Abstract
Ankylosing spondylitis (AS) is a common, inflammatory rheumatic disease that primarily affects the axial skeleton and is associated with sacroiliitis, uveitis, and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine whether plasma from patients with AS contained autoantibodies and, if so, characterize and quantify this response in comparison to patients with rheumatoid arthritis (RA) and healthy controls. Two high density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA, and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis to determine the patterns of signaling cascades or tissue origin. 44% of patients with ankylosing spondylitis demonstrated a broad autoantibody response, as compared with 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The autoantibody responses in the AS patients were targeted toward connective, skeletal, and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic acid programmable protein arrays constitute a powerful tool to study autoimmune diseases.
Highlights
From the ‡Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom, the **Harvard Institute of Proteomics, Harvard Medical School, Cambridge, Massachusetts 02141, the §Central Proteomics Facility, Henry Wellcome Building for Molecular Physiology, Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom, the ‡‡Virginia G
From the screening of nucleic acid programmable protein array (NAPPA) array GST#1, 193 autoantigens were shared by three Ankylosing spondylitis (AS) patients, 82 autoantigens were shared by four AS patients, 30 autoantigens were shared by five AS patients, and three autoantigens were shared by six AS patients (Fig. 4A)
We have used a novel type of protein array screening tool to characterize the autoantibody response in patients with ankylosing spondylitis
Summary
The extremely strong association with the Class I human leukocyte antigen allotype HLA-B27 has led to hypotheses involving CD8 T cell-mediated immunity [3]. Autoantibodies to cyclic citrullinated peptides have proven more specific than rheumatoid factor in diagnosing RA and have been shown to have prognostic value [7]. Increased levels of circulating plasma cells have been reported in AS patients [11], as well as evidence of hypergammaglobulinemia [12]. Aside from these findings, no comprehensive investigation into the presence of autoantibodies in patients with AS has been performed to date.
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