Long-term Ro60 humoral autoimmunity in primary Sjögren's syndrome is maintained by rapid clonal turnover

• Published in: Clinical immunology (Orlando, Fla.) Vol. 148; no. 1; pp. 27 - 34
• Main Authors: Lindop, Rhianna, Arentz, Georgia, Bastian, Isabell, Whyte, Andrew F, Thurgood, Lauren A, Chataway, Tim K, Jackson, Michael W, Gordon, Tom P
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2013
• Subjects: Adult; Aged; Allergy and Immunology; Autoantibodies; Autoantigens - blood; Autoantigens - immunology; Autoimmunity - immunology; Clone Cells; Female; Humans; Humoral autoimmunity; Longitudinal Studies; Mass Spectrometry; Middle Aged; Primary Sjögren's syndrome; Prospective Studies; Retrospective Studies; Ribonucleoproteins - blood; Ribonucleoproteins - immunology; RNA, Small Cytoplasmic - blood; RNA, Small Cytoplasmic - immunology; Ro60; Sequence Analysis, Protein; Sjogren's Syndrome - blood; Sjogren's Syndrome - immunology; Sjogren's Syndrome - pathology; SS; extractable nuclear antigen; RU; Autoantibodies; Fourier transform; Humoral autoimmunity; 60 kDA Ro/SS; FT; AUC; Ro60; area under the dose–response curve; Sjögren's syndrome; enzyme-linked immunosorbent assay; ENA; Primary Sjögren's syndrome; Mass spectrometry; ELISA; resonance units; 60kDA Ro/SS
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2013.03.015

Abstract Long-term humoral autoimmunity to RNA–protein autoantigens is considered a hallmark of systemic autoimmune diseases. We use high resolution Orbitrap mass spectrometric autoantibody sequencing to track the evolution of a Ro60-specific public clonotypic autoantibody in 4 patients with primary Sjögren's syndrome. This clonotype is specified by a VH 3–23/VK 3–20 heavy and light chain pairing. Despite apparent stability by conventional immunoassay, analysis of V-region molecular signatures of clonotypes purified from serum samples collected retrospectively over 7 years revealed sequential clonal replacement. Prospective longitudinal studies confirmed clonotype loss and replacement at approximately three-monthly intervals. Levels of secreted anti-Ro60 clonotypes fluctuated markedly over time, despite minimal changes in clonal affinity. Our novel findings indicate a relentless turnover of short-lived clonotypic variants, masquerading as long-lived Ro60 humoral autoimmunity.