Somatic mutagenesis in autoimmunity

Abstract

Our laboratory investigates systemic autoimmune disease in the context of mouse models of systemic lupus erythematosus (SLE). SLE is associated with high titers of serum autoantibodies of the IgG class that are predominantly directed against nuclear antigens, with pathological manifestations that are considered by many to be characteristic of an immune-complex mediated disease. In this review, we focus on the known and potential roles of somatic mutagenesis in SLE. We will argue that anti-nuclear antibodies (ANA) arise predominantly from nonautoreactive B cells that are transformed into autoreactive cells by the process of somatic hypermutation (SHM), which is normally associated with affinity maturation during the germinal center reaction. We will also discuss the role of SHM in creating antigenic peptides in the V region of the B cell receptor (BCR) and its potential to open an avenue of unregulated T cell help to autoreactive B cells. Finally, we will end this review with new experimental evidence suggesting that spontaneous somatic mutagenesis of genes that regulate B cell survival and activation is a rate-limiting causative factor in the development of ANA.

Keywords::

• Somatic mutation
• autoimmunity
• anti-nuclear antibodies
• lupus
• haplodeficiency

Acknowledgements

We would like to thank Judith Spiegel for proofreading the manuscript.

Declaration of interest : The authors declare no conflict of interest. This work was funded by grants from the National Institutes of Health: R01AI033613, R01AI073945, R01AI093822 and 1F30 DK091102. The authors alone are responsible for the content and writing of the paper.