A B cell apotope of Ro 60 in systemic lupus erythematosus

Abstract

Objective. Previous studies have attempted to segregate anti-60-kd Ro/SSA (anti-Ro 60) responses in systemic lupus erythematosus (SLE) and primary Sjö-gren's syndrome (SS) but have shown limited disease preference. The aim of the present study was to determine whether the presence of autoantibodies against an Ro 60 apotope (an epitope expressed on apoptotic cells) distinguishes anti-Ro 60 responses in SLE and primary SS.Methods. Multiparameter flow cytometry was used to select early apoptotic cells and measure the simultaneous binding of annexin V, propidium iodide, and anti-Ro 60-positive IgG from SLE patients (n ‫؍‬ 21) and patients with primary SS (n ‫؍‬ 19). The specificity of the Ro 60 apotope was determined by inhibition experiments with recombinant and native Ro 60.Results. Autoantibodies against the Ro 60 apotope were prevalent in SLE patients (13 of 21, 62%) and were rarely observed in patients with primary SS (1 of 19, 5%) (P ‫؍‬ 0.0002). Further, within SLE patients, autoantibodies to the Ro 60 apotope strongly distinguished patients with anti-Ro 60 alone (12 of 13, 92%) from those with both anti-Ro 60 and anti-La (1 of 8, 13%) (P ‫؍‬ 0.0005). When we considered all patients with anti-Ro 60 alone, the presence of autoantibodies to the Ro 60 apotope had both high sensitivity (92.3%) and high specificity (85.7%) for SLE compared with primary SS (P ‫؍‬ 0.0012). The presence of autoantibodies to the Ro 60 apotope may therefore be of diagnostic value in patients with isolated anti-Ro 60 responses.Conclusion. The preferential targeting of an Ro 60 apotope exposed on early apoptotic cells in a subset of SLE patients implies disease-specific pathways for the induction of anti-Ro 60 autoimmunity.

Ro 60 functions as a receptor for β2‐glycoprotein I on apoptotic cells

“…In summary, direct binding studies have revealed a high-affinity interaction between ␤ 2 GPI and a region of Ro 60 that expresses an apotope specific for a subset of SLE (4). We also show that Ro 60 exposed on the surface of apoptotic cells is a receptor for ␤ 2 GPI.…”

“…Sera from patients with primary SS and patients with SLE were characterized for anti-Ro 60/La/RNP specificities by counterimmunoelectrophoresis, immunoblot (Inno-Lia; Innogenetics, Ghent, Belgium), and enzyme-linked immunosorbent assay (ELISA) (Relisa; Immuno Concepts, Sacramento, CA) as previously described (4,19). This study was approved by the Clinical Ethics Committee of the Flinders Medical Centre.…”

“…We have recently identified a B cell apotope (defined as an epitope of an intracellular autoantigen that is expressed on the apoptotic cell surface) of Ro 60 within a region of ␣-helical repeats that is recognized specifically by IgG in a subset of SLE patients who were positive for anti-Ro 60 but not anti-La (4). Since this apotope is a potential target for opsonization by transplacental anti-Ro 60 IgG in CHB, masking of the apotope might block the formation of IgG-apoptotic cell complexes and protect the fetal heart against autoantibody-mediated tissue injury.…”

Autoantibodies against Complement C1q Specifically Target C1q Bound on Early Apoptotic Cells

“…In line with our observations, it has recently been shown that a subset of SLE patients produces autoantibodies against a Ro 60 apotope that is exposed on the surface of early apoptotic cells. This immune response was shown to be specific for SLE, because the Ro 60 apotope was almost absent in patients with primary Sjörgen's syndrome (48). In contrast to Abs against the Ro 60 apotope, anti-C1q autoantibodies were shown to strongly correlate with disease activity and are directed against a highly functional molecule.…”

Role of autoantibodies to various Ro60 epitopes in the decrease of lymphocytes seen in systemic lupus erythematosus and primary Sjögren’s syndrome

“…Various factors have been shown to result in the abnormal expression of Ro antigens on the cell surface, and Reed et al (2008Reed et al ( , 2010 held that LCs expressed different Ro60 apotopes. Furthermore, Kurien et al (2012) found that a cross-antigenicity existed between Ro60 and spectrin.…”