are prevalent in systemic sclerosis and associated with pulmonary vascular disease

• Type of Material: Article
• Authors: Thomas Grader-Beck, Johns Hopkins University; Francesco Boin, Johns Hopkins University; Stephan von Gunten, University of Bern; David Smith, Emory University; Antony Rosen, Johns Hopkins University; Bruce S. Bochner, Johns Hopkins University
• Language: English
• Date: 2011-12-01
• Publisher: BMJ Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: BMJ Publishing Group Limited 2011
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/ard.2011.153130
• Title of Journal or Parent Work: Annals of the Rheumatic Diseases
• ISSN: 0003-4967
• Volume: 70
• Issue: 12
• Start Page: 2218
• End Page: 2224
• Grant/Funding Information: Dr. Grader-Beck’s work was supported by the NIH (grants AI-071072 and AR-053503).; Dr. Boin’s work was supported by the Scleroderma Research Foundation and the NIH (grant AR-055667).; Dr. Smith’s work, including glycan array analyses, was supported by the NIH (grant GM-62116).
• Keywords: SCLERODERMA; HYPERTENSION; SJOGRENS-SYNDROME; PROTEOGLYCANS; AUTOANTIBODIES; FIBROBLAST-GROWTH; RECEPTOR; HEPARAN-SULFATE; CLASSIFICATION; Science & Technology; Rheumatology; ANTIENDOTHELIAL CELL ANTIBODIES; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry; Health Sciences, Immunology

Abstract

Background: Glycosylation represents an important modification that regulates biological processes in tissues relevant for disease pathogenesis in systemic sclerosis (SSc), including the endothelium and extracellular matrix. Whether patients with SSc develop antibodies to carbohydrates is not known. Objectives: To determine the prevalence and clinical phenotype associated with serum IgG antibodies recognising distinct glycans in patients with SSc. Methods: Pooled serum samples from patients with SSc and controls were screened for the presence of specific anticarbohydrate antibodies using a novel array containing over 300 glycans. Antibody titres to 4-sulfated N-acetyl-lactosamine (4S-LacNAc, (4OSO3)Galaβ1-4GlcNAc) were determined in 181 individual serum samples from patients with SSc by ELISA and associated with disease phenotype. Results: 4S-LacNAc was identified as a target in pooled SSc serum. Anti-4S-LAcNAc antibodies were detected in 27/181 patients with SSc (14.9%) compared with 1/40 healthy controls (2.5%). Sulfation at position C4 of galactose (4S-LacNAc) was found to be critical for immunogenicity. Anti-4S-LacNAc antibody-positive patients with SSc had a higher prevalence of pulmonary hypertension by echocardiography than anti-4S-LacNAc-negative patients (15/27 (55.7%) vs 49/154 (31.8%), p=0.02) with an OR of 2.6 (95% CI 1.1 to 6.3). Anti-4S-LacNAc-positive patients accounted for 23.4% of all patients with pulmonary hypertension. Conclusion: Serum from patients with SSc contains IgG antibodies targeting distinct sulfated carbohydrates. The presence of anti-4S-LacNAc antibodies is associated with a high prevalence of pulmonary hypertension. These results suggest that specific post-translational carbohydrate modifications may act as important immunogens in SSc and may contribute to disease pathogenesis.