title: Two major autoantibody clusters in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus is a chronic autoimmune disease of complex clinical presentation and etiology and is likely influenced by numerous genetic and environmental factors. While a large number of susceptibility genes have been identified, the production of antibodies against a distinct subset of nuclear proteins remains a primary distinguishing characteristic in disease diagnosis. However, the utility of autoantibody biomarkers for disease sub-classification and grouping remains elusive, in part, because of the difficulty in large scale profiling using a uniform, quantitative platform. In the present study serological profiles of several known SLE antigens, including Sm-D3, RNP-A, RNP-70k, Ro52, Ro60, and La, as well as other cytokine and neuronal antigens were obtained using the luciferase immunoprecipitation systems (LIPS) approach. The resulting autoantibody profiles revealed that 88% of a pilot cohort and 98% of a second independent cohort segregated into one of two distinct clusters defined by autoantibodies against Sm/anti-RNP or Ro/La autoantigens, proteins often involved in RNA binding activities. The Sm/RNP cluster was associated with a higher prevalence of serositis in comparison to the Ro/La cluster (P = 0.0022). However, from the available clinical information, no other clinical characteristics were associated with either cluster. In contrast, evaluation of autoantibodies on an individual basis revealed an association between anti-Sm (P = 0.006), RNP-A (P = 0.018) and RNP-70k (P = 0.010) autoantibodies and mucocutaneous symptoms and between anti-RNP-70k and musculoskeletal manifestations (P = 0.059). Serologically active, but clinically quiescent disease also had a higher prevalence of anti-IFN-α autoantibodies. Based on our findings that most SLE patients belong to either a Sm/RNP or Ro/La autoantigen cluster, these results suggest the possibility that alterations in RNA-RNA-binding protein interactions may play a critical role in triggering and/or the pathogenesis of SLE.
authors.affiliation: Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States of America.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Ching
authors.forename: Peter D
authors.initials: PD
authors.lastname: Burbelo
authors.forename: Christopher
authors.initials: C
authors.lastname: Tipton
authors.forename: Chungwen
authors.initials: C
authors.lastname: Wei
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sanz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology*; D001324:Autoantigens / Q000097:blood / Q000276:immunology; D016000:Cluster Analysis; D015331:Cohort Studies; D006801:Humans; D047468:Immunoprecipitation; D007372:Interferons / Q000276:immunology; D049410:Luciferases, Renilla / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis / Q000208:ethnology / Q000276:immunology*; D009474:Neurons / Q000276:immunology; D010865:Pilot Projects; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007372:Interferons; D049410:Luciferases, Renilla