9G4+Autoantibodies Are an Important Source of Apoptotic Cell Reactivity Associated With High Levels of Disease Activity in Systemic Lupus Erythematosus

• Authors: Scott A. Jenks, Emory University; Elise M. Palmer, University of Rochester; Elides Y. Marin, University of Rochester; Louise Hartson, Emory University; Asiya Seema Chida, University of Rochester; Christopher Richardson, University of Rochester; Ignacio Sanz, Emory University
• Journal Title: Arthritis and Rheumatism
• Volume: Volume 65, Number 12
• Publisher: Wiley | 2013-12-01, Pages 3165-3175
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/art.38138
• Subjects: Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Rheumatology; RECEPTOR TYROSINE KINASES; B-CELLS; ENCODED ANTIBODIES; AUTOANTIBODIES RECOGNIZE; IMMUNE-RESPONSES; NECROTIC CELLS; 9G4 IDIOTOPE; AUTOIMMUNITY; SLE; PHAGOCYTOSIS

Abstract

Objective: To determine the prevalence of anti-apoptotic cell (anti-AC) antibodies with the 9G4 idiotype (9G4+) and the relationship between this and other known 9G4+ specificities and disease activity in patients with systemic lupus erythematosus (SLE). Methods: Serum samples from 60 SLE patients and 40 healthy donors were incubated with apoptotic Jurkat cells and assayed by flow cytometry for the binding of 9G4+ antibodies. The samples were also tested for 9G4+ reactivity against naive B cells and total IgG and IgM anti-AC antibody reactivity. Results: The 9G4+ antibodies bound late ACs in sera from a majority of the SLE patients (60%) but in sera from only 2 healthy control subjects. Among samples with global IgM or IgG anti-AC antibodies, those with 9G4+ anti-AC antibodies predominated. Patients with high levels of 9G4+ anti-AC antibodies were more likely to have active disease. This was the case even in patients with IgG anti-AC antibodies or anti-double-stranded DNA antibodies. Patients with lupus nephritis were also more likely to have 9G4+ anti-AC antibodies. While 9G4+ reactivity to ACs often coincided with anti-B cell reactivity, some samples had distinct anti-AC or anti-B cell reactivity. Conclusion: The 9G4+ antibody represents a major species of anti-AC antibody in SLE serum, and this autoreactivity is associated with disease activity. The anti-AC reactivity of 9G4+ antibodies can be separated from the germline VH4-34-encoded anti-B cell autoreactivity. Our results indicate that ACs are an important antigenic source in SLE that positively selects B cells with intrinsic autoreactivity against other self antigens. This selection of 9G4+ B cells by ACs may represent an important step in disease progression.