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Molecular Medicine

, Volume 14, Issue 11–12, pp 675–681 | Cite as

Pathogenic Autoantibodies in Systemic Lupus Erythematosus Are Derived from Both Self-Reactive and Non-Self-Reactive B Cells

  • Jie Zhang
  • Annett M. Jacobi
  • Tao Wang
  • Betty Diamond
Research Article

Abstract

Previous studies have shown that both murine and human anti-double-stranded DNA (anti-dsDNA) antibodies can develop from non-DNA-reactive B cells and suggest a crucial role for somatic mutation in dsDNA binding. However, since only a limited number of human anti-dsDNA antibodies have been analyzed previously, we could not exclude other mechanisms for the generation of anti-dsDNA antibodies in patients with systemic lupus erythematosus (SLE). Therefore, we isolated IgM anti-dsDNA antibodies from peripheral blood B cells of a patient with SLE. Three somatically mutated IgM anti-DNA antibodies with pathogenic potential (glomerular binding) were reverted to their germline configuration. Although all three IgM anti-dsDNA antibodies came from the same lupus patient, they displayed different profiles. Reversion to the germline sequence of autoantibodies A9 and B5 resulted in decreased dsDNA binding. In contrast, the germline form of G3-recognized dsDNA as well as the mutated counterpart. These results suggest that mutated IgM anti-dsDNA antibodies may develop from both DNA- and non-DNA-reactive B cells. The implications are that B cell activation occurs in response to self and non-self antigens, while selection after activation may be mediated by self antigen in SLE. Moreover, ineffective tolerance checkpoints may exist before and after antigen activation in SLE.

Notes

Acknowledgments

The study was supported by a grant from the National Institutes of Health (BD). AMJ is supported by the Irvington Institute Fellowship Program of the Cancer Research Institute.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Jie Zhang
    • 1
  • Annett M. Jacobi
    • 1
  • Tao Wang
    • 1
  • Betty Diamond
    • 1
  1. 1.The Center for Autoimmune and Musculoskeletal Disease, Feinstein Institute for Medical ResearchNorth Shore-LIJ Health SystemManhassetUSA

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