The role of somatic hypermutation in the generation of pathogenic antibodies in SLE

Abstract

The formation of antibodies against double-stranded (ds)DNA is considered to be the serologic hallmark of systemic lupus erythematosus (SLE) and anti-dsDNA antibodies play an important role in the pathogenesis of the disease. Anti-dsDNA antibodies from lupus mice and SLE patients arise by somatic mutation. Importantly, autoantibodies in which somatic mutations have been reverted to germ-line V regions did not show any measurable autoreactivity, suggesting that anti-dsDNA autoantibodies develop from non-autoreactive B-cells by somatic hypermutation, presumably during the germinal center reaction. As the random nature of somatic hypermutation will inevitably create autoreactive B cells, self-tolerance checkpoints at the postmutational stage of B cell differentiation have to exist that normally prevent the induction of pathogenic anti-dsDNA specificities. This review summarizes the proposed mechanisms for the generation of anti-dsDNA in murine lupus and in SLE patients.

Keywords::

• systemic lupus erythematosus
• somatic mutation
• anti-DNA antibodies
• germinal center

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 423-Project A1) and the Interdisciplinary Center for Clinical Research (IZKF, Project A25) at the University Hospital of the Friedrich-Alexander University.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.